Biodegradable Zn-Mg-Ca-Sr alloy intramedullary nails promote vascularized bone regeneration and suppress osteoclastogenesis for osteoporotic fracture repair

Osteoporotic fractures are commonly associated with impaired bone regeneration and insufficient mechanical stability, posing major challenges for load-bearing internal fixation. Biodegradable metallic implants that combine mechanical support with biological regulation are therefore highly desirable for osteoporotic fracture repair. Here, we designed and evaluated a biodegradable Zn-Mg-Ca-Sr quaternary alloy as small-diameter intramedullary nails (IMNs) for osteoporotic load-bearing fracture fixation. Benefiting from multi-element alloying and hot extrusion, ZnMgCaSr(0.2) exhibited the most favorable overall mechanical performance, featuring high strength, moderate ductility, and a bone-compatible elastic modulus. In vivo bending tests confirmed that implants retained over 60% of their initial load-bearing capacity after 16 weeks. ZnMgCaSr(0.2) showed accelerated yet uniform degradation with compact phosphate-rich corrosion layers and sustained release of Zn²⁺, Mg²⁺, Ca²⁺, and Sr²⁺, while systemic biosafety evaluation revealed no pathological organ damage, abnormal ion accumulation, or hematological/biochemical disorders. In vitro, ZnMgCaSr(0.2) extracts promoted angiogenesis and osteogenesis while inhibiting osteoclastogenesis. In an ovariectomized rat femoral fracture model, ZnMgCaSr(0.2) IMNs enhanced callus formation, bone microstructural reconstruction, and mechanical recovery. Transcriptomic analysis further indicated activation of Wnt, PI3K-Akt, and AMPK signaling, together with suppression of NF-κB signaling. Collectively, ZnMgCaSr(0.2) combines robust mechanical support, controllable biodegradation, favorable biosafety, and multi-target biological regulation, supporting its potential as a load-bearing biodegradable implant for osteoporotic fracture repair. STATEMENT OF SIGNIFICANCE: Biodegradable metals are attractive for fracture fixation, yet many fail in osteoporotic bone because they lose mechanical support too early and provide limited bioactivity in an inflammation-prone niche. We developed small-diameter biodegradable intramedullary nails based on a Zn-Mg-Ca-Sr alloy to address unstable fixation, poor vascularization, and excessive osteoclast activity simultaneously. The optimized ZnMgCaSr(0.2) nails offer adequate initial strength, more uniform and controllable degradation, and favorable in vivo biosafety. Released ions promote endothelial angiogenesis and osteogenic differentiation while suppressing osteoclastogenesis, leading to enhanced vascularized callus formation and faster repair in an ovariectomized rat fracture model. Transcriptomics with in vivo validation indicates activation of PI3K-Akt and AMPK signaling and attenuation of NF-κB signaling.