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

Several antiresorptive drugs are available for the treatment of osteoporosis, but all have limitations. From this perspective, inhibition of cathepsin K is an attractive new target; it is the proteinase responsible for the digestion of bone matrix, and the effects of genetic deficiency in humans (pyknodysostosis) are restricted to the skeleton, where it causes failure of resorption. For these reasons, several cathepsin K inhibitors (CKIs) have been evaluated as possible therapeutics to prevent bone loss. They have been found to be potent and specific inhibitors of resorption. The first-in-class, odanacatib, is already in the late stages of phase 3 trials. Although developed as antiresorptive agents, there is evidence that these agents also possess anabolic activity, the basis for which will be explored in this commentary. Studies in nonhuman primates showed the expected antiresorptive effect of CKIs (1). 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. Conceivably, any tendency of odanacatib to increase periosteal circumference through enhanced bone formation could contribute to the increase in areal bone mineral density (BMD) noted in human studies (see below), given the dependency of the latter measure on bone size. Because periosteal circumference is strongly related to cross-sectional moment of inertia, this action could represent an important mechanism by which CKIs improve bone strength and reduce fracture risk.