Christensen SE, Nissen PH, Vestergaard P, Heickendorff L, Brixen K, Mosekilde L.
Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods.
Clin Endocrinol (Oxf). 2008 Nov;69(5):713-20. doi: 10.1111/j.1365-2265.2008.03259.x. Epub 2008 Apr 10.
Abstract/Text
BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented.
AIM: To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards.
DESIGN: Follow-up approach (direct design).
MATERIALS: We included 54 FHH patients (17 males and 37 females, aged 18-75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19-86 years). All PHPT patients became normocalcaemic following successful neck exploration.
RESULTS: Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0.923 +/- 0.021 (SE)), than the 24-h calcium/creatinine excretion ratio (AUC = 0.903 +/- 0.027) and the 24-h calcium excretion (AUC = 0.876 +/- 0.029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut-off points. Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity of 0.80. Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients.
CONCLUSION: Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis in patients with FHH or PHPT.
Bilezikian JP, Khan AA, Silverberg SJ, Fuleihan GE, Marcocci C, Minisola S, Perrier N, Sitges-Serra A, Thakker RV, Guyatt G, Mannstadt M, Potts JT, Clarke BL, Brandi ML; International Workshop on Primary Hyperparathyroidism.
Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop.
J Bone Miner Res. 2022 Nov;37(11):2293-2314. doi: 10.1002/jbmr.4677. Epub 2022 Oct 17.
Abstract/Text
The last international guidelines on the evaluation and management of primary hyperparathyroidism (PHPT) were published in 2014. Research since that time has led to new insights into epidemiology, pathophysiology, diagnosis, measurements, genetics, outcomes, presentations, new imaging modalities, target and other organ systems, pregnancy, evaluation, and management. Advances in all these areas are demonstrated by the reference list in which the majority of listings were published after the last set of guidelines. It was thus, timely to convene an international group of over 50 experts to review these advances in our knowledge. Four Task Forces considered: 1. Epidemiology, Pathophysiology, and Genetics; 2. Classical and Nonclassical Features; 3. Surgical Aspects; and 4. Management. For Task Force 4 on the Management of PHPT, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology addressed surgical management of asymptomatic PHPT and non-surgical medical management of PHPT. The findings of this systematic review that applied GRADE methods to randomized trials are published as part of this series. Task Force 4 also reviewed a much larger body of new knowledge from observations studies that did not specifically fit the criteria of GRADE methodology. The full reports of these 4 Task Forces immediately follow this summary statement. Distilling the essence of all deliberations of all Task Force reports and Methodological reviews, we offer, in this summary statement, evidence-based recommendations and guidelines for the evaluation and management of PHPT. Different from the conclusions of the last workshop, these deliberations have led to revisions of renal guidelines and more evidence for the other recommendations. The accompanying papers present an in-depth discussion of topics summarized in this report. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
日本内分泌学会、日本糖尿病学会 編：内分泌代謝・糖尿病内科領域専門医研修ガイドブック、診断と治療社、2023.
Cavalier E, Daly AF, Betea D, Pruteanu-Apetrii PN, Delanaye P, Stubbs P, Bradwell AR, Chapelle JP, Beckers A.
The ratio of parathyroid hormone as measured by third- and second-generation assays as a marker for parathyroid carcinoma.
J Clin Endocrinol Metab. 2010 Aug;95(8):3745-9. doi: 10.1210/jc.2009-2791. Epub 2010 Jun 2.
Abstract/Text
BACKGROUND: Parathyroid carcinoma (PCa) is a rare disease that can be difficult to differentiate initially from severe benign parathyroid adenoma. PCa oversecrete the amino form of PTH, which is recognized by third-generation but not by second-generation PTH immunoassays. In normal individuals, the third-generation to second-generation PTH ratio should be less than 1.
OBJECTIVE: Our objective was to study the utility of the third-generation to second-generation PTH ratio as a means of distinguishing PCa patients (n=24) from control groups with and without disorders of calcium secretion, including patients on renal hemodialysis (n=74), postrenal transplantation (n=60), and primary hyperparathyroidism (PHP; n=30).
SETTING AND DESIGN: We conducted a retrospective, laboratory-based study at tertiary referral academic centers.
RESULTS: The mean third-generation to second-generation ratio was 0.58+/-0.10 in the dialysis patients, 0.54+/-0.10 in the renal transplant group, 0.54+/-0.12 in the elderly healthy patients, and 0.68+/-0.11 in the PHP group. All 245 of these patients presented a PTH third-generation to second-generation ratio of less than 1. In contrast, we observed an inverted third-generation to second-generation PTH ratio of more than one in 20 PCa patients, whereas only four PCa patients had a normal ratio of less than 1.
CONCLUSIONS: An inverted third-generation to second-generation PTH ratio occurred in the majority of patients with advanced PCa and was absent in all 245 relevant controls. A third-generation to second-generation PTH ratio higher than 1 had a sensitivity of 83.3% and a specificity of 100% among PHP patients as a marker for PCa. This ratio may be useful to identify patients with PCa earlier and to detect patients either at risk of developing PCa or those in whom recurrence is taking place.
