Publications

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.

Nephrogenic systemic fibrosis (NSF) is a disease of thickened, hard, hyperpigmented skin lesions with or without systemic fibrosis occurring in patients with renal insufficiency and associated with the administration of gadolinium-containing contrast. The pathogenesis of this disease is unclear, and there is no definitive treatment. We describe a 71-yr-old patient with stable chronic lymphocytic leukemia (CLL), end-stage renal disease (ESRD), and NSF who presented with hypercalcemia in 2006. Before onset of renal insufficiency in 2002, serum calcium, phosphorus, and PTH levels were normal. In 2004, the patient began hemodialysis, and he was diagnosed with NSF in 2005, shortly after undergoing an MRI with gadolinium contrast administration. Over the next 6 mo, albumin-corrected serum total calcium levels rose from 9.9 to 13.1 mg/dl (normal range, 8.5-10.5 mg/dl) with normal serum phosphorus levels. On admission in September 2006, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were elevated at 130.7 pg/ml (normal range, 25.1-66.1 pg/ml). Biopsy of an NSF lesion showed increased 25-hydroxyvitamin D(3)-1-alpha hydroxylase (CYP27B1) immunostaining compared with the biopsy from a normal control. This is the first reported association of NSF with hypercalcemia caused by elevated 1,25(OH)(2)D levels. This metabolic disturbance should be sought in future cases to determine a connection between NSF, 1,25(OH)(2)D metabolism, and CYP27B1 activation in the skin, which may shed light on the pathogenesis of this unusual local and systemic fibrosing disorder.

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.

Constitutive activity of the extracellular calcium-sensing receptor (CaSR) has been studied in kindreds with the human disorder autosomal dominant hypocalcemia (ADH) and in an animal model called the Nuf mouse. These families generally showed reduced parathyroid hormone (PTH) secretion and excessive renal calcium (Ca(2+)) excretion. Soft tissues calcifications in the kidney and basal ganglia are frequent (10-50% of ADH cases), and there is a single report of skeletal abnormalities in a family resulting in short stature and premature osteoarthritis. In the latter, a causative mechanism could not be determined. The phenotype of the Nuf mouse is one of ectopic calcifications and cataracts in addition to biochemical abnormalities (low serum Ca(2+) and high serum phosphate concentrations). To better understand the role of CaSRs in the control of osteoblastic function, we generated a transgenic mouse model with constitutively active CaSRs in mature osteoblasts. An analysis of the skeletal phenotype of that mouse indicates that strong signaling by CaSRs in this cell lineage induces alterations in the bone homeostasis reflected in mild osteopenia in male and female mice during growth and in adulthood. These studies indicate that this approach can be readily adapted to assess CaSR actions in other cell systems.

CONTEXT

Inactivating mutations of the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Most mutations are clustered in the N-terminal and Cys-rich regions of the extracellular domain (ECD) and seven-transmembrane domain. Disease-causing mutations are uncommon in the C terminus of ECD.

OBJECTIVE

The aim of the study was to characterize the CaSR mutations causing neonatal severe hyperparathyroidism in a consanguineous family.

METHODS

Parathyroid glands from the index patient were stained for CaSR protein. The CaSR gene was sequenced, mutations were recreated in CaSR cDNA, and HEK293 cells were transfected with the CaSR mutant expression vector. Cellular CaSR targeting was detected by immunoblotting and immunocytochemistry; CaSR activity was assayed by inositol phosphate accumulation, MAPK activation, and single-cell microfluorimetry.

RESULTS

Immunocytochemistry showed reduced intracellular CaSR in patient parathyroids. An in-frame homozygous deletion/insertion mutation, c.1031 > 1034 (delACAAinsT), replaced His344-Asn345 with a single Leu in CaSR loop III. The mutant reduced cell surface expression of CaSR in transfected HEK293 cells. Inositol phosphate accumulation, MAPK activation, and single-cell microfluorimetry revealed blunted signaling responses of the mutant receptor to changes in extracellular Ca(2+) concentration.

