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A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates

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Abstract

Summary

In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites.

Introduction

This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis.

Methods

This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤−2.5 or ≤−1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo.

Results

Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442.

Conclusion

Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.

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Acknowledgments

The authors would like to thank Boyd B Scott, Ph.D., and Jennifer Pawlowski of Merck & Co. Inc. for their assistance in the preparation and submission of this manuscript.

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Corresponding author

Correspondence to F. Cosman.

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Conflicts of interest

FC has received consulting, advisory board, and speaker’s bureau fees or honorarium from the study sponsor, Merck & Co. Inc. FC has received consulting, advisory board, and speaker’s bureau fees or honorarium from Amgen, Eli Lilly, Novartis, GSK, Tarsa, Zosano, Pfizer, Unigene, Asahi-Kasei, and Enteris. FC’s Institution has received grants from Merck, Amgen, Eli Lilly, and Novartis.

NG has received consultancy fees and speaker’s bureau fees from GGM.

MM has received consulting, advisory board, and honorarium from the study sponsor, Merck & Co. Inc. MM has received consulting, advisory board, and honorarium from Amgen and Eli Lilly.

JF has received speaker’s bureau fees or honorarium from Merck & Co. Inc. Institution has received grants from the study sponsor, Merck & Co. Inc.

TDV has received advisory board, travel support, and speaker’s bureau fees or honorarium from the study sponsor, Merck & Co. Inc. TDV has received advisory board, travel support, and speaker’s bureau fees or honorarium from Adcock Ingram, Servier, Amgen, and Pfizer.

Authors AD, NH, AL, ER, SS, JM, and AC are all employees of Merck & Co. Inc and may own stock or stock options.

Funding

This study was funded by Merck & Co. Inc. The study protocol was the responsibility of Merck & Co. Inc. and designed in collaboration with the steering committee composed of the academic authors and various health authorities. All analyses were conducted by scientists at Merck & Co. Inc. All authors had full access to the study data and vouch for the completeness of the data set and the performance of the data analyses. This study was registered with clinicaltrials.gov identifier: with registration number NCT00996801.

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Cosman, F., Gilchrist, N., McClung, M. et al. A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates. Osteoporos Int 27, 377–386 (2016). https://doi.org/10.1007/s00198-015-3392-7

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