Noriko Yoshimura, Shigeyuki Muraki, Hiroyuki Oka, Hiroshi Kawaguchi, Kozo Nakamura, Toru Akune
Cohort profile: research on Osteoarthritis/Osteoporosis Against Disability study.
Int J Epidemiol. 2010 Aug;39(4):988-95. doi: 10.1093/ije/dyp276. Epub 2009 Sep 11.
Abstract/Text
Noriko Yoshimura, Shigeyuki Muraki, Hiroyuki Oka, Akihiko Mabuchi, Yoshio En-Yo, Munehito Yoshida, Akihiko Saika, Hideyo Yoshida, Takao Suzuki, Seizo Yamamoto, Hideaki Ishibashi, Hiroshi Kawaguchi, Kozo Nakamura, Toru Akune
Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: the research on osteoarthritis/osteoporosis against disability study.
J Bone Miner Metab. 2009;27(5):620-8. doi: 10.1007/s00774-009-0080-8. Epub 2009 Jul 1.
Abstract/Text
Musculoskeletal diseases, especially osteoarthritis (OA) and osteoporosis (OP), impair activities of daily life (ADL) and quality of life (QOL) in the elderly. Although preventive strategies for these diseases are urgently required in an aging society, epidemiological data on these diseases are scant. To clarify the prevalence of knee osteoarthritis (KOA), lumbar spondylosis (LS), and osteoporosis (OP) in Japan, and estimate the number of people with these diseases, we started a large-scale population-based cohort study entitled research on osteoarthritis/osteoporosis against disability (ROAD) in 2005. This study involved the collection of clinical information from three cohorts composed of participants located in urban, mountainous, and coastal areas. KOA and LS were radiographically defined as a grade of > or =2 by the Kellgren-Lawrence scale; OP was defined by the criteria of the Japanese Society for Bone and Mineral Research. The 3,040 participants in total were divided into six groups based on their age: < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years. The prevalence of KOA in the age groups < or =39, 40-49, 50-59, 60-69, 70-79, and > or =80 years 0, 9.1, 24.3, 35.2, 48.2, and 51.6%, respectively, in men, and the prevalence in women of the same age groups was 3.2, 11.4, 30.3, 57.1, 71.9, and 80.7%, respectively. With respect to the age groups, the prevalence of LS was 14.3, 45.5, 72.9, 74.6, 85.3, and 90.1% in men, and 9.7, 28.6, 41.7, 55.4, 75.1, and 78.2% in women, respectively. Data of the prevalence of OP at the lumbar spine and femoral neck were also obtained. The estimated number of patients with KOA, LS, and L2-L4 and femoral neck OP in Japan was approximately 25, 38, 6.4, and 11 million, respectively. In summary, we estimated the prevalence of OA and OP, and the number of people affected with these diseases in Japan. The ROAD study will elucidate epidemiological evidence concerning determinants of bone and joint disease.
D Marshall, O Johnell, H Wedel
Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.
BMJ. 1996 May 18;312(7041):1254-9.
Abstract/Text
OBJECTIVE: To determine the ability of measurements of bone density in women to predict later fractures.
DESIGN: Meta-analysis of prospective cohort studies published between 1985 and end of 1994 with a baseline measurement of bone density in women and subsequent follow up for fractures. For comparative purposes, we also reviewed case control studies of hip fractures published between 1990 and 1994.
SUBJECTS: Eleven separate study populations with about 90,000 person years of observation time and over 2000 fractures.
MAIN OUTCOME MEASURES: Relative risk of fracture for a decrease in bone mineral density of one standard deviation below age adjusted mean.
RESULTS: All measuring sites had similar predictive abilities (relative risk 1.5 (95% confidence interval 1.4 to 1.6)) for decrease in bone mineral density except for measurement at spine for predicting vertebral fractures (relative risk 2.3 (1.9 to 2.8)) and measurement at hip for hip fractures (2.6 (2.0 to 3.5)). These results are in accordance with results of case-control studies. Predictive ability of decrease in bone mass was roughly similar to (or, for hip or spine measurements, better than) that of a 1 SD increase in blood pressure for stroke and better than a 1 SD increase in serum cholesterol concentration for cardiovascular disease.
CONCLUSIONS: Measurements of bone mineral density can predict fracture risk but cannot identify individuals who will have a fracture. We do not recommend a programme of screening menopausal women for osteoporosis by measuring bone density.
Olof Johnell, John A Kanis, Anders Oden, Helena Johansson, Chris De Laet, Pierre Delmas, John A Eisman, Seiko Fujiwara, Heikki Kroger, Dan Mellstrom, Pierre J Meunier, L Joseph Melton, Terry O'Neill, Huibert Pols, Jonathan Reeve, Alan Silman, Alan Tenenhouse
Predictive value of BMD for hip and other fractures.
J Bone Miner Res. 2005 Jul;20(7):1185-94. doi: 10.1359/JBMR.050304. Epub 2005 Mar 7.
Abstract/Text
UNLABELLED: The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score.
INTRODUCTION: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value.
MATERIALS AND METHODS: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients.
RESULTS: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value.
CONCLUSIONS: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.
E W Gregg, M A Pereira, C J Caspersen
Physical activity, falls, and fractures among older adults: a review of the epidemiologic evidence.
J Am Geriatr Soc. 2000 Aug;48(8):883-93.
Abstract/Text
OBJECTIVES: Assess the relationship between physical activity and risk for falls and osteoporotic fractures among older adults.
DESIGN: Review and synthesis of published literature.
MEASUREMENTS: We searched the literature using MEDLINE, Current Contents, and the bibliographies of articles identified. We included randomized controlled trials (RCT) of the effects of physical activity on the incidence of falls and case-control and prospective cohort studies of the association of physical activity with osteoporotic fracture risk. We also summarized mechanisms whereby physical activity may influence risk for falls and fractures.
RESULTS: Observational epidemiologic studies and randomized clinical trials evaluating the effectiveness of physical activity programs to prevent falls have been inconclusive. However, many studies have lacked adequate statistical power, and recent trials suggest that exercise, particularly involving balance and lower extremity strength training, may reduce risk of falling. There is consistent evidence from prospective and case-control studies that physical activity is associated with a 20-40% reduced risk of hip fracture relative to sedentary individuals. The few studies that have examined the association between physical activity and risk of other common osteoporotic fractures, such as vertebral and wrist fractures, have not found physical activity to be protective.
CONCLUSIONS: Epidemiologic studies suggest that higher levels of leisure time physical activity prevent hip fractures and RCTs suggest certain exercise programs may reduce risk of falls. Future research needs to evaluate the types and quantity of physical activity needed for optimal protection from falls and identify which populations will benefit most from exercise.
R M Joakimsen, J H Magnus, V Fønnebø
Physical activity and predisposition for hip fractures: a review.
Osteoporos Int. 1997;7(6):503-13.
Abstract/Text
Studies on the association between physical activity and hip fractures are reviewed. All the studies, which comprise four follow-up studies, one nested case-control study and 17 case-control studies, suggest a protective effect of physical activity with regard to hip fractures. The association is strong and consistent with physical activity in leisure, weaker with respect to physical activity at work. The association is present for physical activity from childhood to adult age, and it is consistent in study populations from the USA, Australia, Asia and Northern and Southern Europe, in spite of very different hip fractures incidences in these populations. The magnitude of the association is difficult to assess because of varying criteria for exposure, but to be among the physically active seems to reduce the risk of later hip fracture by up to 50%. It seems that even daily chores, such as climbing stairs and walking, protect against hip fracture.
C De Laet, J A Kanis, A Odén, H Johanson, O Johnell, P Delmas, J A Eisman, H Kroger, S Fujiwara, P Garnero, E V McCloskey, D Mellstrom, L J Melton, P J Meunier, H A P Pols, J Reeve, A Silman, A Tenenhouse
Body mass index as a predictor of fracture risk: a meta-analysis.
Osteoporos Int. 2005 Nov;16(11):1330-8. doi: 10.1007/s00198-005-1863-y. Epub 2005 Jun 1.
Abstract/Text
Low body mass index (BMI) is a well-documented risk factor for future fracture. The aim of this study was to quantify this effect and to explore the association of BMI with fracture risk in relation to age, gender and bone mineral density (BMD) from an international perspective using worldwide data. We studied individual participant data from almost 60,000 men and women from 12 prospective population-based cohorts comprising Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, EPIDOS, OFELY, Kuopio, Hiroshima, and two cohorts from Gothenburg, with a total follow-up of over 250,000 person years. The effects of BMI, BMD, age and gender on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson regression model in each cohort separately. The results of the different studies were then merged. Without information on BMD, the age-adjusted risk for any type of fracture increased significantly with lower BMI. Overall, the risk ratio (RR) per unit higher BMI was 0.98 (95% confidence interval [CI], 0.97-0.99) for any fracture, 0.97 (95% CI, 0.96-0.98) for osteoporotic fracture and 0.93 (95% CI, 0.91-0.94) for hip fracture (all p <0.001). The RR per unit change in BMI was very similar in men and women ( p >0.30). After adjusting for BMD, these RR became 1 for any fracture or osteoporotic fracture and 0.98 for hip fracture (significant in women). The gradient of fracture risk without adjustment for BMD was not linearly distributed across values for BMI. Instead, the contribution to fracture risk was much more marked at low values of BMI than at values above the median. This nonlinear relation of risk with BMI was most evident for hip fracture risk. When compared with a BMI of 25 kg/m(2), a BMI of 20 kg/m(2) was associated with a nearly twofold increase in risk ratio (RR=1.95; 95% CI, 1.71-2.22) for hip fracture. In contrast, a BMI of 30 kg/m(2), when compared with a BMI of 25 kg/m(2), was associated with only a 17% reduction in hip fracture risk (RR=0.83; 95% CI, 0.69-0.99). We conclude that low BMI confers a risk of substantial importance for all fractures that is largely independent of age and sex, but dependent on BMD. The significance of BMI as a risk factor varies according to the level of BMI. Its validation on an international basis permits the use of this risk factor in case-finding strategies.
Beverley Shea, George Wells, Ann Cranney, Nicole Zytaruk, Vivian Robinson, Lauren Griffith, Zulma Ortiz, Joan Peterson, Jonathan Adachi, Peter Tugwell, Gordon Guyatt, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group
Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis.
Endocr Rev. 2002 Aug;23(4):552-9. doi: 10.1210/er.2001-7002.
Abstract/Text
OBJECTIVE: To summarize controlled trials examining the effect of calcium on bone density and fractures in postmenopausal women.
DATA SOURCE: We searched MEDLINE and EMBASE up to 1998 and the Cochrane Controlled Register up to 2000, and we examined citations of relevant articles and proceedings of international meetings. We contacted osteoporosis investigators to identify additional studies, and primary authors for unpublished data.
STUDY SELECTION: We included 15 trials (1806 patients) that randomized postmenopausal women to calcium supplementation or usual calcium intake in the diet and reported bone mineral density of the total body, vertebral spine, hip, or forearm, or recorded the number of fractures, and followed patients for at least 1 yr.
DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and extracted data.
DATA SYNTHESIS: We found calcium to be more effective than placebo in reducing rates of bone loss after two or more years of treatment. The pooled difference in percentage change from baseline was 2.05% [95% confidence interval (CI) 0.24-3.86] for total body bone density, 1.66% (95% CI 0.92-2.39) for the lumbar spine, 1.64% (95% CI 0.70-2.57) for the hip, and 1.91% (95% CI 0.33-3.50) for the distal radius. The relative risk (RR) of fractures of the vertebrae was 0.77, with a wide CI (95% CI 0.54-1.09); the RR for nonvertebral fractures was 0.86 (95% CI 0.43-1.72).
CONCLUSIONS: Calcium supplementation alone has a small positive effect on bone density. The data show a trend toward reduction in vertebral fractures, but do not meaningfully address the possible effect of calcium on reducing the incidence of nonvertebral fractures.
C M Klotzbuecher, P D Ross, P B Landsman, T A Abbott, M Berger
Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis.
J Bone Miner Res. 2000 Apr;15(4):721-39. doi: 10.1359/jbmr.2000.15.4.721.
Abstract/Text
Numerous studies have reported increased risks of hip, spine, and other fractures among people who had previous clinically diagnosed fractures, or who have radiographic evidence of vertebral fractures. However, there is some variability in the magnitudes of associations among studies. We summarized the literature and performed a statistical synthesis of the risk of future fracture, given a history of prior fracture. The strongest associations were observed between prior and subsequent vertebral fractures; women with preexisting vertebral fractures (identified at baseline by vertebral morphometry) had approximately 4 times greater risk of subsequent vertebral fractures than those without prior fractures. This risk increases with the number of prior vertebral fractures. Most studies reported relative risks of approximately 2 for other combinations of prior and future fracture sites (hip, spine, wrist, or any site). The confidence profile method was used to derive a single pooled estimate from the studies that provided sufficient data for other combinations of prior and subsequent fracture sites. Studies of peri- and postmenopausal women with prior fractures had 2.0 (95 % CI = 1.8, 2.1) times the risk of subsequent fracture compared with women without prior fractures. For other studies (including men and women of all ages), the risk was increased by 2.2 (1.9, 2.6) times. We conclude that history of prior fracture at any site is an important risk factor for future fractures. Patients with a history of prior fracture, therefore, should receive further evaluation for osteoporosis and fracture risk.
J A Kanis, O Johnell, C De Laet, H Johansson, A Oden, P Delmas, J Eisman, S Fujiwara, P Garnero, H Kroger, E V McCloskey, D Mellstrom, L J Melton, H Pols, J Reeve, A Silman, A Tenenhouse
A meta-analysis of previous fracture and subsequent fracture risk.
Bone. 2004 Aug;35(2):375-82. doi: 10.1016/j.bone.2004.03.024.
Abstract/Text
Previous fracture is a well-documented risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex, and bone mineral density (BMD). We studied 15259 men and 44902 women from 11 cohorts comprising EVOS/EPOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and two cohorts from Gothenburg. Cohorts were followed for a total of 250000 person-years. The effect of a prior history of fracture on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex, and BMD. The results of the different studies were merged by using the weighted beta-coefficients. A previous fracture history was associated with a significantly increased risk of any fracture compared with individuals without a prior fracture (RR = 1.86; 95% CI = 1.75-1.98). The risk ratio was similar for the outcome of osteoporotic fracture or for hip fracture. There was no significant difference in risk ratio between men and women. Risk ratio (RR) was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any fracture (8%) and for hip fracture (22%). The risk ratio was stable with age except in the case of hip fracture outcome where the risk ratio decreased significantly with age. We conclude that previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.
J A Kanis, O Johnell, A Oden, H Johansson, C De Laet, J A Eisman, S Fujiwara, H Kroger, E V McCloskey, D Mellstrom, L J Melton, H Pols, J Reeve, A Silman, A Tenenhouse
Smoking and fracture risk: a meta-analysis.
Osteoporos Int. 2005 Feb;16(2):155-62. doi: 10.1007/s00198-004-1640-3. Epub 2004 Jun 3.
Abstract/Text
Smoking is widely considered a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the relationship of this risk with age, sex and bone mineral density (BMD). We studied 59,232 men and women (74% female) from ten prospective cohorts comprising EVOS/EPOS, DOES, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, Hiroshima and two cohorts from Gothenburg. Cohorts were followed for a total of 250,000 person-years. The effect of current or past smoking, on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age, sex and BMD. The results of the different studies were merged using the weighted beta-coefficients. Current smoking was associated with a significantly increased risk of any fracture compared to non-smokers (RR=1.25; 95% Confidence Interval (CI)=1.15-1.36). Risk ratio (RR) was adjusted marginally downward when account was taken of BMD, but it remained significantly increased (RR=1.13). For an osteoporotic fracture, the risk was marginally higher (RR=1.29; 95% CI=1.13-1.28). The highest risk was observed for hip fracture (RR=1.84; 95% CI=1.52-2.22), but this was also somewhat lower after adjustment for BMD (RR=1.60; 95% CI=1.27-2.02). Risk ratios were significantly higher in men than in women for all fractures and for osteoporotic fractures, but not for hip fracture. Low BMD accounted for only 23% of the smoking-related risk of hip fracture. Adjustment for body mass index had a small downward effect on risk for all fracture outcomes. For osteoporotic fracture, the risk ratio increased with age, but decreased with age for hip fracture. A smoking history was associated with a significantly increased risk of fracture compared with individuals with no smoking history, but the risk ratios were lower than for current smoking. We conclude that a history of smoking results in fracture risk that is substantially greater than that explained by measurement of BMD. Its validation on an international basis permits the use of this risk factor in case finding strategies.
P Vestergaard, L Mosekilde
Fracture risk associated with smoking: a meta-analysis.
J Intern Med. 2003 Dec;254(6):572-83.
Abstract/Text
OBJECTIVES: To assess fracture risk associated with smoking.
DESIGN: Systematic review.
DATA SOURCES: Cohort, case-control, and cross-sectional studies identified by searching PubMed and EMBASE, and by recursive screening of reference lists.
SUBJECTS: Fifty studies including 512 399 subjects were included.
MAIN OUTCOME MEASURE: Fracture occurrence in current, previous, and never smokers.
RESULTS: Fracture risk was significantly increased in current smokers for all fracture types combined (pooled relative risk 1.26, 95% CI 1.12-1.42) and for hip (1.39, 95% CI 1.23-1.58) and spine fractures (1.76, 95% CI 1.10-2.82), but not for wrist fractures (0.86, 95% CI 0.46-1.60). In previous smokers the estimate was significantly lower for as well all types of fractures (1.02, 95% CI 0.85-1.22, P = 0.03 compared with current smokers), as for hip fractures (1.19, 95% CI 1.06-1.34, P = 0.04). There was a trend towards higher risk estimates in previous smokers for hip fractures in case-control studies than in cohort studies. A similar difference between case-control and cohort studies was not present for current smokers. There was a geographical heterogeneity: the risk of hip fractures associated with current smoking increased with latitude, i.e. the risk was higher in Northern Europe and the USA than in Southern Europe and countries close to the equator.
CONCLUSIONS: Smoking is associated with an increased overall fracture risk, an increased risk of hip and spine but not wrist fractures. Cessation of smoking seems associated with a decrease in fracture risk. The impact of smoking varied geographically with an increase with latitude.
John A Kanis, Helena Johansson, Olof Johnell, Anders Oden, Chris De Laet, John A Eisman, Huibert Pols, Alan Tenenhouse
Alcohol intake as a risk factor for fracture.
Osteoporos Int. 2005 Jul;16(7):737-42. doi: 10.1007/s00198-004-1734-y. Epub 2004 Sep 29.
Abstract/Text
High intakes of alcohol have adverse effects on skeletal health, but evidence for the effects of moderate consumption are less secure. The aim of this study was to quantify this risk on an international basis and explore the relationship of this risk with age, sex, and bone mineral density (BMD). We studied 5,939 men and 11,032 women from three prospectively studied cohorts comprising CaMos, DOES, and the Rotterdam Study. Cohorts were followed for a total of 75,433 person-years. The effect of reported alcohol intake on the risk of any fracture, any osteoporotic fracture, and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined included age and BMD. The results of the different studies were merged using weighted beta-coefficients. Alcohol intake was associated with a significant increase in osteoporotic and hip fracture risk, but the effect was nonlinear. No significant increase in risk was observed at intakes of 2 units or less daily. Above this threshold, alcohol intake was associated with an increased risk of any fracture (risk ratio [RR] = 1.23; 95% CI, 1.06-1.43), any osteoporotic fracture (RR = 1.38; 95% CI, 1.16-1.65), or hip fracture (RR = 1.68; 95% CI, 1.19-2.36). There was no significant interaction with age, BMD, or time since baseline assessment. Risk ratios were moderately but not significantly higher in men than in women, and there was no evidence for a different threshold for effect by gender. We conclude that reported intake of alcohol confers a risk of some importance beyond that explained by BMD. The validation of this risk factor on an international basis permits its use in case-finding strategies.
John A Kanis, Helena Johansson, Anders Oden, Olof Johnell, Chris de Laet, L Joseph Melton III, Alan Tenenhouse, Jonathan Reeve, Alan J Silman, Huibert A P Pols, John A Eisman, Eugene V McCloskey, Dan Mellstrom
A meta-analysis of prior corticosteroid use and fracture risk.
J Bone Miner Res. 2004 Jun;19(6):893-9. doi: 10.1359/JBMR.040134. Epub 2004 Jan 27.
Abstract/Text
UNLABELLED: The relationship between use of corticosteroids and fracture risk was estimated in a meta-analysis of data from seven cohort studies of approximately 42,000 men and women. Current and past use of corticosteroids was an important predictor of fracture risk that was independent of prior fracture and BMD.
INTRODUCTION: The aims of this study were to validate that corticosteroid use is a significant risk factor for fracture in an international setting and to explore the effects of age and sex on this risk.
MATERIALS AND METHODS: We studied 42,500 men and women from seven prospectively studied cohorts followed for 176,000 patient-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, Dubbo Osteoporosis Epidemiology Study (DOES), and prospective cohorts at Sheffield, Rochester, and Gothenburg. The effect of ever use of corticosteroids, BMD, age, and sex on all fracture, osteoporotic fracture, and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients.
RESULTS: Previous corticosteroid use was associated with a significantly increased risk of any fracture, osteoporotic fracture, and hip fracture when adjusted for BMD. Relative risk of any fracture ranged from 1.98 at the age of 50 years to 1.66 at the age of 85 years. For osteoporotic fracture, the range of relative risk was 2.63-1.71, and for hip fracture 4.42-2.48. The estimate of relative risk was higher at younger ages, but not significantly so. No significant difference in risk was seen between men and women. The risk was marginally and not significantly upwardly adjusted when BMD was excluded from the model. The risk was independent of prior fracture. In the three cohorts that documented current corticosteroid use, BMD was significantly reduced at the femoral neck, but fracture risk was still only partly explained by BMD.
CONCLUSION: We conclude that prior and current exposure to corticosteroids confers an increased risk of fracture that is of substantial importance beyond that explained by the measurement of BMD. Its identification on an international basis validates the use of this risk factor in case-finding strategies.
Copyright 2004 American Society for Bone and Mineral Research
T P van Staa, H G M Leufkens, C Cooper
The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.
Osteoporos Int. 2002 Oct;13(10):777-87. doi: 10.1007/s001980200108.
Abstract/Text
Studies of oral corticosteroid dose and loss of bone mineral density have reported inconsistent results. In this meta-analysis, we used information from 66 papers on bone density and 23 papers on fractures to examine the effects of oral corticosteroids on bone mineral density and risk of fracture. Strong correlations were found between cumulative dose and loss of bone mineral density and between daily dose and risk of fracture. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3 to 6 months) and decrease after stopping therapy. The risk remained independent of underlying disease, age and gender. We conclude that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. Early use of preventive measures against corticosteroid-induced osteoporosis is recommended.
J A Kanis, H Johansson, A Oden, O Johnell, C De Laet, J A Eisman, E V McCloskey, D Mellstrom, L J Melton, H A P Pols, J Reeve, A J Silman, A Tenenhouse
A family history of fracture and fracture risk: a meta-analysis.
Bone. 2004 Nov;35(5):1029-37. doi: 10.1016/j.bone.2004.06.017.
Abstract/Text
The aims of the present study were to determine whether a parental history of any fracture or hip fracture specifically are significant risk factors for future fracture in an international setting, and to explore the effects of age, sex and bone mineral density (BMD) on this risk. We studied 34,928 men and women from seven prospectively studied cohorts followed for 134,374 person-years. The cohorts comprised the EPOS/EVOS study, CaMos, the Rotterdam Study, DOES and cohorts at Sheffield, Rochester and Gothenburg. The effect of family history of osteoporotic fracture or of hip fracture in first-degree relatives, BMD and age on all clinical fracture, osteoporotic fracture and hip fracture risk alone was examined using Poisson regression in each cohort and for each sex. The results of the different studies were merged from the weighted beta coefficients. A parental history of fracture was associated with a modest but significantly increased risk of any fracture, osteoporotic fracture and hip fracture in men and women combined. The risk ratio (RR) for any fracture was 1.17 (95% CI=1.07-1.28), for any osteoporotic fracture was 1.18 (95% CI=1.06-1.31), and for hip fracture was 1.49 (95% CI=1.17-1.89). The risk ratio was higher at younger ages but not significantly so. No significant difference in risk was seen between men and women with a parental history for any fracture (RR=1.17 and 1.17, respectively) or for an osteoporotic fracture (RR=1.17 and 1.18, respectively). For hip fracture, the risk ratios were somewhat higher, but not significantly higher, in men than in women (RR=2.02 and 1.38, respectively). A family history of hip fracture in parents was associated with a significant risk both of all osteoporotic fracture (RR 1.54; 95CI=1.25-1.88) and of hip fracture (RR=2.27; 95% CI=1.47-3.49). The risk was not significantly changed when BMD was added to the model. We conclude that a parental history of fracture (particularly a family history of hip fracture) confers an increased risk of fracture that is independent of BMD. Its identification on an international basis supports the use of this risk factor in case-finding strategies.
Takayoshi Sasako, Kohjiro Ueki, Kana Miyake, Yukiko Okazaki, Yasuhiro Takeuchi, Yasuo Ohashi, Mitsuhiko Noda, Takashi Kadowaki
Effect of a Multifactorial Intervention on Fracture in Patients With Type 2 Diabetes: Subanalysis of the J-DOIT3 Study.
J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2116-e2128. doi: 10.1210/clinem/dgab013.
Abstract/Text
AIMS: To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes.
METHODS: Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c < 6.9%, blood pressure <130/80 mm Hg, LDL-cholesterol <120mg/dL) or intensive therapy (HbA1c < 6.2%, blood pressure <120/75 mm Hg, LDL-cholesterol <80mg/dL) (ClinicalTrials.gov registration no. NCT00300976).
RESULTS: The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P = 0.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P = 0.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P < 0.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P = 0.025).
CONCLUSIONS: Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.
T M Vogt, P D Ross, L Palermo, T Musliner, H K Genant, D Black, D E Thompson
Vertebral fracture prevalence among women screened for the Fracture Intervention Trial and a simple clinical tool to screen for undiagnosed vertebral fractures. Fracture Intervention Trial Research Group.
Mayo Clin Proc. 2000 Sep;75(9):888-96.
Abstract/Text
OBJECTIVE: To evaluate the ability of self-reported risk factors to identify postmenopausal women likely to have extant vertebral fractures because approximately two thirds of women with radiographic evidence of vertebral fracture are unaware of the fracture.
PATIENTS AND METHODS: Questionnaire and spinal radiographic data were collected from postmenopausal women with a femoral neck bone mineral density T score of -1.6 or lower during screening for the Fracture Intervention Trial. Logistic regression was used to identify risk factors for extant vertebral fractures and to derive a final multivariable model.
RESULTS: Almost two thirds of 25,816 women 55 years and older met the bone density criterion, and 21% of those had an extant vertebral fracture. The final model consisted of 5 self-reported items: history of vertebral fracture, history of nonvertebral fracture, age, height loss, and diagnosis of osteoporosis. These were combined to yield a Prevalent Vertebral Fracture Index (PVFI). The prevalence of women with vertebral fracture varied from 3.8% to 62.3% over the range PVFI of 0 to greater than 5. Among the 13,051 women screened with spinal radiographs, a PVFI of 4 or greater identified 65.5% of women with vertebral fractures (sensitivity), with a specificity of 68.6%. Excluding 881 women who reported prior vertebral fractures reduced the sensitivity to 53.6 % and increased the specificity to 70.7% but did not alter the fracture prevalence at PVFI values less than 6.
CONCLUSION: In this population, 5 simple questions identified women who were likely to have undiagnosed vertebral fractures. Further research is needed to determine the validity of this index in other populations, including women without low bone mineral density.
L K Koh, W B Sedrine, T P Torralba, A Kung, S Fujiwara, S P Chan, Q R Huang, R Rajatanavin, K S Tsai, H M Park, J Y Reginster, Osteoporosis Self-Assessment Tool for Asians (OSTA) Research Group
A simple tool to identify asian women at increased risk of osteoporosis.
Osteoporos Int. 2001;12(8):699-705.
Abstract/Text
Patients with low bone mineral density (BMD) have a high risk of future fractures, and should be actively considered for treatment to reduce their risk. However, BMD measurements are not widely available in some communities, because of cost and lack of equipment. Simple questionnaires have been designed to help target high-risk women for BMD measurements, thereby avoiding the cost of measuring women at low risk. However, such tools have previously focused on evaluation of non-Asian women. We collected information about numerous risk factors from postmenopausal Asian women in eight countries in Asia using questionnaires, and evaluated the ability of these risk factors to identify women with osteoporosis as defined by femoral neck BMD T-scores < or =-2.5. Multiple variable regression analysis and item reduction yielded a final tool based on only age and body weight. This risk index had a sensitivity of 91% and specificity of 45%, with an area under the curve of 0.79. Previously published risk indices based on larger numbers of variables performed similarly well in this Asian population. Large differences in risk were identified using our index to create three categories: 61% of the high-risk women had osteoporosis, compared with only 15% and 3% of the intermediate- and low-risk women, respectively. The low-risk group represented 40% of all women, for whom BMD measurements are probably not needed unless important risk factors, such as prior nonviolent fracture or corticosteroid use, are present. An existing population-based sample of postmenopausal Japanese women was used to validate our index. In this sample of Japanese women the sensitivity was 98% and specificity was 29%; the low-risk category, for whom BMD is probably unnecessary, represented 25% of all women. We conclude that our index performed well for classifying the risk of osteoporosis among postmenopausal Asian women and applying it would result in more prudent use of BMD technology.
Fujiwara S, et al. Performance of osteoporosis risk indices in a Japanese population. Current Therapeutic Res 2001; 62 586-594.
B Ettinger, D M Black, L Palermo, M C Nevitt, S Melnikoff, S R Cummings
Kyphosis in older women and its relation to back pain, disability and osteopenia: the study of osteoporotic fractures.
Osteoporos Int. 1994 Jan;4(1):55-60.
