Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia

Abstract

Children with acute lymphoblastic leukemia (ALL) often develop bone pain, abnormal gait, and unusual fractures while in remission and receiving continuing chemotherapy. A prospective longitudinal cohort study was undertaken of bone mass and biochemical mineral status in 40 consecutive children (27 male, 13 female, aged 0.3-17.0 years) receiving therapy on the Dana-Farber Cancer Institute protocol 87-01. Radiography, lumbar spine dual-photon absorptiometry, and biochemical measurements of mineral status were performed at diagnosis and at 6-month intervals throughout 24 months of chemotherapy. Eleven patients were not completely evaluated (4 deaths and 7 off study). Radiographic evidence of osteopenia was observed in 10, 64, and 76% at diagnosis, 12 and 24 months, respectively. Fractures occurred in 39% of children during treatment. Reduction in bone mineral content (BMC), as measured by Z scores, occurred in 64% of patients and was most severe in those greater than 11 years of age at diagnosis. Reduction in BMC during the first 6 months of therapy had a positive predictive value of 64%, while an increase in BMC had a negative predictive value of 82% for subsequent fracture. By 6 months of therapy, 31/37 (84%) children were hypomagnesemic, of whom 16 (52%) were hypermagnesuric. Plasma osteocalcin was subnormal at diagnosis in 29/40 (73%) but increased to normal by 6 months of treatment. Vitamin D status was normal throughout, but plasma 1,25-dihydroxyvitamin D remained subnormal in greater than 70% of children. Urinary cross-link N-telopeptide was normal at diagnosis and became elevated in 58% of children by the end of therapy. Suppressed bone mineralization is evident at diagnosis in a minority of children with ALL. Skeletal morbidity and a reduction in bone mineral mass become more prevalent during treatment, with increased bone resorption, perhaps mainly as a consequence of corticosteroid administration.

High Incidence of Vertebral Fractures in Children With Acute Lymphoblastic Leukemia 12 Months After the Initiation of Therapy

“…1 Fractures due to osteoporosis are an important complication of childhood leukemia at diagnosis, as well as during and after ALL therapy. [2][3][4][5][6][7][8][9][10] We recently found that 16% of children with recently diagnosed ALL had vertebral fractures, and that half of the children manifested moderate or severe fractures. Furthermore, each standard deviation (SD) reduction in spine bone mineral density (BMD) Z-score was associated with an 80% increased odds of vertebral fractures.…”

Skeletal morbidity in acute lymphoblastic leukemia of childhood: Effects on bone metabolism

“…Many studies have demonstrated abnormalities of BMD and bone mineral metabolism in children with ALL at diagnosis, as well as during and at the completion of chemotherapy [12][13][14][15][16][17][18] . This report highlights the fact that normal bone turnover appears to recover in survivors of ALL, even in those who were exposed to the more intensive chemotherapy.…”

“…The loss of bone mineral mass in ALL has been well documented [3][4][5] . However, low bone mineral density (BMD) is only relevant if it persists in the long term so survivors do not achieve a normal peak bone mass by adulthood as seen in healthy populations.…”

Bone tissue as the site of action of oncological drugs

“…As early as in 1965, a report was published presenting the results of a study on the effects of methotrexate (MTX) treatment on calcium metabolism, demonstrating elevated levels of this element in urine and stool, its lowered levels in blood serum, and indirectly its increased bone resorption [1]. The above data have been reflected in a clinical setting, in patients treated with MTX for acute myeloid leukaemia, where there have been observed pain and difficult uniting of fractures during the course of treatment and remission upon its completion [2][3][4][5][6][7][8]. Although the high doses of steroids have been of significance, the cytostatic agents have been deemed to play an important role here.…”