Osteosarcoma has a predilection for the metaphyseal portions of the most rapidly growing bones in adolescents and tumours of the humerus tend to occur at a younger age than do tumours of the femur and tibia, corresponding to the earlier growth spurt of the humerus. An explanation to that may be that rapidly proliferating cells might be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Nevertheless, it must be recognized that osteosarcoma arises in many patients well before and long after the adolescent growth spurt.
Radiation is a well-documented aetiologic factor, being implicated in approximately 3% of osteosarcomas. An increased incidence is likely to be seen, as more patients survive long enough after primary irradiation to develop this complication. The interval between irradiation and appearance of osteosarcoma ranges from 4 to more than 40 years (median: 12-16 years). Osteosarcomas have also been associated with the use of intravenous radium 224 and Thorotrast (diagnostic radiocontrast agent). Exposure to alkylating agents may also contribute to its development.
Approximately 2% of patients with Pagetís disease develop osteosarcoma and cases of osteosarcoma in patients older than 40 years are associated almost exclusively with this premalignant condition. Other conditions associated with an increased risk of development of osteosarcoma, are solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Ollierís disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts and sites of metallic implants for benign conditions.
The incidence of osteosarcoma is increased in several well-defined hereditary disorders associated with germ-line alterations of tumour suppressor genes. By far the strongest genetic predisposition to this disease is found in patients with hereditary retinoblastoma (germ-line mutation of the retinoblastoma gene RB1 on chromosome 13q14), where osteosarcoma occurs 2000 times more frequently in the skull after irradiation and 500 times more frequently in the extremities than would be expected in the general population. The Li-Fraumeni syndrome (germ-line mutations in the p53 gene) is associated with a 15-fold increase. Rothmund-Thomson, Bloom and Werner (adult progyria) syndromes are also associated with an increase in osteosarcomas.