Normocalcemic primary hyperparathyroidism.

Normocalcemic primary hyperparathyroidism (PHPT) is a newer phenotype of PHPT defined by elevated PTH concentrations in the setting of normal serum calcium levels. It is increasingly being diagnosed in the setting of evaluation for nephrolithiasis or metabolic bone diseases. It is important to demonstrate that PTH values remain consistently elevated and to measure ionized calcium levels to make the diagnosis. A diagnosis of normocalcemic disease is one of exclusion of secondary forms of hyperparathyroidism, including vitamin D deficiency, renal failure, medications, malabsorption, and hypercalciuria. Lack of rigorous diagnostic criteria and selection bias of the studied populations may explain the different rates of bone and renal complications. The natural history still remains unknown. Caution should be used in recommending surgery, unless clearly indicated. Here we will review the diagnostic features, epidemiology, clinical presentation, natural history, medical and surgical management of normocalcemic PHPT.

Normocalcemic primary hyperparathyroidism

ABSTRACT Normocalcemic primary hyperparathyroidism (PHPT) is a newer phenotype of PHPT defined by elevated PTH concentrations in the setting of normal serum calcium levels. It is increasingly being diagnosed in the setting of evaluation for nephrolithiasis or metabolic bone diseases. It is important to demonstrate that PTH values remain consistently elevated and to measure ionized calcium levels to make the diagnosis. A diagnosis of normocalcemic disease is one of exclusion of secondary forms of hyperparathyroidism, including vitamin D deficiency, renal failure, medications, malabsorption, and hypercalciuria. Lack of rigorous diagnostic criteria and selection bias of the studied populations may explain the different rates of bone and renal complications. The natural history still remains unknown. Caution should be used in recommending surgery, unless clearly indicated. Here we will review the diagnostic features, epidemiology, clinical presentation, natural history, medical and surgical management of normocalcemic PHPT.

Changes in Skeletal Microstructure Through Four Continuous Years of rhPTH(1-84) Therapy in Hypoparathyroidism.

Bone remodeling is reduced in hypoparathyroidism, resulting in increased areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and abnormal skeletal indices by transiliac bone biopsy. We have now studied skeletal microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT) through 4 years of treatment with recombinant human PTH(1-84) (rhPTH[1-84]) in 33 patients with hypoparathyroidism (19 with postsurgical disease, 14 idiopathic). We calculated Z-scores for our cohort compared with previously published normative values. We report results at baseline and 1, 2, and 4 years of continuous therapy with rhPTH(1-84). The majority of patients (62%) took rhPTH(1-84) 100 µg every other day for the majority of the 4 years. At 48 months, areal bone density increased at the lumbar spine (+4.9% ± 0.9%) and femoral neck (+2.4% ± 0.9%), with declines at the total hip (-2.3% ± 0.8%) and ultradistal radius (-2.1% ± 0.7%) (p < .05 for all). By HR-pQCT, at the radius site, very similar to the ultradistal DXA site, total volumetric BMD declined from baseline but remained above normative values at 48 months (Z-score + 0.56). Cortical volumetric BMD was lower than normative controls at baseline at the radius and tibia (Z-scores -1.28 and - 1.69, respectively) and further declined at 48 months (-2.13 and - 2.56, respectively). Cortical porosity was higher than normative controls at baseline at the tibia (Z-score + 0.72) and increased through 48 months of therapy at both sites (Z-scores +1.80 and + 1.40, respectively). Failure load declined from baseline at both the radius and tibia, although remained higher than normative controls at 48 months (Z-scores +1.71 and + 1.17, respectively). This is the first report of noninvasive high-resolution imaging in a cohort of hypoparathyroid patients treated with any PTH therapy for this length of time. The results give insights into the effects of long-term rhPTH(1-84) in hypoparathyroidism. © 2020 American Society for Bone and Mineral Research.

Update on hypoparathyroidism.

