Post hoc Analysis of the FRAME Study – Romosozumab in the Treatment of Osteoporosis in the European Population
An interesting finding from the FRAME study, which evaluated the treatment of postmenopausal women with osteoporosis using romosozumab, was the significant differences in fracture incidence among patients from various geographic regions. The following post hoc analysis specifically focused on data from European women.
FRAME Study – European Segment
The monoclonal antibody romosozumab increases bone formation and suppresses bone resorption by inhibiting sclerostin. This leads to a rapid increase in both trabecular and cortical bone mass and improvement in bone structure and strength. The osteoanabolic effect of romosozumab was evaluated in the international phase III FRAME study involving postmenopausal women with osteoporosis. In this study, romosozumab administered for 12 months followed by 24–36 months of denosumab treatment resulted in early and sustained reductions in the risk of major categories of fractures and significant increases in BMD. Due to the differences in outcomes between women from Central and South America and other parts of the world, data from European patients were analyzed separately.
In the FRAME study, patients were randomized in a 1:1 ratio to receive romosozumab (210 mg) or placebo once monthly subcutaneously under double-blind conditions for 12 months. This was followed by an open-label phase with denosumab (60 mg) administered once every six months up to month 36 for all enrolled participants. This post hoc analysis focused on the incidence of different categories of fractures, changes in BMD from baseline, and the safety of the therapy in the European segment of the evaluated population. European women comprised 42% of patients (n = 3013/7180) in the FRAME study, with 1494 randomized to receive romosozumab and 1519 to receive a placebo.
Results
Fracture Incidence and BMD Changes After 12 Months of Romosozumab Treatment
Over the 12 months, the romosozumab arm showed a significant reduction in the incidence of nonvertebral fractures compared to placebo (1.4% vs. 3.0%; p = 0.004), clinical fractures (1.4% vs. 3.6%; p <0.001), new vertebral fractures (0.4% vs. 2.1%; p < 0.001), and major osteoporotic fractures (0.9% vs. 2.8%; p < 0.001). The risk of femoral neck fracture was numerically lower in the romosozumab arm (0.2% vs. 0.6%; p = 0.092).
Romosozumab increased BMD after 12 months of treatment compared to placebo in the lumbar spine (by 12.3 percentage points; p < 0.001), total hip (by 5.2 percentage points; p < 0.001), and femoral neck (by 5.0 percentage points; p < 0.001).
Fracture Incidence and BMD During Subsequent Denosumab Treatment
The lower incidence of the given categories of fractures persisted in patients randomized to romosozumab even at 24 and 36 months after transitioning all participants to denosumab. At 24 months, during denosumab treatment, the arm initially treated with romosozumab showed a lower risk of nonvertebral fractures compared to the initially placebo-treated arm (2.7% vs. 4.7%; p = 0.004), clinical fractures (2.7% vs. 5.3%; p < 0.001), new vertebral fractures (0.5% vs. 2.8%; p < 0.001), hip fractures (0.3% vs. 1.0%; p = 0.033), and major osteoporotic fractures (1.8% vs. 4.3%; p < 0.001). Even at 36 months, the results showed significantly lower fracture incidences in the arm initially treated with romosozumab, including nonvertebral fractures (4.2% vs. 6.4%; p = 0.011), clinical fractures (4.3% vs. 7.0%; p = 0.001), new vertebral fractures (1.0% vs. 3.2%; p < 0.001), hip fractures (0.5% vs. 1.2%; p = 0.065), and major osteoporotic fractures (3.1% vs. 5.6%; p < 0.001).
At both 24 and 36 months, all patients in both arms saw significant increases in BMD. However, the average percentage change in BMD of the lumbar spine, total hip, and femoral neck compared to study entry was still significantly greater in women randomized to romosozumab (all p < 0.001).
Safety
The overall incidence of adverse events was balanced between both arms during the double-blind period and throughout the entire study period, with a low incidence of serious adverse events leading to treatment discontinuation.
Conclusion
In European women included in the placebo-controlled FRAME study, romosozumab led to early and sustained reductions in the risk of all major categories of fractures and significant increases in BMD. These benefits compared to initial 12-month placebo administration persisted even after transitioning all patients to denosumab.
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Sources:
1. Langdahl B., Hofbauer L., Ferrari S. et al. Romosozumab efficacy and safety in European patients enrolled in the FRAME trial. Osteoporos Int 2022; 33 (12): 2527−2536, doi: 10.1007/s00198-022-06544-2.
2. SPC Evenity. Available at: www.ema.europa.eu/en/documents/product-information/evenity-epar-product-information_cs.pdf
3. SPC Xgeva. Available at: www.ema.europa.eu/en/documents/product-information/xgeva-epar-product-information_cs.pdf
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