Bone Abstracts

The cathepsin K inhibitor odanacatib (ODN) is a bone formation-sparing inhibitor of osteoclastic resorption activity. This drug is currently under development for the treatment of postmenopausal osteoporosis. To support the bone safety profile of ODN, we evaluated the effects of ODN on trabecular bone hard tissue properties in the estrogen-deficient model of the ovariectomized (OVX) rhesus monkeys. Animals (n=16/group, age 11–22 years) were treated immediately after OVX’d with either ODN (2 mg/kg per day; equivalent to estimated daily clinical exposure), Alendronate (ALN; 30 μg/kg per weekly) or vehicle (VEH) for 20 months. Trabecular (Tb) cylindrical cores (~4.25 mm dia.) were extracted from lumbar spine (LV3), and scanned at an isotropic 12 μm resolution using a Scanco μCT 35 scanner. The Tb cores were endcapped and subjected to mechanical compression to record the load–displacement curve. Regression analysis of all groups showed a positive correlation between vBMD and the peak force (PF, r²=0.59), and between peak stress (PS) and bone volume fraction (BV/TV, r²=0.51). These results demonstrated that a normal apparent material property relationship was maintained in the lumbar spine of ODN (r²=0.65 for vBMD vs PF; r²=0.51 for BV/TV vs PS) and ALN (r²=0.54 for vBMD vs PF; r²=0.53 for BV/TV vs PS) treated monkeys. Finite element (FE) models were generated from the cores’ μCT images and subsequently used to estimate the Tb bone hard tissue property (Young’s Modulus) in-silico. The results showed only minor differences between the mean Young’s Modulus of different treatment arms and were not statistically significant (P=0.4, Mean±S.E.M. in GPa: VEH=5.61±0.22; ALN=5.52±0.21; ODN=5.91±0.21). Together with the experimental strength measurements, the FE result demonstrated that ODN treatment for 20 months maintained normal trabecular bone material hard tissue properties in the OVX-monkeys, and was comparable to ALN.