Johnson NA, Carty SE, Tublin ME.
Parathyroid imaging.
Radiol Clin North Am. 2011 May;49(3):489-509, vi. doi: 10.1016/j.rcl.2011.02.009.
Abstract/Text
Primary hyperparathyroidism is a common endocrine disorder caused by the overproduction of parathyroid hormone either by a single adenomatous gland or by multiple adenomatous or hyperplastic glands. Surgical resection of the abnormal parathyroid glands is the standard treatment, the goal of initial parathyroidectomy being durable biochemical cure. Surgeons have recently shifted to more minimally invasive and selective techniques for parathyroid exploration. More selective surgical approaches rely on accurate preoperative imaging techniques to localize abnormal parathyroid glands. It is imperative that radiologists are familiar with imaging features of parathyroid glands as well as the role of imaging in patient care.
Copyright © 2011 Elsevier Inc. All rights reserved.
Kunstman JW, Kirsch JD, Mahajan A, Udelsman R.
Clinical review: Parathyroid localization and implications for clinical management.
J Clin Endocrinol Metab. 2013 Mar;98(3):902-12. doi: 10.1210/jc.2012-3168. Epub 2013 Jan 23.
Abstract/Text
CLINICAL CONTEXT: The prevalence of hyperparathyroidism, especially primary hyperparathyroidism, has increased in recent decades due to improvements in diagnostic techniques with a corresponding surge in parathyroid surgery, leading to the development of focused, minimally invasive surgical approaches. Focused parathyroidectomy is predicated on preoperative localization of suspected parathyroid pathology. As a result, there has been a proliferation of parathyroid imaging modalities and protocols, resulting in confusion about their indications and applications.
EVIDENCE ACQUISITION: Bibliographies from clinical trials and review articles published since 2000 were reviewed and supplemented with targeted searches using biomedical databases. We also employed our extensive clinical experience.
EVIDENCE SYNTHESIS: The best-studied modalities for parathyroid localization are nuclear scintigraphy and sonography and are widely applied as initial studies. Multiple variations exist, and several additional noninvasive imaging techniques, such as computed tomography and magnetic resonance, are described. The exquisite anatomical detail of 4-dimensional computed tomography must be balanced with significant radiation exposure to the thyroid gland. Invasive venous PTH sampling and parathyroid arteriography have important roles in remedial cases. Due to considerable heterogeneity in imaging, multidisciplinary collaboration between endocrinologists, surgeons, and radiologists is beneficial.
CONCLUSIONS: Parathyroid localization is indicated in surgical candidates. Crucial considerations when selecting an imaging study include availability, cost, radiation exposure, local expertise, and accuracy. Additional factors include the patient's anticipated pathology and whether it is de novo or refractory disease. An approach to imaging for patients with primary hyperparathyroidism is presented.
Krol JP, Joosten FBM, de Boer H, Bernsen MLE, Slump CH, Oyen WJG.
Four-dimensional computed tomography as first-line imaging in primary hyperparathyroidism, a retrospective comparison to conventional imaging in a predominantly single adenoma population.
EJNMMI Rep. 2024 May 1;8(1):11. doi: 10.1186/s41824-024-00198-5. Epub 2024 May 1.
Abstract/Text
BACKGROUND: To determine the use of four-dimensional CT as first-line imaging compared to the traditional combination of ultrasound and [99mTc]Tc-Sestamibi SPECT.
MATERIALS AND METHODS: Retrospective review of preoperative imaging in patients with primary hyperparathyroidism, who underwent parathyroidectomy between 2012 and 2021. In one group, the combination ultrasound and [99mTc]Tc-Sestamibi SPECT was used as first-line imaging (n = 54), in the other group four-dimensional CT was the first-line imaging modality (n = 51). Sensitivity and positive predictive value were calculated on patient, lateralisation and localisation level. The need for additional imaging was also assessed for both groups.
RESULTS: Four-dimensional CT had a significantly higher sensitivity compared to the combination of ultrasound/[99mTc]Tc-Sestamibi SPECT on patient and localisation level (70.6% vs. 51.9%, p = 0.049 and 60.8% vs. 35.2%, p = 0.009 respectively). Sensitivity for lateralisation also appeared higher, but did not reach significance (62.7% vs. 44.4%, p = 0.060). Positive predictive value was not significantly higher for four-dimensional CT compared to ultrasound and [99mTc]Tc-Sestamibi SPECT (88.9% vs. 85.7% for lateralisation and 86.1% vs. 67.9% for localisation respectively). Additional imaging was required in 14 patients with four-dimensional CT as first-line imaging (27.4%) consisting of 2 ultrasound/[99mTc]Tc-Sestamibi SPECT and 13 [18F]fluorocholine PET/CT, compared to 24 patients with ultrasound/[99mTc]Tc-Sestamibi SPECT as first-line imaging (44.4%), requiring 22 four-dimensional CT and 9 [18F]fluorocholine PET/CT.
