Radiation-induced fractures can occur with doses of radiation of 50 Gy or more, as is often used in the treatment of Ewing sarcoma of the extremity.[50,51]
Osteonecrosis (also known as aseptic or avascular necrosis) is a rare, but well-recognized skeletal complication observed predominantly in survivors of pediatric hematological malignancies treated with corticosteroids.[24,52,53,54] The condition is characterized by death of one or more segments of bone that most often affects weight-bearing joints, especially the hips and knees. Longitudinal cohort studies have identified a spectrum of clinical manifestations of osteonecrosis, ranging from asymptomatic spontaneously-resolving imaging changes to painful progressive articular collapse requiring joint replacement.[55,56] Symptomatic osteonecrosis characterized by pain, joint swelling, and reduced mobility typically presents during the first 2 years of therapy, particularly in the case of ALL. These symptoms may improve over time, persist, or progress in the years after completion of therapy. In some series, up to 40% of patients required some type of surgical procedure. The prevalence of osteonecrosis has varied from 1% to 22% based on the study population, treatment protocol, method of evaluation, and time from treatment.[54,57,58,59,60,61]
The most important clinical risk factor for osteonecrosis is treatment with substantial doses of glucocorticoids, as is typical in regimens used for ALL, non-Hodgkin lymphoma, and HSCT.[59,62,63,64,65] Delayed intensification therapies for childhood ALL featuring the more potent glucocorticoid, dexamethasone, have been speculated to enhance risk since osteonecrosis was infrequently reported before this approach became more widely used in the 1990s. However, currently available results suggest that cumulative corticosteroid dose may be a better predictor of this complication.[62,66] Higher cholesterol, lower albumin, and higher dexamethasone exposure have been associated with a higher risk of symptomatic osteonecrosis, suggesting that agents like asparaginase may potentiate the osteonecrotic effect of dexamethasone.
Osteonecrosis is more common in adolescents than in children, with the highest risk among those who are older than 10 years.[61,62,66,67] Osteonecrosis also occurs much more frequently in whites than in blacks.[65,66] Studies evaluating the influence of gender on the risk of osteonecrosis have yielded conflicting results, with some suggesting a higher incidence in females [55,66,67] that has not been confirmed by others.[53,55,62] Genetic factors influencing antifolate and glucocorticoid metabolism have also been linked to excess risk of osteonecrosis among survivors. St. Jude Children's Research Hospital investigators observed an almost sixfold (odds ratio = 5.6; 95% confidence interval [CI], 2.7–11.3) risk of osteonecrosis among survivors with polymorphism of the ACP1 gene, which regulates lipid levels and osteoblast differentiation.