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-κB 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 60 mg 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 low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.

RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk.

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.