今日の臨床サポート

サプリメント(ミネラル)

著者: 五十嵐博 武蔵国分寺公園クリニック

監修: 名郷直樹 武蔵国分寺公園クリニック

著者校正済:2022/01/19
現在監修レビュー中
患者向け説明資料

概要・推奨   

ポイント:
  1. 国内においてサプリメントは「いわゆる健康食品」として広く流通している。
  1. サプリメントの効果については検証されてきてはいるものの、処方薬として使用する一部の薬剤を除き、あまり期待するほどの効果が得られていない。
  1. 副作用が懸念されるものもあり、健康被害の報告も散見される。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
五十嵐博 : 原稿料(エイチ・ツー・オー綜合研究所)[2022年]
監修:名郷直樹 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 高用量(75mg/日以上)の亜鉛の投与がかぜの症状短縮に有効と報告されており、「患者が希望すれば短期間のサプリメントとしての摂取は行ってよい」としていたが、かぜ症状が長い傾向にあるとのRCTが報告され、結果が一貫していないため、「患者の強い希望がある場合を除き、亜鉛の摂取は推奨しない」とした。
  1. サプリメントとしてのカルシウム(単剤、またはビタミンDと併用)の骨折予防効果は明確でなく、推奨されないが、乳製品によるカルシウム、蛋白補充が施設入所高齢者の骨折予防に有効とのRCTが報告され、「乳製品によるカルシウム、蛋白補充は、施設入所高齢者における骨折予防として検討してもよい」とした。

まとめ

まとめ  
  1. サプリメントとは、不足する栄養素などを補う目的で利用される栄養補助食品・健康食品のことである。
  1. 健康食品には法律上の定義はなく、広く健康の保持増進に資する食品として販売・利用されるもの全般を指す。そのうち、国が定めた安全性や有効性に関する基準などを満たした「保健機能食品制度」がある。
  1. 健康増進法に基づく保健機能食品には、有効性と安全性が審査された、個別許可制の「特定保健用食品」(1,225品目、平成28年2月2日現在)、特定の成分(ミネラル5種類、ビタミン12種類)含有を表示できる栄養機能食品、平成27年4月から導入された届出制の機能性表示食品がある。
  1. 保健機能食品以外は「いわゆる健康食品」として一般食品と同じように扱われ、原則として、効能効果を表記することは医薬品医療機器法違反となる。
  1. 健康食品の市場規模は約1兆5,000億円(2015年度推定値)、特定保健用食品は6,100億円(2014年度推定値)と増加傾向にある。市場にはサプリメントも広く流通するが、健康被害の報告も散見される。
  1. 高齢者では処方薬とサプリメントの併用は高頻度(50~70%)でみられるとの報告があり、注意が必要である。
  1. 現状でサプリメントとして積極的にすすめられるミネラルは、鉄欠乏のある閉経前成人女性の原因不明の倦怠感に対する鉄であるが、保険診療でも対応可能である。
  1. 鉄欠乏のある閉経前成人女性の倦怠感:フェロミア錠50mg1錠1日1回

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

Sumanth Kumbargere Nagraj, Shetty Naresh, Kandula Srinivas, P Renjith George, Ashish Shrestha, David Levenson, Debra M Ferraiolo
Interventions for the management of taste disturbances.
Cochrane Database Syst Rev. 2014 Nov 26;(11):CD010470. doi: 10.1002/14651858.CD010470.pub2. Epub 2014 Nov 26.
Abstract/Text BACKGROUND: The sense of taste is very much essential to the overall health of the individual. It is a necessary component to enjoying one's food, which in turn provides nutrition to an individual. Any disturbance in taste perception can hamper the quality of life in such patients by influencing their appetite, body weight and psychological well-being. Taste disorders have been treated using different modalities of treatment and there is no consensus for the best intervention. Hence this Cochrane systematic review was undertaken.
OBJECTIVES: To assess the effects of interventions for the management of patients with taste disturbances.
SEARCH METHODS: We searched the Cochrane Oral Health Group Trials Register (to 5 March 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2014), MEDLINE via OVID (1948 to 5 March 2014), EMBASE via OVID (1980 to 5 March 2014), CINAHL via EBSCO (1980 to 5 March 2014) and AMED via OVID (1985 to 5 March 2014). We also searched the relevant clinical trial registries and conference proceedings from the International Association of Dental Research/American Association of Dental Research (to 5 March 2014), Association for Research in Otolaryngology (to 5 March 2014), the US National Institutes of Health Trials Register (to 5 March 2014), metaRegister of Controlled Trials (mRCT) (to 5 March 2014), World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) (to 5 March 2014) and International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Clinical Trials Portal (to 5 March 2014).
SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing any pharmacological agent with a control intervention or any non-pharmacological agent with a control intervention. We also included cross-over trials in the review.
DATA COLLECTION AND ANALYSIS: Two authors independently, and in duplicate, assessed the quality of trials and extracted data. Wherever possible, we contacted study authors for additional information. We collected adverse events information from the trials.
MAIN RESULTS: We included nine trials (seven parallel and two cross-over RCTs) with 566 participants. We assessed three trials (33.3%) as having a low risk of bias, four trials (44.5%) at high risk of bias and two trials (22.2%) as having an unclear risk of bias. We only included studies on taste disorders in this review that were either idiopathic, or resulting from zinc deficiency or chronic renal failure.Of these, eight trials with 529 people compared zinc supplements to placebo for patients with taste disorders. The participants in two trials were children and adolescents with respective mean ages of 10 and 11.2 years and the other six trials had adult participants. Out of these eight, two trials assessed the patient reported outcome for improvement in taste acuity using zinc supplements (RR 1.45, 95% CI 1.0 to 2.1; very low quality evidence). We included three trials in the meta-analysis for overall taste improvement (effect size 0.44, 95% CI 0.23 to 0.65; moderate quality evidence). Two other trials described the results as taste acuity improvement and we conducted subgroup analyses due to clinical heterogeneity. One trial described the results as taste recognition improvement for each taste sensation and we analysed this separately. We also analysed one cross-over trial separately using the first half of the results. None of the zinc trials tested taste discrimination. Only one trial tested taste discrimination using acupuncture (effect size 2.80, 95% CI -1.18 to 6.78; low quality evidence).Out of the eight trials using zinc supplementation, four reported adverse events like eczema, nausea, abdominal pain, diarrhoea, constipation, decrease in blood iron, increase in blood alkaline phosphatase, and minor increase in blood triglycerides. No adverse events were reported in the acupuncture trial.None of the included trials could be included in the meta-analysis for health-related quality of life in taste disorder patients.
AUTHORS' CONCLUSIONS: We found very low quality evidence that was insufficient to conclude on the role of zinc supplements to improve taste perception by patients, however we found moderate quality evidence that zinc supplements improve overall taste improvement in patients with zinc deficiency/idiopathic taste disorders. We also found low quality evidence that zinc supplements improve taste acuity in zinc deficient/idiopathic taste disorders and very low quality evidence for taste recognition improvement in children with taste disorders secondary to chronic renal failure. We did not find any evidence to conclude the role of zinc supplements for improving taste discrimination, or any evidence addressing health-related quality of life due to taste disorders.We found low quality evidence that is not sufficient to conclude on the role of acupuncture for improving taste discrimination in cases of idiopathic dysgeusia (distortion of taste) and hypogeusia (reduced ability to taste). We were unable to draw any conclusions regarding the superiority of zinc supplements or acupuncture as none of the trials compared these interventions.

