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

Abstract

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.

Future directions for new medical entities in osteoporosis

“…Similar data have previously been reported with other cathepsin K inhibitors, namely relacatib and balicatib [35]. An increase of endocortical bone formation and a marked stimulation of periosteal bone formation in the femur of these animals, however, has been reported with odanacatib and balicatib [49,50]. In particular, an increase of modelling-based bone formation occurred on hip cortical surfaces with odanacatib, as well as an increase of femur neck cortical thickness at the highest dose [49], perhaps indicating an interaction between cathepsin K inhibition and mechanical loading.…”

Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation

“…Taken together, these results support the hypothesis that therapeutic manipulation of osteoclast activity via inhibition of cathepsin K can decrease bone resorption, while maintaining or increasing bone formation at remodeling sites. Finally, our finding of an increase in total crosssectional volume and cortical bone volume, without any change in marrow volume after deletion of Ctsk in cells of the osteoclast lineage, suggest that it may also indi rectly affect periosteal modeling-based bone formation, an obser vation also made after pharmacological inhibition of cathepsin K in nonhuman primates (32,33).…”

“…Indeed, it has recently been reported that inhibition of cathepsin K activity with orally administered small molecules not only inhibits the production of markers of bone resorption, but also maintains or enhances bone formation in some animal models (32,33,41,42), and maintains bone for mation markers close to control values in human studies (43,44). Our mouse genetic studies would suggest that the effect of inhibiting cathepsin K on bone formation is indirect and is due to the effect of the compounds on osteoclasts rather than on cells of the osteoblast lineage.…”

Are Cathepsin K Inhibitors Just Another Class of Anti-Resorptives?

“…However, in a recent study, detailed histological analysis of the hip in animals treated with odanacatib revealed a marked increase in periosteal bone formation at both the femoral neck and proximal femur (2). Equivalent findings have been reported after treatment of ovariectomized cynomolgus monkeys for 18 months with another CKI, balicatib (3). Stimulation of periosteal bone formation has previously been reported after treatment with anabolic agents such as teriparatide, but it is not a recognized consequence of antiresorptive therapy.…”