Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension |
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| Authors: | Robert Recker David Dempster Bente Langdahl Hilde Giezek Seth Clark Graham Ellis Tobias de Villiers Ivo Valter Cristiano AF Zerbini Dosinda Cohn Arthur Santora Le T Duong |
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| Institution: | 1. Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA;2. Regional Bone Center, Helen Hayes Hospital, West Haverstraw and Columbia University, New York, NY, USA;3. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark;4. Biostatistics, MSD Europe Inc., Brussels, Belgium;5. Biostatistics, Merck & Co., Inc., Kenilworth, NJ, USA;6. Synexus Helderberg Clinical Research Centre, Somerset West, South Africa;7. Mediclinic Panorama and Department of Obstetrics & Gynaecology, University of Stellenbosch, Cape Town, South Africa;8. Center for Clinical and Basic Research (CCBR), Tallinn, Estonia;9. Centro Paulista de Investigações Clínicas, São Paulo, Brazil;10. Clinical Operations, Merck & Co., Inc., Kenilworth, NJ, USA;11. Clinical, Merck & Co., Inc., Kenilworth, NJ, USA;12. Preclinical Discovery, Merck & Co., Inc., Kenilworth, NJ, USA |
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| Abstract: | Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research. |
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| Keywords: | BONE HISTOMORPHOMETRY BONE MODELING AND REMODELING CLINICAL TRIALS OSTEOPOROSIS THERAPEUTICS |
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