PMID 25425011
Meenu Singh, Rashmi R Das
Zinc for the common cold.
Cochrane Database Syst Rev. 2013 Jun 18;(6):CD001364. doi: 10.1002/14651858.CD001364.pub4. Epub 2013 Jun 18.
Abstract/Text BACKGROUND: The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted in high-income countries since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results.
OBJECTIVES: To assess whether zinc (irrespective of the zinc salt or formulation used) is efficacious in reducing the incidence, severity and duration of common cold symptoms. In addition, we aimed to identify potential sources of heterogeneity in results obtained and to assess their clinical significance.
SEARCH METHODS: In this updated review, we searched CENTRAL (2012, Issue 12), MEDLINE (1966 to January week 2, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013), Web of Science (1985 to January 2013), LILACS (1982 to January 2013), WHO ICTRP and clinicaltrials.gov.
SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality.
MAIN RESULTS: Five trials were identified in the updated searches in January 2013 and two of them did not meet our inclusion criteria. We included 16 therapeutic trials (1387 participants) and two preventive trials (394 participants). Intake of zinc was associated with a significant reduction in the duration (days) (mean difference (MD) -1.03, 95% confidence interval (CI) -1.72 to -0.34) (P = 0.003) (I(2) statistic = 89%) but not the severity of common cold symptoms (MD -1.06, 95% CI -2.36 to 0.23) (P = 0.11) (I(2) statistic = 84%). The proportion of participants who were symptomatic after seven days of treatment was significantly smaller (odds ratio (OR) 0.45, 95% CI 0.20 to 1.00) (P = 0.05) than those in the control, (I(2 )statistic = 75%). The incidence rate ratio (IRR) of developing a cold (IRR 0.64, 95% CI 0.47 to 0.88) (P = 0.006) (I(2) statistic = 88%), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.58, 95% CI 1.19 to 2.09) (P = 0.002), bad taste (OR 2.31, 95% CI 1.71 to 3.11) (P < 0.00001) and nausea (OR 2.15, 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. The very high heterogeneity means that the averaged estimates must be viewed with caution.
AUTHORS' CONCLUSIONS: Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people but some caution is needed due to the heterogeneity of the data. As the zinc lozenges formulation has been widely studied and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. When using zinc lozenges (not as syrup or tablets) the likely benefit has to be balanced against side effects, notably a bad taste and nausea.

PMID 23775705
Michelle Science, Jennie Johnstone, Daniel E Roth, Gordon Guyatt, Mark Loeb
Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials.
CMAJ. 2012 Jul 10;184(10):E551-61. doi: 10.1503/cmaj.111990. Epub 2012 May 7.
Abstract/Text BACKGROUND: Results of randomized controlled trials evaluating zinc for the treatment of the common cold are conflicting. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of zinc for such use.
METHODS: We searched electronic databases and other sources for studies published through to Sept. 30, 2011. We included all randomized controlled trials comparing orally administered zinc with placebo or no treatment. Assessment for study inclusion, data extraction and risk-of-bias analyses were performed in duplicate. We conducted meta-analyses using a random-effects model.
RESULTS: We included 17 trials involving a total of 2121 participants. Compared with patients given placebo, those receiving zinc had a shorter duration of cold symptoms (mean difference -1.65 days, 95% confidence interval [CI] -2.50 to -0.81); however, heterogeneity was high (I(2) = 95%). Zinc shortened the duration of cold symptoms in adults (mean difference -2.63, 95% CI -3.69 to -1.58), but no significant effect was seen among children (mean difference -0.26, 95% CI -0.78 to 0.25). Heterogeneity remained high in all subgroup analyses, including by age, dose of ionized zinc and zinc formulation. The occurrence of any adverse event (risk ratio [RR] 1.24, 95% CI 1.05 to 1.46), bad taste (RR 1.65, 95% CI 1.27 to 2.16) and nausea (RR 1.64, 95% CI 1.19 to 2.27) were more common in the zinc group than in the placebo group.
INTERPRETATION: The results of our meta-analysis showed that oral zinc formulations may shorten the duration of symptoms of the common cold. However, large high-quality trials are needed before definitive recommendations for clinical practice can be made. Adverse effects were common and should be the point of future study, because a good safety and tolerance profile is essential when treating this generally mild illness.

PMID 22566526
Harri Hemilä, Elizabeth Chalker
The effectiveness of high dose zinc acetate lozenges on various common cold symptoms: a meta-analysis.
BMC Fam Pract. 2015 Feb 25;16:24. doi: 10.1186/s12875-015-0237-6. Epub 2015 Feb 25.
Abstract/Text BACKGROUND: A previous meta-analysis found that high dose zinc acetate lozenges reduced the duration of common colds by 42%, whereas low zinc doses had no effect. Lozenges are dissolved in the pharyngeal region, thus there might be some difference in the effect of zinc lozenges on the duration of respiratory symptoms in the pharyngeal region compared with the nasal region. The objective of this study was to determine whether zinc acetate lozenges have different effects on the duration of common cold symptoms originating from different anatomical regions.
METHODS: We analyzed three randomized trials on zinc acetate lozenges for the common cold administering zinc in doses of 80-92 mg/day. All three trials reported the effect of zinc on seven respiratory symptoms, and three systemic symptoms. We pooled the effects of zinc lozenges for each symptom and calculated point estimates and 95% confidence intervals (95% CI).
RESULTS: Zinc acetate lozenges shortened the duration of nasal discharge by 34% (95% CI: 17% to 51%), nasal congestion by 37% (15% to 58%), sneezing by 22% (-1% to 45%), scratchy throat by 33% (8% to 59%), sore throat by 18% (-10% to 46%), hoarseness by 43% (3% to 83%), and cough by 46% (28% to 64%). Zinc lozenges shortened the duration of muscle ache by 54% (18% to 89%), but there was no difference in the duration of headache and fever.
CONCLUSIONS: The effect of zinc acetate lozenges on cold symptoms may be associated with the local availability of zinc from the lozenges, with the levels being highest in the pharyngeal region. However our findings indicate that the effects of zinc ions are not limited to the pharyngeal region. There is no indication that the effect of zinc lozenges on nasal symptoms is less than the effect on the symptoms of the pharyngeal region, which is more exposed to released zinc ions. Given that the adverse effects of zinc in the three trials were minor, zinc acetate lozenges releasing zinc ions at doses of about 80 mg/day may be a useful treatment for the common cold, started within 24 hours, for a time period of less than two weeks.

PMID 25888289
Harri Hemilä
Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage.
JRSM Open. 2017 May;8(5):2054270417694291. doi: 10.1177/2054270417694291. Epub 2017 May 2.
Abstract/Text OBJECTIVE: To compare the efficacy of zinc acetate lozenges with zinc gluconate lozenges in common cold treatment and to examine the dose-dependency of the effect.
DESIGN: Meta-analysis.
SETTING: Placebo-controlled zinc lozenge trials, in which the zinc dose was > 75 mg/day. The pooled effect of zinc lozenges on common cold duration was calculated by using inverse-variance random-effects method.
PARTICIPANTS: Seven randomised trials with 575 participants with naturally acquired common colds.
MAIN OUTCOME MEASURE: Duration of the common cold.
RESULTS: The mean common cold duration was 33% (95% CI 21% to 45%) shorter for the zinc groups of the seven included trials. Three trials that used lozenges composed of zinc acetate found that colds were shortened by 40% and four trials that used zinc gluconate by 28%. The difference between the two salts was not significant: 12 percentage points (95% CI: -12 to + 36). Five trials used zinc doses of 80-92 mg/day, common cold duration was reduced by 33%, and two trials used zinc doses of 192-207 mg/day and found an effect of 35%. The difference between the high-dose and low-dose zinc trials was not significant: 2 percentage points (95% CI: -29 to + 32).
CONCLUSIONS: Properly composed zinc gluconate lozenges may be as effective as zinc acetate lozenges. There is no evidence that zinc doses over 100 mg/day might lead to greater efficacy in the treatment of the common cold. Common cold patients may be encouraged to try zinc lozenges for treating their colds. The optimal lozenge composition and dosage scheme need to be investigated further.

