A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates
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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Osteoporosis international - 27(2015), 1 vom: 10. Nov., Seite 377-386 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cosman, F. [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Bisphosphonate |
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| Anmerkungen: |
© International Osteoporosis Foundation and National Osteoporosis Foundation 2015 |
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| doi: |
10.1007/s00198-015-3392-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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SPR001724010 |
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| 245 | 1 | 2 | |a 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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| 520 | |a 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. | ||
| 650 | 4 | |a Bisphosphonate |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Calcium-sensing receptor antagonist |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Osteoporosis |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Gilchrist, N. |4 aut | |
| 700 | 1 | |a McClung, M. |4 aut | |
| 700 | 1 | |a Foldes, J. |4 aut | |
| 700 | 1 | |a de Villiers, T. |4 aut | |
| 700 | 1 | |a Santora, A. |4 aut | |
| 700 | 1 | |a Leung, A. |4 aut | |
| 700 | 1 | |a Samanta, S. |4 aut | |
| 700 | 1 | |a Heyden, N. |4 aut | |
| 700 | 1 | |a McGinnis, J. P. |4 aut | |
| 700 | 1 | |a Rosenberg, E. |4 aut | |
| 700 | 1 | |a Denker, A. E. |4 aut | |
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