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

Autor: Elizabeth Rosenberg, T. J. de Villiers, J. Foldes, Albert T. Leung, Norman Heyden, Felicia Cosman, Andrew Denker, Arthur C. Santora, N. Gilchrist, Michael R. McClung, J.P. McGinnis, Suvajit Samanta
Rok vydání: 2015
Předmět:
0301 basic medicine
bisphosphonate
medicine.medical_specialty
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Osteoporosis
Administration
Oral
Parathyroid hormone
030209 endocrinology & metabolism
Placebo
Benzoates
Drug Administration Schedule
Bone remodeling
Propanolamines
03 medical and health sciences
0302 clinical medicine
Double-Blind Method
Bone Density
Internal medicine
medicine
Humans
pth
Osteoporosis
Postmenopausal
Aged
Bone mineral
postmenopausal
Lumbar Vertebrae
Bone Density Conservation Agents
Diphosphonates
Dose-Response Relationship
Drug
Femur Neck
business.industry
Antagonist
Middle Aged
Bisphosphonate
randomized clinical trial
medicine.disease
osteoporosis
030104 developmental biology
Endocrinology
Parathyroid Hormone
calcium-sensing receptor antagonist
Female
Hip Joint
Calcium-sensing receptor
business
Receptors
Calcium-Sensing
Biomarkers
Zdroj: Osteoporosis International. 27:377-386
ISSN: 1433-2965
0937-941X
DOI: 10.1007/s00198-015-3392-7
Popis: 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.
Databáze: OpenAIRE
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