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Current treatment of postmenopausal osteoporosis (PMOP) focuses on systemic administration of medication, neglecting to proactively modulate the local microenvironment of skeletal system for superior therapeutic performance. Eldecalcitol (ED‐71), a novel drug for treating osteoporosis, still requires research to overcome high‐frequency delivery and low‐utilization. Here, a bone‐targeting and multishelled nanoparticles are developed for step‐wise release of ED‐71. The nanoparticles are achieved by using the chitosan/alginate outer layer as protective barrier against gastric acid, pectin middle layer as adhesive agent that improved intestinal penetration, and ethylene diamine tetraacetic acid‐grafted mesoporous silica nanomaterials core as bone‐targeting nanocarriers. After oral administration, the ED‐71‐loaded nanoparticles (ME‐ED‐71@PCA) promotes osteogenic differentiation of bone marrow mesenchymal stem cells by reducing intracellular oxidative stress, and inhibits the osteoclast differentiation. ME‐ED‐71@PCA improves bone mass in ovariectomized‐mice by promoting osteogenesis and inhibiting osteoclastogenesis, and the efficacy is more pronounced than ED‐71 alone. ME‐ED‐71@PCA exhibits satisfactory therapeutic performance due to its step‐wise drug release and bone‐targeting compared to ED‐71 administration, providing a new approach to re‐establish bone metabolic homeostasis in PMOP. [ABSTRACT FROM AUTHOR]