The efficacy and safety of the antiresorptive agent denosumab on bone mineral density (BMD) and fracture rates were assessed in an open-label extension, crossover trial of the original 3-year, randomized, placebo-controlled Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months study. [FREEDOM; NCT00089791; Cummings SR et al. N Engl J Med 2009].

Subjects were recruited for the 3-year extension of the trial if they had completed their Year 3 and had not missed more than 1 dose of the study medication (or placebo) during the trial. Of 5928 individuals who were eligible for the extension, 4550 (77%) elected to continue—2343 continued to receive denosumab and 2207 crossed over from placebo to denosumab. All participants received 60 mg of denosumab every 6 months, took supplemental calcium and vitamin D daily, and will be followed for 7 years in the extension—therefore, up to 10 years of treatment with denosumab.

Lead investigator Jacques Brown, MD, CHUQ-CHUL Research Centre, Laval University, Laval, Quebec, Canada, noted that both groups demonstrated a rapid and profound reduction of the resorption marker serum collagen type 1 crosslinked C-telopeptide (CTX) and a similar improvement in levels of the bone formation marker serum type 1 procollagen N-terminal (P1NP) after infusion, with the characteristic attenuation observed at the end of each dosing period.

Participants in the extension phase exhibited continued improvement in BMD. There was a 6-year mean cumulative improvement of 15.2% at the lumbar spine and 7.5% at the total hip. The crossover group experienced a statistically significant (p<0.05) increase in BMD of 9.4% at the lumbar spine and 4.8% at the total hip, increases that were comparable with the denosumab-treated group during the initial 3-year FREEDOM trial.

The annual rate of new vertebral and nonvertebral fractures in the long-term group remained low (Table 1). In the crossover group, the rate of vertebral and nonvertebral fractures was much lower than in the placebo group of FREEDOM.

Adverse events per 100 subject years were similar between the crossover and extension groups. Two participants in the crossover group developed osteonecrosis of the jaw (ONJ), both of which resolved. Two participants in the follow-on group also developed ONJ, and both continue to be followed. There have been no reported atypical femur fractures in either group.

“The continued increase in bone mineral density was surprising,” said Prof. Brown. “With an antiresorptive, we would expect at some point that bone mineral density would plateau; so, it is very surprising to still see a significant increase over 6 years,” he concluded.