Background/Purpose: The bone forming agent romosozumab (Romo) was previously shown to reduce vertebral and clinical fractures in postmenopausal women with osteoporosis. Here we report the efficacy and safety results of the ARCH study (NCT01631214).

Methods: This multicenter double-blind study enrolled postmenopausal women age 55–90 years with osteoporosis and high fracture risk, defined as a BMD T-score ≤‒2.5 at total hip [TH] or femoral neck [FN] and either ≥1 moderate/severe or ≥2 mild vertebral fractures, or a BMD T-score ≤–2.0 at TH or FN and either ≥2 moderate/severe vertebral fractures or a history of a recent hip fracture. Subjects were randomized 1:1 to 210mg Romo SC QM or 70mg alendronate (ALN) PO QW for 12 months, followed by open label 70mg ALN PO QW in both groups. Primary endpoints were subject incidence of new vertebral fracture through 24 months and clinical fracture through the primary analysis (PA). PA was performed when ≥330 clinical fractures had occurred and all subjects had completed the month 24 visit. Nonvertebral fracture at the PA was a secondary endpoint, as was BMD at the lumbar spine, TH, and FN at months 12 and 24. Hip fracture was evaluated as an additional secondary endpoint.

Results: 4093 women (mean age 74, mean TH T-score –2.8) were randomized to Romo or ALN. 12 months of Romo prior to ALN vs ALN alone significantly reduced new vertebral, clinical, nonvertebral, and hip fractures (Table). Treatment with Romo also significantly increased BMD at all sites measured, at months 12 and 24 vs ALN alone (Table). Overall adverse events were balanced between groups. During the open label ALN period, 6 subjects (2 Romo; 4 ALN) were positively adjudicated for AFF and 2 subjects (1 Romo; 1 ALN) for ONJ. Cardiovascular (CV) serious adverse events (SAEs) were independently adjudicated; at 12 months the subject incidence was 2.5% in the Romo group vs 1.9% in the ALN group with cardiac ischemic events at 0.8% vs 0.3% and cerebrovascular events at 0.8% vs 0.3%, respectively.

Conclusion: In postmenopausal women with osteoporosis, Romo 210mg QM followed by ALN significantly reduced new vertebral, clinical, nonvertebral, and hip fracture risk vs ALN alone, suggesting that in osteoporotic patients at high risk for fracture, a treatment regimen starting with Romo followed by ALN leads to superior fracture risk reduction over ALN alone. An observed imbalance in CV SAEs compared with ALN was not seen in the previous placebo-controlled 7180-patient FRAME study and is currently being evaluated.