TY - JOUR
T1 - Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis
T2 - 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension
AU - Recker, Robert
AU - Dempster, David
AU - Langdahl, Bente
AU - Giezek, Hilde
AU - Clark, Seth
AU - Ellis, Graham
AU - de Villiers, Tobias
AU - Valter, Ivo
AU - Zerbini, Cristiano A.F.
AU - Cohn, Dosinda
AU - Santora, Arthur
AU - Duong, Le T.
N1 - Funding Information:
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance, under direction of the authors, was provided by Annette Smith, PhD, of CMC AFFINITY, Complete Medical Communications, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. We also thank Boyd B. Scott (Merck & Co., Inc., Kenilworth, NJ, USA) for editorial support, Steven Doleckyj who was the project manager for this study, Paul Miller who provided study materials or patients, and all of the clinical scientists and the patients who donated biopsies. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA's data sharing policy, including restrictions, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com. Authors' roles: All authors take responsibility for the integrity of the data analysis. Author's Contribution: Conception, design or planning the study: DC, RR, AS; Acquisition of data: RR, BL, CAFZ, IV; Analysis of data: DC, HG, RR, AS, SC, LTD; Interpretation of results: DC, DD, HG, RR, AS, BL, TdV, GE, CAFZ, IV, LTD; All authors contributed to the drafting, reviewing or revising of the manuscript.
Funding Information:
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance, under direction of the authors, was provided by Annette Smith, PhD, of CMC AFFINITY, Complete Medical Communications, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. We also thank Boyd B. Scott (Merck & Co., Inc., Kenilworth, NJ, USA) for editorial support, Steven Doleckyj who was the project manager for this study, Paul Miller who provided study materials or patients, and all of the clinical scientists and the patients who donated biopsies. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA's data sharing policy, including restrictions, is available at http://engagezone.msd.com/ds_documentation.php . Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com .
Funding Information:
RR received funds from Merck & Co., Inc., Kenilworth, NJ, USA to process the biopsies for the trial. DD has received grants from Amgen and Eli Lilly & Co.; consulting fees from Amgen, Eli Lilly & Co., Merck & Co., Inc., Kenilworth, NJ, USA, Radius Health, and Tarsa; speaking fees from Amgen and Eli Lilly & Co.; and medical writing fees from Radius Health. BL has, on behalf of her institution, received a grant from Merck & Co., Inc., Kenilworth, NJ, USA for conducting the trial; has received grants from Eli Lilly & Co., Novo Nordisk, and Orkla Health for research support; and has received personal fees from Amgen, Eli Lilly & Co., Merck & Co., Inc., Kenilworth, NJ, USA, and UCB for advisory boards and lectures. HG, SC, DC, AS, and LTD are, or were at the time of study conduct, employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in the company. TdV has received consulting fees from Merck & Co., Inc., Kenilworth, NJ, USA; speaking fees from Abbott, Aspen, Adcock Ingram, Bayer, Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer; and personal fees from Amgen, Adcock Ingram, and Pfizer for advisory boards. CAFZ has received a grant for research from Merck & Co., Inc., Kenilworth, NJ, USA. GE and IV have no conflicts of interest.
Publisher Copyright:
© 2020 American Society for Bone and Mineral Research
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
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U2 - 10.1002/jbmr.3994
DO - 10.1002/jbmr.3994
M3 - Article
C2 - 32119749
AN - SCOPUS:85085063763
VL - 35
SP - 1289
EP - 1299
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
IS - 7
ER -