Deferoxamine-induced bone dysplasia

Deferoxamine-induced bone dysplasia refers to abnormal bone development that may be present in patients undergoing iron-chelation therapy with deferoxamine. Deferoxamine is often used in patients with β thalassemia major for the prevention and treatment of transfusion-related secondary hemochromatosis.  

Epidemiology

Deferoxamine-induced bone dysplastic changes may be found in the long bones of up to 70% of patients undergoing treatment related to thalassemia ¹. Retardation of growth and metaphyseal changes are more commonly noted in patients who have undergone chelation therapy before the age of three ². 

Clinical presentation

Children present with known chronic anemia (ie β thalassemia) and have been treated long term with deferoxamine to prevent or treat iron overload. Patients may present with a lower than normal height percentile for their age group along with other features such as genu valgum, kyphosis, scoliosis, or a disproportionately short trunk ². Impairment of bone development occurs predominantly in patients receiving high doses (50 mg/kg/day) or treated under the age of three ^3,7. 

Pathology

Treatment of β thalassemia major and other forms of chronic anemia consists of blood transfusions to maintain functional hemoglobin levels compatible with life and avoid complications. As a result of multiple transfusions, the amount of iron that can be bound to transferrin is exceeded leading to a toxic accumulation of non-transferrin-bound iron ⁴. As the body cannot actively remove iron, chelators such as deferoxamine are utilized to lower iron to a safe level. 

While there are a number of theories, the exact mechanism of deferoxamine-induced bone dysplasia is not completely understood. It has been theorized that the loss of minerals such as zinc in chelation therapy may be responsible for the bone abnormalities that may accompany deferoxamine therapy as the drug is also a powerful chelator of zinc ^5,6,8. In addition, deferoxamine is thought to impair fibroblast proliferation, collagen synthesis, and osteoblast activity in the region of the metaphysis ^2,5.

Radiographic features

Plain radiograph

Long bones

• changes are usually bilateral and primarily present in the distal femur, proximal humerus, distal radius, and tibia ²
• course irregular sclerosis of the metaphysis manifesting as broad bands that progress centrally in the direction of the diaphysis in the early stages ⁸ 
• irregular splaying of the epiphyseal-metaphyseal junction with physeal widening ^2,5
• progressive changes that include cyst-like lucencies with cupping and fraying in a manner similar to rickets ^1,2,5
• the diaphysis is generally spared ⁸
• the distal femur is the most frequent site of involvement; often accompanied by genu valgum  ⁵

Spine

• platyspondyly is the most notable spinal feature appearing as anterior elongation with flattening of the vertebral bodies. The severity of this feature is dependent on the age that the therapy started ²
• degenerative disc disease that is either related to iron deposition or deferoxamine therapy ²
• scoliosis which is correlated with long duration of therapy ^2,8
• kyphosis ²

MRI

• metaphyseal defects of low T1 signal intensity and intermediate to high signal intensity on T2-weighted imaging ²

Prognosis

Early recognition of osseous abnormalities is crucial as a reduction in dose has been shown to improve skeletal dysplasia and growth ^1,2. It has been suggested that yearly hand radiography may be useful in monitoring and early diagnosis of deferoxamine-induced bone dysplasia ^3,8.