Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Childhood ALL

Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development

Abstract

We assessed the clinical and treatment factors that predispose survivors of childhood acute lymphoblastic leukemia (ALL) to low bone mineral density (BMD). Using quantitative computed tomography, we determined the frequency of low BMD (defined as >1.645 standard deviations (SD) below the mean) in leukemia survivors treated with multiagent chemotherapy including prednisone and antimetabolite. All participants had completed therapy at least 4 years earlier, remained in continuous complete remission, and had no second malignancies. We statistically correlated BMD results with patient characteristics and treatment histories. Among 141 survivors (median age, 15.9 years; median time after diagnosis, 11.5 years), median BMD z score was −0.78 SD (range, −3.23 to 3.61 SDs). Thirty participants (21%; 95% confidence interval, 15% to 29%) had abnormally low BMD, a proportion significantly (P < 0.0001) greater than the expected 5% in normal populations. Risk factors for BMD decrements included male sex (P = 0.038), Caucasian race (P < 0.0001), and cranial irradiation (P = 0.0087). BMD inversely correlated with cranial irradiation dose. BMD z scores of patients who received higher doses of antimetabolites were lower than those of other patients. Childhood ALL survivors are at risk to have low BMD, especially males, Caucasians, and those who received cranial irradiation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Pui C-H, Evans WE . Acute lymphoblastic leukemia N Engl J Med 1998 339: 605–615

    Article  CAS  Google Scholar 

  2. Gaynon PS, Trigg ME, Heerema NA, Sensel MG, Sather HN, Hammond GD, Bleyer WA . Children's Cancer Group Trials in Childhood acute lymphoblastic leukemia 1983–1995 Leukemia (in press)

  3. Schrappe M, Reiter A, Ludwig W-D, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H . Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and of cranial radiotherapy: results of trial ALL-BFM 90. German–Austrian–Swiss ALL-BFM Study Group Blood 2000 95: 3310–3322

    CAS  PubMed  Google Scholar 

  4. Chestnut CH III . Report from the NIH consensus conference, 1984, and NIH/NOF workshop, 1987. In: Genant HK (ed.) Osteoporosis Update 1987. Radiology Research and Education Foundation: San Francisco 1987 pp 3–6

  5. Cummings SR . Epidemiology of osteoporotic fractures. In: Genant HK (ed.) Osteoporosis Update 1987 Radiology Research and Education Foundation: San Francisco 1987 pp 7–12

    Google Scholar 

  6. Prince RL, Smith M, Dick IM, Price RI, Webb PG, Henderson NK, Harris NM . Prevention of postmenopausal osteoporosis N Engl J Med 1991 325: 1189–1195

    Article  CAS  Google Scholar 

  7. Melton LJ III, Chrischilles EA, Cooper C, Lane AW, Riggs BL . Perspective: how many women have osteoporosis? J Bone Miner Res 1992 7: 1005–1010

    Article  Google Scholar 

  8. Johnston CC Jr, Slemenda CW, Melton LJ III . Clinical use of bone densitometry N Engl J Med 1991 324: 1105–1109

    Article  Google Scholar 

  9. Pui C-H, Boyett JM, Rivera GK, Hancock ML, Sandlund JT, Ribeiro RC, Rubnitz JE, Behm FG, Raimondi SC, Gajjar A, Razzouk B, Campana D, Kun LE, Relling MV, Evans WE . Long-term results of Total Therapy Studies 11, 12, and 13A for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital Leukemia (in press)

  10. Cann CE . Low-dose CT scanning for quantitative spinal mineral analysis Radiology 1981 140: 813–815

    Article  CAS  Google Scholar 

  11. Cann CE . A rational approach to radiation exposure in bone densitometry Radiology 1987 165: 184

    Google Scholar 

  12. Kalendar WA . Effective dose values in bone mineral measurements by photon absorptiometry and computed tomography Osteoporosis Int 1992 2: 82–87

    Article  Google Scholar 

  13. ICRP Publication 60 . 1990 Recommendations of the International Commission on Radiological Protection Ann ICRP 1991 21: 1–3

