Effects of Odanacatib on Bone Mineralization Density Distribution in Thoracic Spine and Femora of Ovariectomized Adult Rhesus Monkeys: A Quantitative Backscattered Electron Imaging Study

Abstract

Odanacatib (ODN) has been developed as a selective inhibitor of cathepsin K, the major cysteine protease in osteoclasts. In adult rhesus monkeys, treatment with ODN prevents ovariectomy-induced bone loss in lumbar vertebrae and hip. In this study, we evaluate the effects of ODN on bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging in vertebral spongiosa, distal femoral metaphyseal and cortical shaft from monkeys (aged 16-23 years), treated with vehicle (n=5) or ODN (6 mg/kg, n=4 or 30 mg/kg, n=4, PO daily) for 21 months. Dual-energy X-ray absorptiometry was measured in a subset of distal femoral samples. In lumbar vertebrae there was a shift to higher mineralization in samples from ODN-treated groups, compared to vehicle: CaMean (+4%), CaPeak (+3%), CaWidth (-9%), CaLow (-28%) in the 6 mg/kg group and CaMean (+5.1%, p<0.023), CaPeak (+3.4%, p<0.046), CaWidth (-15.7%, p=0.06) and CaLow (-38.2%, p<0.034) in the 30 mg/kg group. In distal femoral metaphyseal cancellous bone, there was a clear tendency toward a dose-dependent increase in matrix mineralization, as in the spine. However, primary and osteonal bone of the distal cortical diaphyses showed no significant change in BMDD, whereas bone mineral density was significantly increased after treatment. In ovariectomized monkeys, this study shows that ODN treatment increased trabecular BMDD, consistent with its previously reported ability to reduce cancellous remodeling. Here, ODN also showed no changes in BMDD in cortical bone sites, consistent with its actions on maintaining endocortical and stimulating periosteal bone formation.