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Improving local bone mineral density (BMD) at fracture‐prone sites of bone is a clinical concern for osteoporotic fracture prevention. In this study, a featured radial extracorporeal shock wave (rESW) responsive nano‐drug delivery system (NDDS) is developed for local treatment. Based on a mechanic simulation, a sequence of hollow zoledronic acid (ZOL)‐contained nanoparticles (HZNs) with controllable shell thickness that predicts various mechanical responsive properties is constructed by controlling the deposition time of ZOL and Ca2+ on liposome templates. Attributed to the controllable shell thickness, the fragmentation of HZNs and the release of ZOL and Ca2+ can be precisely controlled with the intervention of rESW. Furthermore, the distinct effect of HZNs with different shell thicknesses on bone metabolism after fragmentation is verified. In vitro co‐culture experiments demonstrate that although HZN2 does not have the strongest osteoclasts inhibitory effect, the best pro‐osteoblasts mineralization results are achieved via maintaining osteoblast‐osteoclast (OB‐OC) communication. In vivo, the HZN2 group also shows the strongest local BMD enhancement after rESW intervention and significantly improves bone‐related parameters and mechanical properties in the ovariectomy (OVX)‐induced osteoporosis (OP) rats. These findings suggest that an adjustable and precise rESW‐responsive NDDS can effectively improve local BMD in OP therapy.

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