Background/Purpose:  Romosozumab (Romo) is an investigational bone-forming monoclonal antibody that binds sclerostin and has a dual effect, increasing bone formation and decreasing bone resorption. Here, we report results of the FRActure study in postmenopausal woMen with ostEoporosis (FRAME) (NCT01575834).

Methods:  This multicenter, randomized, double-blind, placebo-controlled study enrolled postmenopausal women aged 55 to 90 years with osteoporosis (BMD T-score ≤ –2.5 at the total hip or femoral neck). Subjects were randomized 1:1 to subcutaneous placebo (Pbo) or 210 mg Romo monthly for 12 months, followed by subcutaneous denosumab (DMAb) every 6 months for 12 months in both groups. The co-primary endpoints were subject incidence of new vertebral fracture through month (M) 12 and M24. Secondary endpoints included clinical (nonvertebral plus symptomatic vertebral) and nonvertebral fracture, and BMD.

Results:  A total of 7180 women (mean age 71 years, mean total hip T-score –2.5) were enrolled. At M12, Romo reduced new vertebral fracture, with a relative risk reduction (RRR) of 73% (subject incidence of fracture: 1.8% Pbo vs 0.5% Romo; P < 0.001). In subjects who received Romo in year 1, vertebral fracture risk reduction persisted through M24 after both groups transitioned to DMAb (2.5% Pbo/DMAb vs 0.6% Romo/DMAb; RRR 75%; P < 0.001). Romo reduced clinical fracture risk at M12 (2.5% Pbo vs 1.6% Romo; RRR 36%; P = 0.008). Nonvertebral fracture incidence through M12 was 2.1% for Pbo (lower than expected) vs 1.6% for Romo (RRR 25%; P = 0.096), with a similar risk reduction through M24 (Pbo/DMAb vs Romo/DMAb RRR 25%; nominal P = 0.029, adjusted P = 0.057). A preplanned analysis revealed a significant interaction between treatment and geographic region for nonvertebral fracture at M12 (P = 0.042). Nonvertebral fracture incidence in Central/Latin America was 1.2% for Pbo vs 1.5% for Romo, whereas a 42% RRR in nonvertebral fracture was observed in rest-of-world (P = 0.012). Compared to Pbo, Romo increased BMD by 12.7% and 5.8% at the lumbar spine and total hip, respectively, at M12 (P < 0.001). Adverse events were generally balanced between groups, with injection-site reactions in 2.9% of Pbo subjects and 5.2% of Romo subjects during year 1. One atypical femoral fracture and 2 osteonecrosis of the jaw events were positively adjudicated in the Romo group through M24.

Conclusion:  In postmenopausal women with osteoporosis, Romo 210 mg monthly was well tolerated and reduced vertebral and clinical fracture risk vs Pbo at M12; vertebral fracture risk reduction persisted in Romo subjects through M24 after both groups transitioned to DMAb. The sequence of Romo followed by DMAb may be a highly effective treatment for postmenopausal women with osteoporosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fracture-risk-reduction-with-romosozumab-results-of-a-phase-3-study-in-postmenopausal-women-with-osteoporosis/