T. Cusick, C.M. Chen, B.L. Pennypacker, M. Pickarski, D. Kimmel, B.B. Scott, L.T. Duong
Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK). Previously, ODN was shown to increase bone mineral density (BMD) and maintained normal bone strength at the spine in ovariectomized (OVX) rhesus monkey. Here, we further characterize the effects of ODN on BMD, bone strength and dynamic histomorphometric analyses of the hip from the same monkeys. Animals were treated for 21-months with vehicle, 6 or 30mg/kg ODN (p.o., q.d.). ODN increased hip BMD by 11% and 15% (p < 0.01), and ultimate load by 17% (p < 0.05) and 19% (p < 0.01) versus vehicle. Treatment-related increases in ultimate load positively correlated with the increased femoral neck (FN) BMD, BMC and cortical thickness. Histomorphometry of FN and proximal femur (PF) revealed that ODN reduced trabecular and intracortical bone formation rate (BFR), but did not affect long-term endocortical BFR Moreover, ODN stimulated long-term FN and PF periosteal BFR by 3.5- and 6-fold with the 30mg/kg dose versus vehicle, respectively. Osteoclast surfaces were either unaffected or trended higher (∼2-fold) in endocortical and trabecular surfaces in the ODN group. Lastly, ODN increased cortical thickness of FN by 21% (p = 0.08) and PF by 19% (p < 0.05) versus vehicle after 21-months of treatment. Together, both doses of ODN increased bone mass and improved bone strength at the hip. Unlike conventional antiresorptives, ODN displayed site specific effects on trabecular versus cortical bone formation. The drug provided marked increases in periosteal bone formation and cortical thickness in OVX-monkeys, suggesting that CatK inhibition may represent a novel therapeutic approach for the treatment of osteoporosis.