Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. OBJECTIVE: This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. METHODS: This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). RESULTS: By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 µg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. CONCLUSION: TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Basal Ganglia Calcification Is Associated With Local and Systemic Metabolic Mechanisms in Adult Hypoparathyroidism.

CONTEXT: Hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone, which may be associated with soft tissue calcification in the basal ganglia of the brain. OBJECTIVE: To assess the prevalence and factors involved in the pathophysiology of basal ganglia calcification (BGC) in the brain in chronic hypoparathyroidism and to evaluate proposed pathophysiologic mechanisms. DESIGN: Case-control study with retrospective review of medical records over 20 years. SETTING: Single academic medical center. PATIENTS: 142 patients with chronic hypoparathyroidism and computed tomography (CT) head scans followed between January 1, 2000 and July 9, 2020, and 426 age- and sex-matched controls with CT head scans over the same interval. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Demographic, biochemical, and CT head imaging findings, with semiquantitative assessment of volumetric BGC. RESULTS: The study found that 25.4% of 142 patients followed for a median of 17 years after diagnosis of chronic hypoparathyroidism had BGC, which developed at a younger age than in controls. BGC was 5.1-fold more common in nonsurgical patients and less common in postsurgical patients. Low serum calcium and low calcium/phosphate ratio correlated with BGC. Neither serum phosphorus nor calcium × phosphate product predicted BGC. Lower serum calcium was associated with greater volume of BGC. The extent of BGC varied widely, with nonsurgical patients generally having a greater volume and distribution of calcification. CONCLUSIONS: BGC is associated with low serum calcium and low serum calcium/phosphate ratio, which may be related to severity of the disease, its etiology, or duration of treatment.

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

Challenges in the management of chronic hypoparathyroidism.

The first adjunctive hormone therapy for chronic hypoparathyroidism, recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] was approved by the FDA in January 2015. Since the approval of rhPTH(1-84), growing interest has developed in other agents to treat this disorder in both the scientific community and among pharmaceutical companies. For several reasons, conventional therapy with calcium and activated vitamin D supplementation, magnesium supplementation as needed, and occasionally thiazide-type diuretic therapy remains the mainstay of treatment, while endocrinologists and patients are constantly challenged by limitations of conventional treatment. Serum calcium fluctuations, increased urinary calcium, hyperphosphatemia, and a constellation of symptoms that limit mental and physical functioning are frequently associated with conventional therapy. Understanding how conventional treatment and hormone therapy work in terms of pharmacokinetics and pharmacodynamics is key to effectively managing chronic hypoparathyroidism. Multiple questions remain regarding the effectiveness of PTH adjunctive therapy in preventing or slowing the onset and progression of the classical complications of hypoparathyroidism, such as chronic kidney disease, calcium-containing kidney stones, cataracts, or basal ganglia calcification. Several studies point toward an improvement in quality of life during replacement therapy. This review will discuss current clinical and research challenges posed by treatment of chronic hypoparathyroidism.

A Lot of Progress, With More to Be Done: A Response to NIH Pathways to Prevention Report "Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention".

The public health implications of osteoporosis are enormous but the disease remains underdiagnosed and undertreated. In October 2018, the National Institutes of Health (NIH) convened a Pathways to Prevention (P2P) Workshop entitled "Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention" designed to identify research gaps, suggest future research opportunities, and advance the field through an evidence-based assessment. By design, the P2P report focused on "gaps" in our knowledge base. Unfortunately, however, the report did not sufficiently acknowledge the current evidence that unequivocally demonstrates the therapeutic efficacy of existing pharmacologic therapies for osteoporosis, which has the potential to exacerbate the current crises in osteoporosis diagnosis and treatment. © 2019 American Society for Bone and Mineral Research.

MANAGEMENT OF ENDOCRINE DISEASE: Hypoparathyroidism in pregnancy: review and evidence-based recommendations for management.

Purpose Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy. Methods We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review. Conclusions During pregnancy, calcitriol levels increase by two- to-three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.

Standards of care for hypoparathyroidism in adults: a Canadian and International Consensus.

