A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis

Abstract

Context: MK-5442 is an orally bioavailable calcium-sensing receptor antagonist that is hypothesized to stimulate bone formation by stimulating endogenous secretion of a pulse of PTH. Earlier clinical and preclinical studies demonstrated increased bone mineral density (BMD) after treatment.

Objective: Our objective was to identify a dose of MK-5442 that produces osteoanabolic effects without excessive hypercalcemia.

Design and setting: This was a randomized, double-blind, placebo-controlled, parallel-group trial of private or institutional practice.

Participants and intervention: In total, 383 postmenopausal women with osteoporosis were administered daily oral MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo.

Main outcome measures: Serum PTH and calcium, bone turnover markers, areal BMD, and safety were evaluated.

Results: A dose-dependent transient increase in PTH occurred after an MK-5442 dose and lasted more than 3.5 hours. Compared with placebo, significant increases in bone formation markers (serum procollagen 1 N-terminal peptide and bone-specific alkaline phosphatase) were observed by 6 months, whereas bone resorption markers (serum C-telopeptide of type 1 collagen, urine N-telopeptides of type 1 collagen) initially decreased but were also significantly increased by 6 months. Despite the biochemical marker changes suggestive of an anabolic response, there were no statistically significant differences between any dose of MK-5442 and placebo in percent change from baseline at month 6 in any of the BMD endpoints. The frequency of hypercalcemia (trough serum calcium ≥ 10.8 mg/dL) was greater with higher MK-5442 doses.

Conclusion: In postmenopausal women with low bone mass, treatment with MK-5442 resulted in transient pulses of PTH. Bone formation markers increased quickly and bone resorption markers decreased temporarily, suggestive of an anabolic window. However, there were no increases in BMD versus placebo.

Trial registration: ClinicalTrials.gov NCT00960934.

Figures

Figure 1.. Patient disposition.

Figure 2.. Measures of calcium homeostasis.

A, Mean serum PTH (residues 1–84) increases from baseline at predose and 1 and 3.5 hours after administration of MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo at week 1 and months 1 and 6. B, Mean serum calcium (mg/dL) change from baseline at predose and 1 and 3.5 hours after administration of MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo at week 1 and months 1 and 6. Abbreviation: ULN, upper limit of normal.

Figure 3.. BTMs end points.

Graphic representation of the percent change from baseline (95% confidence interval) of BTMs at baseline and 1, 3, and 6 months after treatment with MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo. A, Bone formation markers (P1NP and BSAP). B, Bone resorption markers (CTx and NTx).