Abstract/Text
To test the hypothesis that thoracic kyphosis is associated with substantial pain, disability, and height loss, we measured thoracic curvature, using an architect's flexicurve, of 610 women aged 65-91 years who were recruited from population-based listings. We assessed study subjects for back pain, back-related disability, height loss since age 25 years, perceived state of health, and bone mineral density (BMD) at the spine, calcaneus, proximal radius, and distal radius. Compared with the rest of the cohort, the 10% of women with the most severe kyphosis had 7%-17% lower BMD (p < 0.001) and had lost an additional 2.4 cm height (p < 0.001). However, kyphotic women had no greater back pain, disability caused by back problems, or poorer health. This cross-sectional study suggests that kyphosis is associated with decreased BMD and loss of height but does not cause substantial chronic back pain, disability, or poor health in older women.
A R Martin, E Sornay-Rendu, J M Chandler, F Duboeuf, C J Girman, P D Delmas
The impact of osteoporosis on quality-of-life: the OFELY cohort.
Bone. 2002 Jul;31(1):32-6.
Abstract/Text
Although the long-term outcomes of osteoporosis (Op) such as fracture, kyphosis, and pain are well known, the physical, psychological, and social consequences, beyond fracture and pain, are less clear. The Osteoporosis-targeted Quality-of-life (OPTQoL) questionnaire aimed at assessing the physical difficulty, fears, and adaptations to one's daily life was developed as a cross-sectional instrument to characterize the burden of Op within a community. The purpose of this study was to assess the impact of Op and related factors on community women participating in the OFELY study in France. Femoral neck bone mineral density (BMD) and OPTQoL questionnaire data were collected from women randomly selected from a large insurance company. Data were obtained for 756 women (mean age 59 years, range 36-92), most of whom were white. Women were classified into five groups based on the extent of physical manifestations and family history of Op. Women who had prior fractures, height loss, and/or kyphosis or both reported greater physical difficulty, more adaptations to their lives, and greater fears than women reporting no such changes. Scores on the Physical Difficulty domain, however, did not differ significantly based on BMD alone (BMD T score
P Dargent-Molina, F Favier, H Grandjean, C Baudoin, A M Schott, E Hausherr, P J Meunier, G Bréart
Fall-related factors and risk of hip fracture: the EPIDOS prospective study.
Lancet. 1996 Jul 20;348(9021):145-9.
Abstract/Text
BACKGROUND: Most hip fractures result from falls. However, the role of fall-related factors has seldom been examined. Comparison of the predictive value of these factors with that of bone mineral density (BMD) has important implications for the prevention of hip fractures.
METHODS: We assessed femoral-neck BMD by dual-photon X-ray absorptiometry and potential fall-related risk factors, which included self-reported physical capacity, neuromuscular function, mobility, visual function, and use of medication in 7575 women, aged 75 years or older, with no history of hip fracture recruited at five centres in France. We followed up these women every 4 months to record incident hip fractures. During an average of 1.9 years of follow-up 154 women suffered a first hip fracture.
FINDINGS: In age-adjusted multivariate analyses, we found four independent fall-related predictors of hip fracture: slower gait speed (relative risk = 1 . 4 for 1 SD decrease [95% Cl 1.1-1.6)]; difficulty in doing a tandem (heel-to-toe) walk (1.2 for 1 point on the difficulty score [1.0-1.5]); reduced visual acuity (2.0 for acuity < or = 2/10 [1.1-3.7]); and small calf circumference (1.5 [1.0-2.2]). After adjustment for femoral-neck BMD, neuromuscular impairment--gait speed, tandem walk--and poor vision remained significantly associated with an increased risk of subsequent hip fracture. With high risk defined as the top quartile of risk, the rate of hip fracture among women classified as high risk based on both a high fall-risk status and low BMD was 29 per 1000 women-years, compared with 11 per 1000 for women classified as high risk by either a high fall-risk status or low BMD; for women classified as low risk based on both criteria the rate was five per 1000.
INTERPRETATION: We conclude that neuromuscular and visual impairments, as well as femoral-neck BMD, are significant and independent predictors of the risk of hip fracture in elderly mobile women, and that their combined assessment improves the prediction of hip fractures.
K Okumiya, K Matsubayashi, T Nakamura, M Fujisawa, Y Osaki, Y Doi, T Ozawa
The timed "up & go" test is a useful predictor of falls in community-dwelling older people.
J Am Geriatr Soc. 1998 Jul;46(7):928-30.
Abstract/Text
Saeko Fujiwara, Fumiyoshi Kasagi, Naomi Masunari, Kumiko Naito, Gen Suzuki, Masao Fukunaga
Fracture prediction from bone mineral density in Japanese men and women.
J Bone Miner Res. 2003 Aug;18(8):1547-53. doi: 10.1359/jbmr.2003.18.8.1547.
Abstract/Text
UNLABELLED: In a cohort of 2356 Japanese elderly, after adjusting for age and prevalent vertebral fracture, baseline BMD predicted the risk of spine and hip fracture with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age.
INTRODUCTION: Low bone mineral density (BMD) is one of the most important predictors of a future fracture. However, we are not aware of any reports among Japanese in Japan.
MATERIALS AND METHODS: We examined the association of BMD with risk of fracture of the spine or hip among a cohort of 2356 men and women aged 47-95 years, who were followed up by biennial health examinations. Follow-up averaged 4 years after baseline measurements of BMD that were taken with the use of DXA. Vertebral fracture was assessed using semiquantitative methods, and the diagnosis of hip fracture was based on medical records. Poisson and Cox regression analysis were used.
RESULTS: The incidence was twice as high in women as in men, after adjusting for age. After adjusting for baseline BMD and prevalent vertebral fracture, however, the gender difference was no longer significant. Age, baseline BMD of spine and femoral neck, and prior vertebral fracture predicted vertebral fracture and hip fracture. Loss of absolute BMD of the femoral neck predicted spine fracture, after adjusting for baseline BMD; rates of change in percent BMD, weight, height, body mass index, and age at menopause did not. The predictive value of baseline BMD for vertebral fracture risk was similar in men and women. The relative risk (RR) for vertebral fracture and hip fracture per SD decrease in BMD declined with age, after adjustment for prevalent vertebral fractures.
CONCLUSIONS: Baseline BMD, loss of femoral neck BMD, and prior vertebral fracture predict the risk of spine and hip fracture in Japanese with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age, suggesting that factors other than BMD might play a greater role in the elderly.
Amir Qaseem, Vincenza Snow, Paul Shekelle, Robert Hopkins, Mary Ann Forciea, Douglas K Owens, Clinical Efficacy Assessment Subcommittee of the American College of Physicians
Screening for osteoporosis in men: a clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2008 May 6;148(9):680-4.
Abstract/Text
DESCRIPTION: The American College of Physicians developed this guideline to present the available evidence on risk factors and screening tests for osteoporosis in men.
METHODS: Published literature on this topic was identified by using MEDLINE (1990 to July 2007). Reference mining was done on the retrieved articles, references of previous reviews, and solicited articles from experts. The inclusion criteria for the studies were measuring risk factors for low bone mineral density or osteoporotic fracture in men or comparing 2 different methods of assessment for the presence of osteoporosis in men. This guideline grades the evidence and recommendations by using the American College of Physicians' clinical practice guidelines grading system. RECOMMENDATION 1: The American College of Physicians recommends that clinicians periodically perform individualized assessment of risk factors for osteoporosis in older men (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 2: The American College of Physicians recommends that clinicians obtain dual-energy x-ray absorptiometry for men who are at increased risk for osteoporosis and are candidates for drug therapy (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 3: The American College of Physicians recommends further research to evaluate osteoporosis screening tests in men.
折茂肇, 林史, 福永仁夫ほか． 原発性骨粗鬆症の診断基準（2000 年度改訂版) ． 日骨代謝誌 2001; 18: 76-82.
Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group.
World Health Organ Tech Rep Ser. 1994;843:1-129.
Abstract/Text
G Jiang, R Eastell, N A Barrington, L Ferrar
Comparison of methods for the visual identification of prevalent vertebral fracture in osteoporosis.
Osteoporos Int. 2004 Nov;15(11):887-96. doi: 10.1007/s00198-004-1626-1. Epub 2004 Apr 8.
Abstract/Text
The identification of vertebral fracture in osteoporosis is based mainly on the identification of abnormal variation in vertebral shape, but this can be misleading in the presence of a non-fracture deformity or normal variant of vertebral shape. Qualitative identification of vertebral fracture (Qual) is influenced by the subjectivity of the approach, and although more objective, the semiquantitative method (SQ) can be difficult to apply. In addition, there has been little independent evaluation of SQ in relation to other approaches. We aimed to evaluate a new algorithm-based approach for the qualitative identification of vertebral fracture (ABQ) and to compare it with SQ and Qual. Two radiologists reported spinal radiographs for 372 postmenopausal women using Qual (reader 1), and SQ and ABQ (reader 2). Non-fracture deformities and normal variants were also reported using Qual and ABQ. The prevalence of vertebral fracture by subjects was higher for SQ (24%) than for Qual (11%) and ABQ (7%). Agreement was poor between SQ and the other methods, and moderate between Qual and ABQ. Twenty-two women with vertebral fracture were agreed by all three methods, similar to the total identified by ABQ (25 women). Seventeen women diagnosed with fracture by Qual, had non-fracture deformity or normal variant (but no fracture) according to ABQ. Of the women with SQ fractures, 53% and 70% were identified negative for fracture but positive for non-fracture deformity or normal variant by ABQ and Qual. The main sources of discrepancy between SQ and the other methods were Scheuermann's disease, normal variation, and degenerative change accompanied by short anterior vertebral height. For all methods, bone mineral density (BMD) and BMD Z-scores were lower in women with vertebral fractures than in those with no fractures. Bone mineral density and BMD Z-scores were also lower at the lumbar spine and total body in women with vertebral fractures according to Qual and ABQ than they were for SQ, and were lower in women with SQ fractures agreed by Qual and ABQ, compared with those diagnosed negative for fracture by Qual and ABQ (p<0.01). We conclude that poor agreement between methods arises mainly from difficulties in differentiating true fracture from non-fracture deformity. Our new approach attempts to address this problem but requires further testing in a larger study population.
H K Genant, C Y Wu, C van Kuijk, M C Nevitt
Vertebral fracture assessment using a semiquantitative technique.
J Bone Miner Res. 1993 Sep;8(9):1137-48. doi: 10.1002/jbmr.5650080915.
Abstract/Text
The assessment of vertebral fracture by conventional radiography has been refined and improved using either semiquantitative or quantitative criteria. The inter- and intraobserver variability was determined for a semiquantitative visual approach that we routinely use in clinical studies for assessing prevalent and incident vertebral fractures. In addition, the semiquantitative approach was compared with a quantitative morphometric approach. The incidence and prevalence of vertebral fractures were determined in 57 postmenopausal women (age 65-75 years) by three independent observers. The radiographic basis for fracture definitions and the source of interobserver agreement for the semiquantitative technique. We conclude that the semiquantitative approach can be applied reliably in vertebral fracture assessment when performed using well-defined criteria.
山本吉蔵ほか. 椎体計測のための罫線設定とpointingの基準. 整形外科 1995; 46: 5-17.
D Kiel
Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures.
J Bone Miner Res. 1995 Apr;10(4):518-23. doi: 10.1002/jbmr.5650100403.
Abstract/Text
R D Wasnich, P D Ross, J W Davis, J M Vogel
A comparison of single and multi-site BMC measurements for assessment of spine fracture probability.
J Nucl Med. 1989 Jul;30(7):1166-71.
Abstract/Text
In a prospective study of 699 women, 39 new spine fracture cases were observed during a mean follow-up of 3.6 yr. Spine fracture incidence was compared to initial bone mineral content (BMC) of the calcaneus, distal radius, proximal radius, and the lumbar spine. BMC at all four sites was significantly related to spine fracture incidence. Women at -1 s.d. for calcaneal BMC had a sevenfold greater probability of spine fracture than women at +1 s.d.; women at -2 s.d. had a 50-fold greater probability than women at +2 s.d., even after adjustment for the effects of age. Combinations of BMC at two sites further strengthened the relationship to spine fracture; the best two-site combination is calcaneus and distal radius BMC. Thus women can be categorized and stratified according to future fracture risk, and the selection of postmenopausal women for preventive treatments can be guided by measurements of BMC.
Patrick Haentjens, Jay Magaziner, Cathleen S Colón-Emeric, Dirk Vanderschueren, Koen Milisen, Brigitte Velkeniers, Steven Boonen
Meta-analysis: excess mortality after hip fracture among older women and men.
Ann Intern Med. 2010 Mar 16;152(6):380-90. doi: 10.7326/0003-4819-152-6-201003160-00008.
Abstract/Text
BACKGROUND: Although an increased risk for death after hip fracture is well established, whether this excess mortality persists over time is unclear.
PURPOSE: To determine the magnitude and duration of excess mortality after hip fracture in older men and women.
DATA SOURCES: Electronic search of MEDLINE and EMBASE for English and non-English articles from 1957 to May 2009 and manual search of article references.
STUDY SELECTION: Prospective cohort studies were selected by 2 independent reviewers. The studies had to assess mortality in women (22 cohorts) or men (17 cohorts) aged 50 years or older with hip fracture, carry out a life-table analysis, and display the survival curves of the hip fracture group and age- and sex-matched control groups.
DATA EXTRACTION: Survival curve data and items relevant to study validity and generalizability were independently extracted by 2 reviewers.
DATA SYNTHESIS: Time-to-event meta-analyses showed that the relative hazard for all-cause mortality in the first 3 months after hip fracture was 5.75 (95% CI, 4.94 to 6.67) in women and 7.95 (CI, 6.13 to 10.30) in men. Relative hazards decreased substantially over time but did not return to rates seen in age- and sex-matched control groups. Through use of life-table methods, investigators estimated that white women having a hip fracture at age 80 years have excess annual mortality compared with white women of the same age without a fracture of 8%, 11%, 18%, and 22% at 1, 2, 5, and 10 years after injury, respectively. Men with a hip fracture at age 80 years have excess annual mortality of 18%, 22%, 26%, and 20% at 1, 2, 5, and 10 years after injury, respectively.
LIMITATIONS: Cohort studies varied, sometimes markedly, in size, duration of observation, selection of control populations, ascertainment of death, and adjustment for comorbid conditions. Only published data that displayed findings with survival curves were examined. Publication bias was possible.
CONCLUSION: Older adults have a 5- to 8-fold increased risk for all-cause mortality during the first 3 months after hip fracture. Excess annual mortality persists over time for both women and men, but at any given age, excess annual mortality after hip fracture is higher in men than in women.
PRIMARY FUNDING SOURCE: Fund for Scientific Research and Willy Gepts Foundation, Universitair Ziekenhuis Brussel.
Keizo Sakamoto, Toshitaka Nakamura, Hiroshi Hagino, Naoto Endo, Satoshi Mori, Yoshiteru Muto, Atsushi Harada, Tetsuo Nakano, Seizo Yamamoto, Kazuhiro Kushida, Katsuro Tomita, Mitsuo Yoshimura, Hiroshi Yamamoto
Report on the Japanese Orthopaedic Association's 3-year project observing hip fractures at fixed-point hospitals.
J Orthop Sci. 2006 Mar;11(2):127-34. doi: 10.1007/s00776-005-0998-1.
Abstract/Text
BACKGROUND: The aim of this study was to assess the disability and mortality of hip fractures 1 year after initial visit (postoperatively) at fixed-point hospitals selected by the Japanese Orthopaedic Association Committee on Osteoporosis.
METHOD: A total of 158 core orthopedic hospitals were selected for participation in this research. Subjects were all aged 65 years and older with hip fractures at the selected hospitals between January 1, 1999 and December 31, 2001. A prognostic survey of activities of daily living (ADL), assessed by the long-term care insurance criteria established by the Ministry of Health, Labour, and Welfare of Japan was performed 1 year after the initial visit.
RESULTS: A total of 1992 hip fractures in patients aged 65 to 111 years were treated over the 3 years from 1999 to 2001. Among the 1992 patients, 4537 had femoral neck fractures and 6217 had trochanteric fractures. Surgical treatment was chosen for 85.6% of the femoral neck fractures and 88.2% of the trochanteric fractures. The mean duration from fracture to admission was 3.1 days, and the mean duration from admission to surgery was 11.2 days. The mean duration from surgery to discharge over the 3-year period was 49.8 days. Before hip fracture, the ratio of patients with J1 ("able to go out freely utilizing public transportation") or J2 ("able to visit immediate neighbors independently") on the long-term care insurance criteria was 50.9%. At 1 year after the initial visit, that result represented a decrease of 24.1 percentage points before hip fracture. A total of 70 patients died before undergoing surgery. In the present study, the 1-year mortality rate for the entire patient population over the 3-year period was 10.1%.
CONCLUSIONS: Hip fracture patients show a decrease in the ADL score 1 year after the initial visit. Compared to other countries, the duration of hospitalization is longer in Japan, but the mortality rate is lower.
Kanis JA, on behalf of the World Health Organisation Scientific Group. Assessment of osteoporosis at the primary health care level. WHO Collaborating Centre for Metabolic Bone Diseases; University of Sheffield: 2007.
T Matsumoto, H Hagino, M Shiraki, M Fukunaga, T Nakano, K Takaoka, H Morii, Y Ohashi, T Nakamura
Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study.
Osteoporos Int. 2009 Aug;20(8):1429-37. doi: 10.1007/s00198-008-0816-7. Epub 2008 Dec 20.
Abstract/Text
UNLABELLED: SUMMARY; A randomized placebo-controlled trial was conducted to examine the effect of daily oral 1 mg minodronate on vertebral fractures in 704 postmenopausal women with established osteoporosis for 24 months. Minodronate treatment reduced vertebral fractures by 59% without serious adverse events. Minodronate is a safe and effective bisphosphonate for osteoporosis treatment.
INTRODUCTION: Minodronate increases bone mineral density (BMD) in postmenopausal osteoporotic patients. However, its efficacy in reducing osteoporotic fractures has not been tested.
METHODS: To examine anti-fracture efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 704 postmenopausal women (55 to 80 years) with one to five vertebral fractures and low BMD. Subjects were randomly assigned to receive daily oral 1 mg minodronate (n = 359) or placebo (n = 345) for 24 months, with daily supplements of 600 mg calcium and 200 IU vitamin D(3).
RESULTS: Daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures by 59% (95% CI, 36.6-73.3%). Furthermore, when fractures during the first 6 months were eliminated, the risk of vertebral fractures from 6 to 24 months was reduced by 74% in minodronate-treated group. Minodronate treatment also reduced height loss. Bone turnover markers were suppressed by about 50% after 6 months of minodronate treatment and remained suppressed thereafter. The overall safety profile including gastrointestinal safety was similar between the two groups.
CONCLUSIONS: Daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis.
Toshitaka Nakamura, Toshitsugu Sugimoto, Tetsuo Nakano, Hideaki Kishimoto, Masako Ito, Masao Fukunaga, Hiroshi Hagino, Teruki Sone, Hideki Yoshikawa, Yoshiki Nishizawa, Takuo Fujita, Masataka Shiraki
Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk.
J Clin Endocrinol Metab. 2012 Sep;97(9):3097-106. doi: 10.1210/jc.2011-3479. Epub 2012 Jun 20.
Abstract/Text
CONTEXT: Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density.
OBJECTIVE: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis.
DESIGN AND SETTING: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed.
PATIENTS: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture.
INTERVENTION: Subjects were randomly assigned to receive once-weekly s.c. injections of teriparatide (56.5 μg) or placebo for 72 wk.
MAIN OUTCOME MEASURE: The primary endpoint was the incidence of new vertebral fracture.
RESULTS: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable.
CONCLUSION: Weekly s.c. administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk.
Toshio Matsumoto, Masako Ito, Yasufumi Hayashi, Takako Hirota, Yusuke Tanigawara, Teruki Sone, Masao Fukunaga, Masataka Shiraki, Toshitaka Nakamura
A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures--a randomized, active comparator, double-blind study.
Bone. 2011 Oct;49(4):605-12. doi: 10.1016/j.bone.2011.07.011. Epub 2011 Jul 19.
Abstract/Text
BACKGROUND: Eldecalcitol is an analog of 1,25-dihydroxyvitamin D(3) that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456.
METHODS AND RESULTS: This 3 year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75 μg eldecalcitol versus 1.0 μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92 years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (<50 nmol/L) were supplemented with 400 IU/day vitamin D(3). Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36 months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56-0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11-0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups.
CONCLUSIONS: Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol.
Copyright © 2011 Elsevier Inc. All rights reserved.
Steven R Cummings, Javier San Martin, Michael R McClung, Ethel S Siris, Richard Eastell, Ian R Reid, Pierre Delmas, Holly B Zoog, Matt Austin, Andrea Wang, Stepan Kutilek, Silvano Adami, Jose Zanchetta, Cesar Libanati, Suresh Siddhanti, Claus Christiansen, FREEDOM Trial
Denosumab for prevention of fractures in postmenopausal women with osteoporosis.
N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.
Abstract/Text
BACKGROUND: Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.
METHODS: We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.
RESULTS: As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.
CONCLUSIONS: Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
2009 Massachusetts Medical Society
Dennis M Black, Pierre D Delmas, Richard Eastell, Ian R Reid, Steven Boonen, Jane A Cauley, Felicia Cosman, Péter Lakatos, Ping Chung Leung, Zulema Man, Carlos Mautalen, Peter Mesenbrink, Huilin Hu, John Caminis, Karen Tong, Theresa Rosario-Jansen, Joel Krasnow, Trisha F Hue, Deborah Sellmeyer, Erik Fink Eriksen, Steven R Cummings, HORIZON Pivotal Fracture Trial
Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
N Engl J Med. 2007 May 3;356(18):1809-22. doi: 10.1056/NEJMoa067312.
Abstract/Text
BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period.
METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes.
RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001).
CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)
Copyright 2007 Massachusetts Medical Society.
Toshitaka Nakamura, Tetsuo Nakano, Masako Ito, Hiroshi Hagino, Junko Hashimoto, Masato Tobinai, Hideki Mizunuma, MOVER Study Group
Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis.
Calcif Tissue Int. 2013 Aug;93(2):137-46. doi: 10.1007/s00223-013-9734-6. Epub 2013 May 5.
Abstract/Text
This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77-1.54]; 1 mg, HR 0.88 (95 % CI 0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8-20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2-15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6-16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis.
Catherine MacLean, Sydne Newberry, Margaret Maglione, Maureen McMahon, Veena Ranganath, Marika Suttorp, Walter Mojica, Martha Timmer, Alicia Alexander, Melissa McNamara, Sheetal B Desai, Annie Zhou, Susan Chen, Jason Carter, Carlo Tringale, Di Valentine, Breanne Johnsen, Jennifer Grossman
Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis.
Ann Intern Med. 2008 Feb 5;148(3):197-213. Epub 2007 Dec 17.
Abstract/Text
BACKGROUND: Although several agents are available to treat osteoporosis, the relative efficacy and toxicity of these agents when used to prevent fractures has not been well described.
PURPOSE: To compare the benefits in fracture reduction and the harms from adverse events of various therapies for osteoporosis.
DATA SOURCES: MEDLINE (1966 to November 2007) and other selected databases were searched for English-language studies.
STUDY SELECTION: For the efficacy analysis, investigators selected studies that reported the rate of or risk for fractures. For the adverse event analysis, they selected studies that reported the relationship between an agent and cardiovascular, thromboembolic, or upper gastrointestinal events; malignant conditions; and osteonecrosis.
DATA EXTRACTION: Using a standardized protocol, investigators abstracted data on fractures and adverse events, agents and comparators, study design, and variables of methodological quality.
DATA SYNTHESIS: Good evidence suggests that alendronate, etidronate, ibandronate, risedronate, zoledronic acid, estrogen, parathyroid hormone (1-34), and raloxifene prevent vertebral fractures more than placebo; the evidence for calcitonin was fair. Good evidence suggests that alendronate, risedronate, and estrogen prevent hip fractures more than placebo; the evidence for zoledronic acid was fair. The effects of vitamin D varied with dose, analogue, and study population for both vertebral and hip fractures. Raloxifene, estrogen, and estrogen-progestin increased the risk for thromboembolic events, and etidronate increased the risk for esophageal ulcerations and gastrointestinal perforations, ulcerations, and bleeding.
LIMITATION: Few studies have directly compared different agents or classes of agents used to treat osteoporosis.
CONCLUSION: Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.
Paul D Miller, Gary Hattersley, Bente Juel Riis, Gregory C Williams, Edith Lau, Luis Augusto Russo, Peter Alexandersen, Cristiano A F Zerbini, Ming-yi Hu, Alan G Harris, Lorraine A Fitzpatrick, Felicia Cosman, Claus Christiansen, ACTIVE Study Investigators
Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial.
JAMA. 2016 Aug 16;316(7):722-33. doi: 10.1001/jama.2016.11136.
Abstract/Text
IMPORTANCE: Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor.
OBJECTIVE: To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture.
DESIGN, SETTING, AND PARTICIPANTS: The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤-2.5 and >-5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤-2.0 and >-5.0 or without fracture criteria and a T score ≤-3.0 and >-5.0 could enroll.
INTERVENTIONS: Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months.
MAIN OUTCOMES AND MEASURES: Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants.
RESULTS: Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred less frequently in the active treatment groups vs placebo. The Kaplan-Meier estimated event rate for nonvertebral fracture was lower with abaloparatide vs placebo. BMD increases were greater with abaloparatide than placebo (all P < .001). Incidence of hypercalcemia was lower with abaloparatide (3.4%) vs teriparatide (6.4%) (risk difference [RD], −2.96 [95%CI, −5.12 to −0.87]; P = .006). [table: see text].
CONCLUSIONS AND RELEVANCE: Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01343004.
Toshio Matsumoto, Teruki Sone, Satoshi Soen, Sakae Tanaka, Akiko Yamashita, Tetsuo Inoue
Abaloparatide Increases Lumbar Spine and Hip BMD in Japanese Patients With Osteoporosis: The Phase 3 ACTIVE-J Study.
J Clin Endocrinol Metab. 2022 Sep 28;107(10):e4222-e4231. doi: 10.1210/clinem/dgac486.
Abstract/Text
CONTEXT: Abaloparatide reduced fracture risk in postmenopausal women with osteoporosis in the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE). Its effect in Japanese patients remains unexamined.
OBJECTIVE: This work aimed to determine the efficacy and safety of abaloparatide in increasing bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk.
METHODS: This was a randomized, double-blind, placebo-controlled study conducted in Japan. Postmenopausal women and men with osteoporosis with high fracture risk were given daily subcutaneous 80 µg abaloparatide or placebo for 78 weeks (18 months). The primary end point was percentage change in lumbar spine (LS) BMD from baseline at the last visit. Secondary end points included time-course changes in LS, total hip (TH), and femoral neck (FN) BMDs and bone turnover markers, and cumulative number of fractures.
RESULTS: Abaloparatide increased LS, TH, and FN BMDs (mean [95% CI]) by 12.5% (10.3%-14.8%; P < .001), 4.3% (3.3%-5.3%), and 4.3% (2.9%-5.6%), respectively, vs placebo. Serum procollagen type I N-terminal propeptide increased rapidly to ~ 140% above baseline at 6 weeks and gradually decreased but was approximately 25% higher than baseline at 78 weeks. Serum carboxy-terminal cross-linking telopeptide of type I collagen gradually increased to 50% above baseline at 24 weeks and decreased gradually to the placebo-group level from 60 weeks. Four vertebrae of 3 participants in the placebo group, but none in the abaloparatide group, developed new vertebral fractures. The safety profile was similar to that in the ACTIVE study.
CONCLUSION: In Japanese patients with postmenopausal and male osteoporosis with high fracture risk, abaloparatide for 78 weeks robustly increased LS, TH, and FN BMDs, suggesting a similar efficacy in Japanese patients vs the ACTIVE study population.
© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.
M Stevenson, M Lloyd-Jones, D Papaioannou
Vitamin K to prevent fractures in older women: systematic review and economic evaluation.
Health Technol Assess. 2009 Sep;13(45):iii-xi, 1-134. doi: 10.3310/hta13450.
Abstract/Text
OBJECTIVE: To determine the clinical and cost-effectiveness of vitamin K in preventing osteoporotic fractures in postmenopausal women.
DATA SOURCES: Searches were conducted in May 2007 in MEDLINE, MEDLINE In-Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, AMED, NRR, Science Citation Index and Current Controlled Trials. The MEDLINE search was updated in March 2009.
REVIEW METHODS: Selected studies were assessed and subjected to data extraction and quality assessment using standard methods. Where appropriate, meta-analysis was carried out. A mathematical model was constructed to estimate the cost-effectiveness of vitamin K1.
RESULTS: The electronic literature searches identified 1078 potentially relevant articles. Of these, 14 articles relating to five trials that compared vitamin K with a relevant comparator in postmenopausal women with osteoporosis or osteopenia met the review inclusion criteria. The double-blind ECKO trial compared 5 mg of phylloquinone (vitamin K1) with placebo in Canadian women with osteopenia but without osteoporosis. Four open-label trials used 45 mg of menatetrenone (vitamin K2) in Japanese women with osteoporosis; the comparators were no treatment, etidronate or calcium. The methodological quality of the ECKO trial was good; however, all four menatetrenone trials were poorly reported and three were very small (n < 100 in each group). Phylloquinone was associated with a statistically significant reduction in the risk of clinical fractures relative to placebo [relative risk 0.46, 95% confidence interval (CI) 0.22 to 0.99]; morphometric vertebral fractures were not reported. The smaller menatetrenone trials found that menatetrenone was associated with a reduced risk of morphometric vertebral fractures relative to no treatment or calcium; however, the larger Osteoporosis Fracture (OF) study found no evidence of a reduction in vertebral fracture risk. The three smaller trials found no significant difference between treatment groups in non-vertebral fracture incidence. In the ECKO trial, phylloquinone was not associated with an increase in adverse events. In the menatetrenone trials, adverse event reporting was generally poor; however, in the OF study, menatetrenone was associated with a significantly higher incidence of skin and skin appendage lesions. No published economic evaluations of vitamin K were found and a mathematical model was thus constructed to estimate the cost-effectiveness of vitamin K1. Comparators were alendronate, risedronate and strontium ranelate. Vitamin K1 and alendronate were markedly more cost-effective than either risedronate or strontium ranelate. The base-case results favoured vitamin K1, but this relied on many assumptions, particularly on the efficacy of preventing hip and vertebral fractures. Calculation of the expected value of sampled information was conducted assuming a randomised controlled trial of 5 years' duration comparing alendronate with vitamin K1. The costs incurred in obtaining updated efficacy data from a trial with 2000 women per arm were estimated to be a cost-effective use of resources.