CONCLUSIONS: Four-dimensional CT as the sole first-line parathyroid imaging modality had higher sensitivity than the combination of ultrasound and [99mTc]Tc-Sestamibi SPECT, therefore requiring fewer additional procedures. Although the most costly, [18F]fluorocholine PET/CT was the most effective technique to localise parathyroid adenoma in case all other imaging was negative.
© 2024. The Author(s).
Grayev AM, Gentry LR, Hartman MJ, Chen H, Perlman SB, Reeder SB.
Presurgical localization of parathyroid adenomas with magnetic resonance imaging at 3.0 T: an adjunct method to supplement traditional imaging.
Ann Surg Oncol. 2012 Mar;19(3):981-9. doi: 10.1245/s10434-011-2046-z. Epub 2011 Aug 31.
Abstract/Text
PURPOSE: To investigate the use of a chemical shift-based water-fat separation magnetic resonance imaging (MRI) method, and time-resolved contrast-enhanced MRI at 3 T for improved presurgical localization of parathyroid adenomas.
METHODS: Twenty-five patients with primary hyperparathyroidism were prospectively enrolled. Patients underwent MRI, which was reviewed by two experienced neuroradiologists who were blinded to Tc-99m sestamibi imaging and operative results.
RESULTS: Overall, MRI detected 16 adenomas in 25 patients (sensitivity 64%, positive predictive value 67%), while sestamibi detected 18 of 25 adenomas (sensitivity 72%, positive predictive value 90%). Importantly, MRI was able to detect adenomas in four (57%) of the seven patients whose disease was missed by sestamibi analysis. MRI demonstrated excellent image quality and fat suppression by using a chemical shift-based water-fat separation technique. The time-resolved MRI was considered to be less helpful, although in some cases it was indispensable.
CONCLUSIONS: MRI is an excellent adjunct for preoperative parathyroid localization. The advent of improved fat suppression techniques in the neck, including chemical shift-based water-fat separation, is critical to its utility. Although time-resolved MRI was not always helpful, it was crucial in certain cases. It may prove to be more useful with the development of faster scanning techniques.
Rubin MR, Bilezikian JP, McMahon DJ, Jacobs T, Shane E, Siris E, Udesky J, Silverberg SJ.
The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.
J Clin Endocrinol Metab. 2008 Sep;93(9):3462-70. doi: 10.1210/jc.2007-1215. Epub 2008 Jun 10.
Abstract/Text
CONTEXT: Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue.
OBJECTIVE: The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr.
DESIGN: The study had an observational design.
SETTING: The setting was a referral center.
PATIENTS: Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic.
INTERVENTION: Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery.
MAIN OUTCOME MEASURE: BMD was measured.
RESULTS: Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr.
CONCLUSIONS: Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.
Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J; SIPH Study Group.
Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study).
J Bone Miner Res. 2017 Sep;32(9):1907-1914. doi: 10.1002/jbmr.3177. Epub 2017 Jul 7.
Abstract/Text
Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long-term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm2 and T-scores and on biochemical markers of bone turnover (P1NP and CTX-1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow-up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX-1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm2 ) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm2 ) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long-term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.
© 2017 American Society for Bone and Mineral Research.
Ejlsmark-Svensson H, Rolighed L, Harsløf T, Rejnmark L.
Risk of fractures in primary hyperparathyroidism: a systematic review and meta-analysis.
Osteoporos Int. 2021 Jun;32(6):1053-1060. doi: 10.1007/s00198-021-05822-9. Epub 2021 Feb 1.
Abstract/Text
An increased risk of fractures in primary hyperparathyroidism (PHPT) has been reported in a number of relatively small studies. Performing a systematic literature search, we identified available studies and calculated common estimates by pooling results from the individual studies in a meta-analysis. Searching EMBASE and PubMed, we identified published studies reporting the risk of fractures in PHPT compared to a control group. We calculated odds ratio (OR) with 95% confidence interval (CI). A total of 804 studies were identified of which 12 studies were included. Risk of any fracture was increased compared to controls (OR 2.01; 95% CI, 1.61-2.50; I2 46%, 5 studies). Analysis of fracture risk at specific sites showed an increased risk of fracture at the forearm (OR 2.36; 95% CI, 1.64-3.38; I2 0%, 4 studies) and spine (OR 3.00; 95% CI, 1.41, 6.37, I2 88%, 9 studies). Risk estimate for hip fractures was non-significantly increased (OR 1.27; 95% CI, 0.97-1.66; I2 0%, 3 studies). Risk of vertebral fractures (VFx) was also increased if analyses were restricted to only studies with a healthy control group (OR 5.76; 95% CI, 3.86-8.60; I2 29%, 6 studies), studies including patients with mild PHPT (OR 4.22; 95% CI, 2.20-8.12; I2 57%, 4 studies) or studies including postmenopausal women (OR 8.07; 95% CI, 4.79-13.59; I2 0%, 3 studies). PHPT is associated with an increased risk of fractures. Although a number of studies are limited-it seems that the risk is increased across different skeletal sites including patients with mild PHPT and postmenopausal women.
