Immunometabolic Remodeling in Osteosarcopenia: Inflammaging, Mitochondrial Dysfunction, Gut-Derived Metabolites and Therapeutic Opportunities

Abstract

Osteosarcopenia—defined as the coexistence of sarcopenia and osteoporosis—is increasingly recognized as a clinically important geriatric syndrome associated with falls, fractures, frailty, disability, and mortality. Beyond the simple coexistence of bone and muscle loss, emerging data suggest that osteosarcopenia may reflect systemic dysregulation of the bone–muscle–immune–metabolic network. In this narrative review, we synthesize evidence linking inflammaging, immune-cell polarization, mitochondrial dysfunction, nutrient metabolic dyshomeostasis, and gut-derived metabolites to the pathogenesis of osteosarcopenia. Multiple pathological processes—including chronic low-grade inflammation, Th17/Treg imbalance, macrophage polarization, oxidative stress, impaired mitophagy, insulin resistance, ectopic fat accumulation, and altered microbial metabolites—may converge to disrupt bone–muscle crosstalk. Notably, direct evidence from osteosarcopenic populations remains limited, and many mechanistic insights are extrapolated from osteoporosis, sarcopenia, and aging models. We further discuss current and emerging therapeutic strategies, including exercise, nutritional interventions, anti-osteoporotic agents, metabolic modulators, mitochondrial-targeted therapies, and gut-directed approaches. Longitudinal cohorts, multi-omics studies, and randomized controlled trials are urgently required to validate immunometabolic biomarkers and develop integrated interventions for osteosarcopenia.