CONCLUSIONS: There is currently large uncertainty over whether vitamin K1 is more cost-effective than alendronate; further research is required. It is unlikely that the present prescribing policy (i.e. alendronate as first-line treatment) would be altered.
Florent Richy, Olivier Ethgen, Olivier Bruyere, Jean-Yves Reginster
Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate.
Osteoporos Int. 2004 Apr;15(4):301-10. doi: 10.1007/s00198-003-1570-5. Epub 2004 Jan 22.
Abstract/Text
Vitamin D metabolites alphacalcidol and calcitriol (D-hormones) have been investigated for two decades, but few and conflicting results are available from high-quality randomized controlled trials. Our objectives were to provide an evidence-based update quantitatively summarizing their efficacy on bone mineral density (BMD) and fracture rate. We performed a systematic research of any randomized controlled trial containing relevant data, peer review, data extraction and quality scoring blinded for authors and data sources, and comprehensive meta-analyses of the relevant data. Inclusion criteria were: randomized controlled study, calcitriol or alphacalcidol, BMD or fractures in healthy/osteopenic/osteoporotic patients exposed or not to corticosteroids (CS). Analyses were performed in a conservative fashion using professional dedicated softwares and stratified by outcome, target patients, study quality, and control-group type. Results were expressed as effect size (ES) for bone loss or relative risk (RR) for fracture while allocated to D-hormones vs control. Publication bias and robustness were investigated. Of the trials that were retrieved and subsequently reviewed, 17 papers fitted the inclusion criteria and were assessed. Quality scores ranged from 20 to 100%, the mean (standard deviation) being 72 (22)%. Calcitriol and alphacalcidol were found to have the same efficacy on all outcomes at p>0.13. We globally assessed D-hormones effects in preventing bone loss in patients not exposed to CS, and found positive effect: ES=0.39 ( p<0.001). For lumbar spine, this particular effect was 0.43 ( p<0.001). D-hormones significantly reduced the overall fracture rates: RR=0.52 (0.46; 0.59) and both vertebral and non-vertebral fractures: RR=0.53 (0.47; 0.60) and RR=0.34 (0.16; 0.71), respectively. No statistical difference in response was observed between results from studies on healthy and osteoporotic patients or depending on the fact that controls were allowed to calcium supplementation. Treatment with D-hormones was evaluated for maintaining spinal bone mass in five trials of patients with CS-induced osteoporosis, and provided ES=0.43 at p<0.001. Only two studies specifically addressed the effects of calcitriol on spinal fracture rate. None of them provided significant results, and the global RR did not reach the significance level as well: RR=0.33 (0.07; 1.51). Our data demonstrated efficacy for DH on bone loss and fracture prevention in patients not exposed to CS and on bone loss in patients exposed to CS, in the light of the most reliable scientific evidence. Their efficacy in reducing the number of fractures in patients exposed to CS remains to be determined.
Stuart L Silverman, Claus Christiansen, Harry K Genant, Slobodan Vukicevic, José R Zanchetta, Tobie J de Villiers, Ginger D Constantine, Arkadi A Chines
Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial.
J Bone Miner Res. 2008 Dec;23(12):1923-34. doi: 10.1359/jbmr.080710.
Abstract/Text
In this 3-yr, randomized, double-blind, placebo- and active-controlled study, healthy postmenopausal women with osteoporosis (55-85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent-to-treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T-score or=1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.
Tracey E Howe, Beverley Shea, Lesley J Dawson, Fiona Downie, Ann Murray, Craig Ross, Robin T Harbour, Lynn M Caldwell, Gisela Creed
Exercise for preventing and treating osteoporosis in postmenopausal women.
Cochrane Database Syst Rev. 2011 Jul 6;(7):CD000333. doi: 10.1002/14651858.CD000333.pub2. Epub 2011 Jul 6.
Abstract/Text
BACKGROUND: Osteoporosis is a condition resulting in an increased risk of skeletal fractures due to a reduction in the density of bone tissue. Treatment of osteoporosis typically involves the use of pharmacological agents. In general it is thought that disuse (prolonged periods of inactivity) and unloading of the skeleton promotes reduced bone mass, whereas mechanical loading through exercise increases bone mass.
OBJECTIVES: To examine the effectiveness of exercise interventions in preventing bone loss and fractures in postmenopausal women.
SEARCH STRATEGY: During the update of this review we updated the original search strategy by searching up to December 2010 the following electronic databases: the Cochrane Musculoskeletal Group's Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 12); MEDLINE; EMBASE; HealthSTAR; Sports Discus; CINAHL; PEDro; Web of Science; Controlled Clinical Trials; and AMED. We attempted to identify other studies by contacting experts, searching reference lists and searching trial registers.
SELECTION CRITERIA: All randomised controlled trials (RCTs) that met our predetermined inclusion criteria.
DATA COLLECTION AND ANALYSIS: Pairs of members of the review team extracted the data and assessed trial quality using predetermined forms. For dichotomous outcomes (fractures), we calculated risk ratios (RRs) using a fixed-effect model. For continuous data, we calculated mean differences (MDs) of the percentage change from baseline. Where heterogeneity existed (determined by the I(2) statistic), we used a random-effects model.
MAIN RESULTS: Forty-three RCTs (27 new in this update) with 4320 participants met the inclusion criteria. The most effective type of exercise intervention on bone mineral density (BMD) for the neck of femur appears to be non-weight bearing high force exercise such as progressive resistance strength training for the lower limbs (MD 1.03; 95% confidence interval (CI) 0.24 to 1.82). The most effective intervention for BMD at the spine was combination exercise programmes (MD 3.22; 95% CI 1.80 to 4.64) compared with control groups. Fractures and falls were reported as adverse events in some studies. There was no effect on numbers of fractures (odds ratio (OR) 0.61; 95% CI 0.23 to 1.64). Overall, the quality of the reporting of studies in the meta-analyses was low, in particular in the areas of sequence generation, allocation concealment, blinding and loss to follow-up.
AUTHORS' CONCLUSIONS: Our results suggest a relatively small statistically significant, but possibly important, effect of exercise on bone density compared with control groups. Exercise has the potential to be a safe and effective way to avert bone loss in postmenopausal women.
Nurten Küçükçakır, Lale Altan, Nimet Korkmaz
Effects of Pilates exercises on pain, functional status and quality of life in women with postmenopausal osteoporosis.
J Bodyw Mov Ther. 2013 Apr;17(2):204-11. doi: 10.1016/j.jbmt.2012.07.003. Epub 2012 Aug 9.
Abstract/Text
OBJECTIVE: The present study aimed to evaluate the effects of Pilates exercise program on pain, functional status and quality of life in women with postmenopausal osteoporosis.
DESIGN: The study was performed as a randomized, prospective, controlled and single-blind trial. PARTICIPATIONS: Seventy women (age range, 45-65 years) with the diagnosis of postmenopausal osteoporosis were included.
METHODS AND INTERVENTIONS: Patients were randomly allocated into two groups (home and Pilates exercise groups). Patients in the Pilates exercise group underwent a supervised Pilates exercise program twice a week for one year. Patients in the home exercise group were asked to perform a home exercise program consisting of thoracic extension exercises. Patients were evaluated at baseline and after one year of participation in the exercise programs.
MAIN OUTCOME MEASUREMENTS: Visual Analog Scale for pain, six-minute walking and sit-to-stand tests for functional status, and the Qualeffo-41 Questionnaire and the Short Form-36 (SF-36) for quality of life. Patients were also asked to report the number of falls during the intervention.
RESULTS: At the end of the study, the results of 60 patients were analyzed. A significant improvement was noted in all evaluation parameters at the end of the exercise program in the Pilates exercise group. Except for Qualeffo- Leisure Time Activities, SF-36 physical role limitation and emotional role limitation subscales, a significant improvement was noted in all other evaluation parameters at the end of the exercise program in the home exercise group. Improvement was significantly greater in the Pilates exercise group compared to the home exercise group in all parameters.
CONCLUSION: Pilates exercises may be a safe and an effective treatment alternative for the quality of life in patients with postmenopausal osteoporosis.
Copyright © 2012 Elsevier Ltd. All rights reserved.
E J Bassey, S J Ramsdale
Weight-bearing exercise and ground reaction forces: a 12-month randomized controlled trial of effects on bone mineral density in healthy postmenopausal women.
Bone. 1995 Apr;16(4):469-76.
Abstract/Text
The effects of brief daily exercise on bone mineral density (BMD) were assessed in a randomized controlled trial in 44 healthy postmenopausal women using weight-bearing exercise in a regimen adapted from osteogenic protocols reported in animal studies. BMD was assessed masked using dual energy X-ray absorptiometry at 0, 6, and 12 months. The sites assessed were the proximal femur (neck, Ward's triangle, and trochanter) and the lateral spine (L2-3) to assess the effects of the exercise, and the radius (ultradistal and 33% distal) as a marker for systemic effects. The test group was required to perform 50 "heel drops" daily at home (raising the body weight onto the toes and then letting it drop to the floor keeping the knees and hips extended) and to attend a weekly class of mixed exercises, which included some high-impact activity. The control group also attended a weekly exercise class run by the same teacher, which included only low-impact activity, and did flexibility exercises at home daily. The ground reaction forces (as a ratio of body weight) during heel drops were 2.5 to 3.0 N/N, with a rate of rise of 50-100 kN/sec. A patient with an instrumented femoral implant allowed comparison of compressive axial forces in the shaft of the proximal femur with the ground reaction forces, and these appeared to be transmitted undamped to the shaft of the femur. Initial analysis of BMD in the women showed no significant increases after 12 months of exercise at any site in either group, and the groups did not differ significantly from each other in this respect. Proximity to menopause was not associated with rapid bone loss, and in those who were more than 6 years postmenopausal, there was evidence for a maintenance effect of the exercise in the test group. Compliance (83%) and increases in leg extensor power (15%) were similar in both groups, and when they were combined, BMD was maintained at the trochanter but fell significantly at the radius (p < 0.001).
G Bravo, P Gauthier, P M Roy, H Payette, P Gaulin, M Harvey, L Péloquin, M F Dubois
Impact of a 12-month exercise program on the physical and psychological health of osteopenic women.
J Am Geriatr Soc. 1996 Jul;44(7):756-62.
Abstract/Text
OBJECTIVE: To describe the effect of a supervised physical activity program on the physical and psychological health of osteopenic women.
DESIGN: A randomized controlled trial.
SETTING: Sherbrooke, Quebec, Canada.
PARTICIPANTS: A total of 124 community-living postmenopausal women, between 50 and 70 years of age, with low bone mass took part in the study.
INTERVENTION: Subjects allocated to the experimental group performed weight-bearing exercises (walking, stepping up and down from benches), aerobic dancing, and flexibility exercises for 60 minutes, three times a week, over a period of 12 months. All subjects were invited to attend bi-monthly educational seminars covering topics related to osteoporosis.
OUTCOME MEASURES: Spinal and femoral bone mineral density (BMD), functional fitness (flexibility, coordination, agility, strength/endurance, cardiorespiratory endurance), psychological well-being, back pain intensity, and self-perceived health.
RESULTS: Spinal BMD stabilized in the exercisers while decreasing significantly in the controls (P = .031). No change in femoral BMD was observed in either group (P = .597). Four of the five parameters chosen to evaluate functional fitness, namely flexibility, agility, strength, and endurance, were affected positively by the exercise program (all P < .01). Adjusting for prescores by means of an analysis of covariance revealed a significant difference between the groups in psychological well-being, which favored the exercisers (P = .012). After 12 months, back pain reported by exercisers was lower than that reported by controls (P = .008). Finally, self-perceived health increased in the exercise group, whereas no difference was observed in the control group (P = .790).
CONCLUSION: These results suggest that after 12 months, exercising can produce a significant increase above initial levels in the functional fitness, well-being, and self-perceived health of osteopenic women. Intensity of back pain can also be lowered by exercise. The exercise program succeeded in stabilizing spinal BMD but had no effect on femoral BMD.
D Kerr, A Morton, I Dick, R Prince
Exercise effects on bone mass in postmenopausal women are site-specific and load-dependent.
J Bone Miner Res. 1996 Feb;11(2):218-25. doi: 10.1002/jbmr.5650110211.
Abstract/Text
It is considered that skeletal mass in humans may respond to loading or the number of loading cycles. The aim of this study was to examine the effect of a 1 year progressive resistance training program on the bone mass of 56 postmenopausal women. Assignment was by block randomization to one of two resistance training groups: a strength trained group (3 x 8 repetition maximum) or an endurance group (3 x 20 repetition maximum). The resistance exercises were selected to stress the ipsilateral forearm and hip region. The exercising side was randomly assigned with one side exercised while the alternate side acted as the nonexercise control. Bone mineral density (BMD) was measured every 3 months at the radial forearm and four hip sites using the Hologic QDR 2000 bone densitometer. A linear regression function was fitted for each individual's bone density results, and the slope was compared for the exercise and control side using paired t-tests. The bone mass increase with the strength regimen was significantly greater at the trochanteric hip site (control -0.6 +/- 2.2%, exercise 1.7 +/- 4.1%, p < 0.01), at the intertrochanteric hip site (control -0.1 +/- 2.1%, exercise 1.5 +/- 3.0%, p < 0.05), Ward's triangle (control 0.8 +/- 5.2%, exercise 2.3 +/- 4.0%, p < 0.05), and at the ultradistal radial site (control -1.4 +/- 2.3%, exercise 2.4 +/- 4.3%, p < 0.01). There was no significant increase in BMD with the endurance regimen except at the radius midsite (control -1.0 +/- 2.3%, exercise 0.1 +/- 1.4%, p < 0.01). In both the endurance and the strength group, muscle strength, tested by a one-repetition maximum (1RM) test, increased significantly for all 10 exercises (p < 0.01) and to a similar degree in the two groups. In the strength group but not the endurance group there were significant correlations between the slope of the change in BMD and the percentage increase in strength as follows: trochanter with leg press; intertrochanter with leg press (p < 0.05); and Ward's triangle with hip extension and hip adduction (p < 0.05). Thus these results support the notion of a site-specific response of bone to maximal loading from resistance exercise in that although the trochanter and intertrochanter bone density was elevated by the resistance exercises undertaken, there was no effect on the femoral neck value. Postmenopausal bone mass can be significantly increased by a strength regimen that uses high-load low repetitions but not by an endurance regimen that uses low-load high repetitions. We conclude that the peak load is more important than the number of loading cycles in increasing bone mass in early postmenopausal women.
M A Mayoux-Benhamou, F Bagheri, C Roux, G R Auleley, J P Rabourdin, M Revel
Effect of psoas training on postmenopausal lumbar bone loss: a 3-year follow-up study.
Calcif Tissue Int. 1997 Apr;60(4):348-53.
Abstract/Text
The present study completed a previous randomized trial that demonstrated the protective effect of 1-year psoas training on lumbar bone loss in postmenopausal women. Computerized tomography had been carried out at the beginning (CT1) and at the end (CT2) of this trial. In the present study, 67 women having completed the first trial were asked to practice psoas exercises (60 hip flexions in sitting position with a 5 kg weight on the knee) for 2 additional years with a third CT control at the end of this period (CT3). The aim of this complementary study was to assess the compliance rate and long-term effect on bone of daily psoas muscle training over a longer period. Twenty-one women performed this daily psoas training for 3 years from CT1 to CT3, and 14 acted as controls during the same period. Fourteen women were controls during the first year (from CT1 to CT2) but practiced psoas training during the following 2 years (from CT2 to CT3). Four women were psoas trained during the first year (from CT1 to CT2) and subsequently crossed over to the control group for the last 2 years. The compliance rate was 42%, with an attendance rate of 88%. The lumbar bone loss was lower in the 21 women trained over the 3 years (-3.26 +/- 28.45 mg/cm3) than in the 14 untrained women (-16.79 +/- 8.51 mg/cm3) (P = 0.02). The bone loss was not significantly reduced between the two periods of the study in the 12 women having been controls from CT1 to CT2 and having crossed over to the active training group from CT2 to CT3. Psoas training may be effective against lumbar bone loss. We conclude that specific training may play a contributing role in the preventive strategy to avoid osteoporosis.
A Heinonen, P Kannus, H Sievänen, M Pasanen, P Oja, I Vuori
Good maintenance of high-impact activity-induced bone gain by voluntary, unsupervised exercises: An 8-month follow-up of a randomized controlled trial.
J Bone Miner Res. 1999 Jan;14(1):125-8. doi: 10.1359/jbmr.1999.14.1.125.
Abstract/Text
The purpose of this study was to evaluate whether premenopausal women's voluntary unsupervised aerobic and step training could maintain the skeletal benefits obtained by an 18-month supervised high-impact training, and if so, to what extent. Thirty women of the original 39 study subjects (i. e., persons who completed the preceding 18-month randomized training intervention and who volunteered to continue the training on their own for a further 8 months) and 19 women of the 45 original control subjects (i.e., persons who volunteered to continue as controls) were included. The study group trained an average of twice per week and the training consisted of regular aerobic and step classes provided by local fitness centers. Areal bone mineral density (BMD, g/cm2) was measured from the lumbar spine, femoral neck, trochanter area of the femur, distal femur, patella, proximal tibia, calcaneus, and dominant distal radius at baseline and after 18 and 26 months. During the extended 8-month follow-up, the BMD of the study group increased more at the femoral neck (the intergroup change was +0.9% at 18 months and +2.8% at 26 months, p = 0.004 for the change between 18 and 26 months) and remained at the 18-month level at the distal femur, patella, proximal tibia, and calcaneus. In these sites, the statistically significant changes during the entire 26 months of training were 1.7-4.0% in the training group as compared with the changes of -0.9-1.5% in the control group. In the lumbar spine, BMD decreased from the 18-month level in both groups. In conclusion, the significant BMD increases that were obtained by supervised 18-month high-impact training were effectively maintained with subsequent unsupervised regular aerobic and step classes (twice per week). The finding emphasizes the effectiveness and feasibility of self-controlled aerobic and step exercises in the primary prevention of osteoporosis among healthy premenopausal women.
M Sinaki, E Itoi, H W Wahner, P Wollan, R Gelzcer, B P Mullan, D A Collins, S F Hodgson
Stronger back muscles reduce the incidence of vertebral fractures: a prospective 10 year follow-up of postmenopausal women.
Bone. 2002 Jun;30(6):836-41.
Abstract/Text
The long-term protective effect of stronger back muscles on the spine was determined in 50 healthy white postmenopausal women, aged 58-75 years, 8 years after they had completed a 2 year randomized, controlled trial. Twenty-seven subjects had performed progressive, resistive back-strengthening exercises for 2 years and 23 had served as controls. Bone mineral density, spine radiographs, back extensor strength, biochemical marker values, and level of physical activity were obtained for all subjects at baseline, 2 years, and 10 years. Mean back extensor strength (BES) in the back-exercise (BE) group was 39.4 kg at baseline, 66.8 kg at 2 years (after 2 years of prescribed exercises), and 32.9 kg at 10 years (8 years after cessation of the prescribed exercises). Mean BES in the control (C) group was 36.9 kg at baseline, 49.0 kg at 2 years, and 26.9 kg at 10 years. The difference between the two groups was still statistically significant at 10 year follow-up (p = 0.001). The difference in bone mineral density, which was not significant between the two groups at baseline and 2 year follow-up, was significant at 10 year follow-up (p = 0.0004). The incidence of vertebral compression fracture was 14 fractures in 322 vertebral bodies examined (4.3%) in the C group and 6 fractures in 378 vertebral bodies examined (1.6%) in the BE group (chi-square test, p = 0.0290). The relative risk for compression fracture was 2.7 times greater in the C group than in the BE group. To our knowledge, this is the first study reported in the literature demonstrating the long-term effect of strong back muscles on the reduction of vertebral fractures in estrogen-deficient women.
K Uusi-Rasi, P Kannus, S Cheng, H Sievänen, M Pasanen, A Heinonen, A Nenonen, J Halleen, T Fuerst, H Genant, I Vuori
Effect of alendronate and exercise on bone and physical performance of postmenopausal women: a randomized controlled trial.
Bone. 2003 Jul;33(1):132-43.
Abstract/Text
In this randomized, double-blind, placebo-controlled 12-month trial we evaluated effects of weight- bearing jumping exercise and oral alendronate, alone or in combination, on the mass and structure of bone, risk factors for falling (muscle strength and power, postural sway, and dynamic balance), and cardiorespiratory fitness in postmenopausal women. A total of 164 healthy, sedentary, early postmenopausal women were randomly assigned to one of four experimental groups: (1) 5 mg of alendronate daily plus progressive jumping exercise, (2) 5 mg alendronate, (3) placebo plus progressive jumping exercise, or (4) placebo. The primary endpoint was 12-month change in bone mass and geometry (measured with dual-energy X-ray absorptiometry and peripheral computed tomography at several axial and limb sites) and physical performance; the secondary endpoint was change in biochemical markers of bone turnover. The jumping exercise was conducted an average 1.6 +/- 0.9 (mean +/- SD) times a week. Alendronate daily was effective in increasing bone mass at the lumbar spine (alendronate vs placebo 3.5%; 95% CI, 2.2-4.9%) and femoral neck (1.3%; 95% CI, 0.2-2.4%) but did not affect other bone sites. Exercise alone had no effect on bone mass at the lumbar spine or femoral neck; it had neither an additive nor an interactive effect with alendronate at these bone sites. However, at the distal tibia the mean increase of 3.6% (0.3-7.1%) in the section modulus (that is, bone strength) and 3.7% (0.1-7.3%) increase in the ratio of cortical bone to total bone area were statistically significant in the exercise group compared to the nonexercise group, indicating exercise-induced thickening of the bone cortex. Bone turnover was reduced in alendronate groups only. Alendronate had no effect on physical performance while the jumping exercise improved leg extensor power, dynamic balance, and cardiorespiratory fitness. As conclusion Alendronate is effective in increasing bone mass at the lumbar spine and femoral neck, while exercise is effective in increasing the mechanical properties of bone at some of the most loaded bone sites, as well as improving the participants' muscular performance and dynamic balance. Together alendronate and exercise may effectively decrease the risk of osteoporotic fractures.
Kaiming Chan, Ling Qin, Mingchu Lau, Jean Woo, Szeki Au, Wingyee Choy, Kwongman Lee, Shiuhung Lee
A randomized, prospective study of the effects of Tai Chi Chun exercise on bone mineral density in postmenopausal women.
Arch Phys Med Rehabil. 2004 May;85(5):717-22.
Abstract/Text
OBJECTIVE: To evaluate the potential benefits of programmed Tai Chi Chun (TCC) exercise on the weight-bearing bones of early postmenopausal women.
DESIGN: Age-matched and randomized prospective intervention.
SETTING: University medical school.
PARTICIPANTS: One hundred thirty-two healthy postmenopausal women (mean age, 54.0+/-3.5y) within 10 years of menopause onset were recruited and randomized into the TCC exercise group (n=67) or the sedentary control group (n=65).
INTERVENTION: Supervised TCC exercise was performed by the TCC group for 45 minutes a day, 5 days a week, for 12 months; control subjects retained a sedentary life style. Main outcome measures Bone mineral density (BMD) was measured in the lumbar spine and proximal femur by using dual-energy x-ray absorptiometry and in the distal tibia by using multislice peripheral quantitative computed tomography (pQCT). All BMD measurements were repeated after 12 months in both groups. Fracture rate was also documented.
RESULTS: Baseline measurements showed homogeneity in age, anthropometric variables, and menstruation status between the TCC and control groups. Exactly 81.6% of the subjects in the TCC group and 83.1% of subjects in the control group completed the 12-month follow-up study. BMD measurements revealed a general bone loss in both TCC and sedentary control subjects at all measured skeletal sites, but with a reportedly slower rate in the TCC group. A significant 2.6- to 3.6-fold retardation of bone loss (P<.01) was found in both trabecular and cortical compartments of the distal tibia in the TCC group as compared with the controls, as measured by pQCT. A total of 4 fracture cases were documented during follow-up, including 3 subjects in the control group and 1 in the TCC group.
CONCLUSIONS: This is the first prospective and randomized study to show that a programmed TCC exercise intervention is beneficial for retarding bone loss in weight-bearing bones in early postmenopausal women. Long-term follow-up is needed to substantiate the role of TCC exercise in the prevention of osteoporosis and its related fracture.
S Høidrup, M Grønbaek, A Gottschau, J B Lauritzen, M Schroll
Alcohol intake, beverage preference, and risk of hip fracture in men and women. Copenhagen Centre for Prospective Population Studies.
Am J Epidemiol. 1999 Jun 1;149(11):993-1001.
Abstract/Text
The authors prospectively studied the association between quantity and type of alcohol intake and risk of hip fracture among 17,868 men and 13,917 women. Analyses were based on pooled data from three population studies conducted in 1964-1992 in Copenhagen, Denmark. During follow-up, 500 first hip fractures were identified in women and 307 in men. A low to moderate weekly alcohol intake (1-27 drinks for men and 1-13 drinks for women) was not associated with hip fracture. Among men, the relative risk of hip fracture gradually increased for those who drank 28 drinks or more per week (relative risk (RR) = 1.75, 95% confidence interval (CI) 1.06-2.89 for 28-41 drinks; RR = 5.28, 95% CI 2.60-10.70 for 70 or more drinks) as compared with abstainers. Women who drank 14-27 drinks per week had an age-adjusted relative risk of hip fracture of 1.44 (95% CI 1.03-2.03), but the association weakened after adjustment for confounders (RR = 1.32, 95% CI 0.92-1.87). The risk of hip fracture differed according to the type of alcohol preferred: preferrers of beer had a higher risk of hip fracture (RR = 1.46, 95% CI 1.11-1.91) than preferrers of other types of alcoholic beverages. The corresponding relative risks for preferrers of wine and spirits were 0.77 (95% CI 0.58-1.03) and 0.82 (95% CI 0.58-1.14), respectively. In conclusion, an alcohol intake within the current European drinking limits does not influence the risk of hip fracture, whereas an alcohol intake of more than 27 drinks per week is a major risk factor for men.
Hiroshi Hagino, Yoshiki Nishizawa, Teruki Sone, Hirotoshi Morii, Yuji Taketani, Toshitaka Nakamura, Akira Itabashi, Hideaki Mizunuma, Yasuo Ohashi, Masataka Shiraki, Toshiomi Minamide, Toshio Matsumoto
A double-blinded head-to-head trial of minodronate and alendronate in women with postmenopausal osteoporosis.
Bone. 2009 Jun;44(6):1078-84. doi: 10.1016/j.bone.2009.02.016. Epub 2009 Mar 2.
Abstract/Text
INTRODUCTION: In a randomized, active-controlled, double-blinded, multicenter study, the efficacy and safety of minodronate were examined and compared to that of alendronate.
METHODS: A total of 270 postmenopausal osteoporotic women >or=45 years of age were randomized into the minodronate group (n=135) or alendronate group (n=135). Each subject received 1 mg minodronate or 5 mg alendronate once a day for 12 months.
RESULTS: Both treatment groups showed similar changes in BMD after 12 months. After 1 year of treatment, the lumbar spine BMD increased by 5.86% and 6.29% in the minodronate and alendronate groups, respectively, and the total hip BMD increased by 3.47% and 3.27%, respectively. Bone turnover markers were rapidly reduced within 1 month in both treatment groups. Urine DPD was significantly lower in the minodronate group than in the alendronate group at 6 months, and urine NTX was significantly lower in the minodronate group than in the alendronate group at 1 and 9 months. Both completion rates for the 12-month study and the overall incidence of clinical adverse events, including gastrointestinal events, were similar between the two groups.
CONCLUSIONS: The effects on lumbar and hip BMD and the safety profile of minodronate are comparable to those of alendronate. Minodronate is a promising new potent bisphosphonate for the treatment of osteoporosis.
Marjorie M Luckey, Nigel Gilchrist, Henry G Bone, Michael W Davie, Tobias J de Villiers, Mei Wu, Anastasia G Daifotis, Arthur C Santora, John J Orloff
Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis.
Obstet Gynecol. 2003 Apr;101(4):711-21.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis.
METHODS: We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40-70 years, with lumbar spine and femoral neck bone mineral density T-scores between -2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria.
RESULTS: Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was -0.3% [-0.6, 0.1], well within the prespecified bounds of +/-1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events.
CONCLUSION: Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.
Henry G Bone, David Hosking, Jean-Pierre Devogelaer, Joseph R Tucci, Ronald D Emkey, Richard P Tonino, Jose Adolfo Rodriguez-Portales, Robert W Downs, Jayanti Gupta, Arthur C Santora, Uri A Liberman, Alendronate Phase III Osteoporosis Treatment Study Group
Ten years' experience with alendronate for osteoporosis in postmenopausal women.
N Engl J Med. 2004 Mar 18;350(12):1189-99. doi: 10.1056/NEJMoa030897.
Abstract/Text
BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years.
METHODS: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study.
RESULTS: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit.
CONCLUSIONS: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.
Copyright 2004 Massachusetts Medical Society
Kazuhiro Kushida, Masataka Shiraki, Toshitaka Nakamura, Hideaki Kishimoto, Hirotoshi Morii, Kichizo Yamamoto, Kiyoshi Kaneda, Masao Fukunaga, Tetsuro Inoue, Mitsuyoshi Nakashima, Hajime Orimo
Alendronate reduced vertebral fracture risk in postmenopausal Japanese women with osteoporosis: a 3-year follow-up study.
J Bone Miner Metab. 2004;22(5):462-8. doi: 10.1007/s00774-004-0508-0.
Abstract/Text
The risk-reducing effect of alendronate on vertebral fractures has been consistently reported. In a 2-year, randomized, double-blind, active drug-controlled (1 microg alfacalcidol) double-dummy study, we also reported that alendronate (5.0 mg) had a fracture-reducing effect in Japanese patients with preexisting vertebral fractures. The present report describes the risk-reducing effect of alendronate (5.0 mg) for 3 years in postmenopausal osteoporotic patients. The 3-year treatment period consisted of the original 2-year double-blind study followed by a 1-year extension. A total of 170 postmenopausal female patients were involved in the third year; 90 received alendronate and 80 received alfacalcidol. Both efficacy and safety were analyzed in these 170 patients. Vertebral fracture was determined by quantitative morphometry, and vertebral bone mineral density (BMD) was measured by the DXA method (dual-energy X-ray absorptiometry). The primary efficacy endpoint was the incidence of vertebral fracture, excluding fracture cases that occurred in the first 6 months after treatment initiation. The cumulative incidence of vertebral fracture at 3 years was 7.8% (7/90) in the alendronate group and 18.8% (15/80) in the alfacalcidol group, indicating a significantly reduced risk of fractures in the alendronate group (relative risk = 0.41, 95% CI = 0.18-0.97). Lumbar spine BMD increased by 9.2% in the alendronate group (n = 26) and by 1.4% in the alfacalcidol group (n = 22) at 3 years. The safety profile of alendronate during 3 years of treatment was similar to that of alfacalcidol. The present study thus demonstrated that treatment with alendronate 5.0 mg for 3 years increased vertebral BMD and reduced the risk of vertebral fractures in Japanese, postmenopausal women with osteoporosis.
