Background/Purpose: Romosozumab (Romo), a sclerostin antibody, has a dual effect of increasing bone formation and decreasing bone resorption. In the FRAME study, one year of Romo treatment resulted in large BMD increases at the lumbar spine and total hip versus placebo (PBO); the differences between groups remained after all subjects transitioned to denosumab (DMAb) during the second year of the study (Cosman NEJM 2016). Here, we further characterize the BMD gains during the FRAME study and the effect of building bone with Romo on fracture risk reduction upon transition to DMAb.

Methods: Subjects in FRAME (NCT01575834) were randomized to receive Romo 210 mg QM or PBO for 12 months, after which all subjects received DMAb 60 mg Q6M for an additional 12 months. Endpoints for the current analysis were mean change from baseline in BMD T-score, percent of subjects with a BMD gain, and subject incidence of fractures in the second year of the study, including new vertebral, clinical (nonvertebral plus symptomatic vertebral), and other fracture categories.

Results: There were 7180 subjects in the study (N=3589 Romo, N=3591 PBO). At month 12, mean change from baseline in lumbar spine BMD T-score was 0.88 for Romo and 0.03 for PBO; at month 24, after both treatment groups received DMAb in the second year, the mean change from baseline was 1.11 for Romo/DMAb and 0.38 for PBO/DMAb. At the total hip, the mean changes were 0.32 for Romo and 0.01 for PBO at month 12, with month-24 changes of 0.45 for Romo/DMAb and 0.17 for PBO/DMAb. 99% of subjects in the Romo group showed some increase in BMD at month 12, with 89% achieving ≥ 6% gains in lumbar spine BMD (Figure). Administration of Romo during the first year led to relative risk reductions in fractures between groups during the second year, despite both groups receiving DMAb in year two, with reductions of 81% for vertebral fractures (p < 0.001), 32% for clinical fractures (p = 0.052), and 39% for major osteoporotic fractures (p = 0.034).

Conclusion: Romo resulted in substantial T-score increases after one year; upon transition to DMAb, gains in both groups were similar, resulting in unprecedented BMD gains after treatment with Romo followed by DMAb. As a result of one year of Romo before transition to DMAb, fracture rates were substantially reduced during year two, when subjects in both groups received DMAb. The data support the clinical benefit of rebuilding the skeletal foundation with Romo treatment before transition to DMAb.