Abstract
ABSTRACTThe 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.
Highlights
Osteoporosis is a chronic, progressive condition that generally requires long-term management
Baseline characteristics were similar between the overall population of the denosumab arm of the FREEDOM trial (N = 3902) and the subset of subjects used for the present analysis, who completed 10 years of denosumab treatment (N = 1278; Table 1)
Compared with the virtual twin placebo control group, denosumab treatment for 10 years was associated with a 51% major osteoporotic fracture (MOF) relative risk reduction
Summary
Osteoporosis is a chronic, progressive condition that generally requires long-term management. 1 of 5 n treatment significantly reduced vertebral, nonvertebral, and hip fracture risk; increased lumbar spine and total hip BMD; and reduced bone turnover markers in the pivotal, 3-year FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial in postmenopausal women with osteoporosis.[2] Continued denosumab administration over an additional 7 years of the FREEDOM Extension study was associated with low rates of adverse events, low fracture incidence compared with FREEDOM, and continued increases in BMD without plateau.[3] the lack of a long-term control group in the FREEDOM Extension study limits the ability to evaluate longterm efficacy. Observed 10-year cumulative fracture incidence during FREEDOM and its long-term extension was compared with the estimated 10-year probability of fracture using the FRAX® (fracture risk assessment tool) algorithm[4] and the expected fracture rates in a theoretical group of long-term placebo subjects using the virtual twin method. The previously published[5] virtual twin method uses a Poisson regression model to estimate fracture rates in a hypothetical cohort of placebo controls and has been used to estimate untreated fracture rates with alendronate[5] and denosumab.[6]
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