Osteosarcoma Across the Age Spectrum: Why Outcomes Diverge and Trials Must Adapt.

Osteosarcoma clinical presentation, treatment tolerance, and treatment delivery differ across the age spectrum. Adult cohorts are more heterogeneous, with higher proportions of axial and secondary osteosarcoma and greater variation in comorbidity and treatment intensity. Furthermore, emerging genomic studies suggest age-associated differences in tumor complexity and stress-response pathways, whereas direct age-stratified epigenomic and immune-microenvironment data remain limited. These molecular observations are hypothesis-generating and data currently do not support age-specific treatment selection. This narrative review summarizes clinical and biological evidence across age groups, distinguishes prognostic associations from predictive treatment effects, and identifies major confounders and evidence gaps. The available evidence supports age-inclusive prospective trials that model age explicitly, incorporate biomarker-stratified analyses, and report delivered dose intensity, toxicity, and host factors.