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. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.