Malnutrition is one of the risk factors for bone loss in patients with anorexia nervosa (AN). To clarify the effects of nutritional status on bone metabolism, we examined the relationship between serum levels of nutritional indicators [insulin-like growth factor I (IGF-I), IGF-binding protein-2 (IGFBP-2), and IGFBP-3] and markers for bone metabolism [serum osteocalcin and urinary excretion of C-terminal telopeptide of collagen type I (CrossLaps)] in 45 AN out-patients, including 8 severely malnourished patients who required hospitalization and iv hyperalimentation (IVH). Compared to healthy subjects, serum IGF-I and IGFBP-3 were lower, whereas IGFBP-2 was higher in out-patients who had a body mass index (BMI) less than 16.5 kg/m2. In these patients, urinary excretion of CrossLaps, a marker of bone resorption, was higher, whereas serum osteocalcin, a marker of bone formation, was lower than those in control subjects. All of these parameters were normal in patients whose BMI ranged from 16.5-18.5 kg/m2. Serum levels of osteocalcin correlated positively with BMI (r = 0.512; P<0.0001), IGF-I (r = 0.558; P<0.0001), and IGFBP-3 (r = 0.369; P<0.001) in AN out-patients. In the 8 severely malnourished AN patients, serum levels of IGF-I and osteocalcin significantly increased 3 and 7 days, respectively, after the start of a 5-week IVH therapy regimen and reached normal levels within 5 weeks, accompanied by still elevated urinary excretion of CrossLaps. The present study demonstrates that an improvement in nutritional status in AN patients during IVH therapy rapidly increases the serum IGF-I levels, followed by a progressive increase in osteocalcin, suggesting immediate start of bone formation. However, increased bone resorption appears to continue for at least 5 weeks.