Dual modulation of bone formation and resorption with zoledronic acid-loaded biodegradable magnesium alloy implants improves osteoporotic fracture healing: An in vitro and in vivo study

摘要

Graphical abstract Display Omitted Abstract Osteoporotic fracture (OPF) remains a major clinical challenge for skeletal regeneration. Impaired osteogenesis and excessive remodeling result in prolonged and poor quality of fracture healing. To augment bone formation and inhibit excessive resorption simultaneously, we constructed a biodegradable magnesium-based implant integrated with the anti-catabolic drug zoledronic acid (ZA); this implant exhibits controllable, sustained release of magnesium degradation products and ZA in vitro . The extracts greatly stimulate the osteogenic differentiation of rat-bone marrow-derived mesenchymal stem cells (rBMSCs), while osteoclastogenesis is inhibited by ZA. Implantation of intramedullary nails to fix femur fracture in ovariectomy-induced osteoporotic rats for up to 12?weeks demonstrates magnesium implants alone can enhance OPF repair through promoting callus formation compared to conventional stainless steel, while the combinatory treatment with local ZA release from implant coating further increases bone regeneration rate and callus size, remarkably improves bone quality and mechanical strength and suppresses osteoclasts and bone remodeling, due to the synergistic effect of both agents. The slow and uniform degradation of the implant ensures a steady decrease in bending force, which meets clinical requirements. In summary, biodegradable magnesium-based implants can locally co-deliver magnesium degradation products and zoledronic acid in a controlled manner, and can be superior alternatives for the reconstruction of osteoporosis-related fracture. Statement of Significance Management of osteoporotic fracture has posed a major challenge in orthopedics, as the imbalance between diminished osteogenesis and excessive bone remodeling often leads to delayed and compromised fracture repair. Among various efforts expended on augmenting osteoporotic fracture healing, herein we reported a new strategy by engineering and utilizing a biodegradable magnesium-based implant integrated with local drug delivery, specifically, zoledronic acid (ZA)-loaded polylactic acid/brushite bilayer coating on a biodegradable Mg?Nd?Zn?Zr alloy (denoted as Mg/ZA/CaP), aiming to combine the favorable properties of Mg and zoledronic acid for simultaneous modulation of bone formation and bone resorption. In vitro and in vivo studies demonstrated its superior treatment efficacy along with adequate degradation. It stimulated new bone formation while suppressing remodeling, ascribed to the local release of magnesium degradation products and zoledronic acid. To our knowledge, the enhanced fracture repair capability of Mg-based implants was for the first time demonstrated in an osteoporotic fracture animal model. This innovative biodegradable Mg-based orthopedic implant presents great potential as a superior alternative to current internal fixation devices for treating osteoporotic fracture.