Antonella Barone, Andrea Giusti, Giulio Pioli, Giuseppe Girasole, Monica Razzano, Monica Pizzonia, Ernesto Palummeri, Gerolamo Bianchi
Secondary hyperparathyroidism due to hypovitaminosis D affects bone mineral density response to alendronate in elderly women with osteoporosis: a randomized controlled trial.
J Am Geriatr Soc. 2007 May;55(5):752-7. doi: 10.1111/j.1532-5415.2007.01161.x.
Abstract/Text
OBJECTIVES: To determine whether secondary hyperparathyroidism (HPTH) due to hypovitaminosis D affects bone mineral density (BMD) response to alendronate (ALN) in elderly women with osteoporosis.
DESIGN: Randomized, controlled trial with 1-year follow-up.
SETTING: Two osteoporosis centers in northern Italy.
PARTICIPANTS: Community-dwelling women aged 60 and older with a BMD T-score below -2.5 and secondary HPTH with vitamin D insufficiency.
INTERVENTION: One hundred twenty subjects were randomly assigned to receive ALN 70 mg once a week alone or ALN 70 mg once a week plus calcitriol (1,25D3) 0.5 microg daily.
MEASUREMENTS: BMD measured using dual-energy x-ray absorptiometry at the lumbar spine (L1-L4), femoral neck, and total hip and serum levels of intact PTH at baseline and 12 months.
RESULTS: After 1 year, BMD of the lumbar spine, femoral neck, and total hip significantly increased from baseline in both groups (P<.001). Patients allocated to ALN plus 1,25D3 demonstrated a significantly higher increase in lumbar spine BMD than those receiving ALN alone (mean percentage+/-standard deviation 6.8+/-4.6 vs 3.7+/-3.2, P<.001). Serum levels of PTH did not change significantly at 1 year in the ALN group (mean percentage, -3.7+/-27.1, P=.13) but decreased significantly in the ALN plus 1,25D3 group (-32.1+/-22.1, P<.001). At 12 months, subjects with normalized PTH independent of therapy allocation had a greater increase in lumbar spine BMD than those with persistent HPTH (6.5+/-4.6% vs 3.7+/-3.4%, P<.001). Lumbar spine BMD changes showed a significant negative correlation with PTH at 1 year (correlation coefficient (rho) =-0.399, P<.001) and a positive correlation with PTH changes (i.e., baseline value - 1 year value; rho=0.295, P=.005).
CONCLUSION: Persistence of secondary HPTH reduces BMD response to ALN in older women with osteoporosis.
Ann Cranney, Gordon Guyatt, Lauren Griffith, George Wells, Peter Tugwell, Clifford Rosen, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group
Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis.
Endocr Rev. 2002 Aug;23(4):570-8. doi: 10.1210/er.2001-9002.
Abstract/Text
This section summarizes the results of the seven systematic reviews of osteoporosis therapies published in this series [calcium, vitamin D, hormone replacement therapy (HRT), alendronate, risedronate, raloxifene, and calcitonin] and systematic reviews of etidronate and fluoride we have published elsewhere. We highlight the methodological strengths and weaknesses of the individual studies, and summarize the effects of treatments on the risk of vertebral and nonvertebral fractures and on bone density, including effects in different patient subgroups. We provide an estimate of the expected impact of antiosteoporosis interventions in prevention and treatment populations using the number needed to treat (NNT) as a reference. In addition to the evidence, judgements about the relative weight that one places on weaker and stronger evidence, attitudes toward uncertainty, circumstances of patients' and societal values or preferences will, and should, play an important role in decision-making regarding anti-osteoporosis therapy.
G A Wells, A Cranney, J Peterson, M Boucher, B Shea, V Robinson, D Coyle, P Tugwell
Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001155. doi: 10.1002/14651858.CD001155.pub2. Epub 2008 Jan 23.
Abstract/Text
BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts.
OBJECTIVES: To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007.
SELECTION CRITERIA: Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence.
DATA COLLECTION AND ANALYSIS: We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals.
MAIN RESULTS: Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.
AUTHORS' CONCLUSIONS: At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).
Dennis M Black, Ann V Schwartz, Kristine E Ensrud, Jane A Cauley, Silvina Levis, Sara A Quandt, Suzanne Satterfield, Robert B Wallace, Douglas C Bauer, Lisa Palermo, Lois E Wehren, Antonio Lombardi, Arthur C Santora, Steven R Cummings, FLEX Research Group
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
JAMA. 2006 Dec 27;296(24):2927-38. doi: 10.1001/jama.296.24.2927.
Abstract/Text
CONTEXT: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain.
OBJECTIVE: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years.
DESIGN AND SETTING: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT).
PARTICIPANTS: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment.
INTERVENTION: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003).
MAIN OUTCOME MEASURES: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence.
RESULTS: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens.
CONCLUSIONS: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 00398931.
Socrates E Papapoulos, Sara A Quandt, Uri A Liberman, Marc C Hochberg, Desmond E Thompson
Meta-analysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women.
Osteoporos Int. 2005 May;16(5):468-74. doi: 10.1007/s00198-004-1725-z. Epub 2004 Sep 21.
Abstract/Text
Treatment with alendronate, a potent and specific inhibitor of bone resorption, is known to significantly reduce fracture risk among women with postmenopausal osteoporosis. The purpose of this meta-analysis was to assess the consistency of the effect of alendronate in reducing the risk of hip fracture among different studies and populations. Data from completed, randomized, treatment studies were pooled in a meta-analysis. The duration of the studies ranged from 1-4.5 years. The dose of alendronate ranged from 5-20 mg/day, with over 95% of patients receiving either 5 or 10 mg/day during the trials. In patients with a T-score of less than or equal to -2.0, or with a vertebral fracture, the effect on hip fracture risk consistently favored patients receiving alendronate therapy, with an overall reduction in risk of hip fracture of 45% [95% confidence interval (CI) 16% to 64%, P=0.007]. For patients who met the criteria of osteoporosis, as defined by the World Health Organization (WHO), the overall risk reduction was 55% (95% CI 29% to 72%, P=0.0008). In both analyses we performed a sensitivity analysis by removing one study at a time. The strength of the evidence was not dependent on any one study. We conclude that therapy with alendronate is associated with significant and clinically important reductions in the incidence of hip fracture in women with postmenopausal osteoporosis. The overall reduction is consistent among different patient populations.
Anna M Sawka, Alexandra Papaioannou, Jonathan D Adachi, Amiram Gafni, David A Hanley, Lehana Thabane
Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women.
BMC Musculoskelet Disord. 2005 Jul 11;6:39. doi: 10.1186/1471-2474-6-39. Epub 2005 Jul 11.
Abstract/Text
BACKGROUND: Alendronate has been found to reduce the risk of fractures in postmenopausal women as demonstrated in multiple randomized controlled trials enrolling thousands of women. Yet there is a paucity of such randomized controlled trials in osteoporotic men. Our objective was to systematically review the anti-fracture efficacy of alendronate in men with low bone mass or with a history of prevalent fracture(s) and incorporate prior knowledge of alendronate efficacy in women in the analysis.
METHODS: We examined randomized controlled trials in men comparing the anti-fracture efficacy of alendronate to placebo or calcium or vitamin D, or any combination of these. Studies of men with secondary causes of osteoporosis other than hypogonadism were excluded. We searched the following electronic databases (without language restrictions) for potentially relevant citations: Medline, Medline in Process (1966-May 24/2004), and Embase (1996-2004). We also contacted the manufacturer of the drug in search of other relevant trials. Two reviewers independently identified two trials (including 375 men), which met all inclusion criteria. Data were abstracted by one reviewer and checked by another. Results of the male trials were pooled using Bayesian random effects models, incorporating prior information of anti-fracture efficacy from meta-analyses of women.
RESULTS: The odds ratios of incident fractures in men (with 95% credibility intervals) with alendronate (10 mg daily) were: vertebral fractures, 0.44 (0.23, 0.83) and non-vertebral fractures, 0.60 (0.29, 1.44).
CONCLUSION: In conclusion, alendronate decreases the risk of vertebral fractures in men at risk. There is currently insufficient evidence of a statistically significant reduction of non-vertebral fractures, but the paucity of trials in men limit the statistical power to detect such an effect.
Ann Cranney, Peter Tugwell, Jonathan Adachi, Bruce Weaver, Nicole Zytaruk, Alexandra Papaioannou, Vivian Robinson, Beverley Shea, George Wells, Gordon Guyatt, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group
Meta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis.
Endocr Rev. 2002 Aug;23(4):517-23. doi: 10.1210/er.2001-3002.
Abstract/Text
OBJECTIVE: To review the effect of risedronate on bone density and fractures in postmenopausal women.
DATA SOURCES: We searched MEDLINE from 1966 to the end of 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings.
STUDY SELECTION: We included eight randomized, placebo-controlled trials of postmenopausal women receiving risedronate or placebo with a follow-up of at least one year and providing data on bone density or fracture rate.
DATA EXTRACTION: For each trial, two independent reviewers assessed the methodological quality and abstracted data.
DATA SYNTHESIS: The major methodological limitation of the trials was the loss to follow-up, which was over 20% in most trials and over 35% in the largest study. However, the magnitude of the treatment effect was unrelated to loss to follow-up, and in one of the largest trials, more high-risk patients were lost to follow-up in the control than in the treatment group. The pooled relative risk (RR) for vertebral fractures in women given 2.5 mg or more of risedronate was 0.64 [95% confidence interval (CI) 0.54, 0.77]. The pooled RR of nonvertebral fractures in patients given 2.5 mg or more of risedronate was 0.73 (95% CI 0.61, 0.87). Risedronate produced positive effects on the percentage change in bone density of the lumbar spine, combined forearm, and femoral neck that were generally larger with the 5-mg daily dose than with cyclical administration or the 2.5-mg dose. The pooled estimate of the difference in percentage change between 5 mg risedronate and placebo after the final year of treatment (1.5-3 yr) was 4.54% (95% CI 4.12, 4.97) for the lumbar spine, and 2.75% (95% CI 2.32, 3.17) at the femoral neck.
CONCLUSIONS: Risedronate substantially reduces the risk of both vertebral and nonvertebral fractures. This fracture reduction is accompanied by an increase in bone density of the lumbar spine and femoral neck in both early postmenopausal women and those with established osteoporosis.
Hideaki Kishimoto, Masao Fukunaga, Kazuhiro Kushida, Masataka Shiraki, Akira Itabashi, Hajime Nawata, Toshitaka Nakamura, Hiroaki Ohta, Kunio Takaoka, Yasuo Ohashi, Risedronate Phase III Research Group
Efficacy and tolerability of once-weekly administration of 17.5 mg risedronate in Japanese patients with involutional osteoporosis: a comparison with 2.5-mg once-daily dosage regimen.
J Bone Miner Metab. 2006;24(5):405-13. doi: 10.1007/s00774-006-0706-z.
Abstract/Text
In this multicenter, randomized, double-blind controlled trial, the efficacy and safety of once-weekly dosing with 17.5 mg risedronate was compared with once-daily dosing with 2.5 mg risedronate in Japanese patients with involutional osteoporosis. A total of 496 patients were randomized to receive either once-weekly (n = 249) or once-daily (n = 247) treatment. All patients were supplemented with 200 mg/day calcium. Following 48 weeks of treatment, the mean (+/-SD) percent changes, from baseline, in the bone mineral density of the lumbar spine (L2-L4 BMD) in the once-weekly and once-daily treatment groups were 5.36 +/- 4.27% and 5.87 +/- 4.47%, respectively. The difference between the groups was -0.5% (95% confidence interval: -1.35% to 0.35%), demonstrating that the effect on BMD of once-weekly treatment was not inferior to that of once-daily treatment. The time-course reductions in biochemical markers of bone resorption (urinary N- and C-telopeptide of type I collagen) and bone formation (bone-specific alkaline phosphatase) were similar for the two dosing regimens. There were no differences in the incidence of new vertebral fractures or the worsening of existing fractures between the once-weekly (2.2%) and once-daily (2.7%) dosing regimens. No significant differences were observed between the two dosing regimens in the incidence or the type of adverse events. However, 10.1% of the patients in the once-daily group withdrew due to adverse events as compared to 5.2% in the once-weekly group. Moreover, drug-related adverse events, including upper gastrointestinal disorders and abnormal changes in laboratory parameters, tended to be less in the once-weekly dosing regimen than in the once-daily dosing regimen. In conclusion, once-weekly oral dosing with 17.5 mg risedronate was well tolerated in Japanese osteoporotic patients, and showed equivalent efficacy to once-daily oral dosing with 2.5 mg risedronate. This once-weekly regimen is expected to provide a more convenient therapeutic option as an alternative to daily dosing and to enhance patient compliance in long-term therapy for osteoporosis.
I Fogelman, C Ribot, R Smith, D Ethgen, E Sod, J Y Reginster
Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group.
J Clin Endocrinol Metab. 2000 May;85(5):1895-900. doi: 10.1210/jcem.85.5.6603.
Abstract/Text
Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.
S T Harris, N B Watts, Z Li, A A Chines, D A Hanley, J P Brown
Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis.
Curr Med Res Opin. 2004 May;20(5):757-64. doi: 10.1185/030079904125003566.
Abstract/Text
OBJECTIVE: The efficacy and tolerability of risedronate once-a-week dosing (35 and 50mg) were compared with risedronate daily dosing (5mg) in a 2-year study in women with osteoporosis.
DESIGN AND METHODS: This was a randomized, double-blind, active-control study with lumbar spine bone mineral density (BMD) as the primary efficacy endpoint at 1 year. Subjects were women aged 50 years or older, postmenopausal for at least 5 years, and had either a BMD T-score of -2.5 or lower (lumbar spine or total proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. In addition to risedronate treatment, the subjects received 1000 mg daily of elemental calcium supplementation and received vitamin D if the baseline serum 25-hydroxyvitamin D(3) level was low.
RESULTS: The results after 1 year of treatment were previously published. Of the 1456 women who were randomized and received study medication, 1127 (77%) completed the 2-year study. Over the 2 years of treatment, the incidence of both new vertebral fractures (2.9, 1.5, and 1.7% for the 5, 35, and 50 mg groups, respectively; for women with postmenopausal osteoporosis who p = 0.298) and osteoporosis-related non-vertebral fractures reported as adverse events (5.0, 4.9, and 4.5% for the 5, 35, and 50 mg groups, respectively; p = 0.918) was similar for all 3 treatment groups. The reduction from baseline at Month 24 in bone turnover markers was similar based on an analysis of variance for the 5 mg daily and the 35 mg once-a-week groups. The mean percentage change in lumbar spine BMD after 24 months was 5.17, 4.74, and 5.47% for the 5, 35, and 50 mg groups, respectively. Both the 35 and 50 mg once-a-week treatment groups met the pre-specified criterion of non-inferiority to the 5 mg daily treatment group. No apparent difference in the pattern or distribution of serious and upper gastrointestinal adverse events was observed.
CONCLUSIONS: The 2-year data agree with the 1-year results demonstrating that the risedronate once-a-week doses are comparable in efficacy and safety to the 5 mg daily dose. Risedronate 35 mg once a week is considered the optimal dose want a once-a-week dosing regimen.
Steven Boonen, Eric S Orwoll, Dietrich Wenderoth, Karen J Stoner, Rachelle Eusebio, Pierre D Delmas
Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study.
J Bone Miner Res. 2009 Apr;24(4):719-25. doi: 10.1359/jbmr.081214.
Abstract/Text
Male osteoporosis is increasingly recognized as a major public health issue. This multinational, 2-yr, randomized, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of 35 mg once-a-week risedronate in men with osteoporosis. Patients had to be men >or=30 yr old, with lumbar spine T-score
S T Harris, N B Watts, H K Genant, C D McKeever, T Hangartner, M Keller, C H Chesnut, J Brown, E F Eriksen, M S Hoseyni, D W Axelrod, P D Miller
Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group.
JAMA. 1999 Oct 13;282(14):1344-52.
Abstract/Text
CONTEXT: Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.
OBJECTIVE: To test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998.
INTERVENTIONS: Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low.
MAIN OUTCOME MEASURES: Incidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry.
RESULTS: The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI], 18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65% (95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%). Bone formed during risedronate treatment was histologically normal. The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo.
CONCLUSIONS: These data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis.
J Reginster, H W Minne, O H Sorensen, M Hooper, C Roux, M L Brandi, B Lund, D Ethgen, S Pack, I Roumagnac, R Eastell
Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.
Osteoporos Int. 2000;11(1):83-91.
Abstract/Text
The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n = 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p = 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.
M R McClung, P Geusens, P D Miller, H Zippel, W G Bensen, C Roux, S Adami, I Fogelman, T Diamond, R Eastell, P J Meunier, J Y Reginster, Hip Intervention Program Study Group
Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group.
N Engl J Med. 2001 Feb 1;344(5):333-40. doi: 10.1056/NEJM200102013440503.
Abstract/Text
BACKGROUND: Risedronate increases bone mineral density in elderly women, but whether it prevents hip fracture is not known.
METHODS: We studied 5445 women 70 to 79 years old who had osteoporosis (indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [-4] or lower than -3 plus a nonskeletal risk factor for hip fracture, such as poor gait or a propensity to fall) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than -4 or lower than -3 plus a hip-axis length of 11.1 cm or greater). The women were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the occurrence of hip fracture.
RESULTS: Overall, the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent, as compared with 3.9 percent among those assigned to placebo (relative risk, 0.7; 95 percent confidence interval, 0.6 to 0.9; P=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9 percent, as compared with 3.2 percent among those assigned to placebo (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.9; P=0.009). In the group of women selected primarily on the basis of nonskeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo (P=0.35).
CONCLUSIONS: Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density.
Steven Boonen, Andrea B Klemes, Xiaojie Zhou, Robert Lindsay
Assessment of the relationship between age and the effect of risedronate treatment in women with postmenopausal osteoporosis: a pooled analysis of four studies.
J Am Geriatr Soc. 2010 Apr;58(4):658-63. doi: 10.1111/j.1532-5415.2010.02763.x. Epub 2010 Mar 22.
Abstract/Text
OBJECTIVES: To quantify the effect of age on the incidence of osteoporosis-related fractures and of risedronate treatment on fracture risk in different age groups in women with postmenopausal osteoporosis.
DESIGN: Data from four randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed.
PARTICIPANTS: The analysis population (N=3,229) consisted of postmenopausal women with osteoporosis as determined on the basis of prevalent vertebral fractures, low bone mineral density (BMD), or both.
INTERVENTION: Patients had received risedronate 5 mg daily or placebo for 1 to 3 years.
MEASUREMENTS: The endpoints of interest were the incidence of osteoporosis-related fractures, clinical fractures, nonvertebral fractures, and morphometric vertebral fractures. The effect of age on fracture risk and treatment benefit was examined using Cox regression models with age and treatment as explanatory variables. The 3-year fracture risk was estimated for patients in each treatment group at a given age.
RESULTS: Irrespective of treatment, fracture risks were greater in older patients (P<.001). On average, for every 1-year increase in age, a patient's risk for osteoporosis-related fracture increased 3.6% (95% confidence interval=2.3-5.0%). Irrespective of age, risedronate treatment reduced fracture risk 42%. Risedronate-treated patients had fracture risks similar to those of placebo-treated patients 10 to 20 years younger.
CONCLUSION: Patients treated with risedronate have a significantly lower fracture risk, similar to that of untreated patients 10 to 20 years younger.
西沢良記. ミノドロン酸水和物後期第Ⅱ相臨床試験 ―退行期骨粗鬆症患者に対する臨床試験―. 薬理と 臨床 2008; 18(Suppl.1): S315-27.
Hiroshi Hagino
[New development in bisphosphonate treatment. Review of the preventive effect of minodronic acid on fracture in Japanese patients with osteoporosis].
Clin Calcium. 2009 Jan;19(1):75-84. doi: CliCa09017584.
Abstract/Text
Minodronic acid, a novel bisphosphonate, is one of the osteoporosis medications that has a potent inhibitive action on bone resorption. In this study, we performed additional analyses of the results on the already-reported phase III fracture study using minodronic acid, and reviewed the efficacy in elderly patients aged 75 years or older. The results show that minodronic acid suppressed the occurrence of vertebral fracture in patients aged 75 years or older at higher risk of fracture, in the same way as in patients aged less than 75 years. The phase III fracture study using minodronic acid was the first study that verified the preventive effect on vertebral fracture versus placebo in Japanese patients with osteoporosis. The results of the study compared favorably with placebo-controlled large-scale clinical studies using other agents that were conducted overseas.
Ann Cranney, Peter Tugwell, Nicole Zytaruk, Vivian Robinson, Bruce Weaver, Jonathan Adachi, George Wells, Beverley Shea, Gordon Guyatt, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group
Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis.
Endocr Rev. 2002 Aug;23(4):524-8. doi: 10.1210/er.2001-4002.
Abstract/Text
OBJECTIVE: To review the effect of raloxifene on bone density and fractures in postmenopausal women.
DATA SOURCE: We searched MEDLINE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings.
STUDY SELECTION: We included seven trials that randomized women to raloxifene or placebo, with both groups receiving similar calcium and vitamin D supplementation, and measured bone density for at least one year.
DATA EXTRACTION: For each trial, three independent reviewers abstracted the data and assessed the methodological quality using a validated tool.
DATA SYNTHESIS: Data from one large dominating trial suggest a reduction in vertebral fractures with a relative risk (RR) of 0.60 [95% confidence interval (CI) 0.50-0.70, P < 0.01]. The RR of nonvertebral fractures in patients given 60 mg or more of raloxifene in the larger study was 0.92 (95% CI 0.79-1.07, P = 0.27). Raloxifene resulted in positive effects on the percentage change in bone density, which increased over time and was independent of dose. At the final year, point estimates and 95% CIs for the differences in percent change in bone density (95% CI) between raloxifene and placebo groups were 1.33 (95% CI 0.37-2.30) for total body, 2.51 (95% CI 2.21-2.82) for lumbar spine, 2.05 (95% CI 0.71-3.39) for combined forearm, and 2.11 (95% CI 1.68-2.53) for combined hip (P < 0.01 at all four sites). Results were similar across studies, and formal tests of heterogeneity did not approach conventional statistical significance. Raloxifene slightly increased rates of withdrawal from therapy as a result of adverse effects (RR 1.15, 95% CI 1.00-1.33, P = 0.05). The pooled RR was significant for hot flashes 1.46 (95% CI 1.23-1.74, P < 0.01) and nonsignificant for leg cramps 1.64 (95% CI 0.84-3.20, P = 0.15).
CONCLUSION: Raloxifene increases bone density, and the effect increases over 2 yr. The data suggest a positive impact of raloxifene on vertebral fractures. There was little effect of raloxifene on nonvertebral fractures.
B Ettinger, D M Black, B H Mitlak, R K Knickerbocker, T Nickelsen, H K Genant, C Christiansen, P D Delmas, J R Zanchetta, J Stakkestad, C C Glüer, K Krueger, F J Cohen, S Eckert, K E Ensrud, L V Avioli, P Lips, S R Cummings
Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.
JAMA. 1999 Aug 18;282(7):637-45.
Abstract/Text
CONTEXT: Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known.
OBJECTIVE: To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures.
DESIGN: The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial.
SETTING AND PARTICIPANTS: A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events.
INTERVENTIONS: Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol.
MAIN OUTCOME MEASURES: Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry.
RESULTS: At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P<0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.
CONCLUSIONS: In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.
Deborah Grady, Jane A Cauley, John L Stock, David A Cox, Bruce H Mitlak, Jingli Song, Steven R Cummings
Effect of Raloxifene on all-cause mortality.
Am J Med. 2010 May;123(5):469.e1-7. doi: 10.1016/j.amjmed.2009.12.018.
Abstract/Text
OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, reduces osteoporosis and invasive breast cancer risk but increases risk for venous thromboembolism and fatal stroke in women with or at high risk for coronary heart disease. To assess the risk/benefit of raloxifene as a preventative treatment, we analyzed treatment effects on overall and cause-specific mortality.
METHODS: A pooled analysis of mortality data was performed from large clinical trials of raloxifene (60 mg/day) versus placebo, including the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista studies (7705 postmenopausal osteoporotic women followed for 4 years and a subset of 4011 participants followed for an additional 4 years; 110 deaths) and the Raloxifene Use for the Heart trial (10,101 postmenopausal women with coronary disease or multiple risk factors for coronary disease followed for 5.6 years; 1149 deaths). Cause of death was assessed by blinded adjudicators. Cox proportional hazards regression models compared mortality by treatment assignment in a pooled analysis of trial data from the Multiple Outcomes of Raloxifene Evaluation/Continuing Outcomes Relevant to Evista and Raloxifene Use for the Heart trials.
RESULTS: All-cause mortality was 10% lower among women assigned to raloxifene 60 mg/day versus placebo (relative hazard 0.90; 95% confidence interval, 0.80-1.00; P=.05). Lower overall mortality was primarily due to lower rates of noncardiovascular deaths, especially a lower rate of noncardiovascular, noncancer deaths.
CONCLUSIONS: All-cause mortality was 10% lower in pooled analyses among older postmenopausal women receiving raloxifene 60 mg/day compared with placebo, due primarily to a reduction in noncardiovascular, noncancer deaths. The mechanism whereby raloxifene might reduce the risk of noncardiovascular death is unclear.
Published by Elsevier Inc.
Mohammad Hassan Murad, Matthew T Drake, Rebecca J Mullan, Karen F Mauck, Louise M Stuart, Melanie A Lane, Nisrin O Abu Elnour, Patricia J Erwin, Ahmad Hazem, Milo A Puhan, Tianjing Li, Victor M Montori
Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis.
J Clin Endocrinol Metab. 2012 Jun;97(6):1871-80. doi: 10.1210/jc.2011-3060.
Abstract/Text
CONTEXT: Osteoporosis and osteopenia are associated with increased fracture incidence.
OBJECTIVE: The aim of this study was to determine the comparative effectiveness of different pharmacological agents in reducing the risk of fragility fractures.
DATA SOURCES: We searched multiple databases through 12/9/2011.
STUDY SELECTION: Eligible studies were randomized controlled trials enrolling individuals at risk of developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selective estrogen receptor modulators, denosumab, or calcium and vitamin D.
DATA EXTRACTION: Reviewers working independently and in duplicate determined study eligibility and collected descriptive, methodological quality, and outcome data.
DATA SYNTHESIS: This network meta-analysis included 116 trials (139,647 patients; median age, 64 yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to moderate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30, and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandronate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely less effective, although these data were limited. Calcium and vitamin D were ineffective given separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95% confidence interval, 0.68–0.96).
CONCLUSIONS: Teriparatide, bisphosphonates, and denosumab are most effective in reducing the risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and clinicians need to consider their associated harms and costs.
Pierre D Delmas, Kristine E Ensrud, Jonathan D Adachi, Kristine D Harper, Somnath Sarkar, Carlo Gennari, Jean-Yves Reginster, Huibert A P Pols, Robert R Recker, Steven T Harris, Wentao Wu, Harry K Genant, Dennis M Black, Richard Eastell, Mulitple Outcomes of Raloxifene Evaluation Investigators
Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial.
J Clin Endocrinol Metab. 2002 Aug;87(8):3609-17. doi: 10.1210/jcem.87.8.8750.
Abstract/Text
The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.
Ethel S Siris, Steven T Harris, Richard Eastell, Jose R Zanchetta, Stefan Goemaere, Adolfo Diez-Perez, John L Stock, Jingli Song, Yongming Qu, Pandurang M Kulkarni, Suresh R Siddhanti, Mayme Wong, Steven R Cummings, Continuing Outcomes Relevant to Evista (CORE) Investigators
Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.
J Bone Miner Res. 2005 Sep;20(9):1514-24. doi: 10.1359/JBMR.050509. Epub 2005 May 16.
Abstract/Text
UNLABELLED: In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE.
INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial.
MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE.
RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene.
CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.
H Morii, Y Ohashi, Y Taketani, M Fukunaga, T Nakamura, A Itabashi, S Sarkar, K Harper
Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial.
Osteoporos Int. 2003 Oct;14(10):793-800. doi: 10.1007/s00198-003-1424-1. Epub 2003 Aug 29.
Abstract/Text
The safety and efficacy of raloxifene, a selective estrogen receptor modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p<0.001) through 52 weeks (+3.5%, p<0.001) of therapy, and similar results were observed in the RLX120 group. Markers of bone turnover and total cholesterol and LDL-C were significantly reduced, and no significant treatment-group difference was observed for patients reporting at least one adverse event following randomization. In addition, there were no reported venous thromboembolic events (VTE) in any treatment group. The results of this study demonstrate that raloxifene is associated with early increases in lumbar spine BMD, has favorable effects on biochemical markers of bone turnover and lipid profile, and is well tolerated in postmenopausal Japanese women.
Ego Seeman, Gerald G Crans, Adolfo Diez-Perez, Karen V Pinette, Pierre D Delmas
Anti-vertebral fracture efficacy of raloxifene: a meta-analysis.
Osteoporos Int. 2006 Feb;17(2):313-6. doi: 10.1007/s00198-005-2030-1. Epub 2005 Oct 11.
Abstract/Text
In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced the risk of vertebral fracture. However, a systematic analysis of the anti-vertebral fracture efficacy of raloxifene, which includes the results of newly reported studies, has not been performed. A meta-analysis was carried out using all randomized, double-blind, placebo-controlled trials to determine whether the reduction in the risk for vertebral fracture, reported with raloxifene, was consistent among studies, and to define more accurately the point estimate of the odds ratio. Three prevention studies, two arms of the MORE trial, and three additional treatment studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (MedLine, EMBASE) confirmed that no studies with raloxifene had been excluded from this analysis. The effects of raloxifene 60 mg/day (RLX60) and 120 mg/day pooled with 150 mg/day (RLX120/150) were analyzed by intention to treat. There was no significant heterogeneity among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.60 (0.49, 0.74) for RLX60 and 0.51 (0.41, 0.64) for RLX120/150. From these data we infer that raloxifene consistently reduces the risk of vertebral fracture in postmenopausal women.