El-Hajj Fuleihan G, Chakhtoura M, Cipriani C, Eastell R, Karonova T, Liu JM, Minisola S, Mithal A, Moreira CA, Peacock M, Schini M, Silva B, Walker M, El Zein O, Marcocci C.
Classical and Nonclassical Manifestations of Primary Hyperparathyroidism.
J Bone Miner Res. 2022 Nov;37(11):2330-2350. doi: 10.1002/jbmr.4679. Epub 2022 Oct 17.
Abstract/Text
This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
日本内分泌学会. 多発性内分泌腫瘍症診断の手引き. 2012.
Lundgren E, Lind L, Palmér M, Jakobsson S, Ljunghall S, Rastad J.
Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years.
Surgery. 2001 Dec;130(6):978-85. doi: 10.1067/msy.2001.118377.
Abstract/Text
BACKGROUND: The natural history of mild hyperparathyroidism is incompletely clarified.
METHODS: Consistent hypercalcemia was found in 172 patients (aged 28-86 years) participating in population-based screenings in both 1969 and 1971. Mortality until 1994 was compared with 344 matched, normocalcemic controls from the study population. Altogether, 55 case-control pairs underwent biochemical analysis in 1992, whereas 86 patients had died, 8 were lost to follow-up, and 23 had undergone parathyroid operation.
RESULTS: Mortality was higher (P = .015) in patients younger than 70 years. Cardiovascular diseases were over-represented causes of death. The hazard ratio for hypercalcemia as an independent cause of cardiovascular mortality was 1.72 (95% CI, 1.24-2.37; P < .001). The initially mild hypercalcemia in patients (2.67 +/- 0.07 mmol/L) decreased over time (P = .0001), whereas the serum calcium value remained constant in the controls. Serum calcium and serum parathyroid hormone values in patients were higher than controls at the follow-up (P < .0001, .01, respectively). All but 17 patients were normocalcemic in 1992, and only 2 (1.4%) developed a serum calcium value higher than 3 mmol/L.
CONCLUSIONS: Mild hypercalcemia in patients followed up for more than 2 decades is accompanied by premature cardiovascular death despite trends to spontaneous resolution. The principal cause of hypercalcemia probably is primary hyperparathyroidism, but mechanisms contributing to its regression over time are speculative.
Axelsson KF, Wallander M, Johansson H, Harvey NC, Vandenput L, McCloskey E, Liu E, Kanis JA, Litsne H, Lorentzon M.
Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism.
JAMA Netw Open. 2022 Jun 1;5(6):e2215396. doi: 10.1001/jamanetworkopen.2022.15396. Epub 2022 Jun 1.
Abstract/Text
IMPORTANCE: Patients with primary hyperparathyroidism (pHPT) appear to have an increased risk of fractures and other comorbidities, such as cardiovascular disease, although results from previous studies have been inconsistent. Evidence of the association of parathyroidectomy (PTX) with these outcomes is also limited because of the lack of large well-controlled trials.
OBJECTIVE: To investigate whether untreated pHPT was associated with an increased risk of incident fractures and cardiovascular events (CVEs) and whether PTX was associated with a reduced risk of these outcomes.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included all patients who were diagnosed with pHPT at hospitals in Sweden between July 1, 2006, and December 31, 2017. Each patient was matched with 10 control individuals from the general population by sex, birth year, and county of residence. The patients were followed up until December 31, 2017. Data analyses were performed from October 2021 to April 2022.
MAIN OUTCOMES AND MEASURES: The primary outcomes were fractures, CVEs, and death. Cumulative incidence of events was estimated using the 1-minus Kaplan-Meier estimator of corresponding survival function. Cox proportional hazards regression models were used to calculate hazard ratios (HRs).
RESULTS: A total of 16 374 patients with pHPT were identified (mean [SD] age, 67.5 [12.9] years; 12 806 women [78.2%]), with 163 740 control individuals. The follow-up time was 42 310 person-years for the pHPT group and 803 522 person-years for the control group. Compared with the control group, the pHPT group had a higher risk of any fracture (unadjusted HR, 1.39; 95% CI, 1.31-1.48), hip fracture (unadjusted HR, 1.51; 95% CI, 1.35-1.70), CVEs (unadjusted HR, 1.45; 95% CI, 1.34-1.57), and death (unadjusted HR, 1.72; 95% CI, 1.65-1.80). In a time-dependent Poisson regression model, PTX was associated with a reduced risk of any fracture (HR, 0.83; 95% CI, 0.75-0.93), hip fracture (HR, 0.78; 95% CI, 0.61-0.98), CVEs (HR, 0.84; 95% CI, 0.73-0.97), and death (HR, 0.59; 95% CI, 0.53-0.65).
CONCLUSIONS AND RELEVANCE: Results of this study suggest that pHPT is associated with increased risk of fractures, CVEs, and death, highlighting the importance of identifying patients with this condition to prevent serious unfavorable outcomes. The reduced risk of these outcomes associated with PTX suggests a clinical benefit of surgery.
