title: Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers, mineral density, strength and histomorphometry in ovariectomized cynomolgus monkeys.
abstract: We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30mg/kg/day, p.o.), alendronate (0.05mg/kg/2weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N=20) for 16months. A concurrent Sham group (N=20) was also treated with vehicle for 16months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones.
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: hi.yamada@ono.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ochi
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Drug Development, ONO Pharma UK Ltd., MidCity Place, 71 High Holborn, London WC1V 6EA, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Bruce
authors.affiliation: Drug Development, ONO Pharma UK Ltd., MidCity Place, 71 High Holborn, London WC1V 6EA, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Deacon
authors.affiliation: Discovery Research Laboratories, ONO Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Kawabata
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000000981:diagnostic imaging / Q000502:physiology*; D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D004958:Estradiol / Q000097:blood; D005260:Female; D008252:Macaca fascicularis; D010052:Ovariectomy; D053778:Thiazolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013977:Tibia / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D014057:Tomography, X-Ray Computed
chemical_list: D015415:Biomarkers; C560865:ONO-5334; D053778:Thiazolidines; D004958:Estradiol; D056657:Cathepsin K
keywords: Cathepsin K inhibitor; ONO-5334; Osteoporosis; Ovariectomized cynomolgus monkeys