PURPOSE: To provide practice recommendations for the diagnosis and management of hypoparathyroidism in adults. METHODS: Key questions pertaining to the diagnosis and management of hypoparathyroidism were addressed following a literature review. We searched PubMed, MEDLINE, EMBASE and Cochrane databases from January 2000 to March 2018 using keywords 'hypoparathyroidism, diagnosis, treatment, calcium, PTH, calcidiol, calcitriol, hydrochlorothiazide and pregnancy'. Only English language papers involving humans were included. We excluded letters, reviews and editorials. The quality of evidence was evaluated based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. These standards of care for hypoparathyroidism have been endorsed by the Canadian Society of Endocrinology and Metabolism. RESULTS: Hypoparathyroidism is a rare disease characterized by hypocalcemia, hyperphosphatemia and a low or inappropriately normal serum parathyroid hormone level (PTH). The majority of cases are post-surgical (75%) with nonsurgical causes accounting for the remaining 25% of cases. A careful review is required to determine the etiology of the hypoparathyroidism in individuals with nonsurgical disease. Hypoparathyroidism is associated with significant morbidity and poor quality of life. Treatment requires close monitoring as well as patient education. Conventional therapy with calcium supplements and active vitamin D analogs is effective in improving serum calcium as well as in controlling the symptoms of hypocalcemia. PTH replacement is of value in lowering the doses of calcium and active vitamin D analogs required and may be of value in lowering long-term complications of hypoparathyroidism. This manuscript addresses acute and chronic management of hypoparathyroidism in adults. MAIN CONCLUSIONS: Hypoparathyroidism requires careful evaluation and pharmacologic intervention in order to improve serum calcium and control the symptoms of hypocalcemia. Frequent laboratory monitoring of the biochemical profile and patient education is essential to achieving optimal control of serum calcium.

Recombinant Human Parathyroid Hormone Effect on Health-Related Quality of Life in Adults With Chronic Hypoparathyroidism.

Context: Reduced health-related quality of life (HRQoL) is common in patients with hypoparathyroidism treated conventionally with calcium and active vitamin D supplements. Objective: To examine the effects of recombinant human parathyroid hormone [rhPTH(1-84)] on HRQoL as measured by the 36-Item Short-Form Health Survey (SF-36) during a multinational, randomized, placebo-controlled study. Patients: Adults (N = 122) with chronic hypoparathyroidism. Intervention(s): After an optimization period when calcium and/or active vitamin D supplements were adjusted to reach target serum calcium levels (8.0 to 9.0 mg/dL; 2.0 to 2.2 mmol/L), patients were randomly assigned to receive placebo (n = 39) or rhPTH(1-84) (n = 83) (starting dose, 50 µg/d, could be titrated up to 100 µg/d); supplement doses were adjusted to maintain target serum calcium levels. Main Outcome Measure(s): Change from baseline (postoptimization, at randomization) to week 24 in HRQoL as assessed by the SF-36. Results: Overall, the between-group differences were not statistically significant. However, in the rhPTH(1-84) group, there were significant improvements in the physical component summary score (P = 0.004), and in body pain (P < 0.05), general health (P < 0.05), and vitality (P < 0.001) domains as compared with baseline values. In the placebo group, there were no significant changes for any domains. The magnitude of change between 0 and 24 weeks in SF-36 scores was negatively correlated with baseline scores, such that patients with lower HRQoL at baseline were more likely to experience improvement in response to treatment. Conclusion: Treatment with rhPTH(1-84) may improve HRQoL in adults with hypoparathyroidism.

Hypoparathyroidism.

Hypoparathyroidism is a disease characterized by inadequately low circulating concentrations of parathyroid hormone (PTH) resulting in low calcium levels and increased phosphate levels in the blood. Symptoms of the disease result from increased neuromuscular irritability caused by hypocalcaemia and include tingling, muscle cramps and seizures. The most common cause of the disease is inadvertent removal of, or injury to, the parathyroid glands during neck surgery, followed by genetic, idiopathic and autoimmune aetiologies. Conventional treatment includes activated vitamin D and/or calcium supplements, but this treatment does not fully replace the functions of PTH and can lead to short-term problems (such as hypocalcaemia, hypercalcaemia and increased urinary calcium excretion) and long-term complications (which include nephrocalcinosis, kidney stones and brain calcifications). PTH replacement has emerged as a new treatment option. Clinical trials using human PTH(1-34) and PTH(1-84) showed that this treatment was safe and effective in studies lasting up to 6 years. Recombinant human PTH(1-84) has been approved in the United States and Europe for the management of hypoparathyroidism; however, its effect on long-term complications is still being evaluated. Clinical practice guidelines, which describe the consensus of experts in the field, have been published and recognize the need for more research to optimize care. In this Primer, we summarize current knowledge of the prevalence, pathophysiology, clinical presentation and management of hypoparathyroidism.