PURPOSE OF REVIEW: Hypoparathyroidism is a rare endocrine disorder characterized by low or insufficient parathyroid hormone (PTH) concentrations leading to hypocalcemia, hyperphosphatemia, and markedly reduced bone turnover. Despite being a rare disease, hypoparathyroidism has a profound impact on affected patients. RECENT FINDINGS: Recent epidemiologic surveys demonstrate a prevalence of between 5.3 and 40/100 000, confirming the orphan status of this disease. There is a female predominance, and anterior neck surgery is the most common etiology. Recent studies have better elucidated the chronic manifestations of the disease, impacting quality of life and multiple organ systems including the renal, cardiovascular, and skeletal systems. There are now data on longer term use of parathyroid hormone (PTH) and PTH analogs. SUMMARY: This review focuses on recent contributions to the literature on the prevalence and epidemiology of the disease, risk of chronic manifestations, and treatment with PTH(1-34) and rhPTH(1-84). Further research is needed to determine the pathophysiology of complications in hypoparathyroidism and whether interventions can decrease future risk of these complications. In addition, further data are needed with regards to more physiologic dosing regimens and long-term treatment with PTH and PTH analogs.

Primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management.

Primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management.

Signs and Symptoms of Hypoparathyroidism.

Hypoparathyroidism is associated with a spectrum of clinical manifestations in the acute and chronic settings, from mild to debilitating. Although the acute symptoms of hypocalcemia are primarily due to neuromuscular irritability, the chronic manifestations of hypoparathyroidism may be due to the disease itself or to complications of therapy or to both. The chronic complications of hypoparathyroidism can affect multiple organ systems, including the renal, neurologic, neuropsychiatric, skeletal, and immune systems. Further research is needed to determine the pathophysiology of complications in hypoparathyroidism and whether interventions can decrease the risk of these complications.

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.

Hyperparathyroidism.

Primary hyperparathyroidism is a common endocrine disorder of calcium metabolism characterised by hypercalcaemia and elevated or inappropriately normal concentrations of parathyroid hormone. Almost always, primary hyperparathyroidism is due to a benign overgrowth of parathyroid tissue either as a single gland (80% of cases) or as a multiple gland disorder (15-20% of cases). Primary hyperparathyroidism is generally discovered when asymptomatic but the disease always has the potential to become symptomatic, resulting in bone loss and kidney stones. In countries where biochemical screening tests are not common, symptomatic primary hyperparathyroidism tends to predominate. Another variant of primary hyperparathyroidism has been described in which the serum calcium concentration is within normal range but parathyroid hormone is elevated in the absence of any obvious cause. Primary hyperparathyroidism can be cured by removal of the parathyroid gland or glands but identification of patients who are best advised to have surgery requires consideration of the guidelines that are regularly updated. Recommendations for patients who do not undergo parathyroid surgery include monitoring of serum calcium concentrations and bone density.

Primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common disorder in which parathyroid hormone (PTH) is excessively secreted from one or more of the four parathyroid glands. A single benign parathyroid adenoma is the cause in most people. However, multiglandular disease is not rare and is typically seen in familial PHPT syndromes. The genetics of PHPT is usually monoclonal when a single gland is involved and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumour-suppressor genes. Hypercalcaemia is the biochemical hallmark of PHPT. Usually, the concentration of PTH is frankly increased but can remain within the normal range, which is abnormal in the setting of hypercalcaemia. Normocalcaemic PHPT, a variant in which the serum calcium level is persistently normal but PTH levels are increased in the absence of an obvious inciting stimulus, is now recognized. The clinical presentation of PHPT varies from asymptomatic disease (seen in countries where biochemical screening is routine) to classic symptomatic disease in which renal and/or skeletal complications are observed. Management guidelines have recently been revised to help the clinician to decide on the merits of a parathyroidectomy or a non-surgical course. This Primer covers these areas with particular attention to the epidemiology, clinical presentations, genetics, evaluation and guidelines for the management of PHPT.

Noninvasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism.

