Osteonecrosis in children with acute lymphoblastic leukemia

Abstract

The morbidity and toxicity associated with current intensive treatment protocols for acute lymphoblastic leukemia in childhood become even more important as the vast majority of children can be cured and become long-term survivors. Osteonecrosis is one of the most common therapy-related and debilitating side effects of anti-leukemic treatment and can adversely affect long-term quality of life. Incidence and risk factors vary substantially between study groups and therapeutic regimens. We therefore analyzed 22 clinical trials of childhood acute lymphoblastic leukemia in terms of osteonecrosis incidence and risk factors. Adolescent age is the most significant risk factor, with patients >10 years old at the highest risk. Uncritical modification or even significant reduction of glucocorticoid dosage cannot be recommended at this stage. A novel and innovative approach to reduce osteonecrosis-associated morbidity might be systematic early screening for osteonecrosis by serial magnetic resonance images. However, discriminating patients at risk of functional impairment and debilitating progressive joint disease from asymptomatic patients still remains challenging.

Figure 1.

Schematic illustration of osteonecrosis pathogenesis. (A) Blood supply of bone is delivered by the nutrient arteries, which enter in the dia- and epiphysis and branch into marrow sinusoids. The growth plate receives its blood supply from dia- and epiphyseal vessels and anastomoses in the perichondrium, respectively. (B–C) Bone growth occurs by endochondral bone formation and bone modeling. The bone tissue is continuously turning over, with osteoclasts and osteoblasts being fundamentally involved in this process. In the context of osteonecrosis development, osteoblast differentiation from mesenchymal progenitor cells is disturbed by gradual lipid accumulation within osteoblasts and osteocytes and increased cell death, both mainly induced by GCs (glucocorticosteroids), and results in defective bone repair. (D–E) Bone perfusion is disturbed by intraluminal obliteration induced by lipid emboli and intravascular coagulation and extraluminal obliteration induced by intramedullary lipocyte proliferation and lipid hypertrophy. Intraosseous compartment syndrome may develop, increasingly reducing intramedullary blood flow and predisposing for coagulation in the intraosseous blood vessels. (F–G) Direct blood vessel injury and disruption of the vascular supply to the bone is mainly mediated by damaging effects on the endothelial and smooth muscle cells of nutrient arteries and venous vessels. HSC: hematopoietic stem cell; MP: mesenchymal progenitor cell.