A Bone-Penetrating Precise Controllable Drug Release System Enables Localized Treatment of Osteoporotic Fracture Prevention via Modulating Osteoblast-Osteoclast Communication

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.