Management of Hypoparathyroidism.

Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta-analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 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).

Initial Assessment and Monitoring of Patients with Chronic Hypoparathyroidism: A Systematic Current Practice Survey.

Chronic hypoparathyroidism (HypoPT) is associated with significant morbidity and impaired quality of life (QoL). The goals of management for chronic HypoPT include improvement in QoL and the prevention of both hypo- and hypercalcemia symptoms and long-term complications. Several groups have provided consensus statements and guidelines on the management of HypoPT; however, due to limited evidence, these recommendations have largely been based on literature reviews, expert opinion, and consensus statements. The objective of this study was to use a systematic approach to describe current practice for the initial assessment and follow-up of patients with chronic HypoPT. We developed a survey asking experts in the field to select the responses that best reflect their current practice. The survey found no differences in responses between nonsurgical and postsurgical patient assessment. For new patients, respondents usually performed an assessment of serum lab profile (calcium [either albumin-adjusted or ionized], magnesium, creatinine, phosphate, 25-hydroxyvitamin D), 24-hour urine (creatinine, calcium), and a renal ultrasound to evaluate for the presence of nephrocalcinosis or nephrolithiasis. For follow-up patients, most respondents perform blood tests and urine tests every 6 months or less frequently. The reported clinical practice patterns for monitoring for complications of chronic HypoPT vary considerably among respondents. Based on the responses in this systematic expert practice survey, we provide practice suggestions for initial assessment and follow-up of patients with chronic HypoPT. In addition, we highlight areas with significant variation in practice and identify important areas for future research. © 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).

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

CONTEXT: Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). OBJECTIVE: To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. DESIGN: Prospective open-label trial. SETTING: Tertiary medical center. PARTICIPANTS: Twenty-four subjects with hypoparathyroidism. INTERVENTION: Treatment with rhPTH(1-84) for 8 years. MAIN OUTCOME MEASURES: Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. RESULTS: PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean ± SE, 4.6% ± 1.5%; P = 0.01) and 8 years (2.6% ± 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean ± SE, -3.5% ± 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon. CONCLUSION: rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.

Diagnostic Performance of 4D CT and Sestamibi SPECT/CT in Localizing Parathyroid Adenomas in Primary Hyperparathyroidism.

Background There currently is no consensus on the optimal localization procedure and imaging protocol for parathyroid adenoma. Parathyroid four-dimensional (4D) CT has emerged as a promising method for preoperative localization. Purpose To evaluate the diagnostic performance of parathyroid 4D CT and technetium 99m-sestamibi (hereafter, referred to as sestamibi) SPECT/CT in preoperative localization in patients with primary hyperparathyroidism. Materials and Methods This was a single-institution retrospective study of patients with primary hyperparathyroidism who underwent a combined imaging protocol of sestamibi SPECT/CT and 4D CT (noncontrast, contrast agent-enhanced, arterial, and delayed venous phases) acquired in a single setting from February 2013 to May 2016, with subsequent parathyroidectomy within 6 months. Reference standard for correct localization was on the basis of location denoted on operative reports, with pathologic confirmation of parathyroid adenoma or hyperplasia. By using a four-quadrant analysis, sensitivity, specificity, and area under the curve (AUC) for localization of the hyperfunctioning parathyroid gland or glands at sestamibi SPECT/CT and 4D CT were compared, per modality and in combination. Results Four hundred patients (319 women, 81 men; mean age, 61 years ± 14 [standard deviation]) were evaluated. Similar diagnostic performance was found in both combined 4D CT with sestamibi SPECT/CT and 4D CT alone (area under the curve [AUC], 0.88 [95% CI: 0.86, 0.90] and 0.87 [95% CI: 0.85, 0.90], respectively; P = .82). Both modalities outperformed sestamibi SPECT/CT (AUC, 0.78; 95% CI: 0.76, 0.81; P < .001). Four-dimensional CT showed higher sensitivity than did sestamibi SPECT/CT (sensitivity, 79.3% [414 of 522] vs 58.0% [303 of 522], respectively; P < .001). In a subset analysis, 4D CT had higher sensitivity than sestamibi SPECT/CT in patients with single-gland disease (sensitivity, 92.5% [297 of 321] vs 75.1% [241 of 321], respectively; P < .001) and with multigland disease (sensitivity, 58.2% [117 of 201] vs 30.8% [62 of 201], respectively; P < .001). Conclusion Four-dimensional CT provided superior preoperative localization compared with sestamibi SPECT/CT in patients with single and multigland disease. The combination of the two modalities did not improve diagnostic performance compared with four-dimensional CT alone. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Sinha and Oates in this issue.

