The role of gut microbiota in osteoporosis: underlying mechanisms, clinical associations, and emerging biomaterials.

Osteoporosis is a prevalent metabolic skeletal disorder characterized by reduced bone mass, deteriorated trabecular microarchitecture, and increased fragility fracture risk, imposing substantial global medical, social and economic burdens. Current first-line antiresorptive and anabolic therapeutics are severely constrained by long-term adverse reactions, insufficient patient adherence, and compromised bone microenvironment remodeling capacity, leaving a large unmet clinical demand for multitargeted and translational interventions. The gut-bone axis has been recognized as a core interorgan regulatory signaling network, in which gut microbiota orchestrates bone homeostasis through multiple cascaded mechanisms, including microbial metabolite production (short-chain fatty acids, tryptophan derivatives and bile acids), osteoimmune balance modulation (Th17/Treg axis and macrophage polarization), intestinal barrier maintenance, as well as the regulation of estrogen bioavailability, calcium-phosphorus absorption and vitamin D/VDR signaling. In parallel, advanced functional biomaterials, including modified bone cements, injectable hydrogels, intelligent nanocarriers and immune-regulatory scaffolds, have overcome the defects of conventional bone grafts and inert implant materials, exhibiting tunable mechanical properties, controllable degradation and precise bioactive cargo delivery for osteoporotic bone repair. Notably, the emerging integration of biomaterial engineering with gut-bone axis microbiology has established an innovative "material-microbiota-metabolism-bone" therapeutic paradigm. rationally designed gut-targeted biomaterial platforms, such as metabolite-releasing nanoparticles, probiotic-encapsulated microcarriers and ion-doped multifunctional hydrogels, enable simultaneous local bone defect reconstruction and systemic intestinal microecology homeostasis regulation, thereby alleviating gut dysbiosis-derived chronic inflammation and preventing progressive bone loss. This review systematically elaborates the core molecular and pathological mechanisms by which gut microbiota regulates osteoporosis progression, summarizes the research advances and inherent limitations of traditional bone repair biomaterials, and highlights the latest progress of multifunctional biomaterials targeting gut-bone axis crosstalk. We further conduct a critical comparison of three mainstream administration routes (oral delivery, local bone delivery and systemic delivery) in terms of targeting efficiency, biosafety and clinical applicability, and clarify the translational trade-offs of different material-based strategies. Despite encouraging preclinical outcomes, the clinical translation of gut microbiota-modulating biomaterials remains hindered by individual microbial heterogeneity, long-term biocompatibility risks, and incomplete clarification of material-gut-bone interactive mechanisms. Collectively, this comprehensive review constructs a refined interdisciplinary framework and provides actionable theoretical guidance for the development of next-generation personalized, multi-pathway combined biomaterial therapies for osteoporosis.