Denosumab increases bone mineral density (BMD) and decreases vertebral fracture risk but not nonvertebral fracture risk in postmenopausal women with osteoporosis and diabetes, according to study results published in Bone.
Individuals with diabetes are at increased risk for fracture compared with individuals without diabetes, which does not necessarily correlate with differences in BMD. Therefore, it is important to assess the efficacy of osteoporosis treatments in patients with diabetes. To this end, the study researchers aimed to characterize the effects of the monoclonal antibody denosumab in a subgroup analysis of postmenopausal women with diabetes recruited to the randomized double-blind placebo-controlled FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; ClinicalTrials.gov Identifier: NCT00089791) and FREEDOM Extension (ClinicalTrials.gov Identifier: NCT00523341) trials.
Of the 508 women (aged 60-90 years) with diabetes included in the analysis, 266 (52.4%) received denosumab and 242 (47.6%) received placebo. BMD was measured at the lumbar spine and proximal femur using dual-energy x-ray absorptiometry and vertebral fractures were identified from lumbar spine and lateral thoracic radiographs.
Over the course of the 3-year FREEDOM study, the percent change from baseline in lumbar spine (mean change, 8.6%; 95% CI, 7.7-9.5), total hip (mean change, 4.2%; 95% CI, 3.6-4.8), and femoral neck (mean change, 4.2%; 95% CI, 3.5-4.9) BMD was higher in the denosumab group compared with the placebo group (P <.05 for all) in patients with diabetes. Denosumab also reduced the cumulative incidence of new vertebral fracture to 1.6% compared with 8.0% in the placebo group (risk ratio, 0.2; 95% CI, 0.07-0.61; P =.001) in patients with diabetes.
A higher cumulative incidence of new nonvertebral fractures, however, was observed in women with diabetes in the denosumab group (11.7%) compared with women in the placebo group (5.9%; hazard ratio, 1.94; 95% CI, 1.00-3.77; P =.046). The majority of nonvertebral fractures were observed during the second year of the study and occurred within the forearm and ribs. This trend was not observed in women without diabetes (denosumab vs placebo: hazard ratio, 0.74; 95% CI, 0.62-0.89; P =.001).
During the first 3 years of the FREEDOM Extension, the nonvertebral fracture incidence became comparable between groups. The incidence was similar between long-term denosumab users with and without diabetes and was comparable to the incidence observed in placebo-treated women with diabetes during the initial FREEDOM study. This trend continued over the FREEDOM Extension, with similar exposure-adjusted rates of nonvertebral fracture observed in women with diabetes in the crossover denosumab group over extension years 1 to 7 (1.52 fractures per 100 person-years; 95% CI, 0.70-2.89) as in in the long-term denosumab group over years 4 to 10 (1.72 fractures per 100 person-years; 95% CI, 0.92-2.94). These rates were similar to those in women with diabetes who received placebo in years 1 to 3 of FREEDOM (2.00 fractures per 100 person-years; 95% CI, 1.07-3.43).
The study authors acknowledged that the post hoc nature of the analysis poses several limitations, including small sample numbers and selection bias. Because the original studies were not designed to assess the efficacy of denosumab in patients with diabetes, randomization was not stratified based on this condition.
“[I]n subjects with osteoporosis and diabetes, denosumab treatment led to continued BMD increases, reduced vertebral fracture rates, and an overall low long-term fracture incidence, comparable with those in the broader FREEDOM and FREEDOM Extension study populations,” the researchers concluded. “Nonvertebral fracture incidence was elevated specifically during the second year of FREEDOM but returned to levels comparable to placebo during the subsequent 7 years of follow-up.”
Disclosure: This study was funded by Amgen, Inc. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.
Ferrari S, Eastell R, Napoli N, et al. Denosumab in postmenopausal women with osteoporosis and diabetes: subgroup analysis of FREEDOM and FREEDOM extension. Bone. 2020;134:115268.