Dual-action bisphosphonate hydrogel preserves cortical bone integrity and restores healing cascade in osteoporotic fracture-related infection.

In osteoporotic fracture-related infection (FRI), the coordinated bone healing is compromised by cortical bone lysis and persistent bacterial colonization. Current treatments primarily focus on infection control, but fail to preserve bone microarchitecture or restore disrupted healing cascade, particularly in fragile osteoporotic bone. Here, we develop a bioactive nanocomposite hydrogel based on bisphosphonate-modified hyaluronan (HABP) and either free bisphosphonate (BP) or pyrophosphate (TSPP), carrying antibacterial Ag⁺ ions and Vancomycin. Triggered by the pathological pH of biofilms, this hydrogel enables site-specific release of antimicrobials. In a rat osteoporotic FRI model, prominent cortical bone lysis and osteocyte apoptosis impair healing. HABP hydrogel effectively eradicates the Methicillin-resistant Staphylococcus aureus infection, preserves cortical bone integrity, and rescues osteocyte viability by inhibiting osteoclast activation and osteocyte apoptosis. The TSPP-based formulation, delivering a lower BP dose, enhances callus remodeling. Our study demonstrates the promising potential of the dual-action hydrogel for treating osteoporotic FRI via preventing bone lysis and rejuvenating coordinated healing cascades.