Bilezikian JP, Silverberg SJ, Bandeira F, Cetani F, Chandran M, Cusano NE, Ebeling PR, Formenti AM, Frost M, Gosnell J, Lewiecki EM, Singer FR, Gittoes N, Khan AA, Marcocci C, Rejnmark L, Ye Z, Guyatt G, Potts JT.
Management of Primary Hyperparathyroidism.
J Bone Miner Res. 2022 Nov;37(11):2391-2403. doi: 10.1002/jbmr.4682. Epub 2022 Oct 17.
Abstract/Text
Since the last international guidelines were published in 2014 on the evaluation and management of primary hyperparathyroidism (PHPT), new information has become available with regard to evaluation, diagnosis, epidemiology, genetics, classical and nonclassical manifestations, surgical and nonsurgical approaches, and natural history. To provide the most current summary of these developments, an international group, consisting of over 50 experts in these various aspects of PHPT, was convened. This paper provides the results of the task force that was assigned to review the information on the management of PHPT. For this task force on the management of PHPT, two questions were the subject of systematic reviews using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The full report addressing surgical and nonsurgical management of PHPT, utilizing the GRADE methodology, is published separately in this series. In this report, we summarize the results of that methodological review and expand them to encompass a much larger body of new knowledge that did not specifically fit the criteria of the GRADE methodology. Together, both the systematic and narrative reviews of the literature, summarized in this paper, give the most complete information available to date. A panel of experts then considered the last set of international guidelines in light of the newer data and assessed the need for their revision. This report provides the evidentiary background to the guidelines report. In that report, evidence from all task forces is synthesized into a summary statement and revised guidelines for the evaluation and management of PHPT. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Kongsaree N, Thanyajaroen T, Dechates B, Therawit P, Mahikul W, Ngaosuwan K.
Skeletal impact of parathyroidectomy on patients with primary hyperparathyroidism: a Systematic review and Meta-analysis.
J Clin Endocrinol Metab. 2024 May 13;. doi: 10.1210/clinem/dgae326. Epub 2024 May 13.
Abstract/Text
CONTEXT: Parathyroidectomy is recommended for curing primary hyperparathyroidism (PHPT), although uncertainty remains regarding the extent of fracture risk reduction following surgery.
OBJECTIVE: To compare fracture risk and bone mineral density (BMD) changes in patients with PHPT undergoing parathyroidectomy (PTX) versus observation (OBS).
DATA SOURCES: We systematically searched PubMed, Embase, and the Cochrane Library until September 2022, including randomized controlled trials (RCTs) and cohort studies, and reviewed citations from previous reviews.
STUDY SELECTION: Among 1,260 initial records, 48 eligible articles from 35 studies (5 RCTs; 30 cohorts) included PHPT patients receiving PTX or OBS interventions with reported fracture events at any site, including the hip, spine, or forearm, and/or BMD changes at each location.
DATA EXTRACTION: Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines by two independent reviewers.
DATA SYNTHESIS: In 238,188 PHPT patients (PTX: 73,778 vs. OBS: 164,410), parathyroidectomy significantly reduced fractures at any site (RR, 0.80; 95%CI, 0.74-0.86) compared to observation. In 237,217 patients (PTX: 73,458 vs. OBS: 163,759), the risk of hip fractures decreased (RR, 0.63; 95%CI, 0.52-0.76). No reduction in forearm and vertebral fractures was observed in 3,574 and 3,795 patients, respectively. The annual percentage BMD changes from baseline were higher in the PTX group: femoral neck, 1.91% (95%CI, 1.14-2.68); hip, 1.75% (95%CI, 0.58-2.92); radius, 1.75% (95%CI, 0.31-3.18); spine, 2.13% (95%CI, 1.16-3.10).
CONCLUSIONS: Parathyroidectomy significantly reduced overall and hip fracture risks in PHPT patients. Despite minimal BMD increase, the substantial decrease in fracture risk suggests additional benefits of PTX beyond mineral content enhancement.
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Ye Z, Silverberg SJ, Sreekanta A, Tong K, Wang Y, Chang Y, Zhang M, Guyatt G, Tangamornsuksun W, Zhang Y, Manja V, Bakaa L, Couban RJ, Brandi ML, Clarke B, Khan AA, Mannstadt M, Bilezikian JP.
The Efficacy and Safety of Medical and Surgical Therapy in Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
J Bone Miner Res. 2022 Nov;37(11):2351-2372. doi: 10.1002/jbmr.4685. Epub 2022 Oct 17.