PMID 28515951
Harri Hemilä, Jari Haukka, Marianne Alho, Jussi Vahtera, Mika Kivimäki
Zinc acetate lozenges for the treatment of the common cold: a randomised controlled trial.
BMJ Open. 2020 Jan 23;10(1):e031662. doi: 10.1136/bmjopen-2019-031662. Epub 2020 Jan 23.
Abstract/Text OBJECTIVE: To examine a commercially available zinc acetate lozenge for treating the common cold.
DESIGN: Randomised, double-blinded, placebo-controlled trial.
SETTING: Working population in Finland.
PARTICIPANTS: We included men and women aged ≥18 years who usually had ≥1 cold per winter. Exclusions were pregnancy, lactation, chronic runny nose or chronic cough.
INTERVENTION: We randomised 253 participants to receive a package of lozenges to be taken if they caught the common cold. Of the 253 participants, 88 contracted the common cold and 87 were included in our primary analysis. Zinc acetate lozenges contained 13 mg elemental zinc and placebo lozenges contained sucrose octa-acetate to camouflage the taste of zinc. Instruction to use was six times per day for the maximum of 5 days.
PRIMARY OUTCOME: Rate of recovery from the common cold analysed by Cox regression.
RESULTS: There was no difference in the recovery rate between zinc and placebo participants during the 10-day follow-up (rate ratio for zinc vs placebo=0.68, 95% CI 0.42 to 1.08; p=0.10). The recovery rate for the two groups was similar during the 5-day intervention, but for 2 days after the end of zinc/placebo use, the zinc participants recovered significantly slower compared with the placebo participants (p=0.003). In the zinc group, 37% did not report adverse effects, the corresponding proportion being 69% in the placebo group.
CONCLUSIONS: A commercially available zinc acetate lozenge was not effective in treating the common cold when instructed to be used for 5 days after the first symptoms. Taste has been a common problem in previous zinc lozenge trials, but a third of zinc participants did not complain of any adverse effects. More research is needed to evaluate the characteristics of zinc lozenges that may be clinically efficacious before zinc lozenges can be widely promoted for common cold treatment.
TRIAL REGISTRATION NUMBER: NCT03309995.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 31980506
Emanuele Cereda, Catherine Klersy, Marcella Serioli, Aldo Crespi, Federico D'Andrea, OligoElement Sore Trial Study Group
A nutritional formula enriched with arginine, zinc, and antioxidants for the healing of pressure ulcers: a randomized trial.
Ann Intern Med. 2015 Feb 3;162(3):167-74. doi: 10.7326/M14-0696.
Abstract/Text BACKGROUND: Trials on specific nutritional supplements for the treatment of pressure ulcers (PUs) have been small, inconsistent in their formulations, or unsuccessful in controlling for total supplement calorie or protein content.
OBJECTIVE: To evaluate whether supplementation with arginine, zinc, and antioxidants within a high-calorie, high-protein formula improves PU healing.
DESIGN: Multicenter, randomized, controlled, blinded trial. (ClinicalTrials.gov: NCT01107197).
SETTING: Long-term care and home care services.
PATIENTS: 200 adult malnourished patients with stage II, III, and IV PUs.
INTERVENTIONS: An energy-dense, protein-rich oral formula enriched with arginine, zinc, and antioxidants (400 mL/d) or an equal volume of an isocaloric, isonitrogenous formula for 8 weeks.
MEASUREMENTS: The primary end point was the percentage of change in PU area at 8 weeks. Secondary end points included complete healing, reduction in the PU area of 40% or greater, incidence of wound infections, the total number of dressings at 8 weeks, and the percentage of change in area at 4 weeks.
RESULTS: Supplementation with the enriched formula (n = 101) resulted in a greater reduction in PU area (mean reduction, 60.9% [95% CI, 54.3% to 67.5%]) than with the control formula (n = 99) (45.2% [CI, 38.4% to 52.0%]) (adjusted mean difference, 18.7% [CI, 5.7% to 31.8%]; P = 0.017). A more frequent reduction in area of 40% or greater at 8 weeks was also seen (odds ratio, 1.98 [CI, 1.12 to 3.48]; P = 0.018). No difference was found in terms of the other secondary end points.
LIMITATION: Participation was restricted to patients who were malnourished, were able to drink oral supplements, and were living in long-term care institutions or receiving home care services.
CONCLUSION: Among malnourished patients with PU, 8 weeks of supplementation with an oral nutritional formula enriched with arginine, zinc, and antioxidants improved PU healing.
PRIMARY FUNDING SOURCE: Azienda Ospedaliera Universitaria Maggiore della Carità.

PMID 25643304
Jia-Guo Zhao, Xian-Tie Zeng, Jia Wang, Lin Liu
Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.
JAMA. 2017 Dec 26;318(24):2466-2482. doi: 10.1001/jama.2017.19344.
Abstract/Text Importance: The increased social and economic burdens for osteoporosis-related fractures worldwide make the prevention of such injuries a major public health goal. Previous studies have reached mixed conclusions regarding the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fracture incidence in older adults.
Objective: To investigate whether calcium, vitamin D, or combined calcium and vitamin D supplements are associated with a lower fracture incidence in community-dwelling older adults.
Data Sources: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to December 24, 2016, using the keywords calcium, vitamin D, and fracture to identify systematic reviews or meta-analyses. The primary randomized clinical trials included in systematic reviews or meta-analyses were identified, and an additional search for recently published randomized trials was performed from July 16, 2012, to July 16, 2017.
Study Selection: Randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling adults older than 50 years.
Data Extraction and Synthesis: Two independent reviewers performed the data extraction and assessed study quality. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% CIs using random-effects models.
Main Outcomes and Measures: Hip fracture was defined as the primary outcome. Secondary outcomes were nonvertebral fracture, vertebral fracture, and total fracture.
Results: A total of 33 randomized trials involving 51 145 participants fulfilled the inclusion criteria. There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, -0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, -0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration.
Conclusions and Relevance: In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people.

PMID 29279934
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.

PMID 20671013
Vicky Tai, William Leung, Andrew Grey, Ian R Reid, Mark J Bolland
Calcium intake and bone mineral density: systematic review and meta-analysis.
BMJ. 2015 Sep 29;351:h4183. Epub 2015 Sep 29.
Abstract/Text OBJECTIVE: To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements.
DESIGN: Random effects meta-analysis of randomised controlled trials.
DATA SOURCES: Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome.
RESULTS: We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥ 1000 versus <1000 mg/day and ≤ 500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥ 800 mg/day.
CONCLUSIONS: Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture.

© Tai et al 2015.
PMID 26420598
Mark J Bolland, William Leung, Vicky Tai, Sonja Bastin, Greg D Gamble, Andrew Grey, Ian R Reid
Calcium intake and risk of fracture: systematic review.
BMJ. 2015 Sep 29;351:h4580. Epub 2015 Sep 29.
Abstract/Text OBJECTIVE: To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.
DESIGN: Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses.
DATA SOURCES: Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50.
RESULTS: There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58,573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48,967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56,648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51,775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44,505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.
CONCLUSIONS: Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.

© Bolland et al 2015.
PMID 26420387
Rebecca D Jackson, Andrea Z LaCroix, Margery Gass, Robert B Wallace, John Robbins, Cora E Lewis, Tamsen Bassford, Shirley A A Beresford, Henry R Black, Patricia Blanchette, Denise E Bonds, Robert L Brunner, Robert G Brzyski, Bette Caan, Jane A Cauley, Rowan T Chlebowski, Steven R Cummings, Iris Granek, Jennifer Hays, Gerardo Heiss, Susan L Hendrix, Barbara V Howard, Judith Hsia, F Allan Hubbell, Karen C Johnson, Howard Judd, Jane Morley Kotchen, Lewis H Kuller, Robert D Langer, Norman L Lasser, Marian C Limacher, Shari Ludlam, JoAnn E Manson, Karen L Margolis, Joan McGowan, Judith K Ockene, Mary Jo O'Sullivan, Lawrence Phillips, Ross L Prentice, Gloria E Sarto, Marcia L Stefanick, Linda Van Horn, Jean Wactawski-Wende, Evelyn Whitlock, Garnet L Anderson, Annlouise R Assaf, David Barad, Women's Health Initiative Investigators
Calcium plus vitamin D supplementation and the risk of fractures.
N Engl J Med. 2006 Feb 16;354(7):669-83. doi: 10.1056/NEJMoa055218.
Abstract/Text BACKGROUND: The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.
METHODS: We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.
RESULTS: Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.
CONCLUSIONS: Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).

Copyright 2006 Massachusetts Medical Society
PMID 16481635
S Iuliano, S Poon, J Robbins, M Bui, X Wang, L De Groot, M Van Loan, A Ghasem Zadeh, T Nguyen, E Seeman
Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial.
BMJ. 2021 Oct 20;375:n2364. doi: 10.1136/bmj.n2364. Epub 2021 Oct 20.
Abstract/Text OBJECTIVE: To assess the antifracture efficacy and safety of a nutritional intervention in institutionalised older adults replete in vitamin D but with mean intakes of 600 mg/day calcium and <1 g/kg body weight protein/day.
DESIGN: Two year cluster randomised controlled trial.
SETTING: 60 accredited residential aged care facilities in Australia housing predominantly ambulant residents.
PARTICIPANTS: 7195 permanent residents (4920 (68%) female; mean age 86.0 (SD 8.2) years).
INTERVENTION: Facilities were stratified by location and organisation, with 30 facilities randomised to provide residents with additional milk, yoghurt, and cheese that contained 562 (166) mg/day calcium and 12 (6) g/day protein achieving a total intake of 1142 (353) mg calcium/day and 69 (15) g/day protein (1.1 g/kg body weight). The 30 control facilities maintained their usual menus, with residents consuming 700 (247) mg/day calcium and 58 (14) g/day protein (0.9 g/kg body weight).
MAIN OUTCOME MEASURES: Group differences in incidence of fractures, falls, and all cause mortality.
RESULTS: Data from 27 intervention facilities and 29 control facilities were analysed. A total of 324 fractures (135 hip fractures), 4302 falls, and 1974 deaths were observed. The intervention was associated with risk reductions of 33% for all fractures (121 v 203; hazard ratio 0.67, 95% confidence interval 0.48 to 0.93; P=0.02), 46% for hip fractures (42 v 93; 0.54, 0.35 to 0.83; P=0.005), and 11% for falls (1879 v 2423; 0.89, 0.78 to 0.98; P=0.04). The risk reduction for hip fractures and falls achieved significance at five months (P=0.02) and three months (P=0.004), respectively. Mortality was unchanged (900 v 1074; hazard ratio 1.01, 0.43 to 3.08).
CONCLUSIONS: Improving calcium and protein intakes by using dairy foods is a readily accessible intervention that reduces the risk of falls and fractures commonly occurring in aged care residents.
TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000228785.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 34670754
G C Curhan, W C Willett, F E Speizer, D Spiegelman, M J Stampfer
Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women.
Ann Intern Med. 1997 Apr 1;126(7):497-504.
Abstract/Text BACKGROUND: Calcium intake is believed to play an important role in the formation of kidney stones, but data on the risk factors for stone formation in women are limited.
OBJECTIVE: To examine the association between intake of dietary and supplemental calcium and the risk for kidney stones in women.
DESIGN: Prospective cohort study with 12-year follow-up.
SETTING: Several U.S. states.
PARTICIPANTS: 91,731 women participating in the Nurses' Health Study I who were 34 to 59 years of age in 1980 and had no history of kidney stones.
MEASUREMENTS: Self-administered food-frequency questionnaires were used to assess diet in 1980, 1984, 1986, and 1990. The main outcome measure was incident symptomatic kidney stones.
RESULTS: During 903,849 person-years of follow-up, 864 cases of kidney stones were documented. After adjustment for potential risk factors, intake of dietary calcium was inversely associated with risk for kidney stones and intake of supplemental calcium was positively associated with risk. The relative risk for stone formation in women in the highest quintile of dietary calcium intake compared with women in the lowest quintile was 0.65 (95% CI, 0.50 to 0.83). The relative risk in women who took supplemental calcium compared with women who did not was 1.20 (CI, 1.02 to 1.41). In 67% of women who took supplemental calcium, the calcium either was not consumed with a meal or was consumed with meals whose oxalate content was probably low. Other dietary factors showed the following relative risks among women in the highest quintile of intake compared with those in the lowest quintile: sucrose, 1.52 (CI, 1.18 to 1.96); sodium, 1.30 (CI, 1.05 to 1.62); fluid, 0.61 (CI, 0.48 to 0.78); and potassium, 0.65 (CI, 0.51 to 0.84).
CONCLUSIONS: High intake of dietary calcium appears to decrease risk for symptomatic kidney stones, whereas intake of supplemental calcium may increase risk. Because dietary calcium reduces the absorption of oxalate, the apparently different effects caused by the type of calcium may be associated with the timing of calcium ingestion relative to the amount of oxalate consumed. However, other factors present in dairy products (the major source of dietary calcium) could be responsible for the decreased risk seen with dietary calcium.

PMID 9092314
Leila C Kahwati, Rachel Palmieri Weber, Huiling Pan, Margaret Gourlay, Erin LeBlanc, Manny Coker-Schwimmer, Meera Viswanathan
Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.
JAMA. 2018 Apr 17;319(15):1600-1612. doi: 10.1001/jama.2017.21640.
Abstract/Text Importance: Osteoporotic fractures result in significant morbidity and mortality.
Objective: To update the evidence for benefits and harms of vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults to inform the US Preventive Services Task Force.
Data Sources: PubMed, EMBASE, Cochrane Library, and trial registries through March 21, 2017; references; and experts. Surveillance continued through February 28, 2018.
Study Selection: English-language randomized clinical trials (RCTs) or observational studies of supplementation with vitamin D, calcium, or both among adult populations; studies of populations that were institutionalized or had known vitamin D deficiency, osteoporosis, or prior fracture were excluded.
Data Extraction and Synthesis: Dual, independent review of titles/abstracts and full-text articles and study quality rating using predefined criteria. Random-effects meta-analysis used when at least 3 similar studies were available.
Main Outcomes and Measures: Incident fracture, mortality, kidney stones, cardiovascular events, and cancer.
Results: Eleven RCTs (N = 51 419) in adults 50 years and older conducted over 2 to 7 years were included. Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2686]; absolute risk difference [ARD], -2.26% [95% CI, -4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5496]; pooled ARD, -0.01% [95% CI, -0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36 282]; ARD, -0.35% [95% CI, -1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36 727]; ARD from the larger trial, -0.14% [95% CI, -0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from -1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39 213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1259]; pooled ARD, 0.00% [95% CI, -0.87% to 0.87%]). Supplementation with vitamin D and calcium was not associated with an increase in cancer incidence (3 RCTs [n = 39 213]; pooled ARD, -1.48% [95% CI, -3.32% to 0.35%]).
Conclusions and Relevance: Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones.

PMID 29677308
Judith Hsia, Gerardo Heiss, Hong Ren, Matthew Allison, Nancy C Dolan, Philip Greenland, Susan R Heckbert, Karen C Johnson, JoAnn E Manson, Stephen Sidney, Maurizio Trevisan, Women's Health Initiative Investigators
Calcium/vitamin D supplementation and cardiovascular events.
Circulation. 2007 Feb 20;115(7):846-54. doi: 10.1161/CIRCULATIONAHA.106.673491.
Abstract/Text BACKGROUND: Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women's Health Initiative randomized trial of calcium plus vitamin D supplementation.
METHODS AND RESULTS: We randomized 36,282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D.
CONCLUSIONS: Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.

PMID 17309935
Mark J Bolland, Andrew Grey, Alison Avenell, Greg D Gamble, Ian R Reid
Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.
BMJ. 2011 Apr 19;342:d2040. Epub 2011 Apr 19.
Abstract/Text OBJECTIVES: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.
DESIGN: Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.
RESULTS: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009).
CONCLUSIONS: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

PMID 21505219
Mei Chung, Alice M Tang, Zhuxuan Fu, Ding Ding Wang, Sydne Jennifer Newberry
Calcium Intake and Cardiovascular Disease Risk: An Updated Systematic Review and Meta-analysis.
Ann Intern Med. 2016 Dec 20;165(12):856-866. doi: 10.7326/M16-1165. Epub 2016 Oct 25.
Abstract/Text Background: Conflicting evidence exists regarding potential cardiovascular risks associated with high levels of calcium intake.
Purpose: To update and reanalyze 2 systematic reviews to examine the effects of calcium intake on cardiovascular disease (CVD) among generally healthy adults.
Data Sources: MEDLINE; Cochrane Central Register of Controlled Trials; Scopus, including EMBASE; and previous evidence reports from English-language publications from 1966 to July 2016.
Study Selection: Randomized trials and prospective cohort and nested case-control studies with data on dietary or supplemental intake of calcium, with or without vitamin D, and cardiovascular outcomes.
Data Extraction: Study characteristics and results extracted by 1 reviewer were confirmed by a second reviewer. Two raters independently assessed risk of bias.
Data Synthesis: Overall risk of bias was low for the 4 randomized trials (in 10 publications) and moderate for the 27 observational studies included. The trials did not find statistically significant differences in risk for CVD events or mortality between groups receiving supplements of calcium or calcium plus vitamin D and those receiving placebo. Cohort studies showed no consistent dose-response relationships between total, dietary, or supplemental calcium intake levels and cardiovascular mortality and highly inconsistent dose-response relationships between calcium intake and risks for total stroke or stroke mortality.
Limitations: CVD disease outcomes were secondary end points in all trials. Dose-response metaregression analysis of cohort studies was limited by potential confounding, ecological bias, and imprecise measures of calcium exposures. Data were scarce regarding very high calcium intake-that is, beyond recommended tolerable upper intake levels.
Conclusion: Calcium intake within tolerable upper intake levels (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults.
Primary Funding Source: National Osteoporosis Foundation.

PMID 27776363
L C Clark, G F Combs, B W Turnbull, E H Slate, D K Chalker, J Chow, L S Davis, R A Glover, G F Graham, E G Gross, A Krongrad, J L Lesher, H K Park, B B Sanders, C L Smith, J R Taylor
Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.
JAMA. 1996 Dec 25;276(24):1957-63.
Abstract/Text OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer.
DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial.
SETTING: Seven dermatology clinics in the eastern United States.
PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years.
INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo.
MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers.
RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred.
CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

PMID 8971064
Scott M Lippman, Eric A Klein, Phyllis J Goodman, M Scott Lucia, Ian M Thompson, Leslie G Ford, Howard L Parnes, Lori M Minasian, J Michael Gaziano, Jo Ann Hartline, J Kellogg Parsons, James D Bearden, E David Crawford, Gary E Goodman, Jaime Claudio, Eric Winquist, Elise D Cook, Daniel D Karp, Philip Walther, Michael M Lieber, Alan R Kristal, Amy K Darke, Kathryn B Arnold, Patricia A Ganz, Regina M Santella, Demetrius Albanes, Philip R Taylor, Jeffrey L Probstfield, T J Jagpal, John J Crowley, Frank L Meyskens, Laurence H Baker, Charles A Coltman
Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
JAMA. 2009 Jan 7;301(1):39-51. doi: 10.1001/jama.2008.864. Epub 2008 Dec 9.
Abstract/Text CONTEXT: Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.
OBJECTIVE: To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.
INTERVENTIONS: Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.
MAIN OUTCOME MEASURES: Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.
RESULTS: As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.
CONCLUSION: Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.
TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00006392.

PMID 19066370
Marco Vinceti, Tommaso Filippini, Cinzia Del Giovane, Gabriele Dennert, Marcel Zwahlen, Maree Brinkman, Maurice Pa Zeegers, Markus Horneber, Roberto D'Amico, Catherine M Crespi
Selenium for preventing cancer.
Cochrane Database Syst Rev. 2018 Jan 29;1:CD005195. doi: 10.1002/14651858.CD005195.pub4. Epub 2018 Jan 29.
Abstract/Text BACKGROUND: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer.
OBJECTIVES: To gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans.
SEARCH METHODS: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants.
DATA COLLECTION AND ANALYSIS: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach.
MAIN RESULTS: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation.
AUTHORS' CONCLUSIONS: Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.

PMID 29376219
Karen Rees, Louise Hartley, Camilla Day, Nadine Flowers, Aileen Clarke, Saverio Stranges
Selenium supplementation for the primary prevention of cardiovascular disease.
Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009671. doi: 10.1002/14651858.CD009671.pub2. Epub 2013 Jan 31.
Abstract/Text BACKGROUND: Selenium is a key component of a number of selenoproteins which protect against oxidative stress and have the potential to prevent chronic diseases including cardiovascular disease (CVD). However, observational studies have shown inconsistent associations between selenium intake and CVD risk; in addition, there is concern around a possible increased risk of type 2 diabetes with high selenium exposure.
OBJECTIVES: To determine the effectiveness of selenium only supplementation for the primary prevention of CVD and examine the potential adverse effect of type 2 diabetes.
SEARCH METHODS: The following electronic databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 of 12, October 2012) on The Cochrane Library; MEDLINE (Ovid) (1946 to week 2 October 2012); EMBASE Classic + EMBASE (Ovid) (1947 to 2012 Week 42); CINAHL (EBSCO) (to 24 October 2012); ISI Web of Science (1970 to 24 October 2012); PsycINFO (Ovid) (1806 to week 3 October 2012); Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database and Health Economics Evaluations Database (Issue 4 of 4, October 2012) on The Cochrane Library. Trial registers and reference lists of reviews and articles were searched and experts in the field were approached. No language restrictions were applied.
SELECTION CRITERIA: Randomised controlled trials on the effects of selenium only supplementation on major CVD end-points, mortality, changes in CVD risk factors, and type 2 diabetes were included both in adults of all ages from the general population and in those at high risk of CVD. Trials were only considered where the comparison group was placebo or no intervention. Only studies with at least three months follow-up were included in the meta-analyses, shorter term studies were dealt with descriptively.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information.
MAIN RESULTS: Twelve trials (seven with duration of at least three months) met the inclusion criteria, with 19,715 participants randomised. The two largest trials that were conducted in the USA (SELECT and NPC) reported clinical events. There were no statistically significant effects of selenium supplementation on all cause mortality (RR 0.97, 95% CI 0.88 to 1.08), CVD mortality (RR 0.97, 95% CI 0.79 to 1.2), non-fatal CVD events (RR 0.96, 95% CI 0.89 to 1.04) or all CVD events (fatal and non-fatal) (RR 1.03, 95% CI 0.95 to 1.11). There was a small increased risk of type 2 diabetes with selenium supplementation but this did not reach statistical significance (RR 1.06, 95% CI 0.97 to 1.15). Other adverse effects that increased with selenium supplementation, as reported in the SELECT trial, included alopecia (RR 1.28, 95% CI 1.01 to 1.62) and dermatitis grade 1 to 2 (RR 1.17, 95% CI 1.0 to 1.35). Selenium supplementation reduced total cholesterol but this did not reach statistical significance (WMD - 0.11 mmol/L, 95% CI - 0.3 to 0.07). Mean high density lipoprotein (HDL) levels were unchanged. There was a statistically significant reduction in non-HDL cholesterol (WMD - 0.2 mmol/L, 95% CI - 0.41 to 0.00) in one trial of varying selenium dosage. None of the longer term trials examined effects on blood pressure. Overall, the included studies were regarded as at low risk of bias.
AUTHORS' CONCLUSIONS: The limited trial evidence that is available to date does not support the use of selenium supplements in the primary prevention of CVD.

PMID 23440843
Saverio Stranges, James R Marshall, Raj Natarajan, Richard P Donahue, Maurizio Trevisan, Gerald F Combs, Francesco P Cappuccio, Antonio Ceriello, Mary E Reid
Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial.
Ann Intern Med. 2007 Aug 21;147(4):217-23. Epub 2007 Jul 9.
Abstract/Text BACKGROUND: Findings from animal models suggest that selenium supplementation improves glucose metabolism.
OBJECTIVE: To examine the effect of long-term selenium supplementation on the incidence of type 2 diabetes.
DESIGN: Secondary analysis of a randomized, double-blind, placebo-controlled trial.
SETTING: Areas of low selenium consumption of the eastern United States.
PATIENTS: 1202 persons seen in dermatology clinics who did not have type 2 diabetes at baseline.
INTERVENTION: Oral administration of selenium, 200 microg/d, or placebo.
MEASUREMENTS: Incidence of type 2 diabetes.
RESULTS: During an average follow-up of 7.7 years (SD, 2.7), type 2 diabetes developed in 58 selenium recipients and 39 placebo recipients (incidence, 12.6 cases per 1000 person-years vs. 8.4 cases per 1000 person-years, respectively; hazard ratio, 1.55 [95% CI, 1.03 to 2.33]). The lack of benefit of selenium supplementation on the incidence of type 2 diabetes persisted in analyses stratified by age, sex, body mass index, and smoking status. An exposure-response gradient was found across tertiles of baseline plasma selenium level, with a statistically significantly increased risk for type 2 diabetes in the highest tertile of baseline plasma selenium level (hazard ratio, 2.70 [CI, 1.30 to 5.61]).
LIMITATIONS: Diabetes was a secondary outcome in the parent trial. Diagnoses of diabetes were self-reported but were validated in most participants. The sample was mostly older and white.
CONCLUSIONS: Selenium supplementation does not seem to prevent type 2 diabetes, and it may increase risk for the disease. Click here for related information on selenium.

PMID 17620655
F Verdon, B Burnand, C-L Fallab Stubi, C Bonard, M Graff, A Michaud, T Bischoff, M de Vevey, J-P Studer, L Herzig, C Chapuis, J Tissot, A Pécoud, B Favrat
Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial.
BMJ. 2003 May 24;326(7399):1124. doi: 10.1136/bmj.326.7399.1124.
Abstract/Text OBJECTIVE: To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue.
DESIGN: Double blind randomised placebo controlled trial.
SETTING: Academic primary care centre and eight general practices in western Switzerland.
PARTICIPANTS: 144 women aged 18 to 55, assigned to either oral ferrous sulphate (80 mg/day of elemental iron daily; n=75) or placebo (n=69) for four weeks.
MAIN OUTCOME MEASURES: Level of fatigue, measured by a 10 point visual analogue scale.
RESULTS: 136 (94%) women completed the study. Most had a low serum ferritin concentration; CONCLUSION: Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.

PMID 12763985
Paul Vaucher, Pierre-Louis Druais, Sophie Waldvogel, Bernard Favrat
Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.
CMAJ. 2012 Aug 7;184(11):1247-54. doi: 10.1503/cmaj.110950. Epub 2012 Jul 9.
Abstract/Text BACKGROUND: The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue.
METHODS: We performed a multicentre, parallel, randomized controlled, closed-label, observer-blinded trial. We recruited from the practices of 44 primary care physicians in France from March to July 2006. We randomly assigned 198 women aged 18-53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily; n=102) or placebo (n=96) for 12 weeks. The primary outcome was fatigue as measured on the Current and Past Psychological Scale. Biological markers were measured at 6 and 12 weeks.
RESULTS: The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference -18.9%, 95% CI -34.5 to -3.2; p=0.02), but there were no significant effects on quality of life (p=0.2), depression (p=0.97) or anxiety (p=0.5). Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL; p=0.002) and ferritin (11.4 μg/L; p<0.001) and decreased soluble transferrin receptor (-0.54 mg/L; p<0.001) at 12 weeks.
INTERPRETATION: Iron supplementation should be considered for women with unexplained fatigue who have ferritin levels below 50 μg/L. We suggest assessing the efficiency using blood markers after six weeks of treatment. Trial registration no. EudraCT 2006-000478-56.

PMID 22777991
Michael Sze Yuan Low, Joanna Speedy, Claire E Styles, Luz Maria De-Regil, Sant-Rayn Pasricha
Daily iron supplementation for improving anaemia, iron status and health in menstruating women.
Cochrane Database Syst Rev. 2016 Apr 18;4:CD009747. doi: 10.1002/14651858.CD009747.pub2. Epub 2016 Apr 18.
Abstract/Text BACKGROUND: Iron-deficiency anaemia is highly prevalent among non-pregnant women of reproductive age (menstruating women) worldwide, although the prevalence is highest in lower-income settings. Iron-deficiency anaemia has been associated with a range of adverse health outcomes, which restitution of iron stores using iron supplementation has been considered likely to resolve. Although there have been many trials reporting effects of iron in non-pregnant women, these trials have never been synthesised in a systematic review.
OBJECTIVES: To establish the evidence for effects of daily supplementation with iron on anaemia and iron status, as well as on physical, psychological and neurocognitive health, in menstruating women.
SEARCH METHODS: In November 2015 we searched CENTRAL, Ovid MEDLINE, EMBASE, and nine other databases, as well as four digital thesis repositories. In addition, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and reference lists of relevant reviews.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing daily oral iron supplementation with or without a cointervention (folic acid or vitamin C), for at least five days per week at any dose, to control or placebo using either individual- or cluster-randomisation. Inclusion criteria were menstruating women (or women aged 12 to 50 years) reporting on predefined primary (anaemia, haemoglobin concentration, iron deficiency, iron-deficiency anaemia, all-cause mortality, adverse effects, and cognitive function) or secondary (iron status measured by iron indices, physical exercise performance, psychological health, adherence, anthropometric measures, serum/plasma zinc levels, vitamin A status, and red cell folate) outcomes.
DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of Cochrane.
MAIN RESULTS: The search strategy identified 31,767 records; after screening, 90 full-text reports were assessed for eligibility. We included 67 trials (from 76 reports), recruiting 8506 women; the number of women included in analyses varied greatly between outcomes, with endpoint haemoglobin concentration being the outcome with the largest number of participants analysed (6861 women). Only 10 studies were considered at low overall risk of bias, with most studies presenting insufficient details about trial quality.Women receiving iron were significantly less likely to be anaemic at the end of intervention compared to women receiving control (risk ratio (RR) 0.39 (95% confidence interval (CI) 0.25 to 0.60, 10 studies, 3273 women, moderate quality evidence). Women receiving iron had a higher haemoglobin concentration at the end of intervention compared to women receiving control (mean difference (MD) 5.30, 95% CI 4.14 to 6.45, 51 studies, 6861 women, high quality evidence). Women receiving iron had a reduced risk of iron deficiency compared to women receiving control (RR 0.62, 95% CI 0.50 to 0.76, 7 studies, 1088 women, moderate quality evidence). Only one study (55 women) specifically reported iron-deficiency anaemia and no studies reported mortality. Seven trials recruiting 901 women reported on 'any side effect' and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence). Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence); eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82). Evidence that iron supplementation improves cognitive performance in women is uncertain, as studies could not be meta-analysed and individual studies reported conflicting results. Iron supplementation improved maximal and submaximal exercise performance, and appears to reduce symptomatic fatigue. Although adherence could not be formally meta-analysed due to differences in reporting, there was no evident difference in adherence between women randomised to iron and control.
AUTHORS' CONCLUSIONS: Daily iron supplementation effectively reduces the prevalence of anaemia and iron deficiency, raises haemoglobin and iron stores, improves exercise performance and reduces symptomatic fatigue. These benefits come at the expense of increased gastrointestinal symptomatic side effects.

PMID 27087396
Juan Pablo Peña-Rosas, Luz Maria De-Regil, Maria N Garcia-Casal, Therese Dowswell
Daily oral iron supplementation during pregnancy.
Cochrane Database Syst Rev. 2015 Jul 22;(7):CD004736. doi: 10.1002/14651858.CD004736.pub5. Epub 2015 Jul 22.
Abstract/Text BACKGROUND: Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women, and it is thought to improve other maternal and birth outcomes.
OBJECTIVES: To assess the effects of daily oral iron supplements for pregnant women, either alone or in conjunction with folic acid, or with other vitamins and minerals as a public health intervention in antenatal care.
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 January 2015). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) (26 February 2015) and contacted relevant organisations for the identification of ongoing and unpublished studies (26 February 2015) .
SELECTION CRITERIA: Randomised or quasi-randomised trials evaluating the effects of oral preventive supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy.
DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. We used the GRADE approach to assess the quality of the evidence for primary outcomes.We anticipated high heterogeneity among trials and we pooled trial results using a random-effects model and were cautious in our interpretation of the pooled results: the random-effects model gives the average treatment effect.
MAIN RESULTS: We included 61 trials. Forty-four trials, involving 43,274 women, contributed data and compared the effects of daily oral supplements containing iron versus no iron or placebo.Preventive iron supplementation reduced maternal anaemia at term by 70% (risk ratio (RR) 0.30; 95% confidence interval (CI) 0.19 to 0.46, 14 trials, 2199 women, low quality evidence), iron-deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69, six trials, 1088 women), and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women, low quality evidence). There were no clear differences between groups for severe anaemia in the second or third trimester, or maternal infection during pregnancy (RR 0.22; 95% CI 0.01 to 3.20, nine trials, 2125 women, very low quality evidence; and, RR 1.21; 95% CI 0.33 to 4.46; one trial, 727 women, low quality evidence, respectively), or maternal mortality (RR 0.33; 95% CI 0.01 to 8.19, two trials, 12,560 women, very low quality evidence), or reporting of side effects (RR 1.29; 95% CI 0.83 to 2.02, 11 trials, 2423 women, very low quality evidence). Women receiving iron were on average more likely to have higher haemoglobin (Hb) concentrations at term and in the postpartum period, but were at increased risk of Hb concentrations greater than 130 g/L during pregnancy, and at term.Compared with controls, women taking iron supplements less frequently had low birthweight newborns (8.4% versus 10.3%, average RR 0.84; 95% CI 0.69 to 1.03, 11 trials, 17,613 women, low quality evidence), and preterm babies (RR 0.93; 95% CI 0.84 to 1.03, 13 trials, 19,286 women, moderate quality evidence). They appeared to also deliver slightly heavier babies (mean difference (MD) 23.75; 95% CI -3.02 to 50.51, 15 trials, 18,590 women, moderate quality evidence). None of these results were statistically significant. There were no clear differences between groups for neonatal death (RR 0.91; 95% CI 0.71 to 1.18, four trials, 16,603 infants, low quality evidence), or congenital anomalies (RR 0.88, 95% CI 0.58 to 1.33, four trials, 14,636 infants, low quality evidence).Twenty-three studies were conducted in countries that in 2011 had some malaria risk in parts of the country. In some of these countries/territories, malaria is present only in certain areas or up to a particular altitude. Only two of these studies reported malaria outcomes. There is no evidence that iron supplementation increases placental malaria. For some outcomes heterogeneity was higher than 50%.
AUTHORS' CONCLUSIONS: Supplementation reduces the risk of maternal anaemia and iron deficiency in pregnancy but the positive effect on other maternal and infant outcomes is less clear. Implementation of iron supplementation recommendations may produce heterogeneous results depending on the populations' background risk for low birthweight and anaemia, as well as the level of adherence to the intervention.

PMID 26198451
Marian S McDonagh, Ian Blazina, Tracy Dana, Amy Cantor, Christina Bougatsos
Screening and routine supplementation for iron deficiency anemia: a systematic review.
Pediatrics. 2015 Apr;135(4):723-33. doi: 10.1542/peds.2014-3979.
Abstract/Text BACKGROUND AND OBJECTIVES: Supplementation and screening for iron-deficiency anemia (IDA) in young children may improve growth and development outcomes. The goal of this study was to review the evidence regarding the benefits and harms of screening and routine supplementation for IDA for the US Preventive Services Task Force.
METHODS: We searched Medline and Cochrane databases (1996-August 2014), as well as reference lists of relevant systematic reviews. We included trials and controlled observational studies regarding the effectiveness and harms of routine iron supplementation and screening in children ages 6 to 24 months conducted in developed countries. One author extracted data, which were checked for accuracy by a second author. Dual quality assessment was performed.
RESULTS: No studies of iron supplementation in young children reported on the diagnosis of neurodevelopmental delay. Five of 6 trials sparsely reporting various growth outcomes found no clear benefit of supplementation. After 3 to 12 months, Bayley Scales of Infant Development scores were not significantly different in 2 trials. Ten trials assessing iron supplementation in children reported inconsistent findings for hematologic measures. Evidence regarding the harms of supplementation was limited but did not indicate significant differences. No studies assessed the benefits or harms of screening or the association between improvement in impaired iron status and clinical outcomes. Studies may have been underpowered, and control factors varied and could have confounded results.
CONCLUSIONS: Although some evidence on supplementation for IDA in young children indicates improvements in hematologic values, evidence on clinical outcomes is lacking. No randomized controlled screening studies are available.

Copyright © 2015 by the American Academy of Pediatrics.
PMID 25825534
Jane Thompson, Beverley-Ann Biggs, Sant-Rayn Pasricha
Effects of daily iron supplementation in 2- to 5-year-old children: systematic review and meta-analysis.
Pediatrics. 2013 Apr;131(4):739-53. doi: 10.1542/peds.2012-2256. Epub 2013 Mar 11.
Abstract/Text BACKGROUND AND OBJECTIVES: Iron deficiency (ID) is the most common cause of anemia worldwide. The prevalence is highest among preschool-aged children. Iron is widely administered to children with or at risk for ID, but evidence of benefit among 2- to 5-year-old children has not been evaluated by systematic review. We summarize the evidence for the benefit and safety of daily iron supplementation with regard to hematologic, growth, and cognitive parameters in 2 to 5 year olds.
METHODS: Electronic databases, regional databases, thesis repositories, gray literature, and references of studies and previous reviews were searched. We included randomized controlled trials that compared daily oral iron supplementation with control in 2 to 5 year olds. A random-effects meta-analysis was used to synthesize predefined outcomes reported by at least 2 studies.
RESULTS: Of 9169 references, 15 studies met the inclusion criteria, none of which were at low risk of bias. Children receiving iron supplementation had a mean end point hemoglobin of 6.97 g/L (P < .00001; I(2) = 82%) greater than controls, whereas mean end point ferritin was 11.64 µg/L (P < .0001; I(2) = 48%) greater. No trials reported the effects of iron supplementation on ID or iron deficiency anemia, and only one reported on anemia. Limited evidence suggested that iron supplementation produced a small improvement in cognitive development but had no effect on physical growth.
CONCLUSIONS: In 2 to 5 year olds, daily iron supplementation increases hemoglobin and ferritin. There is a concerning lack of data on the effect of iron supplementation on clinically important outcomes including anemia, ID anemia, ID, and cognitive development. Additional interventional studies in this age group are needed.

PMID 23478873
Anthony A Zehetner, Nigel Orr, Adam Buckmaster, Katrina Williams, Danielle M Wheeler
Iron supplementation for breath-holding attacks in children.
Cochrane Database Syst Rev. 2010 May 12;(5):CD008132. doi: 10.1002/14651858.CD008132.pub2. Epub 2010 May 12.
Abstract/Text BACKGROUND: Breath-holding attacks are common during childhood. Iron supplementation has been claimed to reduce the frequency or severity, or both, of breath-holding attacks in children.
OBJECTIVES: To assess the effect of iron supplementation on the frequency and severity of breath-holding attacks in children.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, CINAHL and the metaRegister of Controlled Trials (up to April 2009). We scanned references of included trials. Pharmaceutical companies manufacturing oral iron supplements and some trial authors were contacted for any unpublished data or trials.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing iron supplementation with placebo or no therapy in children < 18 years with recurrent (more than three) breath-holding episodes. These were reported by an observer.
DATA COLLECTION AND ANALYSIS: The primary outcome was reduction in the frequency (number over time) or severity (leading to cessation of loss of consciousness or convulsive movements), or both, of breath-holding attacks. Two authors (AZ and NO) independently selected studies and extracted data. Study authors were contacted for missing data, where necessary. Risk of bias was assessed using domain-based evaluation. In the presence of low heterogeneity, a fixed-effect meta-analysis was performed with pooled results presented as odds ratios (OR) and 95% confidence intervals (CIs).
MAIN RESULTS: Two trials (87 children) fulfilled the inclusion criteria. In these trials, iron supplementation significantly reduced the frequency of breath-holding attacks in children (OR 76.48; 95% CI 15.65 to 373.72; P < 0.00001). A meta-analysis that solely examined iron supplementation causing complete resolution of breath-holding attacks maintained this significance (OR 53.43; 95% CI 6.57 to 434.57; P = 0.0002).
AUTHORS' CONCLUSIONS: Iron supplementation (at 5 mg/kg/day of elemental iron for 16 weeks) appears to be useful in reducing the frequency and severity of breath-holding attacks. Supplementation is of particular benefit in children with iron deficiency anaemia, responses correlating with the improvements in haemoglobin values. Iron may still be of assistance in children who are not anaemic or who have low, normal haemoglobin levels. Further high-quality randomised control trials of iron supplementation to treat breath-holding attacks in children are required.

