In children with acute lymphoblastic leukemia (ALL), abnormalities in mineral homeostasis and bone mass were first reported by our group in the late 1980s. Prospective longitudinal cohort studies in 40 consecutive patients receiving treatment according to the Dana-Farber Cancer Institute (DFCI) protocol 87-001 and 16 children receiving DFCI protocol 91-001 afforded us the opportunity to explore various etiologies of the observed abnormalities in mineral and bone metabolism, specifically the leukemic disease process and chemotherapeutic drugs such as steroids and aminoglycoside antibiotics. At diagnosis of ALL, G70% of children had abnormally low plasma 1,25-dihydroxyvitamin D, 73% had low osteocalcin and 64% had hypercalciuria, indicating an effect of the leukemic process on vitamin D metabolism and bone turnover. During remission induction, treatment with high-dose steroid (prednisone or dexamethasone) resulted in further reduction in plasma osteocalcin and elevated parathyroid hormone levels. During 24 months of chemotherapymaintained remission, reduction in bone mineral content (BMC), as measured by Z-scores, occurred in 64% of children, most severely affecting those G11 years of age. A reduction in BMC during the first 6 months had a positive predictive value of 64% for subsequent fracture. By the end of 2 years of therapy, fractures occurred in 39% of children and radiographic evidence of osteopenia was found in 83% of the entire study group. Investigations of the biochemical basis of the bone abnormalities revealed that by 6 months hypomagnesemia developed in 84% of children (of whom 52% were hypermagnesuric) and plasma 1,25-dihydroxyvitamin D remained abnormally low in 70%. Altered magnesium status was attributed to renal wastage of magnesium following cyclical prednisone therapy and treatment with aminoglycoside antibiotics such as amikacin for fever accompanying neutropenia. Dietary intake and absorption of magnesium were normal. In 10 children treated for hypomagnesemia with supplemental magnesium for up to 16-20 weeks, plasma magnesium normalized in only 50% of subjects. Int.