CONCLUSION

Deletion of His344-Asn345 in the ECD loop III region affects cell surface targeting of CaSR in transfected cells and in affected parathyroid glands. Absence of conserved Asn345 may interfere with CaSR folding or glycosylation, leading to poor protein targeting to the cell membrane. This loss-of-function mutant indicates that the ECD loop III is required for CaSR activity.

CONTEXT

Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations.

OBJECTIVE

The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity.

DESIGN AND SETTING

The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT.

PATIENTS

Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15).

INTERVENTION

The intervention in this study was treatment with cinacalcet for up to 4.5 yr.

OUTCOMES

Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period.

RESULTS

The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories.

CONCLUSIONS

Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.

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.

CONTEXT

The undercarboxylated form of the osteoblast-secreted protein osteocalcin has favorable effects on fat and glucose metabolism in mice. In human subjects, cross-sectional studies suggest a relevant association.

OBJECTIVE

We investigated whether changes in undercarboxylated osteocalcin (ucOC) during osteoporosis treatment are associated with changes in metabolic parameters.

DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS

We measured ucOC in sera from a subset of osteoporotic postmenopausal women who were treated with PTH(1-84) or alendronate (n = 64 and n = 33, respectively) during the Parathyroid Hormone and Alendronate study.

MAIN OUTCOME MEASURES

We measured serum adiponectin, leptin, and insulin and analyzed existing data on body weight, fat mass, and serum glucose concentration. Three-month changes in ucOC levels were evaluated as predictors of 12-month changes in indices of fat and glucose metabolism.

RESULTS

ucOC levels increased with PTH(1-84) and decreased with alendronate administration (P ≤ 0.01 for both treatment groups). Three-month change in ucOC was inversely associated with 12-month changes in body weight (standardized β = -0.25, P = 0.04) and fat mass (β = -0.23, P = 0.06), after adjustment for the treatment group. Three-month change in ucOC was positively associated with a 12-month change in adiponectin (β = 0.30, P = 0.01), independent of change in fat mass. There were no interactions between treatment and change in ucOC on changes in weight, fat mass, or adiponectin.

CONCLUSIONS

PTH(1-84) increases and alendronate decreases ucOC levels. Changes in ucOC induced by PTH(1-84) and alendronate are associated with changes in metabolic indices. These associations are consistent with observations from animal models and support a role for ucOC in the skeletal regulation of energy metabolism in humans.

We present the case of a 59-year-old woman with a history of plastic surgery at the forehead who complained of progressive indentations at the frontal skull. CT and MR scans revealed significant bone thinning, presenting as lytic skull lesions, which progressed over a period of 3 years. Biopsies were obtained from the lytic lesions and histology showed fibrotic tissue, synthetic residue of previous cosmetic procedure, and no evidence of infection or neoplasm. Progressive cranial bone resorption places the patient at increased risk for cerebral injury. This case highlights a potential complication after cosmetic facial surgery, with bony resorption resulting in both skull deformation and increased risk for cerebral injury.

The extracellular Ca(2+) -sensing receptor (CaR), a G protein-coupled receptor responsible for maintenance of calcium homeostasis, is implicated in regulation of skeletal metabolism. To discern the role of the osteoblast CaR in regulation of bone development and remodeling, we generated mice in which the CaR is excised in a broad population of osteoblasts expressing the 3.6-kb a(1) (I) collagen promoter. Conditional knockouts had abnormal skeletal histology at birth and developed progressively reduced mineralization secondary to retarded osteoblast differentiation, evident by significantly reduced numbers of osteoblasts and decreased expression of collagen I, osteocalcin, and sclerostin mRNAs. Elevated expression of ankylosis protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and osteopontin mRNAs in the conditional knockout indicate altered regulation of genes important in mineralization. Knockout of the osteoblast CaR also resulted in increased expression of the receptor activator of NF-κB ligand (RANKL), the major stimulator of osteoclast differentiation and function, consistent with elevated osteoclast numbers in vivo. Osteoblasts from the conditional knockouts exhibited delayed differentiation, reduced mineralizing capacity, altered expression of regulators of mineralization, and increased ability to promote osteoclastogenesis in coculture experiments. We conclude that CaR signaling in a broad population of osteoblasts is essential for bone development and remodeling and plays an important role in the regulation of differentiation and expression of regulators of bone resorption and mineralization.