Abstract/Text
Both medical and surgical therapy represent potential management options for patients with asymptomatic primary hyperparathyroidism (PHPT). Because uncertainty remains regarding both medical and surgical therapy, this systematic review addresses the efficacy and safety of medical therapy in asymptomatic patients or symptomatic patients who decline surgery and surgery in asymptomatic patients. We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed from inception to December 2020, and included randomized controlled trials in patients with PHPT that compared nonsurgical management with medical therapy versus without medical therapy and surgery versus no surgery in patients with asymptomatic PHPT. For surgical complications we included observational studies. Paired reviewers addressed eligibility, assessed risk of bias, and abstracted data for patient-important outcomes. We conducted random-effects meta-analyses to pool relative risks and mean differences with 95% confidence intervals and used Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to assess quality of evidence for each outcome. For medical therapy, 11 trials reported in 12 publications including 438 patients proved eligible: three addressed alendronate, one denosumab, three cinacalcet, two vitamin D, and two estrogen therapy. Alendronate, denosumab, vitamin D, and estrogen therapy all increased bone density. Cinacalcet probably reduced serum calcium and parathyroid hormone (PTH) levels. Cinacalcet and vitamin D may have a small or no increase in overall adverse events. Very-low-quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab. The trials also provided low-quality evidence for increased bleeding and mastalgia with estrogen therapy. For surgery, six trials presented in 12 reports including 441 patients proved eligible. Surgery achieved biochemical cure in 96.1% (high quality). We found no convincing evidence supporting an impact of surgery on fracture, quality of life, occurrence of kidney stones, and renal function, but the evidence proved low or very low quality. Surgery was associated with an increase in bone mineral density. For patients with symptomatic and asymptomatic PHPT, who are not candidates for parathyroid surgery, cinacalcet probably reduced serum calcium and PTH levels; anti-resorptives increased bone density. For patients with asymptomatic PHPT, surgery usually achieves biochemical cure. These results can help to inform patients and clinicians regarding use of medical therapy and surgery in PHPT. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Koumakis E, Souberbielle JC, Sarfati E, Meunier M, Maury E, Gallimard E, Borderie D, Kahan A, Cormier C.
Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism.
J Clin Endocrinol Metab. 2013 Aug;98(8):3213-20. doi: 10.1210/jc.2013-1518. Epub 2013 Jun 19.
Abstract/Text
CONTEXT: It is unclear whether bone mineral density (BMD) improves in patients with normocalcemic primary hyperparathyroidism (PHPT) after parathyroidectomy (PTX).
OBJECTIVE: The objective of the study was to evaluate and compare the impact of PTX on BMD change at 1 year in normocalcemic vs hypercalcemic PHPT.
DESIGN: This was a longitudinal cohort study.
SETTING: The study took place at a referral center.
PATIENTS: We included 60 PHPT patients (mean age 64.0 ± 10.1 years), successfully treated by PTX by the same surgeon. Two groups were individualized according to baseline serum total (albumin corrected) calcium: 39 patients with normal baseline serum total calcium (normocalcemic group) and 21 patients with hypercalcemia at baseline (hypercalcemic group).
MAIN OUTCOME MEASURE: BMD changes 1 year after PTX were measured.
RESULTS: In the normocalcemic group, BMD increased significantly by +2.3 ± 5.0% at the spine (P = .016) and +1.9 ± 5.7% at the hip (P = .048). In the hypercalcemic group, BMD increased significantly by +4.0 ± 3.8% at the spine (P = .0003) and +3.2 ± 4.2% at the hip (P = .003). There was no difference in these BMD gains between both groups (P > .1). The presence of multiple adenomas or hyperplasia was more frequent in the normocalcemic group than in the hypercalcemic group (P = .04).
CONCLUSION: Our results indicate for the first time that successful PTX in normocalcemic PHPT patients with osteoporosis is followed with mild but significant BMD improvement at the spine and hip at 1 year, comparable with that observed in hypercalcemic PHPT, suggesting that PTX may be beneficial in normocalcemic PHPT.
Chandran M, Bilezikian JP, Lau J, Rajeev R, Yang SP, Samuel M, Parameswaran R.
The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies.
Rev Endocr Metab Disord. 2022 Jun;23(3):485-501. doi: 10.1007/s11154-021-09694-6. Epub 2022 Jan 18.
