The
cysteine protease cathepsin K is involved in osteoclast-mediated
bone resorption. We evaluated the effect of daily oral dosing of an inhibitor of human
cathepsin K (
SB-462795 [
relacatib]) for 9 months on bone turnover, mass, and architecture in
estrogen-deficient cynomolgus monkeys. Ovariectomized animals were treated orally with
relacatib at 1, 3, or 10 mg/kg/day, or oral vehicle plus
alendronate at 0.05 mg/kg by IV injection once every 2 weeks. The control groups, ovariectomized and
sham-ovariectomized animals, received vehicle (all groups n = 20 animals). Samples for
biomarker analysis were collected at various times, bone mass changes were evaluated at 6 and 9 months of treatment, and histomorphometric analysis was performed at 9 months.
Relacatib significantly reduced urinary
N-telopeptide excretion within 1 week of treatment at all dose levels, an effect that was maintained at the highest dose level. At some time points bone formation markers were elevated at the lowest dose of
relacatib. Animals treated with
relacatib had dose-dependent preservation of areal bone mineral density reaching statistical significance in distal femur. In femur neck there was significant preservation of total volumetric BMD (vBMD) by
relacatib. By histomorphometry,
relacatib reduced indices of
bone resorption and formation at cancellous sites as did
alendronate. In cortical bone, osteonal bone formation rate was reduced by
alendronate but preserved at low and medium doses of
relacatib. Thus,
relacatib preserved cortical and cancellous bone mass in ovariectomized monkeys.