Abstract
Osteoporosis is a complex skeletal disorder characterized by reduced bone mineral density and microarchitectural deterioration, leading to an increased risk of fractures. Conventional pharmacotherapies, such as bisphosphonates and selective estrogen receptor modulators, are constrained by poor bioavailability, lack of targeting specificity, and systemic side effects. Unlike previous reviews that examine signaling pathways and nanocarrier design in isolation, this review presents an integrated mechanistic framework wherein specific therapeutic nodes within key bone remodeling pathways—including Wnt/β-catenin, BMP/Smad, and RANKL/RANK/OPG—inform the rational design of nanodelivery systems. Within this framework, four major classes of nanoplatforms—inorganic nanoparticles, polymeric carriers, liposomal systems, and biomimetic vesicles—are systematically evaluated for their ability to engage pathway-specific targets and modulate osteogenesis and osteoclastogenesis. In addition to mechanistic efficacy, each platform is critically assessed for clinical translatability using a multi-dimensional benchmarking approach that encompasses in vivo performance, targeting precision, safety profile, manufacturability, and regulatory readiness. While these nanosystems exhibit significant potential to enhance therapeutic precision, controlled drug release, and safety, challenges such as long-term biosafety, immune interactions, and scalable manufacturing continue to pose barriers to clinical implementation. By integrating mechanistic targeting with translational benchmarking, this review provides a stage-stratified translational roadmap to guide the development of intelligent and clinically translatable nanomedicine strategies for osteoporosis.