Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys.

Unlabelled: Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased.

Introduction: Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys.

Methods: Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham-ovariectomies (group S). Bone mass was measured at 3-6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry.

Results: In both spine and femur, group O animals lost bone mineral density (BMD), and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O, and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment.

Conclusions: Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.