P.J. Masarachia1, B.L. Pennypacker1, M. Pickarski1, K.R. Scott1, G.A. Wesolowski1, S.Y. Smith3, R. Samadfam3, J.E. Goetzmann4, B.B. Scott2, D.B. Kimmel1, L.T. Duong
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 6mg/kg or ODN 30mg/kg (p.o., q.d.) and compared to intact animals. ODN treatment persistently suppressed the bone resorption markers, urinary NTx (75-90%), serum CTx (40-55%), the serum formation markers, BSAP (30-35%) and P1NP (60-70%) 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 (LV1-4) BMD in OVX-animals maintaining a level comparable to intact animals. ODN dose-dependently increased LV1-4 BMD by 7% in the 6mg/kg (p < 0.05 vs. OVX-vehicle) and 15% in the 30mg/kg group (p < 0.05 vs. 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. While ODN reduced bone turnover parameters in trabecular bone, the number of osteoclasts was either maintained or increased in the ODN-treated groups compared to 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-non human primates.