    Article  Google Scholar 

  14. Cann CE . Quantitative CT for determination of bone mineral density: a review Radiology 1988 166: 509–522

    Article  CAS  Google Scholar 

  15. Cann CE, Genant HK . Precise measurement of vertebral mineral content using computed tomography J Comput Assist Tomogr 1980 4: 493–500

    Article  CAS  Google Scholar 

  16. Cann CE, Genant HK, Kolb FO, Ettinger B . Quantitative computed tomography for prediction of vertebral fracture risk Bone 1985 6: 1–7

    Article  CAS  Google Scholar 

  17. Cann CE . Quantitative CT for determination of bone mineral density: a review Radiology 1988 166: 509–522

    Article  CAS  Google Scholar 

  18. Greulich WW, Pyle SI . Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edn Stanford University Press: Stanford 1992 pp 231–251

  19. Styne D . Puberty. In: Greenspan FS, Strewler GJ (eds) Basic and Clinical Endocrinology, 5th edn Appleton and Lange: Stamford 1997 pp 521–546

    Google Scholar 

  20. National Osteoporosis Foundation . Physician's Guide to Prevention and Treatment of Osteoporosis National Osteoporosis Foundation: Washington, DC 1998

    Google Scholar 

  21. Gilsanz V, Carlson ME, Roe TF, Ortega JA . Osteoporosis after cranial irradiation for acute lymphoblastic leukemia J Pediatr 1990 117: 238–244

    Article  CAS  Google Scholar 

  22. Stanisavljevic S, Babcock AL . Fractures in children treated with methotrexate for leukemia Clin Orthop 1977 125: 139–144

    Google Scholar 

  23. Arikoski P, Komulainen J, Voutilainen R, Riikonen P, Parvianen M, Tapanainen P, Knip M, Kroger H . Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia J Pediatr Hematol Oncol 1998 20: 234–240

    Article  CAS  Google Scholar 

  24. Ferrari S, Rizzoli R, Chevalley T, Slosman D, Eisman JA, Bonjour JP . Vitamin-D-receptor-gene polymorphisms and change inlumbar-spine bone mineral density Lancet 1995 345: 423–424

    Article  CAS  Google Scholar 

  25. Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V . Vitamin D–receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent N Engl J Med 1997 337: 77–82

    Article  CAS  Google Scholar 

  26. Howard G, Nguyen T, Morrison N, Watanabe T, Sambrook P, Eisman J, Kelly PJ . Genetic influence on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women J Clin Endocrinol Metab 1995 80: 2800–2805

    CAS  PubMed  Google Scholar 

  27. Krall EA, Parry P, Lichter JB, Dawson-Hughes B . Vitamin D receptor alleles and rates of bone loss: influences of years since menopause and calcium intake J Bone Miner Res 1995 10: 978–984

    Article  CAS  Google Scholar 

  28. Tokita A, Matsumoto H, Morrison NA, Tawa T, Miura Y, Fukamauchi K, Mitsuhashi N, Irimoto M, Yamamori S, Miura M, Watanabe T, Kuwabara T, Yakuta K, Eisman JA . Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women J Bone Miner Res 1996 11: 1003–1009

    Article  CAS  Google Scholar 

  29. Dacou-Voutetakis C, Xypolyta A, Haidas S, Constantinidas M, Papavasiliou C, Zannos-Mariolea L . Irradiation of the head. Immediate effect on growth hormone secretion in children J Clin Endocrinol Metab 1977 44: 791–794

    Article  CAS  Google Scholar 

  30. Shalet SM, Beardwell CG, Pearson D, Jones PH . The effect of varying doses of cerebral irradiation on growth hormone production in childhood Clin Endocrinol 1976 5: 287–290

    Article  CAS  Google Scholar 

  31. Oberfield SE, Nirenberg A, Allen JC, Cohen H, Donahue B, Prasad V, Schiff R, Pang S, Ghavimi F, David R, Chrousos G, Sklar C . Hypothalamic-pituitary-adrenal function following cranial irradiation Horm Res 1997 47: 9–16

    Article  CAS  Google Scholar 

  32. Wara WM, Richards GE, Grumbach MM, Kaplan SL, Sheline GE, Conte FA . Hypopituitarism after irradiation in children Int J Radiat Oncol Biol Phys 1977 2: 549–552