John A Kanis, Olof Johnell, Dennis M Black, Robert W Downs, Somnath Sarkar, Thomas Fuerst, Roberta J Secrest, Imre Pavo
Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial.
Bone. 2003 Sep;33(3):293-300.
Abstract/Text
Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.
Elizabeth Barrett-Connor, Lori Mosca, Peter Collins, Mary Jane Geiger, Deborah Grady, Marcel Kornitzer, Michelle A McNabb, Nanette K Wenger, Raloxifene Use for The Heart (RUTH) Trial Investigators
Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.
N Engl J Med. 2006 Jul 13;355(2):125-37. doi: 10.1056/NEJMoa062462.
Abstract/Text
BACKGROUND: The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established.
METHODS: We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer.
RESULTS: As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000).
CONCLUSIONS: Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).
Copyright 2006 Massachusetts Medical Society.
S Scharla, H Oertel, K Helsberg, F Kessler, F Langer, T Nickelsen
Skeletal pain in postmenopausal women with osteoporosis: prevalence and course during raloxifene treatment in a prospective observational study of 6 months duration.
Curr Med Res Opin. 2006 Dec;22(12):2393-402. doi: 10.1185/030079906X154097.
Abstract/Text
OBJECTIVE: To assess the prevalence of skeletal pain in postmenopausal women before the onset of raloxifene treatment and the further course of pain during treatment in a naturalistic setting.
RESEARCH DESIGN AND METHODS: Prospective, uncontrolled, multicentre, 6-month, observational study in Germany. Clinical, diagnostic and pain data were collected at baseline, 6 weeks and 6 months of raloxifene treatment from 3299 female outpatients with postmenopausal osteoporosis. Physicians assessed the presence or absence of back pain, joint pain and diffuse bone pain at each visit, perceived sleep quality and the use of analgesics. Patients assessed intensity and frequency of pain using a 100 mm visual analogue scale (VAS) and a 5-point scale (from 'rarely' to 'permanently'), respectively.
RESULTS: At baseline, patients had mean (SD) age 67.6 (9.3) years, 89.4% were reported to have reduced bone mineral density, 39.8% had pre-existing fractures and 93.4% had skeletal pain (physician assessment): 85.1% had back pain, 41.8% joint pain and 32.5% diffuse bone pain. Median pain intensity on VAS was 66.0 mm. After 6 months of raloxifene treatment, the frequency and intensity of pain and use of analgesics for skeletal pain decreased consistently by approximately 50%. Pain frequency decreased in 58.2% and increased in 2.3% of patients. The median decrease in pain intensity from baseline to 6 months was 27.0 mm (46%). Patients' subjective quality of sleep improved: the proportion of patients who were reported to sleep well increased from 21.3% at baseline to 46.7% at 6 months. The decrease in relative pain frequency was greatest with diffuse pain (67.6%) followed by joint pain (36.9%) and back pain (32.5%).
CONCLUSION: Raloxifene treatment in postmenopausal women with osteoporosis was associated with a marked reduction of skeletal pain and analgesic consumption and an improvement in subjective sleep quality. Further investigation in a randomised, placebo-controlled trial is warranted.
楊鴻生, 浜谷越郎, 飯國紀子, 高垣範子, 山本尚功, 竹綱正典, 宮内章光, 宗和秀明, 漆原尚巳, 田中清. ラロキシフェン塩酸塩の閉経後骨粗鬆症患者に対するQOL の評価. Osteoporosis Japan 2010; 18 Suppl.
Akira Itabashi, Kousei Yoh, Arkadi A Chines, Takami Miki, Masahiko Takada, Hiroshi Sato, Itsuo Gorai, Toshitsugu Sugimoto, Hideki Mizunuma, Hiroshi Ochi, Ginger D Constantine, Hiroaki Ohta
Effects of bazedoxifene on bone mineral density, bone turnover, and safety in postmenopausal Japanese women with osteoporosis.
J Bone Miner Res. 2011 Mar;26(3):519-29. doi: 10.1002/jbmr.252.
Abstract/Text
This randomized, double-blind, placebo-controlled, dose-response late phase 2 study evaluated the efficacy and safety of bazedoxifene in postmenopausal Japanese women 85 years of age or younger with osteoporosis. Eligible subjects received daily treatment with oral doses of bazedoxifene 20 or 40 mg or placebo for 2 years. Efficacy assessments included bone mineral density (BMD) at the lumbar spine and other skeletal sites, bone turnover marker levels, lipid parameters, and incidence of new fractures. Of 429 randomized subjects, 387 were evaluable for efficacy, and 423 were included in the safety analyses (mean age, 64 years). At 2 years, the mean percent changes from baseline in lumbar spine BMD were significantly greater with bazedoxifene 20 and 40 mg (2.43% and 2.74%, respectively) than with placebo (-0.65%, p < .001 for both). Both bazedoxifene doses significantly improved BMD at the total hip, femoral neck, and greater trochanter compared with placebo (p < .001 for all). Decreases in bone turnover markers were observed with bazedoxifene 20 and 40 mg as early as 12 weeks (p < .05 for all) and were sustained throughout the study. Total and low-density lipoprotein cholesterol levels were significantly decreased from baseline with both bazedoxifene doses compared with placebo (p < .05 for all). Incidences of new vertebral and nonvertebral fractures were similar among the bazedoxifene and placebo groups. Overall, the incidence of adverse events with bazedoxifene 20 and 40 mg was similar to that with placebo. Bazedoxifene significantly improved BMD, reduced bone turnover, and was well tolerated in postmenopausal Japanese women with osteoporosis.
Copyright © 2011 American Society for Bone and Mineral Research.
Silvana Martino, Damon Disch, Sherie A Dowsett, Cheryl A Keech, John L Mershon
Safety assessment of raloxifene over eight years in a clinical trial setting.
Curr Med Res Opin. 2005 Sep;21(9):1441-52. doi: 10.1185/030079905X61839.
Abstract/Text
OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.
METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.
RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively).
CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.
Deborah Layton, Andrea Clarke, Lynda V Wilton, Saad A W Shakir
Safety profile of raloxifene as used in general practice in England: results of a prescription-event monitoring study.
Osteoporos Int. 2005 May;16(5):490-500. doi: 10.1007/s00198-004-1710-6. Epub 2004 Aug 7.
Abstract/Text
Raloxifene, a selective estrogen receptor modulator (SERM) licensed for the prevention of non-traumatic vertebral fractures in postmenopausal women at increased risk of osteoporosis, was launched in the UK in August 1998. The aim of the study was to monitor the safety of raloxifene prescribed in the primary care setting in England using prescription-event monitoring (PEM). Patients were identified by means of prescription data supplied by the Prescription Pricing Authority between September 1998 and November 2000. Demographic and clinical event data were collected from questionnaires posted to primary care physicians (GPs) at least 6 months after the date of the first prescription for each patient. Information on medical events, suspected adverse drug reactions (ADRs), reasons for stopping treatment, pregnancies, and causes of death was requested. Event rates [Incidence Densities (IDs): no. first reports /1000 patient-months of treatment] were calculated. Differences between IDs for events reported in month one (ID(1)) and months 2-6 (ID(2-6)) of treatment were examined. The cohort comprised 13,987 patients [median age 62 years (IQR 55,69); 99.8% female]. The major indication was osteoporosis (40.9%, n=5725). Flushing was the event with the highest ID in month 1 (22.8), reported most frequently by GPs as an ADR to raloxifene (67/461 reports) and as the reason for stopping (700/4592 reports). Events associated with starting treatment included flushing, malaise/lassitude, headache/migraine, nausea/vomiting, sweating, cramp, pain abdomen, dizziness, diarrhea, mastalgia and vaginal hemorrhage. Less common events reported during treatment included deep vein thrombosis (n=13), pulmonary embolism (n=13), thrombophlebitis (n=31) and visual disturbance (n=29). In this study, there were 122 (0.9%) confirmed deaths, of which 32 causes of death were unknown. This study shows that raloxifene is generally well tolerated when used in general practice in England. Potential signals of unrecognised ADRs requiring further evaluation included gastrointestinal adverse symptoms and vaginal hemorrhage. There were also a small number of reports of events associated with venous thromboembolism and visual disorders that require further investigation.
J D Adachi, K G Saag, P D Delmas, U A Liberman, R D Emkey, E Seeman, N E Lane, J M Kaufman, P E Poubelle, F Hawkins, R Correa-Rotter, C J Menkes, J A Rodriguez-Portales, T J Schnitzer, J A Block, J Wing, H H McIlwain, R Westhovens, J Brown, J A Melo-Gomes, B L Gruber, M J Yanover, M O Leite, K G Siminoski, M C Nevitt, J T Sharp, M P Malice, T Dumortier, M Czachur, W Carofano, A Daifotis
Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.
Arthritis Rheum. 2001 Jan;44(1):202-11. doi: 10.1002/1529-0131(200101)44:1<202::AID-ANR27>3.0.CO;2-W.
Abstract/Text
OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids.
METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence.
RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups.
CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.
Jacques E Rossouw, Garnet L Anderson, Ross L Prentice, Andrea Z LaCroix, Charles Kooperberg, Marcia L Stefanick, Rebecca D Jackson, Shirley A A Beresford, Barbara V Howard, Karen C Johnson, Jane Morley Kotchen, Judith Ockene, Writing Group for the Women's Health Initiative Investigators
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
JAMA. 2002 Jul 17;288(3):321-33.
Abstract/Text
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.
OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.
DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.
INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.
CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
JoAnn E Manson, Rowan T Chlebowski, Marcia L Stefanick, Aaron K Aragaki, Jacques E Rossouw, Ross L Prentice, Garnet Anderson, Barbara V Howard, Cynthia A Thomson, Andrea Z LaCroix, Jean Wactawski-Wende, Rebecca D Jackson, Marian Limacher, Karen L Margolis, Sylvia Wassertheil-Smoller, Shirley A Beresford, Jane A Cauley, Charles B Eaton, Margery Gass, Judith Hsia, Karen C Johnson, Charles Kooperberg, Lewis H Kuller, Cora E Lewis, Simin Liu, Lisa W Martin, Judith K Ockene, Mary Jo O'Sullivan, Lynda H Powell, Michael S Simon, Linda Van Horn, Mara Z Vitolins, Robert B Wallace
Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.
JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040.
Abstract/Text
IMPORTANCE: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
OBJECTIVE: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.
DESIGN, SETTING, AND PARTICIPANTS: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.
INTERVENTIONS: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.
MAIN OUTCOMES AND MEASURES: Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.
RESULTS: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.
CONCLUSIONS AND RELEVANCE: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.
Martina Dören, Jan-Ake Nilsson, Olof Johnell
Effects of specific post-menopausal hormone therapies on bone mineral density in post-menopausal women: a meta-analysis.
Hum Reprod. 2003 Aug;18(8):1737-46.
Abstract/Text
BACKGROUND: Long-term post-menopausal hormone therapy (pHT) was often regarded as first-line therapy to prevent fractures in post-menopausal women, a recommendation under scrutiny given the benefit-risk profile of the Women's Health Initiative results of the estrogen-progestin combination. Apart from controlled clinical studies providing data with fractures as an end point, measures of lumbar and hip bone mineral density (BMD) may be used to assess bone-related effects of pHT. The objective of this study was to conduct a systematic review of 2-year trials, published between 1990 and December 2002, and assessing changes in BMD by any estrogen including ethinyl estradiol, any estrogen plus any progestin, or tibolone.
METHODS: We searched MEDLINE, EMBASE and systematic reviews. Thirty-nine randomized, prospective, controlled 2-year trials were analysed in pre-specified groups according to the profile of the compounds.
RESULTS: Virtually all pHT regimens at least maintain BMD at the lumbar spine and the hip compared with baseline; there is no apparent difference between the various estrogenic compounds. Tibolone, a synthetic progestin, appears to be as effective as any estrogen. Most trials were conducted in early post-menopausal women, fewer in women with hysterectomy and/or bilateral oophorectomy.
CONCLUSIONS: The size of impact on BMD does not appear to differ between tibolone and any estrogen compound studied.
Robert Lindsay, J Christopher Gallagher, Michael Kleerekoper, James H Pickar
Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women.
Osteoporos Int. 2005 Apr;16(4):372-9. doi: 10.1007/s00198-004-1773-4. Epub 2005 Jan 15.
Abstract/Text
Lower doses of conjugated estrogens (CE) alone or combined with lower doses of medroxyprogesterone acetate (MPA) increase mean bone mineral density (BMD) from baseline at the spine and hip in early postmenopausal women. However, not all women on therapy gain BMD. The incidence of continued bone loss (defined as a loss of BMD of > 2% from baseline) among women using lower doses of CE and CE/MPA is unknown. This randomized, double-blind, placebo-controlled, multicenter substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) trial investigated the incidence of continued bone loss with lower-dose CE and CE/MPA. Eight hundred twenty-two healthy postmenopausal women with intact uteri received CE 0.625, CE 0.625/MPA 2.5, CE 0.45, CE 0.45/MPA 2.5, CE 0.45/MPA 1.5, CE 0.3, CE 0.3/MPA 1.5 (all doses in mg/day), or placebo for 2 years along with 600 mg/day of calcium. Changes from baseline in spine and total hip BMD were compared among treatment groups in an intent-to-treat analysis. At 12 months, < 10% of women on active treatment lost > 2% of spinal BMD (except CE 0.3/MPA 1.5 [15.6%]), compared with 41.2% of women on placebo. At 24 months, the percentages of women on active treatment who lost > 2% of spine BMD ranged from 4.5% with CE 0.45/MPA 1.5-15.6% with CE 0.3/MPA 1.5, compared with 55.2% of women taking placebo. More than 85% of women on active treatment did not experience continued BMD loss at the hip at 12 months and 24 months, in contrast to 30.6% of women on placebo at 12 months and 36.5% at 24 months. Women receiving active treatment who lost > 2% of spine or hip BMD also had a lesser reduction in biochemical markers of bone turnover. In summary, continued bone loss among early postmenopausal women treated with lower doses of CE or CE/MPA is uncommon.
D J Torgerson, S E Bell-Syer
Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials.
JAMA. 2001 Jun 13;285(22):2891-7.
Abstract/Text
CONTEXT: Hormone replacement therapy (HRT) is widely considered to reduce fractures, but this belief is based on observational data; evidence from randomized trials is lacking.
OBJECTIVE: To conduct a systematic review of all randomized trials of HRT that have reported or collected nonvertebral fracture data but that may not have focused on fracture prevention.
DATA SOURCES: The MEDLINE, EMBASE, Science Citation Index, and Cochrane Controlled Trials Register databases were searched from 1997 through 2000 and a search was conducted of all recent systematic reviews to identify older studies. Authors were contacted to establish whether fracture data had been collected but not reported. Researchers in the field and pharmaceutical companies also were contacted to try to identify unpublished studies.
STUDY SELECTION: Trials were included in which participants had been randomized to at least 12 months of therapy and data on nonvertebral fractures at any other site and due to any cause were available. Of 70 initially identified studies, 22 were included in the analysis.
DATA EXTRACTION: Both investigators extracted data independently and appraised trial quality according to the Jadad scale, which assesses the methods of randomization, concealment allocation, and reporting of withdrawals and dropouts. Disagreements were resolved by discussion.
DATA SYNTHESIS: There was an overall 27% reduction in nonvertebral fractures in a pooled analysis (reduction favoring HRT in relative risk [RR], 0.73; 95% confidence interval [CI], 0.56-0.94; P =.02). This effect was greater among women randomized to HRT who had a mean age younger than 60 years (RR, 0.67; 95% CI, 0.46-0.98; P =.03). Among women with a mean age of 60 years or older, there was a reduced effect (RR, 0.88; 95% CI, 0.71-1.08; P =.22). For hip and wrist fractures alone, the effectiveness of HRT appeared more marked (RR, 0.60; 95% CI, 0.40-0.91; P =.02), particularly for women younger than 60 years (RR, 0.45; 95% CI, 0.26-0.79; P =.005).
CONCLUSIONS: Our meta-analysis of randomized controlled trials of HRT noted a statistically significant reduction in nonvertebral fractures. However, this effect may be attenuated in older women.
Garnet L Anderson, Marian Limacher, Annlouise R Assaf, Tamsen Bassford, Shirley A A Beresford, Henry Black, Denise Bonds, Robert Brunner, Robert Brzyski, Bette Caan, Rowan Chlebowski, David Curb, Margery Gass, Jennifer Hays, Gerardo Heiss, Susan Hendrix, Barbara V Howard, Judith Hsia, Allan Hubbell, Rebecca Jackson, Karen C Johnson, Howard Judd, Jane Morley Kotchen, Lewis Kuller, Andrea Z LaCroix, Dorothy Lane, Robert D Langer, Norman Lasser, Cora E Lewis, JoAnn Manson, Karen Margolis, Judith Ockene, Mary Jo O'Sullivan, Lawrence Phillips, Ross L Prentice, Cheryl Ritenbaugh, John Robbins, Jacques E Rossouw, Gloria Sarto, Marcia L Stefanick, Linda Van Horn, Jean Wactawski-Wende, Robert Wallace, Sylvia Wassertheil-Smoller, Women's Health Initiative Steering Committee
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
JAMA. 2004 Apr 14;291(14):1701-12. doi: 10.1001/jama.291.14.1701.
Abstract/Text
CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.
OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.
INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.
MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.
RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.
CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.
D J Torgerson, S E Bell-Syer
Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials.
BMC Musculoskelet Disord. 2001;2:7. Epub 2001 Nov 6.
Abstract/Text
BACKGROUND: Hormone replacement therapy (HRT) is often seen as the treatment of choice for preventing fractures in women. We undertook a recent meta-analysis of randomised trials which suggested that HRT reduced non-vertebral fractures by 30%. In this analysis we extend that analysis to vertebral fractures.
METHODS: We searched the main electronic databases until the end of August 2001. We sought all randomised controlled trials (RCTs) of HRT where women had been randomised to at least 12 months of HRT or to no HRT.
RESULTS: We found 13 RCTs. Overall there was a 33% reduction in vertebral fractures (95% confidence interval (CI) 45% to 98%).
CONCLUSIONS: This review and meta-analysis showed a significant reduction in vertebral fractures associated with HRT use.
Marianne Canonico, Geneviève Plu-Bureau, Gordon D O Lowe, Pierre-Yves Scarabin
Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
BMJ. 2008 May 31;336(7655):1227-31. doi: 10.1136/bmj.39555.441944.BE. Epub 2008 May 20.
Abstract/Text
OBJECTIVE: To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Medline.
STUDIES REVIEWED: Eight observational studies and nine randomised controlled trials.
INCLUSION CRITERIA: Studies on hormone replacement therapy that reported venous thromboembolism. REVIEW MEASURES: Homogeneity between studies was analysed using chi(2) and I(2) statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.
RESULTS: Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.
CONCLUSION: Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.
L Opatrny, S Dell'Aniello, S Assouline, S Suissa
Hormone replacement therapy use and variations in the risk of breast cancer.
BJOG. 2008 Jan;115(2):169-75; discussion 175. doi: 10.1111/j.1471-0528.2007.01520.x.
Abstract/Text
OBJECTIVE: To determine the effect of different types and formulations of hormone replacement therapy (HRT) on the risk of breast cancer in postmenopausal women.
DESIGN: Population-based case-control study.
SETTING: UK, 1988-2004.
PARTICIPANTS: Women 50-75 years between 1998 and 2004.
MAIN OUTCOME MEASURES: Breast cancer incidence to estimate the rate ratio (RR) associated with use of various HRTs over a 30-year period.
RESULTS: We identified 6347 incident cases of breast cancer that were matched with 31,516 controls. Cases were on average 61 years at diagnosis and 22% had undergone a hysterectomy. The rate of breast cancer was increased with the use of opposed estrogens in oral form (adjusted RR 1.38; 95% CI 1.27-1.49) in contrast to patch form (RR 1.08; 95% CI 0.81-1.43). This rate was similarly elevated with both continuous (RR 1.29; 95% CI 1.07-1.56) and sequential (RR 1.33; 95% CI 1.21-1.46) forms of opposed estrogen. The rate of breast cancer was not increased among exclusive users of unopposed estrogens (RR 0.97; 95% CI 0.86-1.09) or of tibolone (RR 0.86; 95% CI 0.65-1.13). Users of tibolone who had switched from opposed estrogens, however, had an elevated rate (RR 1.29; 95% CI 1.09-1.52). The rate of breast cancer increased by 25% (95% CI 20-30%) with every ten prescriptions of orally administered opposed estrogen.
CONCLUSIONS: The risk of breast cancer varies with the formulation and preparation of HRT. Opposed estrogens (progesterone-estrogen) in oral form are associated with an increased risk of breast cancer, which increases with use. Transdermal opposed estrogens, unopposed estrogens and tibolone do not increase this risk. However, this study is an observational study that carries risks of various biases, and thus the findings need to be interpreted with caution.
Susanna Jaakkola, Heli Lyytinen, Eero Pukkala, Olavi Ylikorkala
Endometrial cancer in postmenopausal women using estradiol-progestin therapy.
Obstet Gynecol. 2009 Dec;114(6):1197-204. doi: 10.1097/AOG.0b013e3181bea950.
Abstract/Text
OBJECTIVE: To estimate the risk of endometrial cancer in all Finnish postmenopausal women using various forms of estradiol-progestin therapy.
METHODS: All Finnish women (aged more than 50 years) who had used estradiol-progestin therapy in 1994-2006 for at least 6 months (n=224,015) were identified from the national medical Reimbursement Registry and linked to the Finnish Cancer Registry. A total of 1,364 type I and 38 type II endometrial cancers were recorded by the end of 2006. The incidence of endometrial cancer in estradiol-progestin therapy users was compared with that in the general population in this cohort study.
RESULTS: The use of a continuous estradiol-progestin therapy regimen for 3 years or more was associated with a 76% reduction of the risk for type 1 cancer (95% confidence interval [CI] 6-60%). In contrast, the use of a sequential estradiol-progestin therapy regimen for at least 5 years was accompanied with a 69% elevation (95% CI 43-96%) if the progestin was added monthly, and with a significantly higher, 276% risk elevation (95% CI 190-379%) if progestin was added at 3-month intervals. Sequential regimens containing norethisterone acetate, medroxyprogesterone acetate or dydrogesterone administered orally showed no significant differences in the endometrial safety. Oral and transdermal norethisterone acetate were associated with similar risk elevations. Women using a monthly sequential estradiol-progestin regimen tended to be diagnosed with endometrial cancer in an earlier stage than the background population.
CONCLUSION: Use of a continuous rather than a sequential estradiol-progestin regimen decreases the risk of endometrial cancer, whereas the route of administration or type of progestin does not differ in terms of endometrial cancer risk.
LEVEL OF EVIDENCE: II.
Francine Grodstein, JoAnn E Manson, Meir J Stampfer, Kathryn Rexrode
Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy.
Arch Intern Med. 2008 Apr 28;168(8):861-6. doi: 10.1001/archinte.168.8.861.
Abstract/Text
BACKGROUND: We evaluated stroke risk associated with hormone therapy (HT) in younger women, in recently menopausal women, and in older women.
METHODS: Prospective, observational analyses were performed in postmenopausal participants of the Nurses' Health Study, from 1976 to 2004, with biennial mailed questionnaires. Proportional hazards models were used to calculate multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs).
RESULTS: We found a significantly increased risk of stroke for women currently taking HT (estrogen alone: RR, 1.39; 95% CI, 1.18-1.63; and estrogen with progestin: RR, 1.27; 95% CI, 1.04-1.56), a finding that is nearly identical to that of the Women's Health Initiative. This increased risk was observed for women initiating HT at young ages or near menopause and at older ages or more than 10 years after menopause. Short-term (<5 years) HT initiated at younger ages was not associated with a clear increase in stroke; however, this apparently null result was based on a small number of cases. The incidence of stroke was relatively low in younger women, and the attributable risk in women aged 50 through 54 years indicated approximately an additional 2 cases of stroke per 10 000 women per year taking hormones. We found a strong relationship between dose of oral conjugated estrogen and stroke, with RRs of 0.93, 1.54, and 1.62 for doses of 0.3, 0.625, and 1.25 mg, respectively (P for trend, <.001).
CONCLUSIONS: Hormone therapy is associated with an increased risk of stroke, and this increased risk does not appear to be related to the timing of the initiation of HT. In younger women, with lower stroke risk, the attributable risk of stroke owing to hormone use is modest and might be minimized by lower doses and shorter treatment duration.
H Jick, L E Derby, M W Myers, C Vasilakis, K M Newton
Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens.
Lancet. 1996 Oct 12;348(9033):981-3. doi: 10.1016/S0140-6736(96)07114-0.
Abstract/Text
BACKGROUND: At the request of researchers in the UK, we conducted a case-control study to explore the relation between use of postmenopausal oestrogen hormone replacement therapy (HRT) and idiopathic venous thromboembolism (VTE).
METHODS: The study was based on information derived from Group Health Cooperative of Puget Sound for the period 1980 to 1994. Women aged 50-74 years admitted to hospital for idiopathic VTE were identified from hospital records. The diagnosis of idiopathic VTE was validated from the clinical record. Women who had medical conditions predisposing to VTE (a history of VTE or cancer, recent trauma, or surgery) were excluded as cases. Four control subjects matched to each case by age, duration of Cooperative membership, and calendar time were identified from the base population. Various potential risk factors were recorded based on record review.
FINDINGS: An initial analysis of 42 cases and 168 matched controls yielded a matched relative risk estimate of 3.6 (95% CI 1.6-7.8) for current users of oestrogens compared with non-users. There was a substantial effect of daily oestrogen dose. The matched relative risk estimates for oestrogen users of 0.325 mg, 0.625 mg, and 1.25 mg or more daily were 2.1, 3.3, and 6.9, respectively. Body-mass index was independently associated with the risk of VTE but did not materially confound the relation of oestrogen and VTE. The absolute risk of idiopathic VTE is estimated to be low (0.9 x 10(-4) woman-years) in non-users of oestrogen; the risk in current users is estimated at 3.2 x 10(-4) woman-years.
INTERPRETATION: The risk of idiopathic VTE is about three times higher among current users of replacement oestrogens than among non-users. However, the absolute risk is low for both groups and accounts for only a modest increase in morbidity.
S R Weiss, H Ellman, M Dolker
A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group.
Obstet Gynecol. 1999 Sep;94(3):330-6.
Abstract/Text
OBJECTIVE: To determine the effects of four doses of a 7-day transdermal 17beta-estradiol (E2) delivery system, including 0.025 mg/day, on bone loss in postmenopausal women.
METHODS: This was a multicenter, double-masked, randomized, placebo-controlled study of the effects of transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day for the prevention of postmenopausal osteoporosis. Efficacy was evaluated from bone mineral density of lumbar vertebrae L2-L4, radius, proximal femur, and total hip measured with dual-energy x-ray absorptiometry. Serum osteocalcin and urinary pyridinoline and deoxypyridinoline concentrations were measured.
RESULTS: At 24 months, E2 doses of 0.025, 0.05, 0.06, and 0.1 mg/day resulted in mean increases in bone mineral density of the lumbar spine of 2.37%, 4.09%, 3.28%, and 4.70%, respectively, and increased bone mineral density of the total hip by 0.26%, 2.85%, 3.05%, and 2.03%, respectively. All increases were statistically significantly greater than placebo, which decreased bone mineral density by 2.49% at the spine and 2.04% at the hip. Consistent and significant improvements in biochemical markers of bone turnover also were noted at various intervals in all treatment groups. The most frequent adverse events were local reactions from the transdermal drug-delivery system, effects of estrogen, and menopausal symptoms.
CONCLUSION: Transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day effectively prevented bone loss in postmenopausal women.
C McKeever, H McIlwain, M Greenwald, N Gupta, S Jayawardene, G Huels, M Roberts
An estradiol matrix transdermal system for the prevention of postmenopausal bone loss.
Clin Ther. 2000 Jul;22(7):845-57. doi: 10.1016/S0149-2918(00)80057-0.
Abstract/Text
OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of 2 years' application of an estradiol matrix transdermal system for the prevention of postmenopausal bone loss.
METHODS: In this multicenter, randomized, placebo-controlled, parallel-group study, 261 surgically or naturally postmenopausal women were randomized to apply the estradiol matrix transdermal system (0.025, 0.0375, 0.05, or 0.1 mg/d) or matching placebo twice a week for 2 years. The study was double blind with respect to treatment (active vs placebo) but not to the dose levels of active treatment (because of the differing sizes and shapes of the patches). In addition to receiving the assigned treatment, the 100 nonhysterectomized women received 2.5 mg medroxyprogesterone acetate daily throughout the study.
RESULTS: The evaluable group (n = 259) had a mean age of 52 years and a mean duration of menopause of 32 months. Following 2 years of treatment, there were significant differences in favor of estradiol between all doses of the estradiol matrix transdermal system and placebo in terms of the percentage change from baseline in the bone mineral density (BMD) of the L1-L4 anteroposterior lumbar spine (0.1 and 0.05 mg/d, P < 0.001; 0.0375 mg/d, P = 0.024; 0.025 mg/d, P = 0.002). Percentage changes from baseline in the BMD of the femoral neck after 2 years of treatment also consistently demonstrated the efficacy of the estradiol matrix transdermal system compared with placebo (all, P < or = 0.044). The estradiol matrix transdermal system was well tolerated.
CONCLUSION: The estradiol matrix transdermal system was effective in preventing postmenopausal bone loss at dosages of 0.025 to 0.1 mg/d, and had a safety profile consistent with the known effects of estrogen/progestin.
Morris Notelovitz, Vivian A John, William R Good
Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women.
Menopause. 2002 Sep-Oct;9(5):343-53.
Abstract/Text
OBJECTIVE: To determine the lowest effective dose of an estradiol (E ) matrix-type transdermal delivery system (EMTDS; Alora) for preventing bone loss in postmenopausal women.
