Duong Le T, Crawford Randy, Scott Kevin, Winkelmann Christopher T, Wu Gouxin, Szczerba Pete, Gentile Michael A
Bone Biology, Merck Research Laboratories, Kenilworth, NJ, USA.
Informatics, Merck Research Laboratories, Kenilworth, NJ, USA.
Bone. 2016 Dec;93:86-96. doi: 10.1016/j.bone.2016.09.012. Epub 2016 Sep 15.
Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7.5μM·h, in food) or ALN (0.2mg/kg/wk, s.c.) and compared to vehicle-treated OVX- (OVX+Veh) or Sham-operated animals. After 8months, treatment was discontinued in half of the ODN group. ODN treatment increased in vivo LV aBMD and trabecular (Tb) vBMD until reaching plateau at month 12 by 16% and 23% vs. baseline, respectively, comparable levels to that in Sham and significantly above OVX+Veh. LV BMD was also higher in ALN that plateaued around month 8 to levels below that in ODN or Sham. ODN treatment resulted in higher BMD, structure and improved biomechanical strength of LV and central femur (CF) to levels similar to Sham. ALN generally showed less robust efficacy compared to ODN. Neither ODN nor ALN influenced material properties at these bone sites following ODN or ALN treatment for 7 remodeling cycles in rabbits. ODN and ALN persistently reduced the bone resorption marker urinary helical peptide over study duration. While ALN reduced the bone formation marker BSAP, ODN treatment did not affect this marker. ODN also preserved histomorphometry-based bone formation indices in LV trabecular, CF endocortical and intracortical surfaces, at the levels of OVX+Veh. Discontinuation of ODN returned bone mass, structure and strength parameters to the comparable respective levels in OVX+Veh. Together, these data demonstrate efficacy and bone safety profile of ODN and suggests the potential long-term benefits of this agent over ALN with respect to accrued bone mass without long-term effects on bone formation.
odanacatib（ODN）是一种选择性可逆组织蛋白酶K抑制剂，可抑制骨吸收，增加骨量，并降低骨质疏松症女性的骨折风险。本研究采用治疗模式进行了为期16个月（约7个重塑周期）的实验，以评估ODN与阿仑膦酸钠（ALN）对去卵巢（OVX）兔腰椎（LV）和股骨的骨量、重塑状态及生物力学特性的影响。本研究还评估了停用ODN对这些参数的影响。将OVX术后7.5个月的兔子用ODN（7.5μM·h，混入食物中）或ALN（0.2mg/kg/周，皮下注射）给药16个月，并与溶媒处理的OVX兔（OVX+Veh）或假手术动物进行比较。8个月后，ODN组的一半兔子停止给药。ODN治疗使体内LV的骨密度（aBMD）和小梁骨（Tb）体积骨密度（vBMD）增加，到第12个月达到平台期，分别比基线水平增加16%和23%，与假手术组相当，且显著高于OVX+Veh组。ALN治疗组LV的BMD也较高，并在第8个月左右达到平台期，但其水平低于ODN组或假手术组。ODN治疗使LV和股骨中段（CF）的BMD、结构及生物力学强度提高到与假手术组相似的水平。与ODN相比，ALN的疗效通常较弱。在兔子经过7个重塑周期的ODN或ALN治疗后，ODN和ALN均未影响这些骨部位的材料特性。在整个研究期间，ODN和ALN持续降低骨吸收标志物尿螺旋肽水平。虽然ALN降低了骨形成标志物骨特异性碱性磷酸酶（BSAP），但ODN治疗未影响该标志物。ODN还使LV小梁骨、CF内皮质和皮质内表面基于组织形态计量学的骨形成指数保持在OVX+Veh组的水平。停用ODN后，骨量、结构和强度参数恢复到与OVX+Veh组相当的水平。总之，这些数据证明了ODN的疗效和骨安全性，并表明该药物相对于ALN在累积骨量方面具有潜在的长期益处，且对骨形成无长期影响。
