title: ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats.
abstract: 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.
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka, 618-8585, Japan.
authors: Yasuo
authors: Y
authors: Ochi
authors: Hiroyuki
authors: H
authors: Yamada
authors: Hiroshi
authors: H
authors: Mori
authors: Naoki
authors: N
authors: Kawada
authors: Ryoji
authors: R
authors: Kayasuga
authors: Yasutomo
authors: Y
authors: Nakanishi
authors: Makoto
authors: M
authors: Tanaka
authors: Akira
authors: A
authors: Imagawa
authors: Kazuyuki
authors: K
authors: Ohmoto
authors: Kazuhito
authors: K
authors: Kawabata
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D005260:Female; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D051381:Rats; D053778:Thiazolidines / Q000494:pharmacology*; D013977:Tibia / Q000378:metabolism* / Q000473:pathology
chemical_list: D050071:Bone Density Conservation Agents; C560865:ONO-5334; D053778:Thiazolidines; D056657:Cathepsin K; C534133:Ctsk protein, rat; D019386:Alendronate