    Article  CAS  Google Scholar 

  33. Lustig RH, Schriock EA, Kaplan SL, Grumbach MM . Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency Pediatrics 1985 76: 274–279

    CAS  PubMed  Google Scholar 

  34. Blatt J, Lee P, Suttner J, Finegold D . Pulsatile growth hormone secretion in children with acute lymphoblastic leukemia after 1800 cGy cranial radiation Int J Radiat Oncol Biol Phys 1988 15: 1001–1006

    Article  CAS  Google Scholar 

  35. Rappaport R, Brauner R . Growth and endocrine disorders secondary to cranial irradiation Pediatr Res 1982 25: 261–267

    Google Scholar 

  36. Boot AM, vd Heuvel MM, Hählen K, deMuinck Keizer SMPF . Bone mineral density of children with acute lymphoblastic leukemia Med Pediatr Oncol 1996 27: 292 (Abstr P-21)

    Google Scholar 

  37. Ragab AH, Frech RS, Vietti TJ . Osteoporotic fractures secondary to methotrexate therapy of acute leukemia in remission Cancer 1970 25: 580–585

    Article  CAS  Google Scholar 

  38. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D . Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis and Bone Disease Osteoporos Int 1997 7: 390–406

    Article  CAS  Google Scholar 

  39. Hoorweg-Nijman JJG, Kardos G, Roos JC, van Dijk HJ, Netelenbos C, Popp-Snijders C, deRidder CM, Delemarre-van de Waal HA . Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia Clin Endocrinol 1999 50: 237–244

    Article  CAS  Google Scholar 

  40. Schwartz AM, Leonidas JC . Methotrexate osteopathy Skeletal Radiol 1984 11: 13–16

    Article  CAS  Google Scholar 

  41. Nesbit M, Krivit W, Heyn R, Sharp H . Acute and chronic effects of methotrexate on hepatic, pulmonary, and skeletal systems Cancer 1976 37:: (Suppl. 2) 1048–1057

    Article  Google Scholar 

  42. Nevinney HB, Krant MJ, Moore EW . Metabolic studies of the effects of methotrexate Metabolism 1965 14: 135–139

    Article  Google Scholar 

  43. Joseph JC . Corticosteroid-induced osteoporosis Am J Hosp Pharm 1994 51: 188–197

    CAS  PubMed  Google Scholar 

  44. Chesney RW, Mazess RB, Hamstra AJ, DeLuca HF . Reduction of serum 1,25-dihydroxyvitamin-D3 in children receiving glucocorticoids Lancet 1978 2: 1123–1125

    Article  CAS  Google Scholar 

  45. Gaynon PS, Lustig RH . The use of glucocorticoids in acute lymphoblastic leukemia of childhood J Pediatr Hematol Oncol 1995 17: 1–12

    Article  CAS  Google Scholar 

  46. Lukert BP, Raisz LG . Glucocorticoid-induced osteoporosis: pathogenesis and management Ann Intern Med 1990 112: 352–364

    Article  CAS  Google Scholar 

  47. Bockman RS, Weinerman SA . Steroid-induced osteoporosis Orthop Clin North Am 1990 21: 97–107

    CAS  PubMed  Google Scholar 

  48. Reid IR . Pathogenesis and treatment of steroid osteoporosis Clin Endocrinol (Oxf) 1989 30: 83–103

    Article  CAS  Google Scholar 

  49. Godschalk M, Levy JR, Downs RW Jr . Glucocorticoids decrease vitamin D receptor number and gene expression in human osteosarcoma cells J Bone Miner Res 1992 7: 21–27

    Article  CAS  Google Scholar 

  50. Halton JM, Atkinson SA, Fraher L, Webber C, Gill GJ, Dawson S, Barr RD . Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia J Bone Miner Res 1999 11: 1774–1783

    Article  Google Scholar 

  51. Munnings F . Osteoporosis: what is the role of exercise? Phys Sports Med 1992 20: 127–138

    Article  CAS  Google Scholar 

  52. Cooper C, Cawley M, Bhalla A, Egger P, Ring F, Morton L, Baker D . Childhood growth, physical activity, and peak bone mass in women J Bone Miner Res 1995 10: 940–947

