Safety Observations With 3 Years of Denosumab Exposure: Comparison Between Subjects Who Received Denosumab During the Randomized FREEDOM Trial and Subjects Who Crossed Over to Denosumab During the FREEDOM Extension

Denosumab is a fully human monoclonal antibody against receptor activator of NF-kappa B ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either lowfrequency AEs or common AEs observed in FREEDOM. (C) 2016 American Society for Bone and Mineral Research.