BACKGROUND: Osteoporosis is a systemic bone disease characterized by decreased bone density and deterioration of bone microstructure, leading to an increased probability of fragility fractures. Once segmental bone defect occurs, it is easy to cause delayed union and nonunion. METHODS: The aim of this study is to investigate the efficacy of extracorporeal shock wave (ESW) and teriparatideloaded hydrogel (T-Gel) combined strategy on the cell activity and differentiation of osteoporosis derived bone marrow mesenchymal stem cells (OP-BMSCs) in vitro and bone regeneration in osteoporotic segmental bone defects in vivo. RESULTS: In vitro, the strategy of combining ESW and T-Gel significantly enhanced OP-BMSCs proliferation, survival, migration, and osteogenic differentiation by up-regulating the alkaline phosphatase activity, mineralization, and expression of runt-related transcription factor-2, type I collagen, osteocalcin, and osteopontin. In the segmental bone defect models of osteoporotic rabbits, MicroCT evaluation and histological observation demonstrated this ESW-combined with T-Gel injection significantly induced bone healing by enhancing the osteogenic activity of the local microenvironment in osteoporotic defects. CONCLUSION In conclusion, ESW-combined with T-Gel injection could regulate the poor osteogenic microenvironment in osteoporotic defects and show potential for enhancing fragility fractures healing.