Osteosarcopenia as a Systems-Level Failure of the Bone-Muscle Functional Unit

Osteosarcopenia-osteoporosis co-occurring with sarcopenia-has a pooled prevalence of 18.5% in older adults (range 5-37%) and carries increased risks of fracture (HR 2.13, 95% CI 1.61-2.81), falls (HR 1.54, 95% CI 1.20-1.97), and mortality (HR 1.75, 95% CI 1.34-2.28). Often framed as simple coexistence, osteosarcopenia is proposed as a systems-level disorder of interconnected bone-muscle degeneration.

We synthesize evidence from molecular biology, systems physiology, and translational research showing that osteosarcopenia is a systems-level failure of the bone-muscle functional unit, a highly integrated structure maintained by bidirectional mechanical coupling, osteokine-myokine exchange, and shared intracellular signaling pathways. We examine how intrinsic aging mechanisms (genomic and epigenetic drift, transcriptional reprogramming, structural co-degeneration, and metabolic-mechanical decoupling) and systemic drivers (inflammaging, adipose dysfunction, gut dysbiosis, and hormonal decline) converge to reconfigure this crosstalk from a homeostatic regulator into a pathological amplifier. At the center of this process is a vicious cycle of declining osteocalcin and irisin alongside rising sclerostin, FGF23, and myostatin, propagated through shared signaling hubs (Wnt/β-catenin, TGF-β/Smad, IGF-1/Akt/FOXO, and NF-κB) and sustained by gut-bone-muscle axes. We advance this systems-level framing as an integrative hypothesis rather than established fact: more-than-additive risk and synergistic treatment effects are not yet demonstrated in humans. Actionable now are dual-tissue screening, guideline-based treatment of each component, and combined exercise and nutritional strategies; biomarker-guided care and crosstalk-targeted pharmacology await prospective validation.

Mechanistic claims in this review are primarily supported by preclinical evidence; human causal evidence remains incomplete. Full statement in Online Resource 1.