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反应作为其他骨转换生物标志物的功能,其他观察到的生物标志物变化,显示odanacatib持续抑制破骨细胞骨去除活性而不阻止破骨细胞生成。
背景:Odanacatib(ODN)是一种口服选择性组织蛋白酶K(CatK)抑制剂,以前在开发骨质疏松症治疗。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)中完成60个月治疗的患者子集(N=112[57ODN,55安慰剂])进行了评估。血清(s)和尿液(u)样品在基线和6-60个月测定10个已知的骨重建生物标志物:sCTx,uαα-和uββCTx/Cr,uNTx/Cr,sNTx,uDPD/Cr,sICTP,sTRAP5b,sPINP,和sBSAP。由于CrossLaps®CTx检测可识别CTx肽以及较大分子量的含CTx肽,包括ICTP,我们建立了一个最佳拟合模型来解释ODN治疗患者的短暂性sCTx降低.
结果:ODN持续降低骨吸收标志物sNTx,uNTx/Cr,uαα-和uββCTx/Cr,和uDPD/Cr,并逐渐增加靶接合标记物sICTP和破骨细胞数量(sTRAP5b),与安慰剂相比,从基线到60个月。sCTx在12个月内随ODN短暂降低,由48个月返回基线。建模表明,ODN组中的sCTx变化主要是由于较大CTx物种的积累增加,包括sICTP。骨形成标志物sPINP和sBSAP显示部分减少,与安慰剂相比,在前6个月,但在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直接抑制破骨细胞骨吸收活性的持续疗效,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的成骨细胞骨形成的独特机制。
背景:NCT00529373。
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.
BACKGROUND: 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.
CONCLUSIONS: 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.
BACKGROUND: NCT00529373.