European Journal of Clinical Investigation · Nov 11, 2026
Osteosarcopenia and Hard Clinical Endpoints: Biological Rationale, Diagnostic Uncertainty and Inconsistent Prognostic Evidence
By Bemporad J, Palermo A, Paradiso A et al.
Background: Osteosarcopenia, the coexistence of osteoporosis and sarcopenia, has emerged as a candidate musculoskeletal aging syndrome, supported by a growing body of mechanistic evidence on crosstalk between bone, muscle and adipose tissue, including mechanotransduction, myokine and osteokine signalling, inflammaging, mitochondrial dysfunction, marrow adiposity, myosteatosis and impaired regenerative capacity. Whether this biological convergence translates into a prognostically autonomous clinical entity remains uncertain. Operational definitions still combine criteria developed separately for osteoporosis and sarcopenia, biologically integrated diagnostic frameworks and validated biomarkers are lacking and longitudinal cohorts differ substantially in case definitions, populations and adjustment strategies. In this narrative review we critically appraise the biological, diagnostic and epidemiological evidence on osteosarcopenia, focusing on hard clinical endpoints (mortality, fractures, falls). Methods: Narrative review based on a structured search of PubMed/MEDLINE, Scopus and Web of Science (inception to October 2026), prioritizing prospective cohorts reporting mortality, fractures, or falls, meta‐analyses and consensus documents. Results: Prospective studies suggest that osteosarcopenia identifies older adults at increased risk of adverse outcomes; however, recent meta‐analytic evidence, including formal interaction analyses, does not consistently support additive or multiplicative effects beyond isolated osteoporosis or sarcopenia alone. Fracture risk appears largely driven by skeletal fragility, while mortality associations overlap substantially with frailty burden and aging‐related vulnerability. Conclusions: Osteosarcopenia is best understood, at present, as a marker of integrated musculoskeletal vulnerability along an aging continuum rather than a discrete syndrome. Future research should prioritize harmonized definitions, biologically integrated phenotyping and adequately powered cohorts capable of testing interaction effects between skeletal and muscular impairment.