Osteosarcoma: Integrating Epidemiological Insights, Genomic Advances, Environmental Determinants, and Novel Therapeutic Strategies in Contemporary Oncological Practice

Osteosarcoma represents the most prevalent primary malignant bone tumour, predominantly affecting children and adolescents with a characteristic bimodal age distribution. Despite significant advances in multimodal treatment approaches over the past four decades, survival outcomes for patients with metastatic or recurrent disease remain disappointingly poor, with five-year survival rates of merely 20-30%. This comprehensive review synthesises current epidemiological data, genomic discoveries, environmental risk factors, diagnostic innovations, and emerging therapeutic modalities in osteosarcoma management. Our analysis reveals that osteosarcoma exhibits complex genomic heterogeneity, with frequent alterations in TP53 (65-90% of cases) and RB1 (70% of cases) genes, alongside dysregulation of critical molecular pathways including PI3K/AKT/mTOR and MAPK signalling cascades. Environmental risk factors, particularly therapeutic radiation exposure and Paget's disease, contribute significantly to secondary osteosarcoma development. Recent diagnostic advances encompass novel biomarkers such as circulating tumour DNA and microRNAs, whilst innovative imaging techniques enhance early detection capabilities. Therapeutically, immunotherapy approaches including chimeric antigen receptor Tcell therapy and immune checkpoint inhibitors show promising preclinical results, though clinical translation remains challenging due to the immunosuppressive tumour microenvironment. Targeted therapies, particularly anti-angiogenic agents and novel drug delivery systems, offer potential avenues for improving treatment efficacy whilst minimising systemic toxicity. This review underscores the necessity for personalised treatment strategies based on molecular subtyping and highlights future research directions essential for improving outcomes in this devastating malignancy.