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

• Published in: Osteoporosis international Vol. 27; no. 1; pp. 377 - 386
• Main Authors: Cosman, F., Gilchrist, N., McClung, M., Foldes, J., de Villiers, T., Santora, A., Leung, A., Samanta, S., Heyden, N., McGinnis, J. P., Rosenberg, E., Denker, A. E.
• Format: Journal Article
• Language: English
• Published: London Springer London 01.01.2016; Springer Nature B.V
• Subjects: Administration, Oral; Aged; Antagonist drugs; Benzoates - therapeutic use; Biomarkers - blood; Bone Density - drug effects; Bone Density Conservation Agents - therapeutic use; Clinical trials; Diphosphonates - administration & dosage; Diphosphonates - therapeutic use; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug therapy; Endocrinology; Female; Femur Neck - physiopathology; Hip Joint - physiopathology; Humans; Lumbar Vertebrae - physiopathology; Medicine; Medicine & Public Health; Menopause; Middle Aged; Original Article; Orthopedics; Osteoporosis; Osteoporosis, Postmenopausal - drug therapy; Osteoporosis, Postmenopausal - physiopathology; Parathyroid Hormone - blood; Propanolamines - therapeutic use; Receptors, Calcium-Sensing - antagonists & inhibitors; Rheumatology; Postmenopausal; Calcium-sensing receptor antagonist; Osteoporosis; Bisphosphonate; Randomized clinical trial; PTH
• ISSN: 0937-941X; 1433-2965
• DOI: 10.1007/s00198-015-3392-7

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.