title: Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys.
abstract: Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK) currently being developed as a once-weekly treatment for osteoporosis. In this study, we evaluated the effects of ODN on bone turnover, bone mineral density (BMD), and bone strength in the lumbar spine of estrogen-deficient, skeletally mature rhesus monkeys. Ovariectomized (OVX) monkeys were treated in prevention mode for 21 months with either vehicle, ODN 6 mg/kg, or ODN 30 mg/kg (p.o., q.d.) and compared with intact animals. ODN treatment persistently suppressed the bone resorption markers (urinary NTx [75% to 90%] and serum CTx [40% to 55%]) and the serum formation markers (BSAP [30% to 35%] and P1NP [60% to 70%]) versus vehicle-treated OVX monkeys. Treatment with ODN also led to dose-dependent increases in serum 1-CTP and maintained estrogen deficiency-elevated Trap-5b levels, supporting the distinct mechanism of CatK inhibition in effectively suppressing bone resorption without reducing osteoclast numbers. ODN at both doses fully prevented bone loss in lumbar vertebrae (L₁ to L₄) BMD in OVX animals, maintaining a level comparable to intact animals. ODN dose-dependently increased L₁ to L₄ BMD by 7% in the 6 mg/kg group (p < 0.05 versus OVX-vehicle) and 15% in the 30 mg/kg group (p < 0.05 versus OVX-vehicle) from baseline. Treatment also trended to increase bone strength, associated with a positive and highly significant correlation (R = 0.838) between peak load and bone mineral content of the lumbar spine. Whereas ODN reduced bone turnover parameters in trabecular bone, the number of osteoclasts was either maintained or increased in the ODN-treated groups compared with the vehicle controls. Taken together, our findings demonstrated that the long-term treatment with ODN effectively suppressed bone turnover without reducing osteoclast number and maintained normal biomechanical properties of the spine of OVX nonhuman primates.
authors: Bone Biology Group, Merck Sharp & Dohme Corp., West Point, PA 19486, USA.
authors: Patricia J
authors: PJ
authors: Masarachia
authors: Brenda L
authors: BL
authors: Pennypacker
authors: Maureen
authors: M
authors: Pickarski
authors: Kevin R
authors: KR
authors: Scott
authors: Gregg A
authors: GA
authors: Wesolowski
authors: Susan Y
authors: SY
authors: Smith
authors: Rani
authors: R
authors: Samadfam
authors: Jason E
authors: JE
authors: Goetzmann
authors: Boyd B
authors: BB
authors: Scott
authors: Donald B
authors: DB
authors: Kimmel
authors: Le T
authors: LT
authors: Duong
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects*; D005260:Female; D008159:Lumbar Vertebrae / Q000187:drug effects*; D008253:Macaca mulatta; D009929:Organ Size / Q000187:drug effects*; D010052:Ovariectomy
chemical_list: D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; C527128:odanacatib