Effects of chemotherapy on bone metabolism and skeletal growth.

In recent years there has been a significant increase in both acute and chronic toxicity associated with the more successful but now highly intensive chemotherapy (CT) regimens used to treat childhood cancers. The incidence of childhood cancers coincides with periods of rapid skeletal development. Consequently, short stature and osteoporosis are important long-term effects in adult survivors. Clinical data indicate that the effects of CT, including glucocorticoids, on final height are due to direct effects of these drugs on the skeleton. The multiple modes of action of CT drugs suggest a complex and diverse influence on chondrocytes, extracellular matrix and bone cells. However, only limited data demonstrate these direct effects on the proliferative capacity of growth plate chondrocytes and on key steps of endochondral ossification, the multistep process that determines rate and extent of long bone growth. Endochondral ossification requires coordinated maturation, proliferation and differentiation of growth plate chondrocytes leading to hypertrophic cells which eventually undergo apoptosis to leave a cartilaginous scaffold that is mineralized prior to the laying down of new bone. Disruption of the physiological cellular activity of growth plate chondrocytes and/or bone cells result in skeletal growth disturbances. Thus, CT drugs which disrupt normal cell division may manifest their effects on the growth plate as either a reduction in cell number and/or the loss of functional integrity of extracellular matrix. Histological and cell kinetic studies, using in vivo and in vitro models of long bone growth, are essential to increase our understanding of the cellular mechanisms involved and to finally determine how the individual growth potential might be maintained during treatment for childhood cancers.