Postmenopausal women who received long-term denosumab had a lower fracture risk and increased bone mineral density (BMD) compared with patients taking placebo, according to recent research published in the Lancet Diabetes & Endocrinology.
Henry G. Bone, MD, from the Michigan Bone and Mineral Clinic in Detroit, Michigan, and colleagues enrolled 7808 women in the multicenter double-blinded placebo-controlled phase 3 Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months trial (FREEDOM; ClinicalTrials.gov identifier: NCT00089791), in which patients were randomly assigned to receive 60 mg denosumab every 6 months or placebo between August 2004 and August 2007. Patients were recruited from 214 centers in North America, Latin America, Europe, Australia, New Guinea and its neighboring islands, and New Zealand.
Of the patients from the original trial, 5928 patients completed FREEDOM and 4550 patients continued treatment in an extension trial (ClinicalTrials.gov identifier: NCT00523341) for an additional 7 years, where patients in the placebo group started treatment with denosumab in addition to patients who received denosumab in the original trial. Of these, 2626 patients completed the extension trial.
The primary end point was safety monitoring, which included adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and hematology), and incidence of denosumab antibody formation among the participants. Secondary outcomes included new vertebral, hip, and nonvertebral fractures, as well as BMD at the lumber spine, total hip, femoral neck, and one-third radius.
All patients who received denosumab experienced a decrease in exposure-adjusted participant incidence adverse event rates year by year, with a rate of 165.3 per 100 participant-years at the first year and a 95.9 adverse event rate per 100 participant-years at 10 years. Adverse events ranged between 11.5 per 100 participant-years and 14.4 per 100 participant-years during the 10-year treatment period.
The researchers noted 7 cases of osteonecrosis of the jaw in the long-term denosumab group and 6 cases in the placebo plus denosumab group in the extension trial. In addition, there was 1 case of atypical femoral fracture in each group during the extension trial.
There were similar rates of new vertebral fractures (0.90%-1.86%) and nonvertebral fractures (0.84%-2.55%) in the long-term denosumab and crossover denosumab groups.
Regarding BMD growth, lumbar spine BMD increased by 21.7%, total hip BMD increased by 9.2%, femoral neck BMD increased by 9.0%, and one-third radius BMD increased by 2.7% for patients in the long-term denosumab group, whereas patients in the crossover group had BMD increases of 16.5% in the lumbar spine, 7.4% in the total hip, 7.1% in the femoral neck, and 2.3% in one-third radius. The long-term group’s gains in BMD confirmed the advantage of timely intervention and continuing treatment, the researchers noted.
“Prolonged reduction of bone remodelling did not result in increased fragility,” the researchers wrote. “In fact, fracture rates remained consistently low throughout the study, similar to rates observed in the active treatment group during FREEDOM and lower than in a virtual long-term placebo cohort.”
Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension [published online May 22, 2017]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(17)30138-9