A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates
UNLABELLED: 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: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA - 27(2016), 1 vom: 01. Jan., Seite 377-86 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cosman, F [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.10.2016 Date Revised 13.11.2018 published: Print-Electronic ClinicalTrials.gov: NCT00996801 Citation Status MEDLINE |
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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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| PPN (Katalog-ID): |
NLM254523803 |
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| 041 | |a eng | ||
| 100 | 1 | |a Cosman, F |e verfasserin |4 aut | |
| 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 |
| 264 | 1 | |c 2016 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 31.10.2016 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT00996801 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a UNLABELLED: 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bisphosphonate | |
| 650 | 4 | |a Calcium-sensing receptor antagonist | |
| 650 | 4 | |a Osteoporosis | |
| 650 | 4 | |a PTH | |
| 650 | 4 | |a Postmenopausal | |
| 650 | 4 | |a Randomized clinical trial | |
| 650 | 7 | |a Benzoates |2 NLM | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Bone Density Conservation Agents |2 NLM | |
| 650 | 7 | |a Diphosphonates |2 NLM | |
| 650 | 7 | |a JTT 305 |2 NLM | |
| 650 | 7 | |a Parathyroid Hormone |2 NLM | |
| 650 | 7 | |a Propanolamines |2 NLM | |
| 650 | 7 | |a Receptors, Calcium-Sensing |2 NLM | |
| 700 | 1 | |a Gilchrist, N |e verfasserin |4 aut | |
| 700 | 1 | |a McClung, M |e verfasserin |4 aut | |
| 700 | 1 | |a Foldes, J |e verfasserin |4 aut | |
| 700 | 1 | |a de Villiers, T |e verfasserin |4 aut | |
| 700 | 1 | |a Santora, A |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, A |e verfasserin |4 aut | |
| 700 | 1 | |a Samanta, S |e verfasserin |4 aut | |
| 700 | 1 | |a Heyden, N |e verfasserin |4 aut | |
| 700 | 1 | |a McGinnis, J P |c 2nd |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenberg, E |e verfasserin |4 aut | |
| 700 | 1 | |a Denker, A E |e verfasserin |4 aut | |
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