Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast–bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis.

中文翻译：

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组织蛋白酶 K 抑制剂治疗骨质疏松症：生物学、潜在临床实用性和经验教训


组织蛋白酶 K 是组织蛋白酶溶酶体蛋白酶家族的半胱氨酸蛋白酶成员。尽管组织蛋白酶 K 在破骨细胞中高度表达，但在多种其他组织中也发现了较低水平的组织蛋白酶 K。组织蛋白酶 K 从破骨细胞分泌到密封的破骨细胞-骨细胞界面中，导致 I 型胶原蛋白的有效降解。人体缺乏组织蛋白酶 K 活性会导致致密性骨质增生，其特征是骨矿物质密度增加和骨折。药理学组织蛋白酶 K 抑制可导致骨矿物质密度在 ≤5 年的治疗中持续增加，并提高脊柱和髋部的骨强度。与其他抗吸收剂相比，组织蛋白酶 K 抑制对于减少骨吸收的生化标志物几乎同样有效，但对于减少骨形成标志物的活性相对较低。尽管为开发组织蛋白酶 K 抑制剂进行了多次努力，但与抑制剂对其他组织蛋白酶的脱靶效应和非骨部位（包括皮肤以及可能的心血管和脑血管部位）的组织蛋白酶 K 抑制有关的潜在担忧延长了监管审批过程。最近完成了一项针对患有骨质疏松症的绝经后女性的 odanacatib 大型多国随机、双盲 III 期研究。尽管该研究证明了多部位骨折的临床相关减少，但在发现 odanacatib 与脑血管意外风险增加相关后，最终从监管审批程序中撤回。尽管如此，组织蛋白酶 K 抑制的潜在生物学和临床效果仍然引起人们极大的兴趣，并且可以指导未来骨质疏松症的治疗方法。