Safety and Efficacy of Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism Randomly Assigned to Receive Fixed 25-µg or 50-µg Daily Doses.

PURPOSE: The present study examined the efficacy and safety of a lower rhPTH(1-84) dose. METHODS: RELAY was a dose-blinded, multicenter, 8-week study of patients with hypoparathyroidism randomized to fixed 25- or 50-µg/d doses of subcutaneous rhPTH(1-84). The primary end point was the percentage of patients at week 8 with supplement reductions in calcium to ≤500 mg/d and in calcitriol to ≤0.25 µg/d, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. The secondary end point was the percentage of patients at week 8 with a ≥50% reduction in calcium and calcitriol doses, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. FINDINGS: Forty-two patients were randomized (25-µg group, n = 19; 50-µg group, n = 23). At week 8, the primary end point was achieved by 4 (21%; 95% CI, 6%-46%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. The secondary end point was achieved by 2 (11%; 95% CI, 1%-33%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. Treatment-emergent adverse events were reported by 11 (58%) patients in the 25-µg group and 17 (74%) patients in the 50-µg group. IMPLICATIONS: Doses as low as 25 µg/d of rhPTH(1-84) are well tolerated and may be effective for a subset of patients. ClinicalTrials.gov identifier: NCT01268098.

Proceedings of the 2016 Santa Fe Bone Symposium: New Concepts in the Management of Osteoporosis and Metabolic Bone Diseases.

The Santa Fe Bone Symposium is an annual meeting of healthcare professionals and clinical researchers that details the clinical relevance of advances in knowledge of skeletal diseases. The 17th Santa Fe Bone Symposium was held in Santa Fe, New Mexico, USA, on August 5-6, 2016. The program included plenary lectures, oral presentations by endocrinology fellows, meet-the-professor sessions, and panel discussions, all aimed to provide ample opportunity for interactive discussions among all participants. Symposium topics included recent developments in the translation of basic bone science to patient care, new clinical practice guidelines for postmenopausal osteoporosis, management of patients with disorders of phosphate metabolism, new and emerging treatments for rare bone diseases, strategies to enhance fracture healing, and an update on Bone Health Extension for Community Healthcare Outcomes, using a teleconferencing platform to elevate the level of knowledge of healthcare professionals in underserved communities to deliver best practice care for skeletal diseases. The highlights and important clinical messages of the 2016 Santa Fe Bone Symposium are provided herein by each of the faculty presenters.

Review of Hypoparathyroidism.

Hypoparathyroidism is a rare endocrine disorder in which parathyroid hormone (PTH) production is abnormally low or absent, resulting in low serum calcium and increased serum phosphorus. The most common cause of hypoparathyroidism is parathyroid gland injury or inadvertent removal during thyroid surgery. Current treatments include supplementation with calcium and active vitamin D, with goal albumin-corrected serum calcium level in the low-normal range of 8-9 mg/dl. Complications of the disease include renal dysfunction, nephrocalcinosis, kidney stones, extracellular calcifications of the basal ganglia, and posterior subcapsular cataracts, as well as low bone turnover and increased bone density. Until January 2015, hypoparathyroidism was the only classic endocrine disease without an available hormone replacement. Recombinant human PTH 1-84, full-length PTH, is now available for a selected group of patients with the disease who are not well controlled on the current standard therapy of calcium and active vitamin D. In addition, the role of PTH replacement on quality of life, intracerebral calcifications, cataracts, improving bone turnover, and reduction of renal complications of the disease remains to be further investigated.

Teriparatide Therapy and Reduced Postoperative Hospitalization for Postsurgical Hypoparathyroidism.

