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.

中文翻译：

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Odanacatib对绝经后骨质疏松妇女骨结构和质量的影响：3期长期Odanacatib骨折试验（LOFT）的5年数据及其扩展。

Odanacatib（ODN）是组织蛋白酶K的选择性口服抑制剂，是先前正在开发的用于治疗骨质疏松症的研究药物。在此分析中，在随机，双盲，安慰剂对照，事件驱动的3期长期Odanacatib骨折试验（LOFT; NCT00529373）中，研究了ODN对骨重塑/建模和结构的影响，并计划进行两次绝经后骨质疏松妇女的盲区扩大。在基线（ODN n = 17，安慰剂n = 23），第24个月（ODN n = 112，安慰剂n = 104），第36个月（ODN n = 42，安慰剂n = 41）和第60个月（ODN n= 27，安慰剂n= 20）通过动态和静态骨组织形态学评估。该子集的基线和5年内BMD变化的患者特征与总体LOFT人群相当。活检的定性评估未发现异常。与ODN的机制一致，随着时间的推移，ODN的破骨细胞数高于安慰剂。关于骨重塑，经过2年的治疗，ODN治疗组与安慰剂治疗组的小梁，皮质内和皮质内表面的动态骨形成指数通常相似。关于骨膜建模，ODN治疗的患者与安慰剂相比，具有骨膜双标签的患者比例和骨形成指数随时间增加。这一发现支持了与安慰剂相比在第60个月观察到的皮质厚度的数值增加。总之，ODN治疗5年并没有减少骨重塑，也没有增加骨膜骨形成患者的比例。这些结果与ODN的作用机理一致，并且与LOFT 3期骨折试验中的安慰剂相比，BMD持续升高且骨折风险降低。©2020美国骨骼和矿物质研究学会。