Romosozumab efficacy on fracture outcomes is greater in patients at high baseline fracture risk: a post hoc analysis of the first year of the frame study

E V McCloskey, H Johansson, N C Harvey, M Lorentzon, Y Shi, J A Kanis, E V McCloskey, H Johansson, N C Harvey, M Lorentzon, Y Shi, J A Kanis

Abstract

This study aimed to determine the interaction between baseline FRAX® fracture probability and romosozumab efficacy. Using an ITT approach, it was determined that the efficacy of romosozumab on clinical fracture, osteoporotic fracture, and major osteoporotic fracture is significantly greater in patients at high baseline fracture risk, when compared with placebo.

Introduction: Post hoc analyses of placebo-controlled osteoporosis treatment studies have shown significantly greater reductions of fracture incidence for higher fracture risk patients. This study determined the interaction between baseline FRAX® fracture probability and romosozumab efficacy in the placebo-controlled first year of the phase 3 FRAME study (NCT01575834).

Methods: Using an ITT approach, an extension of Poisson regression analysis studied the relationship between treatment, FRAX® 10-year probability of major osteoporotic fracture (MOF, calculated without BMD) and risk of first incident fracture (adjusting for age and follow-up time). Treatment interactions considered outcomes of all clinical fractures, osteoporotic fractures, MOF, clinical vertebral fractures, and morphometric vertebral fractures. Two-sided p value of < 0.1 for the interaction between treatment and FRAX® was considered significant.

Results: Compared with placebo, romosozumab reduced the incidence of all fracture outcomes in the first year (range: 32% reduction in MOF [p = 0.07] to 80% reduction in clinical vertebral fractures [p = 0.038]). Significant interactions were observed between efficacy and baseline FRAX® probability for composite outcomes of clinical fractures, osteoporotic fractures, and MOF (p = 0.064-0.084), but not vertebral fractures (p > 0.3). For example, romosozumab decreased all clinical fractures by 22% at the 25th centile of FRAX® probability but the reduction was 41% at the 75th centile. Exclusion of vertebral fractures from each composite fracture outcome (i.e. only nonvertebral fractures included) showed even stronger interactions with baseline FRAX® probability (p = 0.036-0.046).

Conclusions: Efficacy of romosozumab on clinical fracture, osteoporotic fracture, and MOF is significantly greater in patients at high baseline fracture risk compared with placebo.

Keywords: FRAX; Fracture reduction; Fracture risk; Romosozumab.

Conflict of interest statement

Eugene V McCloskey has received consultancy/lecture fees/grant funding/honoraria from ActiveSignal, AgNovos, Amgen, AstraZeneca, Consilient Healthcare, Fresenius Kabi, Gilead, GSK, Hologic, Internis, Lilly, Medtronic, Merck, Novartis, Pfizer, Radius Health, Redx Oncology, Roche, SanofiAventis, Servier, Synexus, Tethys, UCB, Viiv, Warner Chilcott, I3 Innovus, and Unilever, all outside the presented work. Helena Johansson has no conflicts to declare. Nicholas C Harvey has received consultancy/lecture fees/honoraria/grant funding from Alliance for Better Bone Health, Amgen, MSD, Eli Lilly, Radius Health, Servier, Shire, UCB, Consilient Healthcare, and Internis Pharma, all outside the presented work. Mattias Lorentzon has received lecture fees from Amgen, Lilly, Meda, Renapharma, and UCB Pharma, and consulting fees from Amgen, Radius Health, UCB Pharma, Renapharma, and Consilient Health, all outside the presented work. Yifei Shi is an employee and stockholder of Amgen Inc. John A Kanis reports grants from Amgen, Eli Lilly, and Radius Health and consulting fees from Theramex. He led the team that developed FRAX® as director of the then WHO Collaborating Centre for Metabolic Bone Diseases; he has no financial interest in FRAX®.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Effect of romosozumab on any clinical fracture (top left panel), osteoporotic fracture (top right panel), MOF (lower left panel), and nonvertebral fracture (osteoporotic fractures excluding vertebral fractures) (lower right panel) compared with placebo expressed as HR with 95% CIs across the range of MOF probabilities at baseline calculated without BMD
Fig. 2
Fig. 2
Effect of romosozumab on any clinical fracture compared with placebo expressed as the HR with 95% CIs across the range of MOF probabilities (1st to 99th percentile) at baseline calculated without BMD. Dotted lines are derived from the first year of the FRAME study. Solid lines depict the first-year data from the Latin American countries

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