Summary

This post hoc analysis and modeling study examined the mechanism of action of odanacatib using a statistical model to explain sCTx response in ODN-treated patients as a function of other bone-turnover biomarkers that, with other observed biomarker changes, showed that odanacatib persistently inhibited osteoclastic bone removal activity without preventing osteoclastogenesis.

Introduction

Odanacatib (ODN) is an oral selective cathepsin K (CatK) inhibitor, previously in development for osteoporosis treatment. A post hoc analysis examined ODN’s mechanism of action on bone-turnover biomarkers.

Methods

A subset of patients who completed 60 months’ treatment in the Long-Term Odanacatib Fracture Trial (LOFT; NCT00529373) (N = 112 [57 ODN, 55 placebo]) were evaluated. Serum (s) and urine (u) samples were assayed at baseline and months 6–60 for 10 known bone-remodeling biomarkers: sCTx, uαα- and uββCTx/Cr, uNTx/Cr, sNTx, uDPD/Cr, sICTP, sTRAP5b, sPINP, and sBSAP. Because the CrossLaps® CTx assay identifies the CTx peptide as well as larger molecular weight CTx-containing peptides, including ICTP, a best-fit model was developed to explain the transient sCTx reduction in ODN-treated patients.

Results

ODN persistently reduced the bone-resorption markers sNTx, uNTx/Cr, uαα- and uββCTx/Cr, and uDPD/Cr, and gradually increased the target-engagement marker sICTP and osteoclast number (sTRAP5b), versus placebo from baseline to month 60. sCTx was transiently reduced with ODN within 12 months, returning to baseline by month 48. Modeling suggested that sCTx changes in the ODN group were primarily due to increased accumulation of larger CTx species, including sICTP. The bone-formation markers sPINP and sBSAP showed partial reductions, versus placebo, in the first 6 months but approached baseline by months 48–60.

Conclusion

Observed changes in bone-turnover biomarkers support the persistent efficacy of ODN in direct inhibition of osteoclastic bone-resorption activity, without inhibition of osteoclastogenesis. Long-term evaluation also underscores the unique mechanism of ODN on osteoclastic collagen processing and subsequently osteoblastic bone formation.

Trial registration

NCT00529373.

中文翻译：

---

odanacatib 对骨质疏松绝经后妇女骨转换标志物的影响：LOFT 研究的事后分析

概括

这项事后分析和建模研究使用统计模型检查了 odanacatib 的作用机制，以解释 ODN 治疗患者的 sCTx 反应与其他骨转换生物标志物的关系，这些生物标志物与其他观察到的生物标志物变化表明，odanacatib 持续抑制破骨细胞在不阻止破骨细胞生成的情况下进行骨去除活动。

介绍

Odanacatib (ODN) 是一种口服选择性组织蛋白酶 K (CatK) 抑制剂，之前正在开发用于治疗骨质疏松症。事后分析检查了 ODN 对骨转换生物标志物的作用机制。

方法

在长期 Odanacatib 骨折试验 (LOFT; NCT00529373) ( N  = 112 [57 ODN, 55 安慰剂]) 中完成了 60 个月治疗的患者子集进行了评估。在基线和第 6-60 个月对血清 (s) 和尿液 (u) 样本进行了 10 种已知骨重塑生物标志物的检测：sCTx、uαα-和 uββCTx/Cr、uNTx/Cr、sNTx、uDPD/Cr、sICTP、sTRAP5b、 sPINP 和 sBSAP。由于 CrossLaps® CTx 测定可识别 CTx 肽以及较大分子量的含 CTx 肽，包括 ICTP，因此开发了一个最佳拟合模型来解释 ODN 治疗患者的瞬时 sCTx 减少。

结果

从基线到第 60 个月，与安慰剂相比，ODN 持续降低骨吸收标志物 sNTx、uNTx/Cr、uαα-和 uββCTx/Cr 和 uDPD/Cr，并逐渐增加靶标参与标志物 sICTP 和破骨细胞数量 (sTRAP5b)。 sCTx 在 12 个月内用 ODN 暂时降低，到第 48 个月恢复到基线。建模表明，ODN 组的 sCTx 变化主要是由于更大的 CTx 种类的积累增加，包括 sICTP。与安慰剂相比，骨形成标志物 sPINP 和 sBSAP 在前 6 个月显示部分减少，但在第 48-60 个月时接近基线。

结论

观察到的骨转换生物标志物的变化支持 ODN 在直接抑制破骨细胞骨吸收活性方面的持续功效，而不抑制破骨细胞生成。长期评估还强调了 ODN 对破骨细胞胶原加工和随后成骨细胞骨形成的独特机制。

试用注册

NCT00529373。