Odanacatib Treatment Affects Trabecular and Cortical Bone in the Femur of Postmenopausal Women: Results of a Two-Year Placebo-Controlled Trial

Abstract

Odanacatib, a selective cathepsin K inhibitor, increases areal bone mineral density (aBMD) at the spine and hip of postmenopausal women. To gain additional insight into the effects on trabecular and cortical bone, we analyzed quantitative computed tomography (QCT) data of postmenopausal women treated with odanacatib using Medical Image Analysis Framework (MIAF; Institute of Medical Physics, University of Erlangen, Erlangen, Germany). This international, randomized, double-blind, placebo-controlled, 2-year, phase 3 trial enrolled 214 postmenopausal women (mean age 64 years) with low aBMD. Subjects were randomized to odanacatib 50 mg weekly (ODN) or placebo (PBO); all participants received calcium and vitamin D. Hip QCT scans at 24 months were available for 158 women (ODN: n ¼ 78 women; PBO: n ¼ 80 women). There were consistent and significant differential treatment effects (ODN-PBO) for total hip integral (5.4%), trabecular volumetric BMD (vBMD) (12.2%), and cortical vBMD (2.5%) at 24 months. There was no significant differential treatment effect on integral bone volume. Results for bone mineral content (BMC) closely matched those for vBMD for integral and trabecular compartments. However, with small but mostly significant differential increases in cortical volume (1.0% to 1.3%) and thickness (1.4% to 1.9%), the percentage cortical BMC increases were numerically larger than those of vBMD. With a total hip BMC differential treatment effect (ODN-PBO) of nearly 1000 mg, the proportions of BMC attributed to cortical gain were 45%, 44%, 52%, and 40% for the total, neck, trochanter, and intertrochanter subregions, respectively. In postmenopausal women treated for 2 years, odanacatib improved integral, trabecular, and cortical vBMD and BMC at all femur regions relative to placebo when assessed by MIAF. Cortical volume and thickness increased significantly in all regions except the femoral neck. The increase in cortical volume and BMC paralleled the increase in cortical vBMD, demonstrating a consistent effect of ODN on cortical bone. Approximately one-half of the absolute BMC gain occurred in cortical bone.

Cortical Bone: A Challenging Geography

“…However, several technical difficulties still need to be addressed. Engelke and colleagues report an increase in integral (total) hip volume by ∼0.5% in controls and odanacatib‐treated subjects after 24 months of therapy. As this was no greater in the treated group, the authors infer that this is not evidence that odanacatib produces periosteal apposition in humans, as reported in nonhuman primate studies .…”

“…Engelke and colleagues report postmenopausal women randomized to odanacatib or placebo for 2 years who had proximal femur morphology measured using quantitative computed tomography (QCT) and analyzed using Medical Image Analysis Framework (MIAF). The authors report the following: (1) there were no increases in total bone cross sectional area (CSA) despite evidence in subhuman primates suggesting this treatment increases periosteal apposition; (2) cortical thickness (and volume) increased by 1% to 2%, despite there being no evidence that antiresorptives deposit bone upon the endocortical surface; (3) trabecular and cortical volumetric BMD (vBMD) increased and about one‐half of the increase in bone mineral content was cortical even though total CSA did not increase and medullary CSA did not decrease; and (4) cortical vBMD increased despite minimal or no change in periosteal or endocortical dimensions and there was no evidence for a reduction in porosity.…”

“…In this issue of the Journal of Bone and Mineral Research , three articles are published that used state‐of‐the‐art methods of image acquisition and analysis to quantify the effects of therapy on cortical bone morphology . Examples from these articles and several others are given to identify challenges that result from low image resolution and limitations in image processing and analyses.…”

Future directions for new medical entities in osteoporosis

“…Hip quantitative computed tomography and tibia/radius highresolution peripheral computer tomography further indicate a gain of trabecular and, to a lesser extent, cortical volumetric BMD, as well as modest but significant improvements of cortical thickness and area (volume) at these sites [56e58]. The corresponding estimated changes in bone strength were þ3.6% and þ9% at hip and spine, respectively, with odanacatib, compared with a loss of 2% and 5% with placebo, and þ2.6% compared with placebo at distal radius and tibia [57,58]. Overall, all doses were well tolerated and the clinical adverse events, including skin and respiratory events, were balanced compared with placebo.…”

Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment

“…At the distal radius and tibia, total volumetric BMD (vBMD), trabecular vBMD, cortical vBMD, cortical thickness and strength estimated using FEA showed significantly greater improvements with odanacatib compared with placebo. At the hip, the trabecular and cortical compartment were similarly affected by the gains in bone mineral content [55]. The magnitude of these microarchitectural evaluated the same way, although no head-to-head comparison has been made.In another trial, the effect of odanacatib taken after alendronate has been examined.…”