Acute lymphoblastic leukemia (ALL) is the most frequent form of childhood malignancy, with a cure rate that now exceeds 80%. As survival improves, the clinical consequences of ALL and its treatment are increasingly recognized, with skeletal health emerging as an important care issue. The skeletal morbidity that arises in this setting falls into two main categories: osteoporosis (low trauma fractures) and osteonecrosis (in situ bone death). Osteoporosis and necrosis have the potential to cause acute and chronic bone pain, loss of mobility, and permanent skeletal deformity. These adverse outcomes highlight the deleterious impact of ALL and its treatment on focal and systemic bone metabolism.
Up to a third of children with ALL will develop fractures or symptomatic osteonecrosis in the first 5 years. At the same time, recent longitudinal studies have highlighted that most of the bone morbidity occurs in the first 2 years after diagnosis. Vertebral fractures, an important manifestation of osteoporosis in children with leukemia, are frequently asymptomatic and thereby go undetected in the absence of a surveillance programme. On the other hand, vertebral fractures at ALL diagnosis (including mild, asymptomatic vertebral collapse) are among the strongest predictors of future, incident fractures, along with low bone mineral density (BMD) at diagnosis, and higher glucocorticoid exposure. Similarly, osteonecrosis lesions that are evident early in the chemotherapy treatment course (including asymptomatic lesions) predict progression of osteonecrosis at future time points. These important observations highlight the following key concept: understanding the skeletal phenotype early in the childs treatment course (including asymptomatic bone morbidity) is paramount to identifying children at greatest risk for incident fractures and progression of osteonecrotic lesions at subsequent time points.
For most children, leukemia and its related chemotherapy represent transient bone health threats. As such, many children will have the potential for dramatic recovery, including BMD restitution, vertebral body reshaping following fracture, decrease in overall fracture risk, and resolution of osteonecrotic lesions. At the same time, recovery from skeletal morbidity in the leukemia setting is growth-dependent, underscoring the importance of timely diagnosis and appropriate intervention for those who have limited potential for spontaneous vertebral body reshaping and resolution of osteonecrotic lesions due to insufficient residual growth potential.
Different medical interventions have been studied to treat or prevent bone morbidity in children with ALL, including calcium and vitamin D supplementation, calcitriol, and bisphosphonate therapy. Of these, bisphosphonate therapy is associated with the most potent bone-modifying effect, typically reserved for children with osteoporosis and limited potential for spontaneous recovery. Bisphosphonate therapy has also been shown to alleviate pain arising from osteonecrotic lesions; its role in preventing osteonecrosis and its progression is less clear. In older children with advanced osteonecrosis, functional impairment and limited potential for spontaneous recovery, surgical intervention may be warranted.
Disclosure: Receipt of honoraria/consulting fees: Alexion, Novartis.
27 - 30 Jun 2015