Long-term treatment with odanacatib maintains normal trabecular biomechanical properties in ovariectomized adult monkeys as demonstrated by micro-CT-based finite element analysis

Abstract

The cathepsin K inhibitor odanacatib (ODN) is a potent and reversible inhibitor of osteoclastic resorption activity. This drug is currently under development for the treatment of postmenopausal osteoporosis. Previously, we described data on the treatment efficacy of ODN in a preclinical estrogen-deficient model of an ovariectomized (OVX) rhesus monkey using HR-pQCT based finite element analysis (FEA) in vivo estimates of bone strength on the distal radius. To support the bone safety profile of ODN, we report ex vivo data on the apparent and hard tissue biomechanical properties of the trabecular bone of vertebrae of animals after 20 months of dosing in three treatment groups: Vehicle (VEH), ODN (2 mg/kg/day), and ALN (30 μg/kg/week).Biomechanical axial compression tests were performed on cylindrical trabecular samples cored out of the third lumbar vertebra of each animal at the end of the study. The biomechanical test results demonstrated that a normal (positive correlation between bone mineral density and bone strength) apparent material property relationship was maintained in the lumbar spine of ODN and ALN treated non-human primates (NHP). Trabecular bone hard tissue Young's modulus value was estimated using experimentally measured stiffness combined with FEA. The FEA and experimental results demonstrated that ODN treatment for 20 months maintained normal trabecular bone material hard tissue properties in the OVX-monkeys and was comparable to ALN.

Cathepsin K inhibition preserves compressive load in lumbar vertebrae of osteoporotic monkeys

“…Ex vivo volumetric measures of total and trabecular BMD and BMC of vertebral bodies (LV4 and LV5) were obtained from a 0.8 mm-thick slice taken from the middle of each vertebral body excised for biomechanical testing ( Duong et al, 2016a ). Another vertebral site (LV2) was further subjected to μCT scanning at an isotropic 20 μm resolution using a Scanco μCT-40 scanner (Scanco Medical AG, Brütisellen, Switzerland) as previously described ( Cabal et al, 2017 ).…”

Genetic and Molecular Evaluation: Reporting Three Novel Mutations and Creating Awareness of Pycnodysostosis Disease

“…The increase in bone density created significant scientific interest in targeting the enzymatic activity of the CTSK gene to increase bone density in patients with osteoporosis [23,[29][30][31][32][33]. Bone et al [32] and Pirapaharan et al [34] concluded in their studies that low doses of cathepsin K inhibitors increase the levels of CTSK; however, higher doses decrease these levels.…”

Advances in the discovery of cathepsin K inhibitors on bone resorption

“…Moreover, more than 16,000 patients received odanacatib 50 mg weekly, which increased BMD at the lumbar spine and total hip after 5 years by 11.2 and 9.5% in the phase III trial, respectively, and reduced the risk of hip fracture by 47%, non-vertebral fractures by 23%, and clinical vertebral fractures by 72% 70 , 71 . However, odanacatib has been discontinued due to a small increased risk of stroke in the postmenopausal patients, even possessing robust efficacy for treatment of osteoporosis 72 , 73 .…”