Osteoporosis Research Center, School of Medicine, Creighton University, Omaha, NE, USA.
Regional Bone Center, Helen Hayes Hospital, West Haverstraw and Columbia University, New York, NY, USA.
J Bone Miner Res. 2020 Jul;35(7):1289-1299. doi: 10.1002/jbmr.3994. Epub 2020 May 5.
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.
odanacatib（ODN）是一种组织蛋白酶 K 的选择性口服抑制剂，之前是作为骨质疏松症的治疗药物进行研发的。在这项分析中，观察了 ODN 对骨重塑/建模和结构的影响，该分析基于随机、双盲、安慰剂对照、事件驱动的 3 期长期odanacatib 骨折试验（LOFT；NCT00529373）和绝经后骨质疏松症患者的计划双盲扩展研究。共对 386 例经患者同意获得的横骨活检样本（ODN 组 n = 17，安慰剂组 n = 23）、第 24 个月（ODN 组 n = 112，安慰剂组 n = 104）、第 36 个月（ODN 组 n = 42，安慰剂组 n = 41）和第 60 个月（ODN 组 n = 27，安慰剂组 n = 20）进行了动态和静态骨组织形态计量学评估。该亚组患者的基线特征和 5 年期间的 BMD 变化与 LOFT 总体人群相当。对活检样本的定性评估显示无异常。与 ODN 的作用机制一致，随着时间的推移，破骨细胞数量在 ODN 组中高于安慰剂组。关于骨重塑，在接受 2 年治疗后，在接受 ODN 治疗的患者与接受安慰剂治疗的患者中，小梁、皮质内和内皮质表面的动态骨形成指数通常相似。关于骨膜建模，与安慰剂相比，接受 ODN 治疗的患者中，骨膜双标记和骨形成指数随时间推移而增加。这一发现支持了与安慰剂相比，在第 60 个月时观察到的皮质厚度的数值增加。总之，5 年的 ODN 治疗并未减少骨重塑，反而增加了接受骨膜成骨治疗的患者比例。这些结果与 ODN 的作用机制一致，并与 LOFT 3 期骨折试验中与安慰剂相比，持续增加 BMD 和降低骨折风险相关。 © 2020 美国骨骼与矿物质研究学会。
