Dolores Shoback

Clinical practice. Hypoparathyroidism.

Copyright

Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research.

Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease.

EXPRESSION AND SIGNAL TRANSDUCTION OF CALCIUM-SENSING RECEPTORS IN CARTILAGE AND BONE

We previously showed that Ca 21 -sensing receptors (CaRs) are expressed in chondrogenic RCJ3.1C5.18 (C5.18) cells and that changes in extracellular [Ca 21 ] ([Ca 21 ]o) modulate nodule formation and chondrogenic gene expression. In the present study, we detected expression of CaRs in mouse, rat, and bovine cartilage and bone by in situ hybridization, immunocytochemistry, immunoblotting, and RT-PCR; and we tested the effects of CaR agonists on signal transduction in chondrogenic and osteogenic cell lines. In situ hybridization detected CaR transcripts in most articular chondrocytes and in the hypertrophic chondrocytes of the epiphyseal growth plate. Expression of CaR transcripts was weak or absent, however, in proliferating and maturing chondrocytes in the growth plate. In bone, CaR transcripts were present in osteoblasts, osteocytes, and bone marrow cells, but rarely in osteoclasts. A complementary DNA was amplified from mouse growth plate cartilage, which was highly homologous to the human parathyroid CaR sequence. Immunocytochemistry of cartilage and bone with CaR antisera confirmed these findings. Western blotting revealed specific bands (;140 ‐190 kDa) in membrane fractions isolated from growth plate cartilage, primary cultures of rat chondrocytes, and several osteogenic cell lines (SaOS-2, UMR-106, ROS 17/2.8, and MC3T3-E1). InsP responses to high [Ca 21 ]o were evident in C5.18 cells and all osteogenic cell lines tested except for SaOS-2 cells. In the latter, high [Ca 21 ]o reduced PTH-induced cAMP formation. Raising [Ca 21 ]o also increased intracellular free [Ca 21 ]i n SaOS-2 and C5.18 cells. These studies confirm expression of CaRs in cartilage and bone and support the concept that changes in [Ca 21 ]o may couple to signaling pathways important in skeletal metabolism. (Endocrinology 140: 5883‐5893, 1999)

The Extracellular Calcium-Sensing Receptor (CaSR) Is a Critical Modulator of Skeletal Development

The extracellular calcium-sensing receptor (CaSR) is essential for embryonic and postnatal skeletal development. Bone Censor The extracellular calcium-sensing receptor (CaSR) is a guanine nucleotide-binding protein (G protein)–coupled receptor (GPCR) that responds to changes in the concentration of extracellular calcium ([Ca2+]e) and modulates various functions of parathyroid cells (PTCs), chondrocytes (the cells that produce cartilage), osteoblasts, and renal tubular cells. Previous attempts to characterize the CaSR in Casr−/− mice have been hampered by the expression of an alternatively spliced form of the receptor that provides at least partial compensation for loss of the full-length receptor (see the Perspective by Brown and Lian). Chang et al. have now developed mice with cell type–specific knockout of Casr that do not express the alternative receptor. Mice with PTC- or osteoblast-specific deletion of Casr were viable but had postnatal skeletal defects. Unexpectedly, knockout of Casr in chondrocytes was lethal. Mice in which chondrocyte-specific knockout of Casr was induced late in embryonic life were viable but had delayed growth plate development. Together, these findings reveal a previously unappreciated role for the CaSR in embryonic and postnatal skeletal development. The extracellular Ca2+-sensing receptor (CaSR) plays a nonredundant role in the functions of the parathyroid gland (PTG) and the kidney. Severe hyperparathyroidism, premature death, and incomplete gene excision in Casr−/− mice have precluded the assessment of CaSR function in other tissues. We generated mice with tissue-specific deletion of Casr in the PTG, bone, or cartilage. Deletion of Casr in the PTG or bone resulted in profound bone defects, whereas deletion of Casr in chondrocytes (cartilage-producing cells) resulted in death before embryonic day 13 (E13). Mice in which chondrocyte-specific deletion of Casr was induced between E16 and E18 were viable but showed delayed growth plate development. Our data show a critical role for the CaSR in early embryogenesis and skeletal development.

Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension.

In normal subjects, dietary sodium intake modulates renovascular, adrenal, and pressor responses to infused angiotensin II (AII). To examine the hypothesis that this modulation is abnormal in some patients with essential hypertension, we studied 18 hypertensives and 9 normal subjects twice--during dietary sodium restriction and during loading. Paraaminohippurate (PAH) clearance was used to assess renal plasma flow. AII was infused in graded doses (0.3-3.0 ng/kg per min). Plasma aldosterone, cortisol, renin activity, AII, sodium, potassium, and PAH clearance were measured at the onset and end of each AII dose. During dietary sodium repletion, eight of the subjects with essential hypertension showed a normal renovascular response (greater than 125 ml/min per 1.73 m2) to AII infusion (3 ng/kg per min). The decrement in renal blood flow in these normal responders (NR) was 168 +/- 10, which was comparable to the range in normotensive subjects (206 +/- 25 ml/min per 1.73 m2). All of the remaining hypertensive patients, designated abnormal responders (AbR), had lower (less than 125) renal blood flow responses to the same dose of infused AII (mean decrement: 84 +/- 11 ml/min per 1.73 m2) compared with the NR and normotensive subjects. Renal blood flow responses to all AII doses were statistically greater on a high-vs.-low salt diet in the NR (P less than 0.001, chi-square) and normotensives (P = 0.004, chi-square) but sodium intake had no effect on this response in the AbR. Basal renal blood flow in NR increased significantly (P less than 0.001, paired t test) with dietary sodium repletion, from 491 +/- 36 (low salt) to 602 +/- 40 ml/min per 1.73 m2 (high salt), but was almost identical in the AbR on differing dietary sodium intakes (429 +/- 24 vs. 425 +/- 26 ml/min per 1.73 m2). The adrenal responses to sodium intake and infused AII also differed in the two subgroups. In the NR, the adrenal response to AII was significantly greater (P = 0.011, Wilcoxon signed rank test) after sodium restriction. In contrast, there was no significant difference in the aldosterone response to AII infusion between the low and high sodium diets in the AbR. Thus, a substantial subgroup of essential hypertensives has an abnormality in responsiveness to AII in two systems central to volume homeostasis: the kidney and adrenal. They fail to modulate their renal blood flow and aldosterone responses to AII with changes in dietary sodium intake. Moreover, basal renal blood flow does not increase appropriately with increased sodium intake. These abnormalities, which may be due to an increased local production of AII or a defect in the AII receptors in these three target tissues, could contribute to the elevated blood pressure.

Cinacalcet Treatment of Primary Hyperparathyroidism: Biochemical and Bone Densitometric Outcomes in a Five-Year Study

CONTEXT Primary hyperparathyroidism (PHPT) is characterized by chronically elevated serum calcium and inappropriately normal or increased PTH. OBJECTIVE Our objective was to evaluate long-term tolerability, safety, and efficacy of cinacalcet in PHPT patients. DESIGN AND SETTING A 4.5-yr open-label extension study was conducted at 14 study centers in the United States. PATIENTS OR OTHER PARTICIPANTS Forty-five subjects with PHPT from a double-blind, placebo-controlled, 1-yr trial were continued into this study. INTERVENTIONS After the parent study, all subjects were treated with 30 mg cinacalcet twice daily, increasing to 50 mg twice daily during the 12-wk titration if serum calcium levels were 10.3 mg/dl or higher and then maintained on cinacalcet for up to 4.5 yr. MAIN OUTCOME MEASURES Assessments included serum calcium, PTH, phosphate and alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety chemistries and hematology, and adverse events were monitored throughout. RESULTS Compared with baseline, cinacalcet treatment improved biochemical measures of PHPT including reducing serum calcium and PTH and increasing serum phosphate with slight increases in alkaline phosphatase. No changes in z-scores of aBMD at spine, hip, or wrist were seen with annual percent changes, consistent with reports for untreated postmenopausal women or PHPT patients. Safety biochemistries remained normal, and adverse events (most commonly arthralgia, myalgia, diarrhea, respiratory infection, and nausea) were mild to moderate in severity. CONCLUSIONS Treatment of PHPT patients with cinacalcet for up to 5.5 yr maintained normocalcemia, reduced plasma PTH, increased serum phosphate and alkaline phosphatase with no significant effects on aBMD, and was well tolerated.