IMPORTANCE: Up to 20% of patients undergoing thyroidectomy develop hypocalcemia after surgery. Although usually transient, severe symptomatic hypocalcemia may occur. Teriparatide acetate (recombinant human parathyroid hormone 1-34) therapy can rapidly raise calcium levels. OBJECTIVE: To test the hypothesis that teriparatide therapy in patients with postthyroidectomy hypoparathyroidism would expedite relief of symptomatic hypocalcemia and reduce the duration of hospitalization compared with standard treatment. DESIGN, SETTING, AND PARTICIPANTS: Case series of all hospitalized patients 18 years or older treated with teriparatide for symptomatic postthyroidectomy hypocalcemia occurring immediately after thyroidectomy at Mayo Clinic, Rochester, Minnesota, between January 1, 2008, and June 30, 2014. A secondary analysis was performed with matched control and cohort groups having postthyroidectomy hypocalcemia of similar degree who received standard treatment only. Participants included 8 hospitalized patients who received teriparatide therapy after 24 hours of standard treatment (cases) and eight control patients selected from a cohort of 1193 thyroidectomies were matched for age, sex, body mass index, and nadir calcium levels. INTERVENTION: Teriparatide acetate therapy (20 µg twice daily) subcutaneously for 1 week, with the option of continuing at 20 µg/d for up to 3 weeks. MAIN OUTCOMES AND MEASURES: Safety, symptom resolution, calcium supplementation, and duration of hospitalization. RESULTS: Among the 16 case and control patients the median nadir calcium level was 7.1 mg/dL in both groups. Most patients underwent thyroidectomy for thyroid cancer. Teriparatide therapy was safe, with no adverse events noted, and completely eliminated symptomatic hypocalcemia in all treated patients within 24 hours of initiation. Hospital discharge occurred at a median of 1.0 day (interquartile range, 1.0-1.0 day) after teriparatide therapy initiation among cases vs 2.5 days (interquartile range, 1.8-3.0 days) after the equivalent clinical point was reached in controls (P = .01). This value was 2.0 days in the source cohort (P = .02). On hospital discharge, patients had similar calcium levels. Six months after surgery, all patients treated with teriparatide showed partial or complete parathyroid recovery. Calcium supplementation and calcium levels were comparable between the groups. CONCLUSIONS AND RELEVANCE: In this pilot study, teriparatide therapy in patients with postthyroidectomy hypoparathyroidism was safe, rapidly eliminated hypocalcemic symptoms, and likely reduced the duration of hospitalization. Given the limitations of this small study, a large-scale randomized trial is needed to verify these results and to assess the long-term effect of teriparatide therapy on clinical outcomes.

Serum 25-Hydroxyvitamin D Levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range.

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25-hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at-risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non-white populations.

Coexisting primary hyperparathyroidism and sarcoidosis cause increased angiotensin-converting enzyme and decreased parathyroid hormone and phosphate levels.

CONTEXT: Primary hyperparathyroidism (PHPT) and sarcoidosis may separately contribute to abnormal calcium and phosphate metabolism via different mechanisms, and their coexistence is infrequently reported. OBJECTIVE: We sought to characterize a group of 50 patients with coexisting PHPT and sarcoidosis in our institution to evaluate their clinical and laboratory characteristics. DESIGN AND SETTING: This was a retrospective observational study of patients with both disorders at our institution between January 1980 and December 2011. OUTCOME: A cohort of 50 patients was identified, with mean ± SD age 59.6 ± 13.9 years and 86% women. Serum calcium in the cohort was 11.1 ± 1.1 mg/dL, phosphate was 3.3 ± 0.6 mg/dL, and PTH was 76 ± 42 pg/mL. Serum 25-hydroxyvitamin D was 25 ± 9 ng/mL, and serum 1,25-dihydroxyvitamin D was 51 ± 20 pg/mL; 24-hour urine calcium was 275 ± 211 mg. In subjects with sarcoidosis, serum angiotensin-converting enzyme (ACE) was 47.2 ± 37.4 U/L. Sarcoidosis was diagnosed first in 50% of patients, PHPT was diagnosed first in 16% of patients, and sarcoidosis and PHPT were both diagnosed within 6 months of each other in 30% of patients. The interval between the 2 diagnoses when sarcoidosis was diagnosed first was 15.5 ± 12.4 years and was 5.5 ± 6.0 years when PHPT was diagnosed first. Patients with PHPT who had active sarcoidosis had higher serum ACE levels (60.9 ± 38.1 vs 20.2 ± 14.0 U/L, P <.0001), lower PTH levels (60 ± 24 vs 96 ± 41 pg/mL, P = .01), and lower phosphate levels (2.7 ± 0.6 vs 3.2 ± 0.5 mg/dL, P = .02). CONCLUSIONS: Fifty patients with coexisting PHPT and sarcoidosis are described, with patients with PHPT coexisting with clinically active sarcoidosis having increased serum ACE levels and decreased serum PTH and phosphate levels compared with those with inactive sarcoidosis.

