Denosumab is newly developed human monoclonal antibody that acts against receptor activator of NF-κB ligand (RANKL) which in turn decreases osteoclast formation, their function and survival rate. It is approved for the treatment of post-menopausal women with osteoporosis who has increased risk for fracture, among other indications.

 A pivotal 3-year fracture trial FREEDOM was done in which denosumab (60 mg) was administered subcutaneously after every 6 months. The results indicated that there was significant reduction in new vertebral (68%) fractures, hip (40%) fractures, non-vertebral (20%) fractures and bone turnover marker and an increase in bone mineral density (BMD) when comparison was done with placebo in post-menopausal 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). The incidences of these AEs was examined in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). It provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM results. The incidences of these AEs were also examined over 6 years of denosumab treatment (Long-term Group; i.e., comparing a second 3 years of treatment with findings in the first 3 years). Increasing trends did not indicate any imbalances of either low-frequency AEs or common AEs which were observed in FREEDOM.