In hypoparathyroidism, areal bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is above average, and skeletal indices by bone biopsy are abnormal. We used high-resolution peripheral quantitative computed tomography (HRpQCT) and finite element analyses (FEA) to further investigate skeletal microstructure and estimated bone strength. We studied 60 hypoparathyroid subjects on conventional therapy using DXA, HRpQCT, and FEA of the distal radius and tibia compared with normative controls from the Canadian Multicentre Osteoporosis Study. In hypoparathyroid women and men, areal BMD was above average at the lumbar spine and hip sites by DXA; radial BMD was also above average in hypoparathyroid women. Using HRpQCT, cortical volumetric BMD was increased in the hypoparathyroid cohort compared with controls at both the radius and tibia. Cortical porosity was reduced at both sites in pre- and postmenopausal women and at the tibia in young men with a downward trend at the radius in men. At the tibia, trabecular number was increased in premenopausal women and men and trabecular thickness was lower in women. Ultimate stress and failure load at both sites for the hypoparathyroid subjects were similar to controls. Using a linear regression model, at both radius and tibia, each increment in age decreased ultimate stress and failure load, whereas each increment in duration of hypoparathyroidism increased these same indices. These results provide additional evidence for the critical role of parathyroid hormone in regulating skeletal microstructure. Longer disease duration may mitigate the adverse effects of age on estimated bone strength in hypoparathyroidism.

An overview of normocalcemic primary hyperparathyroidism.

PURPOSE OF REVIEW: Normocalcemic primary hyperparathyroidism (PHPT) received special attention in the publication of the conference proceedings from the Fourth International Workshop on the Management of Asymptomatic PHPT, although much remains unknown about the disorder. RECENT FINDINGS: Observational studies have found that despite maintaining normocalcemia, patients with normocalcemic PHPT have a high incidence of kidney stones and osteoporosis. Small studies focusing on the cardiovascular implications of normocalcemic PHPT have shown a possible association with hypertension and an atherogenic lipid profile, but not insulin resistance. Recent data from small cohorts show that subjects with normocalcemic PHPT respond to medical therapy and have a positive densitometric response following parathyroid surgery. SUMMARY: The available evidence suggests that patients with normocalcemic PHPT develop complications of PHPT, despite having normal calcium levels. Most data come from referral populations and information regarding a mild, asymptomatic form of the disease is lacking. Future research requires a standardized approach to the diagnostic criteria of normocalcemic PHPT.

Skeletal Effects of Smoking.

Smoking is a leading cause of preventable death and disability. Smoking has long been identified as a risk factor for osteoporosis, with data showing that older smokers have decreased bone mineral density and increased fracture risk compared to nonsmokers, particularly at the hip. The increase in fracture risk in smokers is out of proportion to the effects on bone density, indicating deficits in bone quality. Advanced imaging techniques have demonstrated microarchitectural deterioration in smokers, particularly in the trabecular compartment. The mechanisms by which smoking affects skeletal health remain unclear, although multiple pathways have been proposed. Smoking cessation may at least partially reverse the adverse effects of smoking on the skeleton.

PTH(1-84) replacement therapy for the treatment of hypoparathyroidism.

Hypoparathyroidism is a rare disease characterized by hypocalcemia and insufficient circulating levels of parathyroid hormone (PTH). Conventional therapy includes calcium and active vitamin D supplementation, often in large doses. Therapy with calcium and vitamin D, however, does not address certain problematic aspects of the disease, including abnormal bone metabolism and reduced quality of life. Hypoparathyroidism is the only classic endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved treatment. PTH(1-84) may soon become a therapeutic option for patients with hypoparathyroidism. PTH (1-84) has been demonstrated to maintain serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation. Data from bone densitometry, bone turnover markers and histomorphometry of bone biopsy specimens show positive structural and dynamic effects on the skeleton. PTH replacement therapy may also be associated with improved quality of life. PTH(1-84) replacement therapy for hypoparathyroidism is promising, although further acquisition of long-term data is needed.

Parathyroid hormone 1-84 alters circulating vascular endothelial growth factor levels in hypoparathyroidism.

CONTEXT: We previously reported on four patients treated with PTH(1-84) who recovered from postoperative hypoparathyroidism many years after onset. Because vascular endothelial growth factor (VEGF) has been shown to be necessary for the induction of PTH-mediated angiogenesis, we postulated a possible role for VEGF in the recovery of parathyroid function in these subjects. OBJECTIVE: Our objective was to measure VEGF levels in subjects with hypoparathyroidism who regained parathyroid gland function and matched controls. SETTING AND DESIGN: Subjects with hypoparathyroidism who regained parathyroid gland function were each matched to two hypoparathyroid controls by postoperative etiology, age (within 5 y), menopausal status, and duration of hypoparathyroidism. We measured serum VEGF levels at baseline and through 48 months of PTH(1-84) therapy. RESULTS: VEGF levels increased after the initiation of PTH(1-84) therapy for the entire cohort, from 309.7 ± 162 pg/ml at baseline to 380.2 ± 178 pg/ml at 12 months (P = .03). Levels trended downward thereafter. There were no significant differences in VEGF levels between the subjects with recovery of parathyroid function and the matched controls. CONCLUSIONS: PTH(1-84) alters serum VEGF levels in subjects with hypoparathyroidism. Additional investigation is necessary to understand the mechanisms by which some subjects with postoperative hypoparathyroidism recover parathyroid gland function.