Quality of Life in Hypoparathyroidism Improves With rhPTH(1-84) Throughout 8 Years of Therapy.

CONTEXT: Calcium and vitamin D treatment does not improve reduced quality of life (QOL) in hypoparathyroidism. Recombinant human (rh) PTH(1-84) therapy improves QOL metrics for up to 5 years. Data on QOL beyond this time point are not available. OBJECTIVES: To evaluate the effects of 8 years of rhPTH(1-84) therapy on QOL and factors associated with long-term benefit. DESIGN: Prospective, open-label trial. SETTING: Referral center. PATIENTS: Twenty patients with hypoparathyoidism. MAIN OUTCOME MEASURES: RAND 36-Item Short Form Health Survey (SF-36). RESULTS: rhPTH therapy led to substantial improvement in five of the eight SF-36 domains [vitality, social functioning (SF), mental health (MH), bodily pain (BP) and general health] and three of these domains (SF, MH, BP) were no longer lower than the reference population. The improvement in the mental component summary (MCS) score was sustained through 8 years, while the physical component summary (PCS) score improved through 6 years. A lower baseline QOL score was associated with greater improvement. A threshold value <238 (MCS) and <245 (PCS) predicted long-term improvement in 90% and 100% of the cohort, respectively. In patients whose calcium supplementation was reduced, MCS and PCS scores improved more than those whose supplementation did not decline to the same extent. Improvement in PCS was greater in patients whose calcitriol dosage was reduced and duration of disease was shorter. CONCLUSIONS: rhPTH(1-84) improves long-term well-being in hypoparathyroidism. The improvements are most prominent in those with impaired SF-36 at baseline and those whose requirements for conventional therapy decreased substantially.

Current Understanding of Epidemiology, Pathophysiology, and Management of Atypical Femur Fractures.

PURPOSE OF REVIEW: To summarize reports published since the 2013 American Society of Bone and Mineral Research Task Force Report on atypical femoral fractures (AFF). RECENT FINDINGS: The absolute incidence of AFFs remains low. AFFs are primarily associated with prolonged bisphosphonate (BP) exposure, but have also been reported in unexposed patients and those receiving denosumab for osteoporosis and metastatic bone disease. Asians may be more susceptible to AFFs. Lateral femoral bowing and varus hip geometry, which increase loading forces on the lateral femoral cortex, may increase AFF risk. Altered bone material properties associated with BP therapy may predispose to AFFs by permitting initiation and increasing propagation of micro-cracks. Relevant genetic mutations have been reported in patients with AFFs. Single X-ray absorptiometry femur scans permit early detection of incomplete and/or asymptomatic AFFs. Orthopedists recommend intramedullary rods for complete AFFs and for incomplete, radiologically advanced AFFs associated with pain and/or marrow edema on MRI. Teriparatide may advance AFF healing but few data support its efficacy. Greater understanding of biological and genetic predisposition to AFF may allow characterization of individual risk prior to initiating osteoporosis therapy and help allay fear in those at low risk for this complication, which remains rare in comparison to the osteoporotic fractures prevented by antiresorptive therapy.

Occult urolithiasis in asymptomatic primary hyperparathyroidism.