DESIGN: This double-blind, double-dummy, randomized, placebo-controlled, multicenter study enrolled 355 nonosteoporotic postmenopausal women who had been hysterectomized with or without oophorectomy at least 12 months earlier. Participants were randomly assigned to one of three doses of the EMTDS (0.025, 0.05, or 0.075 mg/day) or placebo administered twice weekly. Lumbar bone mineral density (LBMD) was measured by dual-energy x-ray absorptiometry at screening and after 1 and 2 years of treatment. Safety was assessed at regularly scheduled visits.
RESULTS: EMTDS provided statistically significant and clinically meaningful changes in LBMD relative to placebo. At 2 years, LBMD declined from baseline by 0.59% in the placebo group, but it increased from baseline by 1.65% ( = 0.0065), 4.08% ( = 0.0001), and 4.82% ( = 0.0001) in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. The corresponding responder rates (defined as no change or increase in LBMD at endpoint) were 39.7% for placebo, 59.6%, 79.3%, and 83.9% in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. Mean serum E concentrations were proportional to the dose of the E transdermal system and did not accumulate over the course of the study. Adverse events were generally comparable across treatment groups, with the majority being mild or moderate in severity and unrelated to study medication. Mammogram findings and other safety assessments were also comparable across groups and did not reveal any safety concerns with 2-y transdermal E treatment.
CONCLUSIONS: The EMTDS (Alora) administered twice weekly improves lumbar bone mineral density in healthy postmenopausal women, with the benefit of treatment evident by 1 year. The lowest effective dose is 0.025 mg/day.
N H Bjarnason, I Byrjalsen, C Hassager, J Haarbo, C Christiansen
Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss.
Am J Obstet Gynecol. 2000 Sep;183(3):550-60. doi: 10.1067/mob.2000.106595.
Abstract/Text
OBJECTIVE: Our purpose was to study combinations of estradiol and gestodene for prevention of bone loss in early postmenopausal women.
STUDY DESIGN: We randomly assigned 278 healthy, early postmenopausal women to receive either 2 mg 17beta-estradiol sequentially combined with 25 microg gestodene (group 2/25s), 2 mg estradiol sequentially combined with 50 microg gestodene (group 2/50s), 1 mg estradiol sequentially combined with 25 microg gestodene (group 1/25s), 1 mg estradiol continuously combined with 25 mg gestodene (group 1/25c), or placebo.
RESULTS: After 3 years the changes in bone mineral density of the spine were as follows (mean +/- SEM): group 2/25s, 7. 41% +/- 0.72%; group 2/50s, 8.53% +/- 0.90%; group 1.25s, 6.67% +/- 0.88%; group 1/25c, 4.44% +/- 0.59%; and placebo group, -2.03% +/- 0. 64%. The changes in bone mineral density were mirrored in the biochemical bone markers. The average responses for the urinary C-terminal telopeptide fragments of type I collagen corrected for creatinine excretion were as follows (mean of baseline +/- SEM): group 2/25s, -68.8% +/- 0.03%; group 2/50s, -72.8% +/- 0.02%; group 1/25s, -60.7% +/- 0.03%; group 1/25c, -52.28% +/- 0.04%; and placebo group, 6.5% +/- 0.09%. Beneficial lipid effects were found in all active groups. The decreases in low-density lipoprotein were as follows (mean +/- SEM): group 2/25s, -13.7% +/- 3.0%; group 2/50s, -14.6% +/- 3.2%; group 1/25s, -9.28% +/- 2.2%; group 1/25c, -9.92% +/- 2.4%; and placebo group, 1.53% +/- 1.9%.
CONCLUSION: These results demonstrate that estradiol therapy with 1 mg estradiol is fully protective against early postmenopausal bone loss.
Matthias Schaefers, Christoph Muysers, Peter Alexandersen, Claus Christiansen
Effect of microdose transdermal 17beta-estradiol compared with raloxifene in the prevention of bone loss in healthy postmenopausal women: a 2-year, randomized, double-blind trial.
Menopause. 2009 May-Jun;16(3):559-65. doi: 10.1097/gme.0b013e31818ebfba.
Abstract/Text
OBJECTIVE: Declining estrogen levels after menopause result in bone loss and increased fracture risk. This study investigated whether transdermal microdose 17beta-estradiol (E2) has efficacy and safety comparable to those of raloxifene, a selective estrogen-receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis.
METHODS: This study involved a multicenter, randomized, double-blind, active-controlled, noninferiority trial in 500 osteopenic postmenopausal women comparing transdermal microdose E2 (0.014 mg/d) versus oral raloxifene (60 mg/d), administered for 2 years. Percent change from baseline in bone mineral density at the lumbar spine was measured after 2 years of treatment. Secondary endpoints included proportion of women with no loss of bone mineral density in lumbar spine, change in bone mineral density at hip, biochemical markers of bone turnover, and safety parameters.
RESULTS: In the per protocol set, lumbar spine bone mineral density increased by 2.4% (95% CI, 1.9-2.9) with microdose E2 versus 3.0% (95% CI, 2.5-3.5) with raloxifene after 2 years; 77.3% of E2 recipients and 80.5% of those taking raloxifene had no bone loss in the lumbar spine. Both treatments were well tolerated. Most women (99% in the E2 group and 100% in the raloxifene group) showed no histological evidence of endometrial stimulation after 2 years. Mean dense area in breast mammograms was 19.8% in the E2 group versus 19.0% in the raloxifene group after 2 years.
CONCLUSIONS: Transdermal microdose E2 was similarly effective as raloxifene in preventing bone loss at the lumbar spine. Both treatments were well tolerated, with no clinically significant effect on endometrium or breast density.
H Mizunuma, Y Taketani, H Ohta, H Honjo, I Gorai, A Itabashi, M Shiraki
Dose effects of oral estradiol on bone mineral density in Japanese women with osteoporosis.
Climacteric. 2010 Feb;13(1):72-83. doi: 10.3109/13697130902926910.
Abstract/Text
OBJECTIVES: This 2-year study compared 0.5 and 1.0 mg oral estradiol (E(2)), with or without levonorgestrel (LNG), for the treatment of postmenopausal osteoporosis in Japanese women.
METHODS: Japanese women with osteoporosis after natural menopause or bilateral oophorectomy were randomized to receive E(2) 0.5 or 1.0 mg/day with LNG 40 microg as required, or placebo, for 52 weeks. Women treated with E(2) in the first year continued therapy at the same doses in the second year. Efficacy, safety and pharmacokinetics were assessed.
RESULTS: There were 73 women randomized to E(2) 0.5 mg, 157 to E(2) 1.0 mg and 79 to placebo. Lumbar bone mineral density at 52 weeks increased significantly more with E(2) 1.0 mg (p < 0.001) and 0.5 mg (p < 0.001) than with placebo (no change). After 2 years, a 10% increase in bone mineral density with E(2) 1.0 mg was significantly greater than with E(2) 0.5 mg (8%; p = 0.008). E(2) was associated with an acceptable safety and tolerability profile, with slightly more adverse events with E(2) 1.0 than 0.5 mg. Serum E(2) concentration increased in a dose-dependent manner.
CONCLUSION: This study showed that E(2), at both 1.0 mg and 0.5 mg doses, was effective in increasing bone mineral density with an acceptable safety and tolerability profile in Japanese postmenopausal women with osteoporosis but that the bone mineral density response was higher with the 1.0 mg dose.
B Lees, J C Stevenson
The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17 beta and dydrogesterone.
Osteoporos Int. 2001;12(4):251-8.
Abstract/Text
Low-dose hormone replacement therapy (HRT) in postmenopausal women may produce fewer side-effects but its efficacy in the prevention of bone loss and osteoporosis is not established. To address this we compared the effect of 1 mg estradiol-17 beta with a 2 mg dose, in combination with cyclical dydrogesterone, in the prevention of postmenopausal bone loss. We conducted a multicenter double-masked prospective randomized, placebo-controlled study in 595 apparently healthy postmenopausal women randomized to either placebo, or continuous oral estradiol-17 beta 1 mg or 2 mg with sequential dydrogesterone for 2 years. The primary endpoint was the percentage change from baseline in bone mineral density (BMD) in the lumbar spine (LS) and femoral neck (FN) of actively treated groups compared with placebo. Women taking either 1 mg or 2 mg estradiol-17 beta showed a significant increase in BMD of the LS (mean +/- SD, 5.2 +/- 3.8% and 6.7 +/- 4.0% respectively, both p < 0.001) whilst BMD in the placebo group decreased (-1.9 +/- 4.0%). Increases were also observed in FN BMD in both treated groups (2.7 +/- 4.2% and 2.5 +/- 5.2% respectively, both p < 0.001) in contrast to the placebo group (-1.8 +/- 4.8%). The oldest women showed the greatest treatment response. One milligram estradiol-17 beta in combination with dydrogesterone is effective in conserving LS and proximal femur bone mass, both of which are clinically important sites of osteoporotic fracture, and is as effective as 2 mg in preventing FN bone. The lower dose of estradiol-17 beta is a particularly suitable treatment for osteoporosis management in older women since it should minimize side-effects and improve the acceptability of HRT.
S Arrenbrecht, A J M Boermans
Effects of transdermal estradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial.
Osteoporos Int. 2002;13(2):176-83. doi: 10.1007/s001980200010.
Abstract/Text
This 2-year, double-masked, randomized, placebo-controlled trial was designed to evaluate the safety and efficacy in preventing bone loss in postmenopausal women of two doses of transdermal 17betaestradiol (estradiol) delivered by a matrix patch, compared with placebo. One hundred and sixty healthy, hysterectomized postmenopausal volunteers aged 40-60 years with serum estradiol levels < 20 pg/ml were started on treatment at four centers in The Netherlands. Every 6 months, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, non-dominant wrist and left hip, and markers of bone turnover were assessed in urine and serum. The treatment arms were: estradiol, 100 microg/day (E-100, n = 53), oestradiol, 50 microg/day (E-50, n = 54), placebo (P-100, placebo to E-100, n = 27 or P-50, placebo to E-50, n = 26). Treatment was continued for up to 2 years. After 24 months, BMD of the lumbar spine in the E-100 group differed by 7.7% [5.8-9.5%] (mean [95% confidence interval]) from the placebo group and showed a mean (s.e.m.) increase in BMD from baseline of 5.9% (0.69%). For the E-50 group the difference compared with placebo was 6.2% [4.4-8.0%] and the absolute increase was 4.5% (0.62%); in the placebo group, the absolute change was -2.3% (0.48%). In the total wrist, the changes were: E-100: difference compared with placebo 2.5% [1.5 3.6%], absolute increase 0.6% (0.3%); E-50: difference compared with placebo 2.9% [1.8-3.9%], absolute increase 0.7% (0.25%); and absolute change on placebo: -2.5% (0.35%). In the total hip, the changes were: E-100: difference compared with placebo 3.7% [2.2-5.2%], absolute increase 2.8% (0.5%); E-50: difference compared with placebo: 3.2% [1,8-4.7%], absolute change 2.4% (0.36%); and absolute change on placebo -1.4% (0.66%). Three markers of bone turnover--serum bone-specific alkaline phosphatase, serum osteocalcin and urinary CTX--fell significantly during the trial. Breast pain was reported by 8% of women on placebo, by 6% of women on E-50 and by 17% of women on E-100. Estradiol delivered by the E-50 matrix patch effectively reversed bone loss in hysterectomized postmenopausal women with few side-effects. The marginal additional gain in BMD with the higher dose may be offset by a more important side effect profile.
E G Lufkin, H W Wahner, W M O'Fallon, S F Hodgson, M A Kotowicz, A W Lane, H L Judd, R H Caplan, B L Riggs
Treatment of postmenopausal osteoporosis with transdermal estrogen.
Ann Intern Med. 1992 Jul 1;117(1):1-9.
Abstract/Text
OBJECTIVE: To evaluate the tolerance and effectiveness of transdermal estrogen for women with established postmenopausal osteoporosis and vertebral fractures.
DESIGN: Double-blind, randomized, placebo-controlled clinical trial lasting 1 year.
SETTING: Referral-based outpatient clinic.
PATIENTS: Seventy-five postmenopausal women, 47 to 75 years of age, with one or more vertebral fractures due to osteoporosis.
INTERVENTIONS: Thirty-nine women received dermal patches delivering 0.1 mg of 17 beta-estradiol for days 1 to 21 and oral medroxyprogesterone acetate for days 11 to 21 of a 28-day cycle. Another 39 women received placebo.
MEASUREMENTS: Bone turnover assessed by biochemical markers and iliac bone histomorphometry; bone loss assessed by serial measurement of bone density; and vertebral fracture rate.
RESULTS: Compared with the placebo group, the median annual percentage change in bone mineral density in the estrogen group reflected increased or steady-state bone mineral density at the lumbar spine (5.3 compared with 0.2; P = 0.007), femoral trochanter (7.6 compared with 2.1; P = 0.03), and midradius (1.0 compared with -2.6, P less than 0.001) but showed no significant difference at the femoral neck (2.6 compared with 1.4; P = 0.17). Estrogen treatment uniformly decreased bone turnover as assessed by several methods including serum osteocalcin concentration (median change, -0.35 compared with 0.02 nmol/L; P less than 0.001). Histomorphometric evaluation of iliac biopsy samples confirmed the effect of estrogen on bone formation rate per bone volume (median change, -12.9 compared with -6.2% per year; P = 0.004). Also, 8 new fractures occurred in 7 women in the estrogen group, whereas 20 occurred in 12 women in the placebo group, yielding a lower vertebral fracture rate in the estrogen group (relative risk, 0.39; 95% CI, 0.16 to 0.95).
CONCLUSIONS: Transdermal estradiol treatment is effective in postmenopausal women with established osteoporosis.
L Mosekilde, H Beck-Nielsen, O H Sørensen, S P Nielsen, P Charles, P Vestergaard, A P Hermann, J Gram, T B Hansen, B Abrahamsen, E N Ebbesen, L Stilgren, L B Jensen, C Brot, B Hansen, C L Tofteng, P Eiken, N Kolthoff
Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish Osteoporosis Prevention Study.
Maturitas. 2000 Oct 31;36(3):181-93.
Abstract/Text
OBJECTIVES: To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario.
METHODS: Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women.
RESULTS: After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years.
CONCLUSIONS: It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.
折茂肇，橋本勉，白木正孝ほか. 大腿骨頸部骨折全国頻度調査 1992 年における新発生患者数の推定と5年間の推移. 日本医事新報1995; 3707: 27-30.
Nicholas Harvey, Elaine Dennison, Cyrus Cooper
Osteoporosis: impact on health and economics.
Nat Rev Rheumatol. 2010 Feb;6(2):99-105. doi: 10.1038/nrrheum.2009.260.
Abstract/Text
Osteoporosis is a major public health problem through associated fragility fractures. The most common sites of fracture are the hip, spine and wrist, and these have an enormous health and economic impact. All fractures result in some degree of morbidity, but fractures at the hip are associated with the worst outcomes. The worldwide direct and indirect annual costs of hip fracture in 1990 were estimated at US$34.8 billion, and are expected to increase substantially over the next 50 years. Fracture incidence varies between populations, and is set to increase over coming decades as the global population becomes more elderly. This effect will be particularly marked in the developing world, which is additionally assuming more-westernized lifestyles that predispose to increased fracture risk. Strategies to target those at high risk of fracture have been developed, but preventative measures at the public health level are also urgently needed to reduce the burden of this devastating disease.
Yoshimura N, Kinoshita H, Oka H, et al. Cumulative Incidence and Changes in Prevalence of Vertebral Fractures in a Rural Japanese Community: A 10-year Follow-up of the Miyama Cohort. Archives Osteoporos 2006; DOI 0.1007/s11657-006-0007-0.
Eric Orwoll, Christence S Teglbjærg, Bente L Langdahl, Roland Chapurlat, Edward Czerwinski, David L Kendler, Jean-Yves Reginster, Alan Kivitz, E Michael Lewiecki, Paul D Miller, Michael A Bolognese, Michael R McClung, Henry G Bone, Östen Ljunggren, Bo Abrahamsen, Ugis Gruntmanis, Yu-Ching Yang, Rachel B Wagman, Suresh Siddhanti, Andreas Grauer, Jesse W Hall, Steven Boonen
A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density.
J Clin Endocrinol Metab. 2012 Sep;97(9):3161-9. doi: 10.1210/jc.2012-1569. Epub 2012 Jun 21.
Abstract/Text
CONTEXT: Men with low bone mineral density (BMD) were treated with denosumab.
OBJECTIVE: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment.
DESIGN, SUBJECTS, AND INTERVENTION: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD.
MAIN OUTCOME MEASURE: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12.
RESULTS: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups.
CONCLUSIONS: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.
N Freemantle, C Cooper, A Diez-Perez, M Gitlin, H Radcliffe, S Shepherd, C Roux
Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis.
Osteoporos Int. 2013 Jan;24(1):209-17. doi: 10.1007/s00198-012-2068-9. Epub 2012 Jul 26.
Abstract/Text
UNLABELLED: Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis.
INTRODUCTION: This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials.
METHODS: Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents.
RESULTS: Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures.
CONCLUSIONS: The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis.
T Lin, C Wang, X-Z Cai, X Zhao, M-M Shi, Z-M Ying, F-Z Yuan, C Guo, S-G Yan
Comparison of clinical efficacy and safety between denosumab and alendronate in postmenopausal women with osteoporosis: a meta-analysis.
Int J Clin Pract. 2012 Apr;66(4):399-408. doi: 10.1111/j.1742-1241.2011.02806.x. Epub 2012 Feb 7.
Abstract/Text
The aim of this study was to perform a head-to-head comparison of efficacy and safety profile between 60 mg denosumab (Den) subcutaneously (SC) per 6 months (Q6M) and 70 mg alendronate (Aln) orally per week (QW) for postmenopausal women with low bone mineral density. We searched electronic databases comparing efficacy and safety of Den SC Q6M and Aln QW in postmenopausal women. The primary outcomes of efficacy evaluation in included trials were incidence of clinical fracture in both groups and bone mineral density (BMD) at different skeletal sites. And adverse events (AEs), including incidence of neoplasms and infections, were considered as secondary outcomes. Following the instructions of 'Cochrane Handbook for systematic Reviews of Interventions 5.0.2', we identified eligible studies, evaluated the methodological quality and abstracted relevant data. Four heterogeneous randomised controlled trials (RCTs) involving 1942 women were identified. The results of review showed low evidence quality that supported the hypothesis the denosumab vs. alendronate could reduce risk of fracture [OR (95% CI) 1.42 (0.84 to 2.40), 11 more women per 1000 (from 4 fewer to 36 more), p = 0.19] but the moderate to high quality evidence suggesting treatment with 60 mg Den SC Q6M was more effective for postmenopausal women in increasing BMD [at distal radius (DR), total hip (TH), lumbar spine (LS), and femoral neck (FN)]. Hazards of neoplasms [OR (95% CI) 1.10 (0.65 to 1.86), 3 more per 1000 (from 10 fewer to 24 more), p = 0.62] or infections [OR (95% CI) 0.95 (0.79 to 1.15), 12 fewer per 1000 (from 53 fewer to 33 more,), p = 0.62] were appeared to be similar.Our review suggested within 1 year 60 mg Den SC Q6M treatment was more effective in increasing bone mass but could not reduce the fracture risk to a greater extent than 70 mg Aln QW therapy. Also the Den SC Q6M therapy did not increase the risks of neoplasms and infections compared with Aln QW.
© 2012 Blackwell Publishing Ltd.
David L Kendler, Christian Roux, Claude Laurent Benhamou, Jacques P Brown, Michael Lillestol, Suresh Siddhanti, Hoi-Shen Man, Javier San Martin, Henry G Bone
Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy.
J Bone Miner Res. 2010 Jan;25(1):72-81. doi: 10.1359/jbmr.090716.
Abstract/Text
Patients treated with bisphosphonates for osteoporosis may discontinue or require a switch to other therapies. Denosumab binds to RANKL and is a potent inhibitor of bone resorption that has been shown to increase bone mineral density (BMD) and decrease fracture risk in postmenopausal women with osteoporosis. This was a multicenter, international, randomized, double-blind, double-dummy study in 504 postmenopausal women > or = 55 years of age with a BMD T-score of -2.0 or less and -4.0 or more who had been receiving alendronate therapy for at least 6 months. Subjects received open-label branded alendronate 70 mg once weekly for 1 month and then were randomly assigned to either continued weekly alendronate therapy or subcutaneous denosumab 60 mg every 6 months and were followed for 12 months. Changes in BMD and biochemical markers of bone turnover were evaluated. In subjects transitioning to denosumab, total hip BMD increased by 1.90% at month 12 compared with a 1.05% increase in subjects continuing on alendronate (p < .0001). Significantly greater BMD gains with denosumab compared with alendronate also were achieved at 12 months at the lumbar spine, femoral neck, and 1/3 radius (all p < .0125). Median serum CTX levels remained near baseline in the alendronate group and were significantly decreased versus alendronate (p < .0001) at all time points with denosumab. Adverse events and serious adverse events were balanced between groups. No clinical hypocalcemic adverse events were reported. Transition to denosumab produced greater increases in BMD at all measured skeletal sites and a greater reduction in bone turnover than did continued alendronate with a similar safety profile in both groups.
2010 American Society for Bone and Mineral Research
Ego Seeman, Pierre D Delmas, David A Hanley, Deborah Sellmeyer, Angela M Cheung, Elizabeth Shane, Ann Kearns, Thierry Thomas, Steven K Boyd, Stephanie Boutroy, Cesar Bogado, Sharmila Majumdar, Michelle Fan, Cesar Libanati, Jose Zanchetta
Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate.
J Bone Miner Res. 2010 Aug;25(8):1886-94. doi: 10.1002/jbmr.81.
Abstract/Text
The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double-blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C-telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (-2.1% to -0.8%) at the distal radius after 12 months. Alendronate prevented the decline (-0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p < or = .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.
Michael R McClung, E Michael Lewiecki, Stanley B Cohen, Michael A Bolognese, Grattan C Woodson, Alfred H Moffett, Munro Peacock, Paul D Miller, Samuel N Lederman, Charles H Chesnut, Douglas Lain, Alan J Kivitz, Donna L Holloway, Charlie Zhang, Mark C Peterson, Pirow J Bekker, AMG 162 Bone Loss Study Group
Denosumab in postmenopausal women with low bone mineral density.
N Engl J Med. 2006 Feb 23;354(8):821-31. doi: 10.1056/NEJMoa044459.
Abstract/Text
BACKGROUND: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action.
METHODS: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase.
RESULTS: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent.
CONCLUSIONS: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).
Copyright 2006 Massachusetts Medical Society.
Chris Recknor, Edward Czerwinski, Henry G Bone, Sydney L Bonnick, Neil Binkley, Santiago Palacios, Alfred Moffett, Suresh Siddhanti, Irene Ferreira, Prayashi Ghelani, Rachel B Wagman, Jesse W Hall, Michael A Bolognese, Claude-Laurent Benhamou
Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial.
Obstet Gynecol. 2013 Jun;121(6):1291-9. doi: 10.1097/AOG.0b013e318291718c.
Abstract/Text
OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate.
METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy.
RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups.
CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.
Elizabeth J Samelson, Paul D Miller, Claus Christiansen, Nadia S Daizadeh, Luanda Grazette, Mary S Anthony, Ogo Egbuna, Andrea Wang, Suresh R Siddhanti, Angela M Cheung, Nathalie Franchimont, Douglas P Kiel
RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk.
J Bone Miner Res. 2014 Feb;29(2):450-7. doi: 10.1002/jbmr.2043.
Abstract/Text
Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.
© 2014 American Society for Bone and Mineral Research.
Michael Gnant, Georg Pfeiler, Peter C Dubsky, Michael Hubalek, Richard Greil, Raimund Jakesz, Viktor Wette, Marija Balic, Ferdinand Haslbauer, Elisabeth Melbinger, Vesna Bjelic-Radisic, Silvia Artner-Matuschek, Florian Fitzal, Christian Marth, Paul Sevelda, Brigitte Mlineritsch, Günther G Steger, Diether Manfreda, Ruth Exner, Daniel Egle, Jonas Bergh, Franz Kainberger, Susan Talbot, Douglas Warner, Christian Fesl, Christian F Singer, Austrian Breast and Colorectal Cancer Study Group
Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.
Lancet. 2015 Aug 1;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. Epub 2015 May 31.
Abstract/Text
BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer.
METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374.
FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug.
INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice.
FUNDING: Amgen.
Copyright © 2015 Elsevier Ltd. All rights reserved.
R M Neer, C D Arnaud, J R Zanchetta, R Prince, G A Gaich, J Y Reginster, A B Hodsman, E F Eriksen, S Ish-Shalom, H K Genant, O Wang, B H Mitlak
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.
N Engl J Med. 2001 May 10;344(19):1434-41. doi: 10.1056/NEJM200105103441904.
Abstract/Text
BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown.
METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry.
RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache).
CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.
Jean-Jacques Body, Gregory A Gaich, Wim H Scheele, Pandurang M Kulkarni, Paul D Miller, Anne Peretz, Robin K Dore, Ricardo Correa-Rotter, Alexandra Papaioannou, David C Cumming, Anthony B Hodsman
A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis.
J Clin Endocrinol Metab. 2002 Oct;87(10):4528-35. doi: 10.1210/jc.2002-020334.
Abstract/Text
Teriparatide (rDNA origin) injection [recombinant human PTH (1-34)] stimulates bone formation, increases bone mineral density (BMD), and restores bone architecture and integrity. In contrast, bisphosphonates reduce bone resorption and increase BMD. We compared the effects of teriparatide and alendronate sodium on BMD, nonvertebral fracture incidence, and bone turnover in 146 postmenopausal women with osteoporosis. Women were randomized to either once-daily sc injections of teriparatide 40 micro g plus oral placebo (n = 73) or oral alendronate 10 mg plus placebo injection (n = 73). Median duration of treatment was 14 months. At 3 months, teriparatide increased lumbar spine BMD significantly more than did alendronate (P < 0.001). Lumbar spine-BMD increased by 12.2% in the teriparatide group and 5.6% in the alendronate group (P < 0.001 teriparatide vs. alendronate). Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased, compared with alendronate (P < or = 0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P < 0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate.
Michael R McClung, Javier San Martin, Paul D Miller, Roberto Civitelli, Francisco Bandeira, Molly Omizo, David W Donley, Gail P Dalsky, Erik F Eriksen
Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass.
Arch Intern Med. 2005 Aug 8-22;165(15):1762-8. doi: 10.1001/archinte.165.15.1762.
Abstract/Text
BACKGROUND: Antiresorptive agents for the treatment of osteoporosis suppress bone remodeling and reestablish bone turnover at a lower rate to reduce bone loss. Recombinant teriparatide (human parathyroid hormone 1-34) stimulates bone formation, increases bone mass, and improves bone microarchitecture. We contrasted the effects of once-daily doses of 20 mug of teriparatide and 10 mg of alendronate sodium on bone mineral density (BMD) and markers of bone turnover.
METHODS: Markers of bone turnover and areal BMD were assessed in 203 postmenopausal women with osteoporosis in an 18-month randomized parallel double-blind study; volumetric BMD was measured in a subset of women.
RESULTS: Teriparatide significantly increased markers of bone turnover that peaked at 6 months (serum procollagen type I N-terminal propeptide, 218%, and urinary N-telopeptide corrected for creatinine, 58%; P<.001); alendronate significantly decreased the markers at 6 months (-67% and -72%, respectively; P<.001). At 18 months, areal and volumetric spine BMDs were significantly higher with teriparatide than with alendronate (10.3% vs 5.5% [P<.001] and 19.0% vs 3.8% [P<.01], respectively). Areal femoral neck BMD was significantly higher than baseline in the teriparatide and alendronate groups (3.9% and 3.5%, respectively). There were no significant differences in trabecular femoral neck BMD between the teriparatide and alendronate groups (4.9% and 2.2%, respectively). Cortical volumetric femoral neck BMD was significantly different between the teriparatide and alendronate groups (-1.2% and 7.7%, respectively; P = .05).
CONCLUSION: Two distinct options for the management of osteoporosis lead to increases in BMD by opposite mechanisms of action on bone remodeling.
Akimitsu Miyauchi, Toshio Matsumoto, Hirofumi Shigeta, Mika Tsujimoto, Daniel Thiebaud, Toshitaka Nakamura
Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose-response study.
J Bone Miner Metab. 2008;26(6):624-34. doi: 10.1007/s00774-008-0871-3. Epub 2008 Nov 1.
Abstract/Text
The dose-response efficacy and safety with three doses of teriparatide and placebo was assessed, using once-daily subcutaneous injections for 24 weeks, in Japanese postmenopausal women with osteoporosis at high risk of fracture for reasons of preexisting fracture(s), advanced age, and/or low bone mineral density (BMD). In this multicenter, randomized, placebo-controlled study, 159 subjects were randomized and 154 subjects were included for analysis. Teriparatide (10-microg, 20-microg, and 40-microg doses) showed a statistically significant increase with increasing treatment dose as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams' test when compared with placebo (P < 0.001). The mean (+/-SD) percent change in lumbar spine, femoral neck, and total hip BMD with the 20-microg dose from baseline to endpoint was 6.40% +/- 4.76%, 1.83% +/- 7.13%, and 1.91% +/- 3.60%, respectively. Rapid and sustained increases in bone formation markers [type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-specific alkaline phosphatase (BAP)], followed by late increases in a bone resorption marker [type I collagen cross-linked C-telopeptide (CTX)], were observed for the teriparatide treatment groups (20-microg, 40-microg), suggesting a persistent, positive, balanced anabolic effect of teriparatide. Optimal adherence was achieved by this daily self-injection treatment. Regarding safety, most of the adverse events were mild to moderate in severity. No study drug-or study procedure-related serious adverse events were reported during the treatment period. These results observed in Japanese patients may support the observation that teriparatide stimulates bone formation in patients with osteoporosis at a high risk of fracture.
Akimitsu Miyauchi, Toshio Matsumoto, Toshitsugu Sugimoto, Mika Tsujimoto, Margaret R Warner, Toshitaka Nakamura
Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases.
Bone. 2010 Sep;47(3):493-502. doi: 10.1016/j.bone.2010.05.022. Epub 2010 May 24.
