Effect of 3 year Denosumab Treatment on Hip Structure in Japanese Postmenopausal Women and Men with Osteoporosis

Introduction Denosumab inhibits bone resorption by binding to and inactivating RANK ligand (RANKL), a key mediator of osteoclast formation, maturation and activation. As in the pivotal phase 3 study, FREEDOM, in predominantly postmenopausal Caucasian women with osteoporosis the efficacy of denosumab was evaluated by the phase 3 study, DIRECT, in Japanese osteoporosis patients. The study showed that 2-year treatment of denosumab significantly reduced risk of new vertebral fracture by 74.0% compared to placebo. However, there have been no data showing actions on Japanese bone architecture. Objectives Here we evaluate the effect of denosumab to hip geometry by hip structural analysis using dual-energy X-ray absorptiometry (DXA) data in Japanese. Methods The images for 687 patients derived from DIRECT study were evaluable for HSA. DIRECT study consisted of a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase, in which all subjects received denosumab. Hip geometry was analyzed using Hologic Apex DXA software version 13.5 (Madison, WI). Measurements include: BMD as average pixel value in the profile, bone outer diameter, endocortical diameter, mineralized bone cross-sectional area, average cortical thickness, cross-sectional moment of inertia (CSMI) as BMD times square of the distance from the center of mass, section modulus as CSMI divided by Dmax (maximum distance between the center of the mass and the outer cortex), buckling ratio as the ratio of bone diameter to average cortical thickness, and Dmax. Percent changes from baseline in HSA parameters at each time point were analyzed using one-sample t-test. Comparisons between the treatment groups for the percent changes in HSA parameters at each time point were performed using a two-sample t-test. Results The images for 687 patients applicable to HSA were used in the present study. The baseline characteristics were similar to those in the total 952 participants. Compared to placebo, denosumab significantly increased BMD, cortical thickness and cross sectional area in all of the three analyzed areas: the narrow neck, intertrochanter and femoral shaft. The subsequent derived mechanical parameters, cross-sectional moment of inertia, section modulus and buckling ratio, were also improved by denosumab. In addition, the improvement of these parameters was also observed in the patients that had switched from placebo to denosumab treatment. Conclusions The present study reveals 3-year effect of denosumab on the geometrical parameters of hip bone structure. The improving effects suggest underlying mechanism for anti-fracture effect of denosumab in Japanese.