OBJECTIVE: Recent international guidelines suggest renal imaging to detect occult urolithiasis in all patients with asymptomatic primary hyperparathyroidism (PHPT), but data regarding their prevalence and associated risk factors are limited. We evaluated the prevalence and risk factors for occult urolithiasis. METHODS: Cross-sectional analysis of 96 asymptomatic PHPT patients from a university hospital in the United States with and without occult nephrolithiasis. RESULTS: Occult urolithiasis was identified in 21% of patients. Stone formers had 47% higher 24-hour urinary calcium excretion (p = 0.002). Although available in only a subset of patients (n = 28), activated vitamin D [1,25(OH)2D] was 29% higher (p = 0.02) in stone formers. There was no difference in demographics, BMI, calcium or vitamin D intake, other biochemistries, renal function, BMD, or fractures. Receiver operating characteristic curves indicated that urinary calcium excretion and 1,25(OH)2D had an area under the curve of 0.724 (p = 0.003) and 0.750 (p = 0.04), respectively. A urinary calcium threshold of >211mg/day provided a sensitivity of 84.2% and a specificity of 55.3% while a 1,25(OH)2D threshold of >91pg/mL provided a sensitivity and specificity of 62.5% and 90.0% respectively for the presence of stones. CONCLUSION: Occult urolithiasis is present in about one-fifth of patients with asymptomatic PHPT and is associated with higher urinary calcium and 1,25(OH)2D. Given that most patients will not have occult urolithiasis, targeted imaging in those most likely to have occult stones rather than screening all asymptomatic PHPT patients may be useful. The higher sensitivity of urinary calcium versus 1,25(OH)2D suggests screening those with higher urinary calcium may be an appropriate approach.

Pre-operative localization of abnormal parathyroid tissue by 99mTc-sestamibi in primary hyperparathyroidism using four-quadrant site analysis: an evaluation of the predictive value of vitamin D deficiency.

CONTEXT: Accurate preoperative localization of abnormal parathyroid tissue aids importantly in minimally invasive parathyroidectomy in patients with primary hyperparathyroidism. Vitamin D deficiency may possibly influence the success and characteristics of pre-operative localization because it is associated with more active disease and possibly larger adenomas. This could increase the sensitivity of the sestamibi to identify abnormal parathyroid tissue, but earlier reports are conflicting. Vitamin D deficiency could also influence the nature of preoperative localization because it could lead to multi-gland stimulation of parathyroid tissue giving an appearance of multi-gland disease, which may lower accuracy of preoperative localization with sestamibi. OBJECTIVE: To examine the relationship between vitamin D deficiency and correct parathyroid tissue localization by four-pole thyroid quadrant analysis. DESIGN: Retrospective study. SETTING: Referral center. PARTICIPANTS: A total of 138 patients were divided into three groups according to the level of 25OHD; <20 ng/mL (vitamin D deficient), ≥20 to <30 ng/mL (vitamin D insufficient) and ≥30 ng/mL (vitamin D replete). MAIN OUTCOMES: Quadrant localization using 99mTc-sestamibi/SPECT. RESULTS: Among those with single-gland disease, the proportion of patients with correct quadrant localization were 60.0, 68.3 and 63.5% (p = 0.778), and the accuracy of sestamibi was 89.3, 90.6 and 89.9% for the deficient, insufficiency and replete groups, respectively. Among those with multi-gland disease, the proportion of patients with correct quadrant localization were 50.0, 25.0 and 18.2% (p = 0.619) while the accuracy was 50.0, 50.0 and 45.5%, respectively. Multi-gland disease did not occur more frequently in any of the three groups (p = 0.296). CONCLUSIONS: Vitamin D levels do not affect the accuracy of preoperative localization with sestamibi.

Trabecular Bone Score in Obese and Nonobese Subjects With Primary Hyperparathyroidism Before and After Parathyroidectomy.

Context: Obesity has been shown to be unfavorable to skeletal microarchitecture when assessed by trabecular bone score (TBS). The influence of adiposity on skeletal microstructure in primary hyperparathyroidism (PHPT) has not yet been evaluated. Objective: To investigate the effect of obesity on TBS and bone mineral density (BMD) in subjects with PHPT at baseline and through 2 years after parathyroidectomy. Design: Prospective observational study. Setting: Referral center. Patients or Other Participants: Thirty men and women with PHPT undergoing parathyroid surgery. Main Outcome Measures: TBS and BMD by dual-energy X-ray absorptiometry (DXA). Results: There were notable improvements in lumbar spine and femoral neck BMD in the obese (lumbar spine: 4.3 ± 4.7%, femoral neck: 3.8 ± 6.6%; P < 0.05 for both) and nonobese subjects (lumbar spine: 3.8 ± 5.6%, femoral neck 3.1 ± 5.0%; P < 0.05 for both) but no marked change in TBS in either group at 24 months postparathyroidectomy. Obese subjects had fully degraded TBS values compared with the nonobese subjects, whose TBS values were minimally below normal throughout the study (baseline: 1.199 ± 0.086 vs 1.327 ± 0.099, respectively; P = 0.003; 24 months: 1.181 ± 0.061 vs 1.352 ± 0.114, respectively; P = 0.001), despite improvements in BMD. Conclusions: The detrimental effect of obesity on TBS, an index of bone quality, was demonstrated in subjects with PHPT. Obesity was associated with fully degraded skeletal microarchitecture as measured by TBS in PHPT, despite similar values in bone density by DXA compared with nonobese subjects. TBS values did not improve postparathyroidectomy in either obese or nonobese subjects.