Fanconi's syndrome in HIV+ adults: report of three cases and literature review.

We diagnosed Fanconis syndrome (phosphate depletion and dysfunction of the renal tubules) in three HIV+ patients. This was temporally related to their HIV treatment. Physicians caring for patients with HIV should recognize the association of this rare syndrome with antiretroviral medications and monitor their patients carefully.

Medical Management of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop

BACKGROUND Primary hyperparathyroidism (PHPT) is a common endocrine disorder that is frequently asymptomatic. The 2002 International Workshop on Asymptomatic PHPT addressed medical management of asymptomatic PHPT and summarized the data on nonsurgical approaches to this disease. At the Third International Workshop on Asymptomatic PHPT held in May 2008, this subject was reviewed again in light of data that have since become available. We present the results of a literature review of advances in the medical management of PHPT. METHODS A series of questions was developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies evaluating the management of PHPT with bisphosphonates, hormone replacement therapy, raloxifene, and calcimimetics was conducted. Existing guidelines and recent unpublished data were also reviewed. All selected relevant articles were reviewed, and the questions developed by the International Task Force were addressed by the Consensus Panel. RESULTS Bisphosphonates and hormone replacement therapy are effective in decreasing bone turnover in patients with PHPT and improving bone mineral density (BMD). Fracture data are not available with either treatment. Raloxifene also lowers bone turnover in patients with PHPT. None of these agents, however, significantly lowers serum calcium or PTH levels. The calcimimetic cinacalcet reduces both serum calcium and PTH levels and raises serum phosphorus. Cinacalcet does not, however, reduce bone turnover or improve BMD. CONCLUSIONS Bisphosphonates and hormone replacement therapy provide skeletal protection in patients with PHPT. Limited data are available regarding skeletal protection in patients with PHPT treated with raloxifene. Calcimimetics favorably alter serum calcium and PTH in PHPT but do not significantly affect either bone turnover or BMD. Medical management of asymptomatic PHPT is a promising option for those who are not candidates for parathyroidectomy.

Cinacalcet Reduces Serum Calcium Concentrations in Patients with Intractable Primary Hyperparathyroidism

CONTEXT Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia. OBJECTIVE The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT. DESIGN This was an open-label, single-arm study comprising a titration phase of variable duration (2-16 wk) and a maintenance phase of up to 136 wk. SETTING The study was conducted at 23 centers in Europe, the United States, and Canada. PATIENTS The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter). INTERVENTION During the titration phase, cinacalcet dosages were titrated every 2 wk (30 mg twice daily to 90 mg four times daily) for 16 wk until serum calcium was 10 mg/dl or less (2.5 mmol/liter). If serum calcium increased during the maintenance phase, additional increases in the cinacalcet dose were permitted. MAIN OUTCOME MEASURE The primary end point was the proportion of patients experiencing a reduction in serum calcium of 1 mg/dl or greater (0.25 mmol/liter) at the end of the titration phase. RESULTS Mean +/- sd baseline serum calcium was 12.7 +/- 0.8 mg/dl (3.2 +/- 0.2 mmol/liter). At the end of titration, a 1 mg/dl or greater reduction in serum calcium was achieved in 15 patients (88%). Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. The most common adverse events were nausea, vomiting, and paresthesias. CONCLUSIONS In patients with intractable PHPT, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.

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.