Abstract/Text
This multicenter study assessed the safety and efficacy of teriparatide 20 microg/day in Japanese men and women with osteoporosis at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled treatment period followed by second and third treatment periods (to 18 and 24 months, respectively,) in which all subjects received open-label teriparatide. Subjects (93% female; median age 70 years) were randomized 2:1 to teriparatide versus placebo (randomized at baseline, teriparatide n=137, placebo-teriparatide n=70; entering the second period, teriparatide n=119, placebo-teriparatide n=59; entering the third period, teriparatide n=102, placebo-teriparatide n=50). For subjects with measurements at 12 months, teriparatide significantly increased bone mineral density (BMD) at the lumbar spine L2-L4 (mean percent change+/-SD, teriparatide 10.04+/-5.23% versus placebo-teriparatide 0.19+/-4.33%), the femoral neck (teriparatide 2.01+/-4.63% versus placebo-teriparatide 0.44+/-3.97%), and the total hip (teriparatide 2.72+/-4.04% versus placebo-teriparatide -0.26+/-3.42%). In the placebo-teriparatide group at 24 months (12-month teriparatide dosing) BMD increased by 9.11+/-5.14% at the lumbar spine, 2.19+/-4.81% at the femoral neck and 2.46+/-3.54% at the total hip. In the teriparatide group at 18 and 24 months, BMD increased from baseline at the lumbar spine by 11.93+/-5.79% and 13.42+/-6.12%, respectively; at the femoral neck by 2.68+/-4.45% and 3.26+/-4.25%, respectively; and at the total hip by 3.02+/-3.79% and 3.67+/-3.98%, respectively. Serum procollagen I N-terminal pro-peptide (PINP) increased rapidly with teriparatide treatment (P<0.001 versus placebo at 1 month) and changed from baseline in the teriparatide and placebo-teriparatide groups at 12 months by a median of 78.95% and -17.23%, respectively, (P<0.001) and at 24 months by 49.24% and 76.12%, respectively. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs were comparable in the teriparatide and placebo-teriparatide groups. These data show that teriparatide 20 microg/day was well tolerated and stimulated bone formation in Japanese subjects with osteoporosis at high risk of fracture during 18 and 24 months of treatment.
Copyright 2010 Elsevier Inc. All rights reserved.
E S Orwoll, W H Scheele, S Paul, S Adami, U Syversen, A Diez-Perez, J M Kaufman, A D Clancy, G A Gaich
The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.
J Bone Miner Res. 2003 Jan;18(1):9-17. doi: 10.1359/jbmr.2003.18.1.9.
Abstract/Text
Teriparatide [rhPTH(1-34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 microg, or teriparatide 40 microg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microg) and 9.0% (40 microg) above baseline (p < 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 microg; p = 0.029) and 2.9% (40 microg; p < 0.001), and whole body bone mineral content increased 0.6% (20 microg; p = 0.021) and 0.9% (40 microg;p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-microg groups, but more frequent in the 40-microg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.
Kenneth G Saag, Jose R Zanchetta, Jean-Pierre Devogelaer, Robert A Adler, Richard Eastell, Kyoungah See, John H Krege, Kelly Krohn, Margaret R Warner
Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial.
Arthritis Rheum. 2009 Nov;60(11):3346-55. doi: 10.1002/art.24879.
Abstract/Text
OBJECTIVE: To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP).
METHODS: This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety.
RESULTS: Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001).
CONCLUSION: Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.
M C Nevitt, P Chen, D P Kiel, J-Y Reginster, R K Dore, J R Zanchetta, E V Glass, J H Krege
Reduction in the risk of developing back pain persists at least 30 months after discontinuation of teriparatide treatment: a meta-analysis.
Osteoporos Int. 2006;17(11):1630-7. doi: 10.1007/s00198-006-0177-z. Epub 2006 Aug 8.
Abstract/Text
INTRODUCTION: Teriparatide [rhPTH (1-34)] reduces fracture risk, and in a published meta-analysis of clinical trials, teriparatide-treated patients had reduced incidence of back pain relative to placebo or to antiresorptive drugs. The aim of this study was to evaluate back pain in teriparatide-treated versus comparator-treated patients during an interval including controlled clinical trials plus 30 months of additional follow-up.
METHODS: A meta-analysis of four completed randomized, double-blinded trials of teriparatide [rhPTH (1-34)] versus comparator was performed. A multivariate Cox proportional hazards model was used to assess the heterogeneity of results and to estimate the relative risk of back pain.
RESULTS: Patients in the pooled teriparatide group had reduced risk for any back pain [relative risk, 0.73 (95% CI, 0.61-0.87)], moderate or severe back pain [0.72 (0.58-0.89)], and severe back pain [0.39 (0.25-0.61)] compared with pooled controls, from initiation of the study drug through the end of follow-up. Sensitivity analysis showed that the results were robust to the removal of each individual trial from the meta-analysis. Separate meta-analyses comparing teriparatide versus placebo or antiresorptive drugs gave similar results.
CONCLUSIONS: Teriparatide-treated patients had a reduced incidence of back pain versus those receiving a comparator during an observation encompassing clinical trials plus 30 months of posttreatment observation.
Felicia Cosman, Erik Fink Eriksen, Chris Recknor, Paul D Miller, Núria Guañabens, Christian Kasperk, Philemon Papanastasiou, Aimee Readie, Hanumantha Rao, Jürg A Gasser, Christina Bucci-Rechtweg, Steven Boonen
Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis.
J Bone Miner Res. 2011 Mar;26(3):503-11. doi: 10.1002/jbmr.238.
Abstract/Text
Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1-34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1-year multicenter, multinational, randomized, partial double-blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total-hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52-week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N-terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β-C-telopeptide of type I collagen [β-CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA-based BMD (e.g., quantitative computed tomography and finite-element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered.
Copyright © 2011 American Society for Bone and Mineral Research.
Joy N Tsai, Alexander V Uihlein, Hang Lee, Ruchit Kumbhani, Erica Siwila-Sackman, Elizabeth A McKay, Sherri-Ann M Burnett-Bowie, Robert M Neer, Benjamin Z Leder
Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial.
Lancet. 2013 Jul 6;382(9886):50-6. doi: 10.1016/S0140-6736(13)60856-9. Epub 2013 May 15.
Abstract/Text
BACKGROUND: Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone.
METHODS: From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 μg teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380.
FINDINGS: 94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9·1%, [SD 3·9]) than in the teriparatide (6·2% [4·6], p=0·0139) or denosumab (5·5% [3·3], p=0·0005) groups. Femoral-neck BMD also increased more in the combination group (4·2% [3·0]) than in the teriparatide (0·8% [4·1], p=0·0007) and denosumab (2·1% [3·8], p=0·0238) groups, as did total-hip BMD (combination, 4·9% [2·9]; teriparatide, 0·7% [2·7], p<0·0001; denosumab 2·5% [2·6], p=0·0011).
INTERPRETATION: Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture.
FUNDING: Amgen, Eli Lilly, National Center for Research Resources.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Benjamin Z Leder, Joy N Tsai, Alexander V Uihlein, Sherri-Ann M Burnett-Bowie, Yuli Zhu, Katelyn Foley, Hang Lee, Robert M Neer
Two years of Denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial.
J Clin Endocrinol Metab. 2014 May;99(5):1694-700. doi: 10.1210/jc.2013-4440. Epub 2014 Feb 11.
Abstract/Text
CONTEXT: Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone.
OBJECTIVE: The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent.
DESIGN: Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months.
PARTICIPANTS: Participants were 94 postmenopausal women with osteoporosis.
OUTCOME MEASURES: Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.
RESULTS: At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.
CONCLUSIONS: Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
Kenneth G Saag, Jeffrey Petersen, Maria Luisa Brandi, Andrew C Karaplis, Mattias Lorentzon, Thierry Thomas, Judy Maddox, Michelle Fan, Paul D Meisner, Andreas Grauer
Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis.
N Engl J Med. 2017 Oct 12;377(15):1417-1427. doi: 10.1056/NEJMoa1708322. Epub 2017 Sep 11.
Abstract/Text
BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.
METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.
RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.
CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).
Felicia Cosman, Daria B Crittenden, Jonathan D Adachi, Neil Binkley, Edward Czerwinski, Serge Ferrari, Lorenz C Hofbauer, Edith Lau, E Michael Lewiecki, Akimitsu Miyauchi, Cristiano A F Zerbini, Cassandra E Milmont, Li Chen, Judy Maddox, Paul D Meisner, Cesar Libanati, Andreas Grauer
Romosozumab Treatment in Postmenopausal Women with Osteoporosis.
N Engl J Med. 2016 Oct 20;375(16):1532-1543. doi: 10.1056/NEJMoa1607948. Epub 2016 Sep 18.
Abstract/Text
BACKGROUND: Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption.
METHODS: We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures.
RESULTS: At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group.
CONCLUSIONS: In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).
Emmanuel Papadimitropoulos, George Wells, Beverley Shea, William Gillespie, Bruce Weaver, Nicole Zytaruk, Ann Cranney, Jonathan Adachi, Peter Tugwell, Robert Josse, Carol Greenwood, Gordon Guyatt, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group
Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
Endocr Rev. 2002 Aug;23(4):560-9. doi: 10.1210/er.2001-8002.
Abstract/Text
OBJECTIVE: To review the effect of vitamin D on bone density and fractures in postmenopausal women.
DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 1999 and examined citations of relevant articles and proceedings of international meetings. We contacted osteoporosis investigators and primary authors to identify additional studies and to obtain unpublished data.
STUDY SELECTION: We included 25 trials that randomized women to standard or hydroxylated vitamin D with or without calcium supplementation or a control and measured bone density or fracture incidence for at least 1 yr.
DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data.
DATA SYNTHESIS: Vitamin D reduced the incidence of vertebral fractures [relative risk (RR) 0.63, 95% confidence interval (CI) 0.45-0.88, P < 0.01) and showed a trend toward reduced incidence of nonvertebral fractures (RR 0.77, 95% CI 0.57-1.04, P = 0.09). Most patients in the trials that evaluated vertebral fractures received hydroxylated vitamin D, and most patients in the trials that evaluated nonvertebral fractures received standard vitamin D. Hydroxylated vitamin D had a consistently larger impact on bone density than did standard vitamin D. For instance, total body differences in percentage change between hydroxylated vitamin D and control were 2.06 (0.72, 3.40) and 0.40 (-0.25, 1.06) for standard vitamin D. At the lumbar spine and forearm sites, hydroxylated vitamin D doses above 50 microg yield larger effects than lower doses. Vitamin D resulted in an increased risk of discontinuing medication in comparison to control as a result of either symptomatic adverse effects or abnormal laboratory results (RR 1.37, 95% CI 1.01-1.88), an effect that was similar in trials of standard and hydroxylated vitamin D.
CONCLUSIONS: Vitamin D decreases vertebral fractures and may decrease nonvertebral fractures. The available data are uninformative regarding the relative effects of standard and hydroxylated vitamin D.
J C Gallagher, S E Fowler, J R Detter, S S Sherman
Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss.
J Clin Endocrinol Metab. 2001 Aug;86(8):3618-28. doi: 10.1210/jcem.86.8.7703.
Abstract/Text
Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol, are important factors in the pathogenesis of age-related bone loss. The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on bone loss in elderly women. Four hundred eighty-nine elderly women with normal bone density for their age, aged 65-77 yr, were entered into a randomized double blind, placebo-controlled trial. Women were randomized to one of four groups: conjugated estrogens (0.625 mg, daily) to women without a uterus (estrogen replacement therapy) plus medroxyprogesterone acetate (2.5 mg, daily) to women with a uterus (hormone replacement therapy), calcitriol (0.25 microg twice daily), a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol, or placebos for 3 yr. The primary outcome was the change in bone mineral density of the femoral neck and spine. In the intent to treat analysis, hormone therapy (hormone replacement therapy/estrogen replacement therapy) produced a mean (+/-1 SD) increase in bone mineral density of 2.98% (+/-5.45%) at the femoral neck (P < 0.0001) and 4.36% (+/-6.42%) at the spine (P < 0.0001). There were parallel increases in total hip and trochanter bone mineral density. Calcitriol increased bone mineral density 0.10% (+/- 4.27%) at the femoral neck (P = 0.57) and 1.65% (+/- 4.83%) at the spine (P < 0.0124). The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol increased bone mineral density 3.80% (+/-4.95%) at the femoral neck (P < 0.001), 4.91% (+/-6.0%) at the spine (P < 0.0001), and parallel changes at the total hip and trochanter. All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck, spine, total hip and trochanter. There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis. In a secondary analysis of the effect in women who were adherent to treatment, calcitriol had a more significant effect on spine (P = 0.003) and total hip (P = 0.004). The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups. Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter (P = 0.007) and total hip bone mineral density (P = 0.0017). In summary, hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinically relevant sites in a group of elderly women, with normal bone density for their age. Calcitriol was effective in increasing spine bone mineral density. In the adherent women, combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone.
M Shikari, K Kushida, K Yamazaki, T Nagai, T Inoue, H Orimo
Effects of 2 years' treatment of osteoporosis with 1 alpha-hydroxy vitamin D3 on bone mineral density and incidence of fracture: a placebo-controlled, double-blind prospective study.
Endocr J. 1996 Apr;43(2):211-20.
Abstract/Text
A two-year double-blind study monitored and evaluated the effects of 1 alpha-hydroxy vitamin D3 (1 alpha(OH)D3) on the lumbar (L2-4BMD) and total body bone mineral densities (TBBMD) and occurrence of fracture in 113 female osteoporotic patients receiving 0.75 micrograms/day of 1 alpha(OH)D3 (n = 57) or a placebo (n = 56) with calcium supplementation in both groups. L2-4BMD increased 1.81.% and 2.32% after one and 2 years in the 1 alpha (OH)D3 group, but decreased 1.89% (P < 0.05) and 0.28% in the placebo group. A significant difference (P < 0.01) existed between the two groups after one year. TBBMD decreased significantly in the placebo group by 3.34% (P < 0.01) and 3.52% after one and 2 years. Six new fractures occurred in the control group, but only two in the 1 alpha(OH)D3 group (Odd's ratio = 0.343, 95% confidence range; 0.0648-1.815). There were no serious adverse effects of the 1 alpha(OH)D3 treatment. It was concluded that two-year treatment with 1 alpha(OH)D3 increased the lumbar BMD and inhibited the decrease in TBBMD. Although it was not significant, new fracture occurrence in the 1 alpha(OH)D3 group was around 1/3 of that in the control group.
Hayashi Y, Fujita T, Inoue T. Decrease of vertebral fracture in osteoporotics by administration of 1α-hydroxy-vitamin D3. J Bone Mineral Metab 1992; 10: 184-8.
S M Ott, C H Chesnut
Calcitriol treatment is not effective in postmenopausal osteoporosis.
Ann Intern Med. 1989 Feb 15;110(4):267-74.
Abstract/Text
STUDY OBJECTIVE: To determine if calcitriol is an effective treatment in postmenopausal osteoporosis.
DESIGN: Double-blind, randomized clinical trial of 2 years' duration.
SETTING: University medical center with patients recruited by media announcements.
PATIENTS: Eighty-six postmenopausal women with vertebral compression fractures.
INTERVENTIONS: Patients were treated with calcitriol or placebo. Mean dose was 0.43 micrograms/d. Dietary calcium was 1000 mg/d (24.9 mmol/d). The medication dose and dietary calcium were adjusted for hypercalciuria or hypercalcemia.
MEASUREMENTS AND MAIN RESULTS: No significant differences between placebo and control groups were seen in the percent change in total body calcium (0.4% +/- 1.0 compared with 0.0% +/- 0.9), single photon absorptiometry (-0.5% +/- 1.2 compared with -3.1% +/- 0.9) or dual photon absorptiometry (0.0% +/- 1.7 compared with -1.0% +/- 2.2). New fractures were seen in 16% of the placebo group and 26% of the calcitriol groups, so the difference in percent fractures was 10% (95% CI, -5.7% to 25.7%). Bone biopsies did not show changes in either group. The calcitriol group had significantly higher serum and urine calcium values, but renal function was not worse than in the placebo group.
CONCLUSIONS: Calcitriol is not an effective treatment for established postmenopausal osteoporosis.
M W Tilyard, G F Spears, J Thomson, S Dovey
Treatment of postmenopausal osteoporosis with calcitriol or calcium.
N Engl J Med. 1992 Feb 6;326(6):357-62. doi: 10.1056/NEJM199202063260601.
Abstract/Text
BACKGROUND AND METHODS: Osteoporosis is a common problem whose management is controversial. To evaluate the efficacy and safety of calcitriol (1,25-dihydroxyvitamin D3) in the treatment of postmenopausal osteoporosis, we conducted a three-year prospective, multicenter, single-blind study in 622 women who had one or more vertebral compression fractures. The women were randomly assigned to receive treatment with calcitriol (0.25 micrograms twice a day) or supplemental calcium (1 g of elemental calcium daily) for three years. New vertebral fractures were detected by means of lateral roentgenography of the spine each year, and calcium absorption was measured in 392 of the women.
RESULTS: The women who received calcitriol had a significant reduction in the rate of new vertebral fractures during the second and third years of treatment, as compared with the women who received calcium (second year, 9.3 vs. 25.0 fractures per 100 patient-years; third year, 9.9 vs. 31.5 fractures per 100 patient-years; P less than 0.001). This effect was evident only in women who had had five or fewer vertebral fractures at base line (second year, 5.2 vs. 25.3 fractures per 100 patient-years; third year, 4.2 vs. 31.0 fractures per 100 patient-years; P less than 0.0001). The groups also differed significantly in the number of peripheral fractures; 11 such fractures occurred in 11 women in the calcitriol group, whereas 24 occurred in 22 women in the calcium group (P less than 0.05). There was no significant difference between the groups in the incidence of side effects requiring withdrawal of treatment (8.6 percent in the calcitriol group vs. 6.5 percent in the calcium group).
CONCLUSIONS: Continuous treatment of postmenopausal osteoporosis with calcitriol for three years is safe and significantly reduces the rate of new vertebral fractures in women with this disorder.
Toshio Matsumoto, Takami Miki, Hiroshi Hagino, Toshitsugu Sugimoto, Sumiaki Okamoto, Takako Hirota, Yusuke Tanigawara, Yasufumi Hayashi, Masao Fukunaga, Masataka Shiraki, Toshitaka Nakamura
A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial.
J Clin Endocrinol Metab. 2005 Sep;90(9):5031-6. doi: 10.1210/jc.2004-2552. Epub 2005 Jun 21.
Abstract/Text
CONTEXT: ED-71 has been shown to increase lumbar bone mineral density (BMD) in osteoporotic subjects. However, vitamin D insufficiency might have influenced the effect of ED-71 on BMD.
OBJECTIVE: Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation.
DESIGN, SETTING, AND PATIENTS: We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49-87 yr of age).
INTERVENTIONS: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 microg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D(3).
MAIN OUTCOME MEASURES: We assessed changes in lumbar and hip BMD and bone turnover markers from baseline.
RESULTS: Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 microg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 microg ED-71 (-0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 microg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively, but none of them developed sustained hypercalcemia.
CONCLUSIONS: These results demonstrate that ED-71 treatment at around 0.75 microg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.
Heike A Bischoff-Ferrari, Bess Dawson-Hughes, Walter C Willett, Hannes B Staehelin, Marlet G Bazemore, Robert Y Zee, John B Wong
Effect of Vitamin D on falls: a meta-analysis.
JAMA. 2004 Apr 28;291(16):1999-2006. doi: 10.1001/jama.291.16.1999.
Abstract/Text
CONTEXT: Falls among elderly individuals occur frequently, increase with age, and lead to substantial morbidity and mortality. The role of vitamin D in preventing falls among elderly people has not been well established.
OBJECTIVE: To assess the effectiveness of vitamin D in preventing an older person from falling.
DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Register from January 1960 to February 2004, EMBASE from January 1991 to February 2004, clinical experts, bibliographies, and abstracts. Search terms included trial terms: randomized-controlled trial or controlled-clinical trial or random-allocation or double-blind method, or single-blind method or uncontrolled-trials with vitamin D terms: cholecalciferol or hydroxycholecalciferols or calcifediol or dihydroxycholecalciferols or calcitriol or vitamin D/aa[analogs & derivates] or ergocalciferol or vitamin D/bl[blood]; and with accidental falls or falls, and humans.
STUDY SELECTION: We included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations (mean age, 60 years) that examined falls resulting from low trauma for which the method of fall ascertainment and definition of falls were defined explicitly. Studies including patients in unstable health states were excluded. Five of 38 identified studies were included in the primary analysis and 5 other studies were included in a sensitivity analysis.
DATA EXTRACTION: Independent extraction by 3 authors using predefined data fields including study quality indicators.
DATA SYNTHESIS: Based on 5 RCTs involving 1237 participants, vitamin D reduced the corrected odds ratio (OR) of falling by 22% (corrected OR, 0.78; 95% confidence interval [CI], 0.64-0.92) compared with patients receiving calcium or placebo. From the pooled risk difference, the number needed to treat (NNT) was 15 (95% CI, 8-53), or equivalently 15 patients would need to be treated with vitamin D to prevent 1 person from falling. The inclusion of 5 additional studies, involving 10 001 participants, in a sensitivity analysis resulted in a smaller but still significant effect size (corrected RR, 0.87; 95% CI, 0.80-0.96). Subgroup analyses suggested that the effect size was independent of calcium supplementation, type of vitamin D, duration of therapy, and sex, but reduced sample sizes made the results statistically nonsignificant for calcium supplementation, cholecalciferol, and among men.
CONCLUSIONS: Vitamin D supplementation appears to reduce the risk of falls among ambulatory or institutionalized older individuals with stable health by more than 20%. Further studies examining the effect of alternative types of vitamin D and their doses, the role of calcium supplementation, and effects in men should be considered.
Benjamin M P Tang, Guy D Eslick, Caryl Nowson, Caroline Smith, Alan Bensoussan
Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.
Lancet. 2007 Aug 25;370(9588):657-66. doi: 10.1016/S0140-6736(07)61342-7.
Abstract/Text
BACKGROUND: Whether calcium supplementation can reduce osteoporotic fractures is uncertain. We did a meta-analysis to include all the randomised trials in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss.
METHODS: We identified 29 randomised trials (n=63 897) using electronic databases, supplemented by a hand-search of reference lists, review articles, and conference abstracts. All randomised trials that recruited people aged 50 years or older were eligible. The main outcomes were fractures of all types and percentage change of bone-mineral density from baseline. Data were pooled by use of a random-effect model.
FINDINGS: In trials that reported fracture as an outcome (17 trials, n=52 625), treatment was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83-0.95; p=0.0004). In trials that reported bone-mineral density as an outcome (23 trials, n=41 419), the treatment was associated with a reduced rate of bone loss of 0.54% (0.35-0.73; p<0.0001) at the hip and 1.19% (0.76-1.61%; p<0.0001) in the spine. The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p<0.0001). The treatment effect was better with calcium doses of 1200 mg or more than with doses less than 1200 mg (0.80 vs 0.94; p=0.006), and with vitamin D doses of 800 IU or more than with doses less than 800 IU (0.84 vs 0.87; p=0.03).
INTERPRETATION: Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation).
Ian R Reid, Barbara Mason, Anne Horne, Ruth Ames, Helen E Reid, Usha Bava, Mark J Bolland, Gregory D Gamble
Randomized controlled trial of calcium in healthy older women.
Am J Med. 2006 Sep;119(9):777-85. doi: 10.1016/j.amjmed.2006.02.038.
Abstract/Text
PURPOSE: Calcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent.
METHODS: A randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74+/-4 years) was performed to assess the effects on bone density and fracture incidence over 5 years.
RESULTS: Follow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population (P=.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common.
CONCLUSIONS: Calcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.
R R Recker, S Hinders, K M Davies, R P Heaney, M R Stegman, J M Lappe, D B Kimmel
Correcting calcium nutritional deficiency prevents spine fractures in elderly women.
J Bone Miner Res. 1996 Dec;11(12):1961-6. doi: 10.1002/jbmr.5650111218.
Abstract/Text
We tested the spine antifracture and bone sparing efficacy of 1.2 g/day of oral calcium as carbonate in two groups of elderly women, one with prevalent fractures (PF, n = 94) on entry and the other without (NPF, n = 103). It was a prospective randomized, double-blind, placebo-controlled trial in mostly rural communities in women over age 60 who were living independently and were consuming < 1 g/day of calcium. We obtained annual lateral spine radiographs and semiannual forearm bone density over 4.3 +/- 1.1 years and determined vertebral fractures by radiographic morphometry augmented by physician assessment. In the PF group, 15 of 53 subjects on calcium had incident fractures, compared with 21 of 41 on placebo (p = 0.023, chi2). Calcium did not reduce the rate of incident fractures in the NPF group. Those with a prevalent fracture on entry and not treated with calcium were 2.8 times more likely to experience an incident fracture than all others. Change in the forearm bone mass on placebo in the PF group was -1.24 +/- 2.41%/year compared with +0.31 +/- 1.80%/year on calcium (p < 0.001). In the NPF group, the difference was less: -0.39 +/- 2.08%/year versus 0.00 +/- 1.64%/year (p = 0.2). We conclude that in elderly postmenopausal women with spine fractures and selfselected calcium intakes of < 1 g/day, a calcium supplement of 1.2 g/day reduces the incidence of spine fractures and halts measurable bone loss.
Richard L Prince, Amanda Devine, Satvinder S Dhaliwal, Ian M Dick
Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.
Arch Intern Med. 2006 Apr 24;166(8):869-75. doi: 10.1001/archinte.166.8.869.
Abstract/Text
BACKGROUND: Increased dietary calcium intake has been proposed as a population-based public health intervention to prevent osteoporotic fractures. We have examined whether calcium supplementation decreases clinical fracture risk in elderly women and its mechanism of action.
METHODS: Five-year, double-blind, placebo-controlled study of 1460 women recruited from the population and older than 70 years (mean age, 75 years) who were randomized to receive calcium carbonate, 600 mg twice per day, or identical placebo. The primary end points included clinical incident osteoporotic fractures, vertebral deformity, and adverse events ascertained in 5 years. Bone structure was also measured using dual x-ray absorptiometry of the hip and whole body, quantitative ultrasonography of the heel, and peripheral quantitative computed tomography of the distal radius.
RESULTS: Among our patients, 16.1% sustained 1 or more clinical osteoporotic fractures. In the intention-to-treat analysis, calcium supplementation did not significantly reduce fracture risk (hazard ratio, 0.87; 95% confidence interval, 0.67-1.12). However, 830 patients (56.8%) who took 80% or more of their tablets (calcium or placebo) per year had reduced fracture incidence in the calcium compared with the placebo groups (10.2% vs 15.4%; hazard ratio, 0.66; 95% confidence interval, 0.45-0.97). Calcium-treated patients had improved quantitative ultrasonography findings of the heel, femoral neck and whole-body dual x-ray absorptiometry data, and bone strength compared with placebo-treated patients. Of the 92 000 adverse events recorded, constipation was the only event increased by the treatment (calcium group, 13.4%; placebo group, 9.1%).
CONCLUSION: Supplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant.
A M Grant, A Avenell, M K Campbell, A M McDonald, G S MacLennan, G C McPherson, F H Anderson, C Cooper, R M Francis, C Donaldson, W J Gillespie, C M Robinson, D J Torgerson, W A Wallace, RECORD Trial Group
Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial.
Lancet. 2005 May 7-13;365(9471):1621-8. doi: 10.1016/S0140-6736(05)63013-9.
Abstract/Text
BACKGROUND: Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.
METHODS: In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.
FINDINGS: 698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.
INTERPRETATION: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people.
Jill Porthouse, Sarah Cockayne, Christine King, Lucy Saxon, Elizabeth Steele, Terry Aspray, Mike Baverstock, Yvonne Birks, Jo Dumville, Roger Francis, Cynthia Iglesias, Suezann Puffer, Anne Sutcliffe, Ian Watt, David J Torgerson
Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.
BMJ. 2005 Apr 30;330(7498):1003. doi: 10.1136/bmj.330.7498.1003.
Abstract/Text
OBJECTIVE: To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
DESIGN: Pragmatic open randomised controlled trial.
SETTING: Practice nurse led clinics in primary care.
PARTICIPANTS: 3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
INTERVENTION: Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
MAIN OUTCOME MEASURES: Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
RESULTS: 69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
CONCLUSION: We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry.
Heike A Bischoff-Ferrari, Bess Dawson-Hughes, John A Baron, Peter Burckhardt, Ruifeng Li, Donna Spiegelman, Bonny Specker, John E Orav, John B Wong, Hannes B Staehelin, Eilis O'Reilly, Douglas P Kiel, Walter C Willett
Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials.
Am J Clin Nutr. 2007 Dec;86(6):1780-90.
Abstract/Text
BACKGROUND: The role of total calcium intake in the prevention of hip fracture risk has not been well established.
OBJECTIVE: The objective of the study was to assess the relation of calcium intake to the risk of hip fracture on the basis of meta-analyses of cohort studies and clinical trials.
RESULTS: In women (7 prospective cohort studies, 170,991 women, 2,954 hip fractures), there was no association between total calcium intake and hip fracture risk [pooled risk ratio (RR) per 300 mg total Ca/d = 1.01; 95% CI: 0.97, 1.05]. In men (5 prospective cohort studies, 68,606 men, 214 hip fractures), the pooled RR per 300 mg total Ca/d was 0.92 (95% CI: 0.82, 1.03). On the basis of 5 clinical trials (n = 5666 women, primarily postmenopausal, plus 1074 men) with 814 nonvertebral fractures, the pooled RR for nonvertebral fractures between calcium supplementation (800-1600 mg/d) and placebo was 0.92 (95% CI: 0.81, 1.05). On the basis of 4 clinical trials with separate results for hip fracture (6,504 subjects with 139 hip fractures), the pooled RR between calcium and placebo was 1.64 (95% CI:1.02, 2.64). Sensitivity analyses including 2 additional small trials with <100 participants or per-protocol results did not substantially alter results.
CONCLUSIONS: Pooled results from prospective cohort studies suggest that calcium intake is not significantly associated with hip fracture risk in women or men. Pooled results from randomized controlled trials show no reduction in hip fracture risk with calcium supplementation, and an increased risk is possible. For any nonvertebral fractures, there was a neutral effect in the randomized trials.
Mark J Bolland, Alison Avenell, John A Baron, Andrew Grey, Graeme S MacLennan, Greg D Gamble, Ian R Reid
Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.
