Effects of eight-month treatment with ONO-5334, a cathepsin K inhibitor, on bone metabolism, strength and microstructure in ovariectomized cynomolgus monkeys.
This study examined the effect of ONO-5334, a cathepsin K inhibitor, on bone turnover, mineral density (BMD), mechanical strength and microstructure in ovariectomized (OVX) cynomolgus monkeys. Vehicle, ONO-5334 (3, 10 or 30 mg/kg) or alendronate (0.5 mg/kg) was orally administered for eight months to sham- and OVX-operated monkeys. ONO-5334 dose-dependently suppressed OVX-induced increase in bone turnover markers (urinary C-terminal cross-linking telopeptide of type I collagen (CTX) and serum osteocalcin). At the dose of 30 mg/kg, ONO-5334 maintained urinary CTX at nearly zero level and kept serum osteocalcin around the level of the sham animals. Marker levels in the alendronate-treated animals were similar to those in the sham animals throughout the study. ONO-5334 dose-dependently reversed the effect of OVX on vertebral BMD as measured by dual-energy X-ray absorptiometry (DXA) with improvement of bone mechanical strength. Both ONO-5334 and alendronate suppressed OVX-induced changes in vertebral microstructure and turnover state. In the femoral neck, peripheral quantitative computed tomography (pQCT) analysis showed that ONO-5334 increased total and cortical BMD. In particular, ONO-5334 significantly increased cortical BMD with improvement of bone mechanical strength. In microstructural analysis, alendronate suppressed OVX-induced increase in femoral mid-shaft osteonal bone formation rate (BFR) to a level below that recorded in the sham group, whereas ONO-5334 at 30 mg/kg did not suppress periosteal, osteonal and endocortical BFR. This finding supports the significant effect of ONO-5334 on cortical BMD and mechanical strength in the femoral neck. The results of this study suggest that ONO-5334 has good therapeutic potential for the treatment of osteoporosis.
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan. Electronic address: y.ochi@ono.co.jp.
Yasuo
Y
Ochi
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Hiroyuki
H
Yamada
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Hiroshi
H
Mori
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Yasutomo
Y
Nakanishi
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Satoshi
S
Nishikawa
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Ryoji
R
Kayasuga
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Naoki
N
Kawada
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Akiko
A
Kunishige
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Yasuaki
Y
Hashimoto
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Makoto
M
Tanaka
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Masafumi
M
Sugitani
Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai Shimamoto-cho Mishima-gun, Osaka 618-8585, Japan.
Kazuhito
K
Kawabata
D015502:Absorptiometry, Photon; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D008252:Macaca fascicularis; D010052:Ovariectomy; D053778:Thiazolidines / Q000494:pharmacology*
D015853:Cysteine Proteinase Inhibitors; C560865:ONO-5334; D053778:Thiazolidines; D056657:Cathepsin K
Bone metabolism; Bone mineral density; Bone strength; CATHEPSIN K; ONO-5334