This study compared the effects of
ONO-5334, a
cathepsin K inhibitor, with those of
alendronate on bone mass and strength in ovariectomized rats.
Ovariectomy resulted in significant elevation in urinary
deoxypyridinoline and plasma C-terminal cross-linking telopeptide of
type I collagen (CTX) 8 weeks after surgery. Peripheral quantitative computed tomography analysis showed that total, trabecular, and cortical bone
mineral content (BMC) decreased in the proximal tibia, which was paralleled with a significant decline in bone strength. Treatment with
ONO-5334 (0.12, 0.6, 3 or 15 mg/kg) once daily for 8 weeks dose-dependently restored the decrease in total BMC and bone mineral density (BMD) in the proximal tibia and suppressed urinary
deoxypyridinoline and plasma CTX levels.
Alendronate (1 mg/kg, once daily) also fully restored these bone mass parameters. Separate analysis of trabecular and cortical bones, however, showed that
ONO-5334 only partially restored trabecular BMD and BMC at 15 mg/kg, whereas
alendronate fully restored these parameters. On the other hand,
ONO-5334 increased both cortical BMD and BMC with an effect more potent than that of
alendronate. Bone geometric analysis indicated that
ONO-5334 at 15 mg/kg decreased endosteal circumference without affecting periosteal circumference, resulting in marked increase in cortical thickness. Interestingly, the effects of
ONO-5334 on bone strength parameters were more prominent than those of
alendronate, although the two test compounds had a similar effect on total BMC. Taken together, our results indicate that
ONO-5334 has pharmacological characteristics different from those of
alendronate and may offer a unique
therapy for patients with
osteoporosis.