A phase 2a randomized, placebo-controlled trial evaluated denosumab's effect on erosive hand osteoarthritis (OA). Denosumab, a RANKL inhibitor, was administered every 3 months to 51 patients (41 female) versus 49 placebo recipients (37 female) over 48 weeks. The primary endpoint was the change in the Ghent University Scoring System (GUSS) at week 24, with a significant difference of 8.9 (95% CI 1.0–16.9; P=0.024) observed between groups. This effect was confirmed at week 48, with a difference of 14.3 (95% CI 4.6–24.0; P=0.003). Denosumab reduced new erosive joints (OR 0.24; 95% CI 0.08–0.72; P=0.009) and improved structural changes. Adverse events were more frequent in the placebo group (125 vs. 97 events). Denosumab showed structure-modifying effects, reducing erosive progression and preventing new erosive joints. The study demonstrated that denosumab could slow structural damage in erosive hand OA, with long-term benefits observed in the extension phase. Safety was comparable to previous studies, and denosumab showed consistent radiographic benefits. The results suggest that denosumab may be a promising treatment for erosive hand OA, targeting structural damage rather than just symptoms. The study highlights the need for further research to confirm these findings in larger, multicenter trials.A phase 2a randomized, placebo-controlled trial evaluated denosumab's effect on erosive hand osteoarthritis (OA). Denosumab, a RANKL inhibitor, was administered every 3 months to 51 patients (41 female) versus 49 placebo recipients (37 female) over 48 weeks. The primary endpoint was the change in the Ghent University Scoring System (GUSS) at week 24, with a significant difference of 8.9 (95% CI 1.0–16.9; P=0.024) observed between groups. This effect was confirmed at week 48, with a difference of 14.3 (95% CI 4.6–24.0; P=0.003). Denosumab reduced new erosive joints (OR 0.24; 95% CI 0.08–0.72; P=0.009) and improved structural changes. Adverse events were more frequent in the placebo group (125 vs. 97 events). Denosumab showed structure-modifying effects, reducing erosive progression and preventing new erosive joints. The study demonstrated that denosumab could slow structural damage in erosive hand OA, with long-term benefits observed in the extension phase. Safety was comparable to previous studies, and denosumab showed consistent radiographic benefits. The results suggest that denosumab may be a promising treatment for erosive hand OA, targeting structural damage rather than just symptoms. The study highlights the need for further research to confirm these findings in larger, multicenter trials.