Skeletal Microstructure and Estimated Bone Strength Improve Following Parathyroidectomy in Primary Hyperparathyroidism.

Context: High-resolution peripheral quantitative computed tomography (HRpQCT) is a noninvasive imaging technology that can provide insight into skeletal microstructure and strength. In asymptomatic primary hyperparathyroidism (PHPT), HRpQCT imaging has demonstrated both decreased cortical and trabecular indices, consistent with evidence for increased fracture risk. There are limited data regarding changes in HRpQCT parameters postparathyroidectomy. Objective: To evaluate changes in skeletal microstructure by HRpQCT in subjects with PHPT after parathyroidectomy. Design: We studied 29 subjects with PHPT (21 women, 8 men) with HRpQCT at baseline and 6, 12, 18, and 24 months postparathyroidectomy. Main Outcome Measures: Volumetric bone mineral density, microarchitectural indices, and finite element analysis at the distal radius and tibia. Results: At both the radius and tibia, there were significant improvements in total, cortical, and trabecular volumetric bone density as early as 6 months postparathyroidectomy (24-month values for total volumetric bone density, radius: +2.8 ± 4%, tibia: +4.4 ± 4%; P < 0.0001 for both), cortical thickness (radius: +1.1 ± 2%, tibia: +2.0 ± 3%; P < 0.01 for both), and trabecular bone volume (radius: +3.8 ± 5%, tibia: +3.2 ± 4%; P < 0.0001 for both). At both sites, by finite element analysis, stiffness and failure load were improved starting at 6 months postparathyroidectomy (24-month values for failure load, radius: +6.2 ± 6%, tibia: +4.8 ± 7%; P < 0.0001 for both). Conclusions: These results provide information about skeletal microarchitecture in subjects with PHPT followed through 2 years after parathyroidectomy. Estimated bone strength is improved, consistent with data showing decreased fracture risk postparathyroidectomy.

Surgery or no surgery: What works best for the kidneys in primary hyperparathyroidism? A study in a multi-ethnic Asian population.

INTRODUCTION: Whether parathyroidectomy is more beneficial to renal function when compared to medical therapy or observation in primary hyperparathyroidism (PHPT) is unclear. Neither has this premise been explored in non-Caucasian populations. The estimated glomerular filtration rate (eGFR) threshold below which parathyroid hormone (PTH) levels rise if at all in PHPT has also not been established. We determined if surgery was superior to medical therapy and observation in a multi-ethnic Asian patient population with PHPT and whether there was an eGFR threshold below which PTH levels further increased in them. METHODS: Retrospective evaluation of patients with PHPT. RESULTS: There were 68.6% Chinese, 17.4% Malays, 10.7% Indians, and 3.3% Eurasians. The median (interquartile range) follow-up was 18.0 months (4.5-46.8). At last follow-up, eGFR in the surgical (80 ± 30 ml/min) was higher than the medical (52 ± 32 ml/min) or observation groups (48 ± 33 ml/min); P < 0.01. This difference persisted after adjusting for age, gender, ethnicity, pre-intervention eGFR levels, nephrolithiasis, serum calcium, phosphate, urinary calcium, and duration of follow-up; P = 0.035. There was no definite eGFR level below which PTH values rose. CONCLUSION: Our study provides compelling evidence that in PHPT, surgery may be associated with a better renal outcome compared to medical management or observation. This has to be confirmed through prospective randomized controlled trials and the reasons for this finding have to be elucidated through functional and histological measures. The finding in our study of a lack of a specific eGFR threshold below which PTH levels further rose challenges the concept of a fixed renal threshold for secondary elevations of PTH in PHPT.