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Late Effects of Treatment for Childhood Cancer (PDQ®): Treatment - Health Professional Information [NCI] - Late Effects of the Musculoskeletal System


Most of our knowledge about cancer and its treatment effects on bone mineralization has been derived from studies of children with ALL.[24,33] In this group, the leukemic process, and possibly vitamin D deficiency, may play a role in the alterations in bone metabolism and bone mass observed at diagnosis.[37] Antileukemic therapy causes further bone mineral density loss, [38] which has been reported to normalize over time [39,40] or to persist for many years after completion of therapy.[41,42] Clinical factors predicting higher risk for low bone mineral density include treatment with high cumulative doses of methotrexate (>40 g/m2), high cumulative doses of corticosteroids (>9 g/m2), and use of more potent glucocorticoids like dexamethasone.[41,43,44] Investigations evaluating the contribution of cranial radiation to the risk of low bone mineral density in childhood cancer survivors have yielded conflicting results.[41,45] Bone mineral density deficits that are likely multifactorial in etiology have been reported in allogeneic hematopoietic cell transplant recipients conditioned with TBI.[46,47] French investigators observed a significant risk for lower femoral bone mineral density among adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation (HSCT) who had gonadal deficiency.[48] Hormonal therapy has been shown to enhance bone mineral density of adolescent girls diagnosed with hypogonadism after HSCT.[49][Level of evidence: 3iiiC]

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.[54] 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.[61]

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