Causes of Bone Sarcoma
For the majority of bone sarcomas, no specific etiology has been established. A few predisposing factors have been identified, including genetics, radiation therapy, chemotherapy, preexisting benign tumors and conditions, trauma, and orthopedic implants.

Genetic Factors
Children with familial retinoblastoma have a 13q chromosome deletion and an increased incidence of osteosarcoma. Li-Fraumeni syndrome is also associated with an increased risk of bone sarcomas as well as other cancers, such as breast cancer, leukemia, soft-tissue sarcoma, and brain and adrenal cortical tumors. Li-Fraumeni syndrome results from a genetic loss of TP53. A maternal history of breast cancer or melanoma has been suggested as a risk factor in at least one study. Screening of at-risk families and surveillance of affected individuals for these syndromes may permit earlier diagnosis and more effective treatment in these populations. There is some preliminary evidence that pleomorphisms in the microsatellite region of the promoters for downstream targets of EWS/Fli1 may make certain populations at increased risk for developing Ewing sarcoma.

Radiation Therapy
Bone sarcomas constitute a rare, but devastating, consequence of therapeutic irradiation. Radiation-associated sarcomas develop within the radiation field, usually after a latent period of at least 3 years, occurring anytime thereafter. The majority of these tumors are osteosarcomas. MFH and other histologies also can arise within a radiation field.

Chemotherapy
Alkylating agents and anthracyclines administered for unrelated cancers have been implicated as etiologic factors in the development of second malignant neoplasms, particularly osteosarcoma.

Preexisting Benign Tumors/Conditions
Osteosarcomas can arise in association with Paget disease and rarely in association with benign bone tumors (ie, fibrous dysplasia). Chondrosarcomas can develop in the cartilaginous component of osteochondromas (solitary and multiple hereditary exostosis) and in patients with enchondromatosis (Ollier disease and Maffucci syndrome). MFH can arise in association with bone infarcts.

Trauma
A traumatic event often prompts medical intervention, at which time the bone sarcoma is detected. Interestingly, experimental inflammation via wounding in animal models infected with the Rous sarcoma virus led to sarcomagenesis. Such a finding is truly intriguing. Nonetheless, the incidence of trauma relative to that of sarcomas certainly implies inflammation alone is not causative.