Fibrous dysplasia of bone associated with primary hyperparathyroidism.

OBJECTIVE: Fibrous dysplasia of bone and primary hyperparathyroidism (PHPT) may occur in patients with McCune-Albright Syndrome. A small number of cases with both diagnoses that are not associated with the above-mentioned genetic disorder have been published in the literature. It is uncertain if these disorders are linked in some way. In the present study, we aimed to further explore a potential relationship between PHPT and fibrous dysplasia of bone. METHODS: We conducted a retrospective review of all cases seen at Mayo Clinic, Rochester, Minnesota, between 1976 and 2011 that were diagnosed with both PHPT and fibrous dysplasia of bone. RESULTS: We identified 10 patients who were diagnosed with both PHPT and fibrous dysplasia of bone. Fibrous dysplasia was polyostotic in 7 (70%) cases. It affected the lower extremities in 6 (60%) patients, the skull or facial bones in 4 (40%), and was localized to one rib in 1 patient (10%). In 4 patients, fibrous dysplasia was diagnosed first, between 9 to 50 years before being diagnosed with PHPT. Two cases of fibrous dysplasia were recognized between 2 and 5 years after the diagnosis of PHPT. The remaining 4 patients were diagnosed with both conditions at approximately the same time. CONCLUSION: It remains unclear if the association between fibrous dysplasia of bone and PHPT is more than coincidental, although the possibility of a rare familial genetic syndrome is not completely excluded.

Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study.

BACKGROUND: Hypoparathyroidism results in impaired mineral homoeostasis, including hypocalcaemia and hyperphosphataemia. Treatment with high-dose oral calcium and active vitamin D does not provide adequate or consistent control of biochemical indices and can lead to serious long-term complications. We aimed to test the efficacy, safety, and tolerability of once-daily recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) in adults with hypoparathyroidism. METHODS: In this double-blind, placebo-controlled, randomised phase 3 study (REPLACE), we recruited patients with hypoparathyroidism (≥ 18 months duration) aged 18-85 years from 33 sites in eight countries. After an optimisation period, during which calcium and active vitamin D doses were adjusted to achieve consistent albumin-corrected serum calcium, patients were randomly assigned (2:1) via an interactive voice response system to 50 µg per day of rhPTH(1-84) or placebo for 24 weeks. Active vitamin D and calcium were progressively reduced, while rhPTH(1-84) could be titrated up from 50 µg to 75 µg and then 100 µg (weeks 0-5). The primary endpoint was the proportion of patients at week 24 who achieved a 50% or greater reduction from baseline in their daily dose of oral calcium and active vitamin D while maintaining a serum calcium concentration greater than or the same as baseline concentrations and less than or equal to the upper limit of normal, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00732615. FINDINGS: Between June 23, 2009, and Feb 28, 2011, 134 eligible patients were recruited and randomly assigned to rhPTH(1-84) (n=90) or placebo (n=44). Six patients in the rhPTH(1-84) group and seven in the placebo group discontinued before study end. 48 (53%) patients in the rhPTH(1-84) group achieved the primary endpoint compared with one (2%) patient in the placebo group (percentage difference 51.1%, 95% CI 39.9-62.3; p<0.0001). The proportions of patients who had at least one adverse event were similar between groups (84 [93%] patients in the rhPTH[1-84] group vs 44 [100%] patients in the placebo group), with hypocalcaemia, muscle spasm, paraesthesias, headache, and nausea being the most common adverse events. The proportions of patients with serious adverse events were also similar between the rhPTH(1-84) group (ten [11%] patients) and the placebo group (four [9%] patients). INTERPRETATION: 50 µg, 75 µg, or 100 µg per day of rhPTH(1-84), administered subcutaneously in the outpatient setting, is efficacious and well tolerated as a PTH replacement therapy for patients with hypoparathyroidism.

Vitamin D insufficiency.

Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials.