Bone Biology Group, Merck Research Laboratories, West Point, PA, USA.
J Bone Miner Res. 2011 Feb;26(2):252-62. doi: 10.1002/jbmr.223.
Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13-weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L-006235 (L-235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX-vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L-235 had no effect. Similarly, endocortical bone-formation rate and the number of double-labeled Haversian canals in the femoral diaphysis were not affected by L-235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady-state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX-vehicle control to levels comparable with sham or ALN. ODN also dose-dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L-235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption.
两种组织蛋白酶 K 抑制剂 (CatKIs) 与阿仑膦酸钠 (ALN) 进行了比较，以评估它们对去卵巢 (OVX) 兔骨吸收和形成的影响。OVX 模型通过证明手术后 13 周兔腰椎骨密度 (LV BMD) 显著丢失 (9.8%至 12.8%) 得到验证，雌激素或 ALN 可预防这种丢失。一种强效的 CatKI，L-006235 (L-235)，每天 10mg/kg 剂量给药 27 周，显著降低 LV BMD 丢失 (p <.01)，与 OVX-载体对照相比。ALN 使脊柱松质骨矿化表面减少 70%，而 L-235 没有影响。同样，股骨骨干的内皮质骨形成率和双标记哈弗氏管数量也不受 L-235 的影响。为了证实 CatKI 对骨形成的保护作用，odanacatib (ODN) 在食物中给药，以实现 OVX 兔 27 周时每天 4 或 9µM 的稳态暴露。两种剂量的 ODN 均能预防 LV BMD 丢失 (p <.05 和 p <.001)，与 OVX-载体对照相比，使 BMD 水平与假手术或 ALN 相当。ODN 还剂量依赖性地增加了股骨近端、股骨颈和转子的骨密度。与 L-235 相似，ODN 并未减少任何研究部位的骨形成。中央股骨和脊柱的峰值负荷与骨矿物质含量之间的正相关且高度相关，表明 ODN 治疗保留了相关骨骼部位的正常生物力学特性。虽然 CatKIs 在预防成年 OVX 兔的骨丢失方面与 ALN 具有相似的疗效，但这种新型抗吸收药物与 ALN 不同，它能保留骨形成，可能通过将骨形成与骨吸收分离来实现。
