Bone Abstracts

Odanacatib (ODN), a selective and reversible cathepsin K inhibitor was shown to histomorphometrically reduce trabecular (Tb) and intracortical (Ic) bone remodeling while preserving endocortical (Ec) and stimulating periosteal (Ps) bone formation (BF) in monkeys. Here, we investigate the bone site specific mechanism of ODN on bone modeling (Mo) versus remodeling (Re)-based osteons. Rhesus monkeys (13–19 yrs, n=8–11/group) were ovariectomized and treated with vehicle or ODN (6 or 30 mg/kg, q.d., p.o.) for 21-months. Calcein labels at 15-d interval were given around 12-mo. of dosing. Lumbar vertebrae (LV) and central femur (CF) were subjected to dynamic histomorphometric and cement line analyses and only newly formed hemiosteons (Ho) were evaluated. At LV Tb surface, ODN dose-dependently reduced the number of remodeling hemiosteons (Re.Ho.N) without changing the mean wall thickness (W.Th) vs. vehicle. Note that the number of modeling hemiosteons (Mo.Ho.N) was very low at Tb surface of the aged monkeys and ODN did not change this parameter. Overall in Tb LV, ODN dose-dependently reduced mineralizing surface, mineral apposition rate, bone formation rate (BFR/BS) and activation frequency (Tb.AcF). In the CF, ODN also decreased both Ic and Ec Re.Ho.N and the high dose tended to reduce Ec BFR/BS and AcF. Similar to Tb surface, Ec.Re.W.Th was unchanged in ODN vs. Veh. Remarkably, ODN significantly increased modeling bone formation in both Ec and Ps surfaces of the CF. ODN dose-dependently increased Ec.Mo parameters, including Mo.Ho.N, Mo.AcF, Mo.W.Th and BFR/BS. At Ps surface, ODN also increased all BF parameters in a dose-dependent manner. The results demonstrated that ODN reduces remodeling while stimulating modeling-based hemiosteons, and thus increased the ratio of modeling to remodeling units. These findings explain the bone site specific actions of ODN on trabecular and cortical surfaces in OVX-monkeys. Furthermore, the mechanisms of ODN on modeling-based bone formation differentiate this agent from the standard anti-resorptives.