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J Bone Miner Res. 2020 Mar 2. doi: 10.1002/jbmr.3994. [Epub ahead of print]

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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Creighton University, Omaha, Nebraska, USA.
Helen Hayes Hospital, West Haverstraw and Columbia University, New York, New York, USA.
Aarhus University Hospital, Aarhus, Denmark.
MSD Europe Inc., Brussels, Belgium.
Merck & Co., Inc., Kenilworth, New Jersey, USA.
Synexus Helderberg Clinical Research Centre, Somerset West, South Africa.
Mediclinic Panorama and Department of Obstetrics & Gynaecology, University of Stellenbosch, Cape Town, South Africa.
CCBR, Tallinn, Estonia.
Centro Paulista de Investigações Clínicas, São Paulo, Brazil.


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), -36 (ODN n = 42, placebo n = 41), and - 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- versus placebo-treated patients after 2 years' 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. This article is protected by copyright. All rights reserved.


Bone histomorphometry; bone modeling and remodeling; clinical trials; osteoporosis; therapeutics


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