Romosozumab super-responders in clinical practice: insights from a large Italian multicenter cohort of women with severe postmenopausal osteoporosis

Summary: Limited data on romosozumab super-responders. In 149 Italian women with severe osteoporosis, mean LS BMD gain was + 13.7%; 18% were super-responders (≥ 20%). Predictors: high CTX/age/low Z-score for LS; prior femoral fracture for FN. Highlights site-specific response drivers in real-world setting. Purpose: To evaluate romosozumab effectiveness in a large Italian multicentre cohort of women with severe postmenopausal osteoporosis and identify predictors of high-magnitude densitometric response. Real-world evidence on romosozumab is expanding, yet data on high-magnitude response variability and clinical determinants of “super-responder” phenotypes remain limited. Methods: Retrospective analysis of postmenopausal women who completed 12 months of romosozumab across five Italian centers. DXA scans were performed at baseline and after treatment. Data included clinical history, morphometric and clinical fractures, and prior anti-osteoporotic therapies. “Very good responders” were defined as ≥ 10% BMD gain; “super-responders” as ≥ 20%. Multivariate logistic regression identified independent predictors. Results: 149 women (mean age 69.4 ± 9.9 years) were included. Prevalent vertebral (85.2%), femoral (30.9%), and non-vertebral (49.0%) fractures were common; 82% had prior therapy. Mean BMD gains were + 13.7% at lumbar spine (LS), + 5.9% at femoral neck (FN), and + 4.4% at total hip (TH). Very good responders (≥ 10%) occurred in 65.2% at LS, 17.8% at FN, and 13.3% at TH; super-responders (≥ 20%) in 17.8% at LS and 5.9% at FN. LS super-response was independently associated with higher baseline CTX (OR 1.42; p = 0.018), older age (OR 1.10 per year; p = 0.036), and lower baseline LS Z-score (OR 0.29; p = 0.003). FN super-response linked to prior femoral fracture (OR 14.6; p = 0.020). Conclusion: Romosozumab demonstrated high effectiveness in this real-world cohort, with a substantial proportion achieving high-magnitude BMD responses despite extensive prior treatment. Distinct site-specific predictors emerged: bone turnover and age/Z-score for LS, prior femoral fracture for FN.