    Article  CAS  Google Scholar 

  53. McCulloch RG, Bailey DA, Houston CS, Dodd BL . Effects of physical activity, dietary calcium intake and selected lifestyle factors on bone density in young women Can Med Assoc J 1990 142: 221–227

    CAS  Google Scholar 

  54. Sentipal JM, Wardlaw GM, Mahan J, Matkovic V . Influence of calcium intake and growth indexes on vertebral bone mineral density in young females Am J Clin Nutr 1991 54: 425–428

    Article  CAS  Google Scholar 

  55. Gilsanz V, Roe TF, Antunes J, Carlson M, Duarte ML, Goodman WG . Effect of calcium on bone density in growing rabbits Am J Physiol 1991 260: E471–E476

    CAS  PubMed  Google Scholar 

  56. Johnston CC, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, Peacock M . Calcium supplementation and increases in bone mineral density in children N Engl J Med 1992 327: 82–87

    Article  Google Scholar 

  57. Matkovic V, Fontana D, Tominac C, Goel P . Chesnut CH III. Factors that influence peak bone mass formation: a study of calcium balance and the inheritance of bone mass in adolescent famales Am J Clin Nutr 1990 52: 878–888

    Article  CAS  Google Scholar 

  58. Gilsanz V, Gibbens DT, Roe TF, Carlson M, Senac MO, Boechat MI, Huang HK, Schulz EE, Libanati CR, Cann CC . Vertebral bone density in children: effect of puberty Radiology 1988 166: 847–850

    Article  CAS  Google Scholar 

  59. Finkelstein JS, Neer RM, Biller BM, Crawford JD, Klibanski A . Osteopenia in men with a history of delayed puberty N Engl J Med 1992 326: 600–604

    Article  CAS  Google Scholar 

  60. Warner JT, Evans WD, Dunstan FDJ, Bell W, Gregory JW . Relative osteopenia following treatment for childhood acute lymphoblastic leukemia Med Pediatr Oncol 1996 27: 241 (Abstr O-121)

    Google Scholar 

  61. Henderson RC, Madsen CD, Davis C, Gold SH . Bone density in survivors of childhood malignancies J Pediatr Hematol Oncol 1996 18: 367–371

    Article  CAS  Google Scholar 

  62. Southard RN, Morris JD, Mahan JD, Hayes JR, Torch MA . Bone mass in healthy children: measurement with quantitative DXA Radiology 1991 179: 735–738

    Article  CAS  Google Scholar 

  63. Clinical indications for bone mass measurements . A report from the Scientific Advisory Board of the National Osteoporosis Foundation J Bone Miner Res 1989 4: (Suppl. 2) 1–28

    Google Scholar 

  64. Gilsanz V, Gibbens DT, Carlson M, Boechat MI, Cann CE, Schulz EE . Peak trabecular vertebral density: a comparison of adolescent and adult females Calcif Tissue Int 1988 43: 260–262

    Article  CAS  Google Scholar 

  65. Brennan BMD, Rahim A, Adams JA, Eden OB, Shalet SM . Reduced bone mineral density in young adult following cure of acute lymphoblastic leukaemia in childhood Br J Cancer 1999 79: 1859–1863

    Article  CAS  Google Scholar 

  66. Nussey SS, Hyer SL, Brada M, Leiper AD, Pazianas M . Bone mineralization after treatment of growth hormone deficiency in survivors of childhood malignancy Acta Paediatr Suppl 1994 399: 9–14

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Sherri Patterson and Margie Zacher for medical record reviews and data entry, Drs Russell Chesney and Laura Carbone for advice on study design and data interpretation, Ms Myra Hazard for patient recruitment, and Dr Julia Cay for editorial advice and manuscript preparation. This work was supported in part by grants P30 CA-21765 and P01 CA-23099 from the National Cancer Institute, by the American Lebanese Syrian Associated Charities (ALSAC), by the Society for Pediatric Radiology and by a Center of Excellence Grant from the State of Tennessee.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaste, S., Jones-Wallace, D., Rose, S. et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 15, 728–734 (2001). https://doi.org/10.1038/sj.leu.2402078

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402078

Keywords

This article is cited by

Search

Quick links