Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2–L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual-energy X-ray absorptiometry in 46 children (age 2.9–16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy-terminal propeptide (PICP), and type I collagen carboxy-terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6-month follow-up. A significant decrease in lumbar BMDvol (–2.1%, p < 0.05), and in femoral BMDareal (–9.9%, p = 0.0001) and BMDvol (–8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow-up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.