Bone disease in primary hyperparathyroidism.

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.

Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.

OBJECTIVE: This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT. PARTICIPANTS: This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed. EVIDENCE: Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up. CONSENSUS PROCESS: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel. CONCLUSIONS: 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism) is increasing, data on the clinical presentation and natural history of this phenotype are limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current data do not support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomical or functional abnormalities. 6) Some patients with mild PHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.

Bone disease in primary hyperparathyroidism / Doença óssea no hiperparatiroidismo primário

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.

A doença óssea no hiperparatiroidismo primário grave é representada pela osteíte fibrosa cística (OFC). Dor óssea, deformidades esqueléticas e fraturas patológicas são achados comuns na OFC. A densidade mineral óssea está, usualmente, extremamente diminuída na OFC, mas é reversível após a cura cirúrgica. Os sinais e sintomas da doença óssea grave incluem dor óssea, fraturas patológicas e fraqueza muscular proximal com hiper-reflexia. O comprometimento ósseo é tipicamente caracterizado pela aparência em “sal-e-pimenta” nos ossos do crânio, erosões ósseas e reabsorção das falanges, tumores marrons e cistos. Na radiografia, observam-se desmineralização difusa e fraturas patológicas especialmente nos ossos longos das extremidades. No hiperparatiroidismo primário (HPTP) sintomático grave, as concentrações séricas de cálcio e PTH estão usualmente bem elevadas e o comprometimento renal se caracteriza pela presença de urolitíase e nefrocalcinose. Uma nova tecnologia, recentemente aprovada para uso clínico nos Estados Unidos e na Europa, torna-se provável se difundir rapidamente, pois utiliza as imagens geradas pela densitometria DXA. O escore trabecular ósseo (TBS), obtido por meio da análise do nível da textura cinza das imagens dos corpos vertebrais, fornece informações indiretas sobre a microarquitetura trabecular. Novos métodos, como a tomografia de alta resolução quantitativa periférica computadorizada (HRpqCT), têm proporcionado conhecimentos adicionais sobre os achados da microarquitetura esquelética no HPTP.

Recovery of parathyroid hormone secretion and function in postoperative hypoparathyroidism: a case series.

CONTEXT: Transient and permanent postoperative hypoparathyroidism are recognized complications of neck surgery. Postoperative hypoparathyroidism is usually considered permanent when it persists for 6 months; in rare cases, recovery of hypoparathyroidism through 1 year has been described. Recovery of hypoparathyroidism years after diagnosis has not previously been reported. OBJECTIVE: We report four patients being treated with PTH(1-84) in a research protocol who recovered from postoperative hypoparathyroidism many years after onset. METHODS: Recovery from hypoparathyroidism was established by: 1) serum calcium and PTH levels within the normal range off PTH(1-84) treatment for at least 1 week; 2) requirement for daily calcium supplementation reduced to ≤1 g; and 3) no supplemental active vitamin D therapy. RESULTS: Hypoparathyroidism developed in three subjects after repeated neck surgery for primary hyperparathyroidism and in one subject after total thyroidectomy for Graves' disease. Parathyroid tissue autotransplant was performed in two of the four subjects. Two had undetectable PTH levels at study entry, whereas the other two subjects had detectable, although low, PTH levels. Hypoparathyroidism had been present for at least 8 years, and in one case for 16 years. The recovery of parathyroid function followed treatment with PTH(1-84) for 36 to 63 months. CONCLUSIONS: Although it remains relatively rare, this report documents recovery of long-term postoperative hypoparathyroidism many years after the initial diagnosis. A potential role for exogenous PTH is intriguing with several plausible mechanisms.