PMID 20464763
Scott R Garrison, G Michael Allan, Ravneet K Sekhon, Vijaya M Musini, Karim M Khan
Magnesium for skeletal muscle cramps.
Cochrane Database Syst Rev. 2012 Sep 12;(9):CD009402. doi: 10.1002/14651858.CD009402.pub2. Epub 2012 Sep 12.
Abstract/Text BACKGROUND: Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this indication has never been evaluated by systematic review.
OBJECTIVES: To assess the effects of magnesium supplementation compared to no treatment, placebo control or other cramp therapies in people with skeletal muscle cramps.  
SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), LILACS (January 1982 to September 2011), CINAHL Plus (January 1937 to September 2011), AMED (January 1985 to October 2011) and SPORTDiscus (January 1975 to September 2011).
SELECTION CRITERIA: Randomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp). We considered comparisons of magnesium with no treatment, placebo control, or other therapy.
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted data. Two authors assessed risk of bias. We attempted to contact all study authors and obtained patient level data for three of the included trials, one of which was unpublished. All data on adverse effects were collected from the included RCTs.
MAIN RESULTS: We identified seven trials (five parallel, two cross-over) enrolling a total of 406 individuals amongst whom 118 cross-over participants additionally served as their own controls. Three trials enrolled women with pregnancy-associated leg cramps (N = 202) and four trials enrolled idiopathic cramp sufferers (N = 322 including cross-over controls). Magnesium was compared to placebo in six trials and to no treatment in one trial.For idiopathic cramps (largely older adults presumed to have nocturnal leg cramps), differences in measures of cramp frequency, magnesium versus placebo, were small, not statistically significant, and without heterogeneity (I(2) = 0%). This includes the primary endpoint, percentage change from baseline in the number of cramps per week at four weeks (-3.93%, 95% confidence interval (CI) -21.12% to 13.26%, moderate quality evidence) and the difference in the number of cramps per week at four weeks (0.01 cramps/week, 95% CI -0.52 to 0.55, moderate quality evidence). The percentage of individuals experiencing a 25% or better reduction in cramp rate from baseline was also no different, being 8% lower in the magnesium group (95% CI -28% to 12%, moderate quality evidence). Similarly, no statistically significant difference was found at four weeks in measures of cramp intensity (moderate quality evidence) or cramp duration (low quality evidence).Meta-analysis was not possible for trials of pregnancy-associated leg cramps. The single study comparing magnesium to no treatment failed to find statistically significant benefit on a three-point ordinal scale of overall treatment efficacy. The two trials comparing magnesium to placebo differed in that one trial found no benefit on frequency or intensity measures while the other found benefit for both.Withdrawals due to adverse events were not significantly different than placebo. While we could not determine the number of subjects with minor adverse events, studies of oral magnesium generally described potential side effects as similar in frequency to placebo.
AUTHORS' CONCLUSIONS: It is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease).

PMID 22972143
Noga Roguin Maor, Mordechai Alperin, Elena Shturman, Hassan Khairaldeen, Moran Friedman, Khaled Karkabi, Uzi Milman
Effect of Magnesium Oxide Supplementation on Nocturnal Leg Cramps: A Randomized Clinical Trial.
JAMA Intern Med. 2017 May 1;177(5):617-623. doi: 10.1001/jamainternmed.2016.9261.
Abstract/Text Importance: Magnesium supplements are widely marketed for prophylaxis of nocturnal leg cramps (NLC) despite no evidence of significant benefit.
Objective: To determine whether magnesium oxide is better than placebo for NLC prophylaxis.
Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial of 2 weeks eligibility screening followed by 4 weeks of treatment was conducted in northern Israel, from February to October 2013. An intention-to-treat data analysis was performed from March 22, 2014, to April 17, 2016. We used a volunteer sample of community-dwelling individuals experiencing NLC, 21 years or older, with 4 or more documented episodes of NLC during 2 weeks of screening.
Interventions: Capsules containing either magnesium oxide or a similar-looking placebo to be taken orally, once daily at bedtime for a period of 4 weeks.
Main Outcomes and Measures: The primary outcome was the difference in the mean number of NLC per week between the screening and treatment phases. Secondary outcomes included severity and duration of NLC, quality of life, and quality of sleep.
Results: Of the 166 volunteers, 72 (43%) were excluded, of whom 15 declined to participate and 57 did not meet the inclusion criteria. Of the 94 individuals (39% male; mean [SD] age, 64.9 [11.1] years) randomly assigned to magnesium oxide (48) or placebo (46), 6 did not complete the study protocol (3 in each group). Mean (SD) change of NLC was -3.41 (4.05) (from 7.84 [5.68] to 4.44 [5.66]) and -3.03 (4.53) (from 8.51 [5.20] to 5.48 [4.93]) per week in the magnesium oxide and placebo groups, respectively, a difference between groups of 0.38 (0.48) NLC per week (P = .67 in an intention-to-treat analysis). There were no between-group differences in the severity and duration of NLC, quality of life, or quality of sleep.
Conclusions and Relevance: Oral magnesium oxide was not superior to placebo for older adults experiencing NLC. The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC.
Trial Registration: clinicaltrials.gov Identifier: NCT01709968.

PMID 28241153
A M Galløe, H S Rasmussen, L N Jørgensen, P Aurup, S Balsløv, C Cintin, N Graudal, P McNair
Influence of oral magnesium supplementation on cardiac events among survivors of an acute myocardial infarction.
BMJ. 1993 Sep 4;307(6904):585-7.
Abstract/Text OBJECTIVE: To investigate the effect of long term oral magnesium treatment on incidence of cardiac events among survivors of an acute myocardial infarction.
DESIGN: Double blind, placebo controlled parallel study in which patients were randomised to treatment or placebo.
SETTING: Two coronary care units and corresponding outpatient clinics.
SUBJECTS: 468 survivors of an acute myocardial infarction (289 men and 178 women) aged 31-92.
INTERVENTIONS: One tablet of 15 mmol magnesium hydroxide or placebo daily for one year.
MAIN OUTCOME MEASURES: Incidences of reinfarction, sudden death, and coronary artery bypass grafting in one year.
RESULTS: There was no significant difference between treatment and placebo groups in the incidence of each of the three cardiac events, but when the events were combined and drop outs were excluded from calculations there was a significantly higher incidence of events in the treatment group (56/167 v 33/153; relative risk 1.55 (95% confidence interval 1.07 to 2.25); p = 0.02). When the timing of events was incorporated by means of a Kaplan-Meier plot the treatment group showed a significantly higher incidence of events whether drop outs were included or excluded (p < 0.025).
CONCLUSION: Long term oral treatment with 15 mmol magnesium daily doses not reduce the incidence of cardiac events in survivors of an acute myocardial infarction and, indeed, seems to increase the risk of developing a cardiac event. Consequently, this treatment cannot be recommended as secondary prophylaxis for such patients.

PMID 8401013

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