Estimation of long‐term efficacy of Denosumab treatment in postmenopausal women with osteoporosis: a FRAX‐ and virtual twin‐based post hoc analysis from the FREEDOM and FREEDOM extension trials

The 3-year placebo-controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7-year open-label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long-term control group, thus limiting the ability to fully evaluate long-term efficacy. This analysis provides a quantitative estimate of the long-term antifracture efficacy of denosumab based on two approaches: comparison with FRAX®- (Fracture Risk Assessment Tool-) and virtual twin-estimated 10-year fracture rates. Subjects who were randomized to denosumab in the FREEDOM trial, continued into the Extension study, completed the 10-year visit, and missed ≤1 dose in the FREEDOM trial and ≤1 dose in the Extension (n = 1278) were included in the analysis. The 10-year observed cumulative incidence of major osteoporotic fracture (MOF) and hip fractures was compared with the 10-year fracture probability predicted at baseline by FRAX, a computer-based fracture risk algorithm, and with that estimated for a hypothetical cohort of 10-year placebo controls (virtual twins). The observed 10-year fracture incidence was lower than the 10-year probability predicted by FRAX for both MOF (10.75% [95% CI, 9.05 to 12.46] versus 15.63% [95% CI, 15.08 to 16.18], respectively), and hip fractures (1.17% [95% CI, 0.58 to 1.76] versus 5.62% [95% CI, 5.28 to 5.97], respectively). The observed fracture incidence was also lower than the fracture rate estimated in a hypothetical cohort of 10-year placebo controls for MOF (23.13% [95% CI, 17.76 to 28.87]; relative risk 0.49 [95% CI, 0.36 to 0.64]). These data support the long-term efficacy of denosumab in reducing MOF and hip fractures in postmenopausal women with osteoporosis.