Anorexia nervosa (AN) is a life-threatening eating disorder characterized by an inability to maintain a normal body weight and amenorrhoea, often associated with osteoporosis and increased risk of fragility fractures. Bone metabolism, including markers of bone turnover (serum total alkaline phosphatase, bone alkaline phosphatase [bone AP], osteocalcin [OC] and type I collagen C-telopeptide breakdown products [sCTX]) and bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) at the spine and at the hip, were evaluated in 55 consecutive women with AN undergoing a 3-month intensive nutritional rehabilitation program. The control group was constituted of 25 healthy young medical students. In AN patients body weight increased during the 3-month nutritional program from 37.8+/-5.1 (mean+/-SD) to 51.5+/-4.5 kg. The corresponding BMI rose to values >17.5 kg/m(2) in all patients. Mean BMD significantly rose by 2.6+/-3.5% and 1.1+/-3.6% at the hip and at the spine, respectively. The markers of bone formation, serum bone AP and osteocalcin, significantly rose by two-folds, while sCTX decreased by 16%. The changes in hip BMD were positively related (p<0.005) to changes in body weight and in bone AP (p<0.02) while the changes in spine BMD were positively related to changes in serum osteocalcin (p<0.05). In the 25 patients who attended the 12-month posttreatment control, mean body weight significantly decreased by 3.6+/-6.0 kg and this was not associated with any significant change in BMD values. In the patients in whom BMI fell again below 17.5 kg/m(2) hip BMD values decreased significantly. On the contrary, in the patients who maintained BMI >17.5 kg/m(2), BMD values continued to rise up to values over the 15-month observation of 4.8+/-6.2 and 7.1+/-12.1 at the spine and hip, respectively. In conclusion, we have demonstrated that substantial gains in weight in women with chronic AN are associated with remarkable increases in BMD at both the hip and the spine. If weight is maintained, the overall improvement approach 1 SD within 1 year. The changes in both weight and BMD are correlated with improvements in bone formation markers and diminutions in a marker of bone resorption.