Abstract/Text
Cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR) reduces parathyroid hormone (PTH) secretion by increasing the sensitivity of the CaSR on parathyroid cells. We conducted a systematic review and meta-analysis on the safety and efficacy of cinacalcet in Primary Hyperparathyroidism (PHPT). MEDLINE, Embase, BIOSIS, and the Cochrane Library were searched for published articles (from database inception to Sept 2020). All double-blind RCTs and cohort studies that reported data on the efficacy and safety of cinacalcet therapy in individuals ≥ 18 with PHPT were included. Random effect meta-analysis was performed to estimate the efficacy of cinacalcet in lowering serum calcium and PTH levels compared with placebo. 4 RCTs (177 participants) and 17 cohort studies (763 participants) were eligible for final analysis. Pooled results from the RCTs suggest that, when compared to placebo and administered for up to 28 weeks, cinacalcet normalizes serum calcium (≤ 10.3 mg/dl) in patients with PHPT [RR 20 (95% CI 6.04 - 68.52, I2 = 0%, pheterogeneity < 0·00001)]. Serum PTH levels decreased significantly after 2 weeks and up to 28 weeks after treatment with cinacalcet. In the pooled analysis of the 17 cohort studies, serum calcium levels normalized in 76% (95% CI 66% to 86%; I2 = 92%, pheterogeneity < 0·00001) of patients regardless of the duration of treatment. In most studies, PTH levels decreased by 13% to 55%. No RCT reported on BMD as a primary or secondary outcome, and no improvement in BMD was noted in the 2 non-randomized studies that reported densitometric findings. No significant difference in urinary calcium was noted with cinacalcet therapy in either the RCTs or non-randomized studies. There was no significant difference in overall adverse events (AE) (RD 0.01, 95% CI -0.07 to 0.26) compared to placebo noted in the RCTs. In the non-randomized studies, pooled weighted AE rate was 45% (95% CI 32 to 59%). Risk of bias was low in 2/4 RCTs and 6/17cohort studies; risk was intermediate in 2/4 RCTs and 8/17 cohort studies, and risk was high in 3/17 cohort studies. In PHPT, cinacalcet lowers serum calcium and PTH with greater effects on calcium than on PTH in the short term. In the doses reported, the drug is safe with tolerable side effects. These findings can help inform targeted medical therapy of PHPT in those for whom lowering the serum calcium is indicated and for whom parathyroidectomy is not an option.
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Takeuchi Y, Nishida Y, Kondo Y, Imanishi Y, Fukumoto S.
Evocalcet in patients with primary hyperparathyroidism: an open-label, single-arm, multicenter, 52-week, dose-titration phase III study.
J Bone Miner Metab. 2020 Sep;38(5):687-694. doi: 10.1007/s00774-020-01097-y. Epub 2020 Apr 9.
Abstract/Text
INTRODUCTION: Primary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical.
MATERIALS AND METHODS: We conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day).
RESULTS: Fourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4-93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0-86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs.
CONCLUSION: Evocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.
Khan AA, Bilezikian JP, Kung AW, Ahmed MM, Dubois SJ, Ho AY, Schussheim D, Rubin MR, Shaikh AM, Silverberg SJ, Standish TI, Syed Z, Syed ZA.
Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial.
J Clin Endocrinol Metab. 2004 Jul;89(7):3319-25. doi: 10.1210/jc.2003-030908.
Abstract/Text
Primary hyperparathyroidism (PHPT) is often associated with reduced bone mineral density (BMD). A randomized, double-blind, placebo-controlled trial was conducted to determine whether alendronate (ALN), 10 mg daily, maintains or improves BMD in patients with PHPT. Eligible patients had asymptomatic PHPT and did not meet surgical guidelines or refused surgery. Forty-four patients randomized to placebo or active treatment arms were stratified for gender. At 12 months, patients taking placebo crossed over to active treatment. All patients were on active treatment in yr 2. The primary outcome index, BMD, at the lumbar spine (LS), femoral neck, total hip, and distal one third radius was measured every 6 months by dual-energy x-ray absorptiometry. Calcium, phosphorous, PTH, bone-specific alkaline phosphatase (BSAP) activity, urinary calcium, and urinary N-telopeptide (NTX) excretion were monitored every 3 months. Treatment with alendronate over 2 yr was associated with a significant (6.85%; micro(d) = 0.052; +/-0.94% se; P < 0.001) increase in LS BMD in comparison with baseline. Total hip BMD increased significantly at 12 months with alendronate by 4.01% (micro(d) = 0.027; +/-0.77% se; P < 0.001) from baseline and remained stable over the next 12 months of therapy. BMD at the one third radius site did not show any statistically significant change in the alendronate-treated group at 12 or 24 months of therapy. At 24 months, the alendronate-treated group showed a 3.67% (micro(d) = 0.022; +/-1.63% se; P = 0.038) gain in bone density at the femoral neck site in comparison with baseline. The placebo group, when crossed over to alendronate at 12 months, showed a significant change of 4.1% (micro(d) = 0.034; +/-1.12% se; P = 0.003) in the LS BMD and 1.7% (micro(d) = 0.012; +/-0.81% se; P = 0.009) at the total hip site in comparison with baseline. There was no statistically significant change seen in the placebo group at 12 months at any BMD site and no significant change at 24 months for the distal one third radius or femoral neck sites. Alendronate was associated with marked reductions in bone turnover markers with rapid decreases in urinary NTX excretion by 66% (micro(d) = -60.27; +/-13.5% se; P < 0.001) at 3 months and decreases in BSAP by 49% at 6 months (micro(d) = -15.98; +/-6.32% se; P < 0.001) and by 53% at 9 and 12 months (micro(d) = -17.11; +/-7.85% se; P < 0.001; micro(d) = -17.36; +/-6.96% se; P < 0.001, respectively) of therapy. In the placebo group, NTX and BSAP levels remained elevated. Serum calcium (total and ionized), PTH, and urine calcium did not change with alendronate therapy. In PHPT, alendronate significantly increases BMD at the LS at 12 and 24 months from baseline values. Significant reductions in bone turnover occur with stable serum calcium and PTH levels. Alendronate may be a useful alternative to parathyroidectomy in asymptomatic PHPT among those with low BMD.