BMJ. 2010 Jul 29;341:c3691. Epub 2010 Jul 29.
Abstract/Text
OBJECTIVE: To investigate whether calcium supplements increase the risk of cardiovascular events.
DESIGN: Patient level and trial level meta-analyses.
DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010.
STUDY SELECTION: Eligible studies were randomised, placebo controlled trials of calcium supplements (>or=500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than one year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self reports, hospital admissions, and death certificates.
RESULTS: 15 trials were eligible for inclusion, five with patient level data (8151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11 921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038).
CONCLUSIONS: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.
S Boonen, D A Wahl, L Nauroy, M L Brandi, M L Bouxsein, J Goldhahn, E M Lewiecki, G P Lyritis, D Marsh, K Obrant, S Silverman, E Siris, K Akesson, CSA Fracture Working Group of International Osteoporosis Foundation
Balloon kyphoplasty and vertebroplasty in the management of vertebral compression fractures.
Osteoporos Int. 2011 Dec;22(12):2915-34. doi: 10.1007/s00198-011-1639-5. Epub 2011 Jul 26.
Abstract/Text
Vertebral compression fractures (VCFs) are the most prevalent fractures in osteoporotic patients. The classical conservative management of these fractures is through rest, pain medication, bracing and muscle relaxants. The aim of this paper is to review prospective controlled studies comparing the efficacy and safety of minimally invasive techniques for vertebral augmentation, vertebroplasty (VP) and balloon kyphoplasty (BKP), versus non-surgical management (NSM). The Fracture Working Group of the International Osteoporosis Foundation conducted a literature search and developed a review paper on VP and BKP. The results presented for the direct management of osteoporotic VCFs focused on clinical outcomes of these three different procedures, including reduction in pain, improvement of function and mobility, vertebral height restoration and decrease in spinal curvature (kyphosis). Overall, VP and BKP are generally safe procedures that provide quicker pain relief, mobility recovery and in some cases vertebral height restoration than conventional conservative medical treatment, at least in the short term. However, the long-term benefits and safety in terms of risk of subsequent vertebral fractures have not been clearly demonstrated and further prospective randomized studies are needed with standards for reporting. Referral physicians should be aware of VP/BKP and their potential to reduce the health impairment of patients with VCFs. However, VP and BKP are not substitutes for appropriate evaluation and treatment of osteoporosis to reduce the risk of future fractures.
D Courteix, C Jaffré, E Lespessailles, L Benhamou
Cumulative effects of calcium supplementation and physical activity on bone accretion in premenarchal children: a double-blind randomised placebo-controlled trial.
Int J Sports Med. 2005 Jun;26(5):332-8. doi: 10.1055/s-2004-821040.
Abstract/Text
High calcium intake combined with physical activity during childhood have been shown to improve bone mass accrual and bone mineral density. Our aim was to study the combined effect of calcium and exercise on bone gain in children. Two milk-powder products containing either 800 mg of calcium phosphate (calcium) or not (placebo) were randomly allocated to 113 healthy premenarchal girls on a daily basis for 1 year. The group was composed of 63 exercise (7.2 +/- 4 hours of exercise/week) and 50 sedentary (1.2 +/- 0.8 hours of exercise/week) children. The final experiment had 4 groups: exercise/calcium (n = 12), exercise/placebo (n = 42), sedentary/calcium (n = 10), and sedentary/placebo (n = 21). Bone mineral density (BMD) at 6 skeletal sites and body composition were determined by DXA. Bone age was calculated and the daily spontaneous calcium intake was assessed by a frequency questionnaire. All the tests were performed at baseline and 1 year by the same observer. BMD gains were significantly greater in the exercise/calcium group than in other groups at the total body (increase of 6.3 %, p < 0.05), lumbar spine (11 %, p < 0.05), femoral neck (8.2 %, p < 0.02), and Ward's triangle (9.3 %, p < 0.01). There was no difference between the other groups. These data suggest that calcium supplementation increases the effect of physical exercise on bone mineral acquisition in the period preceding puberty, and that calcium supplementation without physical activity does not improve the BMD acquisition during this period. Physical exercise that stimulates bone accretion needs a high calcium intake to be completely effective.
J C Ruiz, C Mandel, M Garabedian
Influence of spontaneous calcium intake and physical exercise on the vertebral and femoral bone mineral density of children and adolescents.
J Bone Miner Res. 1995 May;10(5):675-82. doi: 10.1002/jbmr.5650100502.
Abstract/Text
Peak bone mass is determined mainly by genetic-ethnic factors, but environmental factors such as calcium intake and physical activity during childhood and adolescence could play a role. We have measured the bone mineral density (BMD) of 151 healthy children and adolescents, ages 7-15.3 years. Density was measured by dual X-ray absorptiometry (DXA) at two sites (lumbar verterbrae L1-L4 and the upper femur), and the data were analyzed in terms of the height, weight, sexual maturation, spontaneous calcium intake, and physical activity. Of the children, 57-71% had calcium intakes below 1000 mg/day. BMD increased with pubertal maturation from 0.68 +/- 0.08 to 0.92 +/- 0.09 g/cm2 (vertebral bone density, VBD) and from 0.87 +/- 0.10 to 1.03 +/- 0.09 g/cm2 (femoral bone density, FBD) between Tanner stage 1 and 5. Multiple regression analysis showed that body weight and Tanner stage were main determinants of bone density when expressed as g/cm2. The weekly duration of sports activity also influenced both the vertebral (p < 0.001) and femoral (p = 0.01) sites, especially in girls and during puberty. Dietary calcium appeared to be another independent determinant of BMD, especially before puberty, at the vertebral (p = 0.02) site. Most important, dietary calcium was found to be the main determinant of vertebral mineral density, when expressed as z score, in both sexes. Moreover, 93% of the 28 children with low vertebral z score values (below -1) and 84% of the 31 children with low femoral z score values (below -1) had dietary calcium intakes below 1000 mg/day.
Kun Zhu, Xueqin Du, Heather Greenfield, Qian Zhang, Guansheng Ma, Xiaoqi Hu, David R Fraser
Bone mass in Chinese premenarcheal girls: the roles of body composition, calcium intake and physical activity.
Br J Nutr. 2004 Dec;92(6):985-93.
Abstract/Text
The association of growth and anthropometric characteristics and lifestyle factors with bone mass and second metacarpal radiogrammetry parameters was evaluated in 373 healthy Chinese premenarcheal girls aged 9-11 years. Bone mineral content (BMC) and density (BMD) and bone area (BA) of distal forearm, proximal forearm and total body, bone mineral-free lean (BMFL) mass and fat mass were measured by dual-energy X-ray absorptiometry. Metacarpal bone periosteal and medullary diameters were measured. Dietary intakes were assessed by 7 d food record and physical activity (PA) by questionnaire. BMFL and fat mass together explained 6.3 and 51.6% of the variation in total body BMC and BMD, respectively. BMFL mass contributed to a substantial proportion of the variation in forearm BMC and BMD and periosteal diameter (10.4-41.0%). The corresponding BA explained 14.8-80.4% of the variation in BMC. Other minor but significant predictors of total body bone mass were Ca intake, height, age and PA score (BMD only), and of forearm bone mass were PA score, bone age, height and fat mass. Nevertheless, after adjusting for bone and body size and for age or bone age, subjects with Ca intake above the median (417 mg/d) had 1.8% greater total body BMC (P<0.001), and subjects with PA scores above the median had 2.4-2.5% greater distal and proximal forearm BMC (P<0.05) than those below. Vitamin D intake negatively associated with medullary diameter (partial R2 1.7%). The results indicate that premenarcheal girls should be encouraged to optimise nutrition and Ca intake and exercise regularly to achieve maximum peak bone mass.
W T Lee, S S Leung, M Y Ng, S F Wang, Y C Xu, W P Zeng, J Lau
Bone mineral content of two populations of Chinese children with different calcium intakes.
Bone Miner. 1993 Dec;23(3):195-206.
Abstract/Text
Bone mineral content (BMC) of 5-year-old Chinese children (115 children in Jiangmen, China and 128 children in Hong Kong) was evaluated by single-photon absorptiometry at the distal 1/3 radius. The mean (S.D.) calcium intakes of children of Jiangmen and Hong Kong were 244 (46) and 542 (332) mg/day, respectively. The mean BMC, weight and height of Jiangmen children were significantly less than Hong Kong children by 14%, 10% and 4%, respectively (P < 0.001). Multiple regression analysis showed that 62% of the variance in BMC was explained by bone width (BW), weight and regional location (P < 0.0001). A regional difference in BMC of 0.0303 g/cm (P < 0.0001) still remained after adjusting for BW and weight by multiple regression analysis. When comparing sub-groups of children in the two regions with comparable low current calcium intake at 5 years, the BMC of Jiangmen children was still significantly lower than Hong Kong children even when potential confounders were adjusted (P < 0.003). The study suggests that the regional discrepancy in BMC might be explained by long-term habitual calcium intake and physical activity.
C Mølgaard, B L Thomsen, K F Michaelsen
The influence of calcium intake and physical activity on bone mineral content and bone size in healthy children and adolescents.
Osteoporos Int. 2001;12(10):887-94.
Abstract/Text
Studies of determinants of bone mineralization during growth are relevant to the attempt to increase peak bone mass. The aim of this study was to examine how calcium intake and physical activity influence bone size (bone area, BA), accretion in BA, whole body bone mineral content (BMC) and accretion in BMC. BA and BMC were examined by dual-energy X-ray absorptiometry (Hologic 1000/W) in healthy girls (n = 192) and boys (n = 140) aged 5-19 years at baseline and 1 year later. Calcium intake was assessed three times by a food frequency questionnaire and physical activity three times by a 24 h recall questionnaire. The influence of calcium intake and physical activity was examined by multiple regression. BA was size-adjusted by including height and weight in all analyses, and BMC was size-adjusted by including BA, height and weight in all analyses. Size-adjusted average BA was associated neither with average calcium intake nor with average physical activity. Size-adjusted accretion in BA was borderline associated with the average calcium intake in boys only (p = 0.07). Size-adjusted average BMC was positively associated with average calcium intake (p) = 0.03 girls; p = 0.07 boys) and borderline associated with average physical activity level in boys (p = 0.07) but not girls (p = 0.7). Size-adjusted accretion in BMC was significantly associated neither with average calcium intake nor with average physical activity level, but was associated with change in calcium intake over the 1 year observation period in boys (p = 0.03) but not girls (p = 0.9). In conclusion, we found that size-adjusted BMC in school-aged children was positively associated with average calcium intake. Size-adjusted accretion in BMC was positively associated with change in dietary calcium intake in boys only. To what degree this is caused by a reduction in remodeling space is unknown.
J A Langlois, M E Mussolino, M Visser, A C Looker, T Harris, J Madans
Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: the NHANES I epidemiologic follow-up study.
Osteoporos Int. 2001;12(9):763-8. doi: 10.1007/s001980170053.
Abstract/Text
Although weight loss increases bone loss and hip fracture risk in older women, little is known about the relation between weight loss in middle-aged women and subsequent hip fracture risk. The objective of this study was to determine the association between weight loss from reported maximum body weight in middle-aged and older women and the risk of hip fracture. Data were from a nationally representative sample of 2180 community-dwelling white women aged 50-74 years from the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey (NHEFS). In this prospective cohort study, incident hip fracture was ascertained during 22 years of follow-up. The adjusted relative risks associated with weight loss of 10% or more from maximum body weight were elevated for both middle-aged (RR 2.54; 95% CI 1.10-5.86) and older women (RR 2.04; 95% CI 1.37-3.04). For both ages combined, women in the lowest tertile of body mass index at maximum who lost 10% or more of weight had the highest risk of hip fracture (RR 2.37; 95% CI 1.32-4.27). Weight loss from maximum reported body weight in women aged 50-64 years and 65-74 years increased their risk of hip fracture, especially among those who were relatively thin. Weight loss of 10% or more from maximum weight among both middle-aged and older women is an important indicator of hip fracture risk.
Marrissa Martyn-St James, Sean Carroll
Meta-analysis of walking for preservation of bone mineral density in postmenopausal women.
Bone. 2008 Sep;43(3):521-31. doi: 10.1016/j.bone.2008.05.012. Epub 2008 May 26.
Abstract/Text
Whilst exercise is recommended for optimum bone health in adult women, there are few systematic reviews of the efficacy of walking as singular exercise therapy for postmenopausal bone loss. The aim of this study was to assess the effects of prescribed walking programmes on bone mineral density (BMD) at the hip and spine in postmenopausal women and to determine if effects are modified by variations in protocol design. We undertook a systematic review and meta-analysis of randomised (RCTs) and non-randomised controlled trials. Electronic bibliographic databases, key journals and reference lists of reviews and articles were searched to identify studies for inclusion. Randomised and non-randomised controlled trials assessing the effects of walking on lumbar spine, femoral neck and total hip BMD, measured by radiographic techniques, among sedentary postmenopausal women were eligible for inclusion. Two independent reviewers assessed studies for eligibility. Reported absolute BMD outcomes were combined in the analysis. Weighted mean differences (WMD) were calculated using a fixed and random-effects models. Heterogeneity among trials was examined using the Q statistic and I2 methods. Potential publication bias was assessed through funnel plot inspection. Assessment of trial quality was also performed using the widely used instrument devised by Jadad et al. [Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Cont Clin Trials 1996; 17:1-12]. Eight trials were eligible for inclusion. Treatment duration ranged from 6 to 24 months. All eight trials reported BMD data at the lumbar spine following walking interventions among postmenopausal women. Meta-analysis showed no significant change in BMD at this site [WMD (fixed-effect) 0.007 g/cm2 95% CI (-0.001 to 0.016); P=0.09)]. BMD data at the femoral neck were available from five trials among postmenopausal women. Results were inconsistent (I2=51.4%) in showing a positive effect of walking on BMD at this site [WMD (random-effects) 0.014 g/cm2 95% CI (0.000 to 0.028); P=0.05). Insufficient data were available for meta-analysis of the total hip site. Funnel plots showed some asymmetry for negative lumbar spine BMD outcomes. Trial quality scores ranged from 0 to 3 from the Jadad scale of 0 to 5. We conclude that regular walking has no significant effect on preservation of BMD at the spine in postmenopausal women, whilst significant positive effects at femoral neck are evident. However, diverse methodological and reporting discrepancies are apparent in the published trials on which these conclusions are based. Other forms of exercise that provide greater targeted skeletal loading may be required to preserve bone mineral density in this population.
George A Kelley, Kristi S Kelley, Wendy M Kohrt
Exercise and bone mineral density in premenopausal women: a meta-analysis of randomized controlled trials.
Int J Endocrinol. 2013;2013:741639. doi: 10.1155/2013/741639. Epub 2013 Jan 17.
Abstract/Text
Objective. Examine the effects of exercise on femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) in premenopausal women. Methods. Meta-analysis of randomized controlled exercise trials ≥24 weeks in premenopausal women. Standardized effect sizes (g) were calculated for each result and pooled using random-effects models, Z score alpha values, 95% confidence intervals (CIs), and number needed to treat (NNT). Heterogeneity was examined using Q and I(2). Moderator and predictor analyses using mixed-effects ANOVA and simple metaregression were conducted. Statistical significance was set at P ≤ 0.05. Results. Statistically significant improvements were found for both FN (7g's, 466 participants, g = 0.342, 95% CI = 0.132, 0.553, P = 0.001, Q = 10.8, P = 0.22, I(2) = 25.7%, NNT = 5) and LS (6g's, 402 participants, g = 0.201, 95% CI = 0.009, 0.394, P = 0.04, Q = 3.3, P = 0.65, I(2) = 0%, NNT = 9) BMD. A trend for greater benefits in FN BMD was observed for studies published in countries other than the United States and for those who participated in home versus facility-based exercise. Statistically significant, or a trend for statistically significant, associations were observed for 7 different moderators and predictors, 6 for FN BMD and 1 for LS BMD. Conclusions. Exercise benefits FN and LS BMD in premenopausal women. The observed moderators and predictors deserve further investigation in well-designed randomized controlled trials.
K A Bolam, J G Z van Uffelen, D R Taaffe
The effect of physical exercise on bone density in middle-aged and older men: a systematic review.
Osteoporos Int. 2013 Nov;24(11):2749-62. doi: 10.1007/s00198-013-2346-1. Epub 2013 Apr 4.
Abstract/Text
Although trials have shown that exercise has positive effects on bone mineral density (BMD), the majority of exercise trials have been conducted in older women. The aim of this study was to systematically review trials examining the effect of weight-bearing and resistance-based exercise modalities on the BMD of hip and lumbar spine of middle-aged and older men. Eight electronic databases were searched in August 2012. Randomised controlled or controlled trials that assessed the effect of weight-bearing and resistance-based exercise interventions on BMD measured by dual-energy x-ray absorptiometry, and reported effects in middle-aged and older men were included. Eight trials detailed in nine papers were included. The interventions included walking (n = 2), resistance training (n = 3), walking + resistance training (n = 1), resistance training + impact-loading activities (n = 1) and resistance training + Tai Chi (n = 1). Five of the eight trials achieved a score of less than 50% on the modified Delphi quality rating scale. Further, there was heterogeneity in the type, intensity, frequency and duration of the exercise regimens. Effects of exercise varied greatly among studies, with six interventions having a positive effect on BMD and two interventions having no significant effect. It appears that resistance training alone or in combination with impact-loading activities are most osteogenic for this population, whereas the walking trials had limited effect on BMD. Therefore, regular resistance training and impact-loading activities should be considered as a strategy to prevent osteoporosis in middle-aged and older men. High quality randomised controlled trials are needed to establish the optimal exercise prescription.
Catherine Sherrington, Julie C Whitney, Stephen R Lord, Robert D Herbert, Robert G Cumming, Jacqueline C T Close
Effective exercise for the prevention of falls: a systematic review and meta-analysis.
J Am Geriatr Soc. 2008 Dec;56(12):2234-43. doi: 10.1111/j.1532-5415.2008.02014.x.
Abstract/Text
OBJECTIVES: To determine the effects of exercise on falls prevention in older people and establish whether particular trial characteristics or components of exercise programs are associated with larger reductions in falls.
DESIGN: Systematic review with meta-analysis. Randomized controlled trials that compared fall rates in older people who undertook exercise programs with fall rates in those who did not exercise were included.
SETTING: Older people.
PARTICIPANTS: General community and residential care.
MEASUREMENTS: Fall rates.
RESULTS: The pooled estimate of the effect of exercise was that it reduced the rate of falling by 17% (44 trials with 9,603 participants, rate ratio (RR)=0.83, 95% confidence interval (CI)=0.75-0.91, P<.001, I(2)=62%). The greatest relative effects of exercise on fall rates (RR=0.58, 95% CI=0.48-0.69, 68% of between-study variability explained) were seen in programs that included a combination of a higher total dose of exercise (>50 hours over the trial period) and challenging balance exercises (exercises conducted while standing in which people aimed to stand with their feet closer together or on one leg, minimize use of their hands to assist, and practice controlled movements of the center of mass) and did not include a walking program.
CONCLUSION: Exercise can prevent falls in older people. Greater relative effects are seen in programs that include exercises that challenge balance, use a higher dose of exercise, and do not include a walking program. Service providers can use these findings to design and implement exercise programs for falls prevention.
T Koike, Y Orito, H Toyoda, M Tada, R Sugama, M Hoshino, Y Nakao, S Kobayashi, K Kondo, Y Hirota, K Takaoka
External hip protectors are effective for the elderly with higher-than-average risk factors for hip fractures.
Osteoporos Int. 2009 Sep;20(9):1613-20. doi: 10.1007/s00198-008-0824-7. Epub 2009 Jan 10.
Abstract/Text
UNLABELLED: In our cluster randomised controlled trial for efficacy of hip protector with 672 ambulatory elderly women, a hip protector was more effective for prevention of hip fractures in residents with fall history (n = 202; hazard ratio (HR), 0.375; 95%CI, 0.14-0.98; p = 0.05) and body-mass index (BMI) < or = 19.0 (n = 206; HR, 0.37; 95%CI, 0.14-0.95; p = 0.04) by a Cox proportional hazards regression model.
INTRODUCTION: Hip fractures result from both osteoporosis and falling. A potentially cost-effective method of preventing hip fractures involves the use of hip protectors but recent studies have revealed the uncertain effectiveness of hip protectors even in institutional settings.
METHODS: This study was a cluster randomised controlled trial with nursing homes. We randomly assigned 76 homes with 672 ambulatory but frail elderly women. Several risk factors were assessed at baseline and incorporated into a Cox proportional hazards regression model. UMIN Clinical Trials Registry number is UMIN000000467. Research period was between January 2004 and March 2006.
RESULTS: In the intervention group, 19 hip fractures occurred (54.0/1,000 person-years), whereas 39 hip fractures occurred in the control group (78.8/1,000 person-years). Hazard ratio of hip fracture in the intervention group was 0.56 (95%CI, 0.31-1.03; p = 0.06) after adjusting for risk factors. In subgroup analysis, hip protectors were more effective for prevention of hip fractures in residents with fall history (n = 202; HR, 0.375; 95%CI, 0.14-0.98; p = 0.05) and BMI < or = 19.0 (n = 206; HR, 0.37; 95%CI, 0.14-0.95; p = 0.04). Overall compliance with use of hip protectors was 79.7%.
CONCLUSION: Risk of hip fracture can be reduced by hip protectors among elderly women with fall history and low BMI.
K G Saag, R Emkey, T J Schnitzer, J P Brown, F Hawkins, S Goemaere, G Thamsborg, U A Liberman, P D Delmas, M P Malice, M Czachur, A G Daifotis
Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group.
N Engl J Med. 1998 Jul 30;339(5):292-9. doi: 10.1056/NEJM199807303390502.
Abstract/Text
BACKGROUND: Osteoporosis is a common complication of long-term glucocorticoid therapy for which there is no well-proved preventive or restorative treatment.
METHODS: We carried out two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women, 17 to 83 years of age, who were receiving glucocorticoid therapy. The primary end point was the difference in the mean percent change in lumbar-spine bone density from base line to week 48 between the groups. Secondary outcomes included changes in bone density of the hip, biochemical markers of bone turnover, and the incidence of new vertebral fractures.
RESULTS: The mean (+/-SE) bone density of the lumbar spine increased by 2.1+/-0.3 percent and 2.9+/-0.3 percent, respectively, in the groups that received 5 and 10 mg of alendronate per day (P<0.001) and decreased by 0.4+/-0.3 percent in the placebo group. The femoral-neck bone density increased by 1.2+/-0.4 percent and 1.0+/-0.4 percent in the respective alendronate groups (P<0.01) and decreased by 1.2+/-0.4 percent in the placebo group (P<0.01). The bone density of the trochanter and total body also increased significantly in the patients treated with alendronate. There were proportionally fewer new vertebral fractures in the alendronate groups (overall incidence, 2.3 percent) than in the placebo group (3.7 percent) (relative risk, 0.6; 95 percent confidence interval, 0.1 to 4.4). Markers of bone turnover decreased significantly in the alendronate groups (P<0.001). There were no differences in serious adverse effects among the three groups, but there was a small increase in nonserious upper gastrointestinal effects in the group receiving 10 mg of alendronate.
CONCLUSIONS: Alendronate increases bone density in patients receiving glucocorticoid therapy.
Adam M Brufsky, Linda D Bosserman, Richard R Caradonna, Barbara B Haley, C Michael Jones, Halle C F Moore, Lixian Jin, Ghulam M Warsi, Solveig G Ericson, Edith A Perez
Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results.
Clin Breast Cancer. 2009 May;9(2):77-85. doi: 10.3816/CBC.2009.n.015.
Abstract/Text
BACKGROUND: Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss.
PATIENTS AND METHODS: In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis.
RESULTS: Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P < .0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%.
CONCLUSION: Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.
Catherine Van Poznak, Rosemary A Hannon, John R Mackey, Mario Campone, Justus P Apffelstaedt, Glen Clack, David Barlow, Andreas Makris, Richard Eastell
Prevention of aromatase inhibitor-induced bone loss using risedronate: the SABRE trial.
J Clin Oncol. 2010 Feb 20;28(6):967-75. doi: 10.1200/JCO.2009.24.5902. Epub 2010 Jan 11.
Abstract/Text
PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.
James E Lester, David Dodwell, Omprakash P Purohit, Sandra A Gutcher, Susan P Ellis, Ruth Thorpe, Janet M Horsman, Janet E Brown, Rosemary A Hannon, Robert E Coleman
Prevention of anastrozole-induced bone loss with monthly oral ibandronate during adjuvant aromatase inhibitor therapy for breast cancer.
Clin Cancer Res. 2008 Oct 1;14(19):6336-42. doi: 10.1158/1078-0432.CCR-07-5101.
Abstract/Text
PURPOSE: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole.
EXPERIMENTAL DESIGN: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score -1.0 to -2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo.
RESULTS: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range -8.9, +19.9) and +0.60% (range -9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost -3.22% (range -16.0, +4.3) at the lumbar spine and -3.90% (range -12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone-specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively).
CONCLUSIONS: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.
Susan L Greenspan, Joel B Nelson, Donald L Trump, Neil M Resnick
Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial.
Ann Intern Med. 2007 Mar 20;146(6):416-24.
Abstract/Text
BACKGROUND: Androgen deprivation therapy (ADT) in men with prostate cancer is associated with bone loss and fractures.
OBJECTIVE: To determine whether once-weekly oral bisphosphonate can prevent bone loss and reduce bone turnover in men receiving ADT.
DESIGN: Randomized, double-blind, placebo-controlled, partial crossover trial. First-year, preplanned analysis of a 2-group, parallel-design phase.
SETTING: University medical center.
PATIENTS: 112 men with nonmetastatic prostate cancer receiving ADT.
INTERVENTION: Alendronate, 70 mg once weekly, or placebo. All patients received calcium and vitamin D supplementation.
MEASUREMENTS: Bone mineral density of the spine and hip and markers of bone resorption and formation.
RESULTS: At baseline, 39% of men had osteoporosis and 52% had low bone mass. In men treated with alendronate, bone mineral density increased over 1 year by 3.7% (95% CI, 2.8% to 4.6%; P < 0.001) at the spine and 1.6% (CI, 0.4% to 2.8%; P = 0.008) at the femoral neck. Men in the placebo group had losses of 1.4% (CI, -2.7% to - 0.03%; P = 0.045) at the spine and 0.7% (CI, -1.5% to 0.01%; P = 0.081) at the femoral neck. At 12 months, the difference between the 2 groups was 5.1 percentage points (CI, 3.5 to 6.7 percentage points; P < 0.001) at the spine and was 2.3 percentage points (CI, 1.0 to 3.7 percentage points; P < 0.001) at the femoral neck. Bone turnover statistically significantly decreased with active therapy compared with placebo. The groups did not differ in adverse events.
LIMITATIONS: The study was short (1 year) and was not powered to detect differences in the frequency of fractures.
CONCLUSIONS: Bone loss that occurred with ADT was prevented and improved with once-weekly oral alendronate. Because most men have low bone mass or osteoporosis, physicians should assess their patients' bone density and provide preventive and therapeutic measures as appropriate. ClinicalTrials.gov registration number: NCT00048841.
M R Smith, F J McGovern, A L Zietman, M A Fallon, D L Hayden, D A Schoenfeld, P W Kantoff, J S Finkelstein
Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer.
N Engl J Med. 2001 Sep 27;345(13):948-55. doi: 10.1056/NEJMoa010845.
Abstract/Text
BACKGROUND: Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist.
METHODS: In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study.
RESULTS: In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02).
CONCLUSIONS: Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.
Matthew R Smith, James Eastham, Donald M Gleason, Daniel Shasha, Simon Tchekmedyian, Norman Zinner
Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.
J Urol. 2003 Jun;169(6):2008-12. doi: 10.1097/01.ju.0000063820.94994.95.
Abstract/Text
PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer.
MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry.
RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated.
CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.
M Dror Michaelson, Donald S Kaufman, Hang Lee, Francis J McGovern, Philip W Kantoff, Mary Anne Fallon, Joel S Finkelstein, Matthew R Smith
Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer.
J Clin Oncol. 2007 Mar 20;25(9):1038-42. doi: 10.1200/JCO.2006.07.3361.
Abstract/Text
PURPOSE: Gonadotropin-releasing hormone (GnRH) agonists decrease bone mineral density (BMD) and increase fracture risk in men with prostate cancer. Annual zoledronic acid increases BMD in postmenopausal women, but its efficacy in hypogonadal men is not known.
PATIENTS AND METHODS: In a 12-month study, 40 men with nonmetastatic prostate cancer who were receiving a GnRH agonist and had T scores more than -2.5 were randomly assigned to zoledronic acid (4 mg intravenously on day 1 only) or placebo. BMD of the posteroanterior lumbar spine and proximal femur were measured by dual-energy x-ray absorptiometry.
RESULTS: Mean (+/- SE) BMD of the posteroanterior lumbar spine decreased by 3.1% +/- 1.0% in men assigned to placebo and increased by 4.0% +/- 1.0% in men assigned to zoledronic acid (P < .001). BMD of the total hip decreased by 1.9% +/- 0.7% in men assigned to placebo and increased by 0.7% +/- 0.5% in men assigned to zoledronic acid (P = .004). Similar between-group differences were observed for the femoral neck and trochanter. Serum N-telopeptide, a marker of osteoclast activity, decreased significantly after zoledronic acid treatment.
CONCLUSION: In men receiving a GnRH agonist, a single treatment with zoledronic acid significantly increased BMD and durably suppressed serum N-telopeptide levels for 12 months. Annual zoledronic acid may be a convenient and effective strategy to prevent bone loss in hypogonadal men.
Matthew R Smith, Blair Egerdie, Narciso Hernández Toriz, Robert Feldman, Teuvo L J Tammela, Fred Saad, Jiri Heracek, Maciej Szwedowski, Chunlei Ke, Amy Kupic, Benjamin Z Leder, Carsten Goessl, Denosumab HALT Prostate Cancer Study Group
Denosumab in men receiving androgen-deprivation therapy for prostate cancer.
N Engl J Med. 2009 Aug 20;361(8):745-55. doi: 10.1056/NEJMoa0809003. Epub 2009 Aug 11.
Abstract/Text
BACKGROUND: Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.
METHODS: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.
RESULTS: At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups.
CONCLUSIONS: Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.)
2009 Massachusetts Medical Society
