Injectable Plant Phosphate Coordination Compound-Based Adhesive Hydrogel Accelerates Osteoporotic Fracture Healing by Restoring Osteoclast/Osteoblast Imbalance

Osteoporotic fractures are notoriously difficult to heal due to an imbalance between osteoblasts and osteoclasts. Current treatments often have limited efficacy or adverse side effects, necessitating safer and more effective solutions. Here, we developed an injectable plant-derived phosphate coordination compound-based adhesive hydrogel (MgPA-Gel) to restore bone homeostasis by integrating magnesium ions (Mg 2+ )–phytic acid (PA) nanoparticles with aminated gelatin (Gel-NH 2 ) and aldehydated starch (AS). This hydrogel can firmly adhere to irregular bone surfaces at the fracture site and degrades in the acidic osteoporotic microenvironment, releasing PA and Mg 2+ to modulate osteoclast and osteoblast activity. PA inhibits osteoclastogenesis by promoting monocyte secretion of cellular communication network factor 1 (CCN1), which disrupts Receptor Activator of Nuclear Factor-κB Ligand (RANKL)–Receptor Activator of Nuclear Factor-κB (RANK) signaling, while Mg 2+ enhances osteoblast differentiation from bone marrow stem cells. Hydrogel implantation synergistically augmented the fracture healing cascade in osteoporotic bone, achieving an 84.6% improvement in bending resistance compared to standalone intramedullary stabilization in ovariectomized (OVX) rats. This study highlights the potential of PA-based coordination compounds as a promising strategy for osteoporotic fracture treatment.