Synergistic effects of denosumab and BMP-2 on bone regeneration in critical-sized femoral defects in ovariectomized rats

Osteoporotic bone defects pose significant clinical challenges due to poor natural repair capacity. Denosumab (DNB) strongly inhibits osteoclast activity, while Bone morphogenetic protein-2 (BMP-2) effectively promotes bone formation; however, it remains unclear whether combining DNB and BMP-2 can enhance bone repair in estrogen deficiency-induced osteoporosis. We investigated the effects of local BMP-2 implantation and systemic DNB treatment on bone regeneration in ovariectomized (OVX) rats. Micro-computed tomography(Micro-CT) and H&E staining showed that DNB and BMP-2 synergistically accelerated healing of osteoporotic bone defects over 12 weeks. Immunofluorescence, immunohistochemistry, and biomechanical analyses revealed that DNB/BMP-2 increased expression of osteopontin(OPN), osteoclastogenesis inhibitory factor(OPG) and Runt-related transcription factor 2 (RUNX2), and decreased tartrate-resistant acid phosphatase (TRAP) and Tumor Necrosis Factor-α (TNF-α) levels compared to the OVX group (all P < 0.05). Moreover, DNB/BMP-2 significantly improved torsional stiffness and maximum compressive force versus either treatment alone (all P < 0.05). The findings demonstrate that systemic DNB combined with local BMP-2 rapidly promotes femoral metaphyseal bone regeneration in osteoporotic rats.