Camponovo C, Aubry-Rozier B, Lamy O, Gonzalez Rodriguez E.
Hypercalcemia upon denosumab withdrawal in primary hyperparathyroidism: a case report and literature review.
Osteoporos Int. 2020 Dec;31(12):2485-2491. doi: 10.1007/s00198-020-05676-7. Epub 2020 Oct 15.
Abstract/Text
Denosumab discontinuation is associated with a rapid increase in bone resorption and a decrease in bone mineral density. Spontaneous vertebral fractures may occur as a side effect of the rebound of bone resorption. Cases of rebound-linked hypercalcemia have also been described, moderate in women with osteoporosis and breast cancer and severe in children receiving oncological doses of denosumab. We report the case of an adult woman with primary hyperparathyroidism and moderate hypercalcemia, treated with denosumab for osteoporosis, who developed severe hypercalcemia and spontaneous vertebral fractures (SVFs) after denosumab discontinuation. An 86-year-old woman with densitometric osteoporosis was treated for 3 years with 60 mg of subcutaneous denosumab every 6 months. She was known to have primary hyperparathyroidism, with a serum albumin-corrected calcium of 2.82 mmol/l (NV 2.15-2.5) at the end of denosumab effect. Nine months after the last denosumab injection, she was hospitalized due to worsening overall health. Clinical evaluation revealed severe hypercalcemia (calcium 3.35 mmol/l). Very high values of bone turnover markers (BTMs) suggested a rebound effect due to denosumab discontinuation. An X-ray showed multiple new SVFs. After injection of denosumab 60 mg, serum calcium rapidly decreased and BTMs were dramatically reduced. A surgical approach by minimally invasive parathyroidectomy allowed for definite resolution of hyperparathyroidism and hypercalcemia. This case suggests that hypercalcemia can be a side consequence of denosumab discontinuation, which can become severe when other causes of hypercalcemia, such as primary hyperparathyroidism, are present.
Leere JS, Karmisholt J, Robaczyk M, Lykkeboe S, Handberg A, Steinkohl E, Brøndum Frøkjær J, Vestergaard P.
Denosumab and cinacalcet for primary hyperparathyroidism (DENOCINA): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Diabetes Endocrinol. 2020 May;8(5):407-417. doi: 10.1016/S2213-8587(20)30063-2.
Abstract/Text
BACKGROUND: Medical treatment options for primary hyperparathyroidism are scarce. We aimed to assess the efficacy of denosumab and combined with cinacalcet in patients with primary hyperparathyroidism.
METHODS: In this randomised, single-centre, proof-of-concept, double-blind trial, patients aged at least 18 years with primary hyperparathyroidism were recruited from the Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark. Key eligibility criteria were a T-score between -1·0 and -3·5 at the lumbar spine, femoral neck, or total hip. Patients were assigned (1:1:1) via permuted block randomisation to receive 30 mg cinacalcet per day plus 60 mg denosumab subcutaneously every 6 months (n=14; combination group) for 1 year, denosumab plus placebo (n=16; denosumab group) for 1 year, or placebo plus placebo injection (n=15; placebo group) for 1 year. Primary outcomes were changes in bone mineral density (BMD) measured by dual x-ray absorptiometry at the lumbar spine, total hip, femoral neck, and distal forearm after 1 year. Additionally, effects on bone-metabolic biochemistry were explored. Patients and investigators were masked. All enrolled patients were included in efficacy analyses. The trial was done in an outpatient setting and is registered at ClinicalTrials.gov, NCT03027557, and has been completed.
FINDINGS: Between March 14, 2017, and March 16, 2018 we recruited 285 participants. 16 patients were randomly allocated to the denosumab group, 15 to the combination group, and 15 to the placebo group. Dropout was limited to one patient in the combination group. Compared with placebo, BMD improved in groups receiving denosumab: lumbar spine (combination group 5·4% [95% CI 2·7-8·1], denosumab group 6·9% [95% CI 4·2-9·6]; p<0·0001), total hip (combination group 5·0% [3·0-6·9], denosumab group 4·1% [2·5-5·8]; p<0·0001), and femoral neck (combination group 4·5% [1·9-7·9]; p=0·0008, denosumab group 3·8% [1·4-6·3]; p=0·0022]). Changes in BMD at the third distal forearm were borderline significant. Six non-fatal serious adverse events occurred (combination group [n=2], denosumab group [n=1], placebo group [n=3]). The overall prevalence of adverse events did not differ between treatment groups, and no fatal adverse events occurred.
INTERPRETATION: Evidence suggested denosumab was effective in improving BMD and lowering bone turnover in patients with primary hyperparathyroidism irrespective of cinacalcet treatment and might be a valid option for patients in which surgery is undesirable.
FUNDING: Aalborg University Hospital and Aalborg University, Denmark.
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