Abstract
Children treated for acute lymphoblastic leukemia may develop reduced bone mineral density during treatment, but there is little information on the mechanisms involved. In a prospective, longitudinal study on 15 children with ALL, we undertook serial measurements of markers of bone and collagen turnover, insulin-like growth factor (IGF)-I and its binding proteins (IGFBPs)-3 and -2 during the second year of continuing chemotherapy. In eight patients we also measured lower leg length by knemometry. Height SD scores, lower leg length velocity, IGF-I, and markers of bone collagen turnover did not differ significantly from healthy children. However, bone alkaline phosphatase, a marker of the differentiated osteoblast, was lower (mean SD score, −0.64;p < 0.0001), whereas procollagen type III N-terminal propeptide (P3NP, a marker of soft tissue collagen turnover; mean SD score, +0.93, p < 0.05), IGFBP-3 (mean SD score, +0.76;p < 0.01), and IGFBP-2 (mean SD score, +1.24, p = 0.01) were all higher than in healthy children. IGFBP-3 decreased during episodes of afebrile neutropenia (p < 0.05). Within 3 mo after completion of treatment, bone ALP increased in all eight patients, but collagen markers showed little change. IGFBP-2 returned to normal posttreatment, but P3NP and IGFBP-3 remained significantly elevated compared with healthy children (mean SD scores, +1.51 and +1.36, respectively;p < 0.01). We conclude that continuing chemotherapy was associated with normal growth and bone collagen turnover but enhanced soft tissue collagen turnover. Bone bone alkaline phosphatase was low throughout treatment, which suggests impaired osteoblast differentiation resulting from a direct effect of chemotherapy on bone. Although the effect was reversible, the long-term implications for bone health in survivors remain uncertain.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ALL:
-
acute lymphoblastic leukemia
- BMD:
-
bone mineral density
- PICP:
-
C-terminal propeptide of type I collagen
- ALP:
-
alkaline phosphatase
- ICTP:
-
C-terminal telopeptide of type I collagen
- P3NP:
-
N-terminal propeptide of type III collagen
- IGFBP:
-
IGF binding protein
- LLLV:
-
lower leg length velocity
References
Berglund G, Karlberg J, Marky I, Mellander L 1985 A longitudinal study of growth in children with acute lymphoblastic leukemia. Acta Paediatr 74: 530–533
Möell C, Garwicz S, Marky I, Mellander L, Karlberg J 1988 Growth in children treated for acute lymphoblastic leukemia with and without prophylactic cranial irradiation. Acta Paediatr Scand 77: 688–692
Clayton PE, Shalet SM, Morris-Jones PH, Price DA 1988 Growth in children treated for acute lymphoblastic leukaemia. Lancet I: 460
Marky I, Samuelsson B-O, Mellander L, Karlberg J 1991 Longitudinal growth in children with non-Hodgkin's lymphoma and children with acute lymphoblastic leukemia: comparison between unirradiated and irradiated patients. Med Pediatr Oncol 19: 96–99
Thun-Hohenstein L, Frisch H, Schuster E 1992 Growth after radiotherapy and chemotherapy in children with leukemia or lymphoma. Horm Res 37: 91–95
Tamminga RYJ, Kamps WA, Drayer NM, Humphrey GB 1992 Longitudinal anthropometric study in children with acute lymphoblastic leukaemia. Acta Paediatr 81: 61–65
Hokken-Koelega ACS, Van Doorn JWD, Hählen K, Stijnen T, De Muinck Keizer-Schrama SMPF, Drop SLS 1993 Long-term effects of treatment for acute lymphoblastic leukemia with and without cranial irradiation on growth and puberty: a comparative study. Pediatr Res 33: 577–582
Caruso-Nicoletti M, Mancuso M, Spadaro G, Dibenedetto SP, DiCataldo A, Schiliró G 1993 Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia. Eur J Pediatr 152: 730–733
Holm K, Nysom K, Hertz H, Müller J 1994 Normal final height after treatment for acute lymphoblastic leukemia without irradiation. Acta Paediatr 83: 1287–1290
Wallace WHB, Kelnar CJH 1996 The effect of chemotherapy on growth and endocrine function in childhood. In: CJH Kelnar (ed) Baillière's Clinical Paediatrics: Paediatric Endocrinology. Baillière Tindall, London, pp 333–347
Mohnike K, Dörffel W, Timme J, Kluba U, Aumann V, Vorwerk P, Mittler U 1997 Final height and puberty in 40 patients after antileukaemic treatment during childhood. Eur J Paediatr 156: 272–276
Ahmed SF, Wallace WHB, Kelnar CJH 1997 An anthropometric study of children during intensive chemotherapy for acute lymphoblastic leukaemia. Horm Res 48: 178–183
Ahmed SF, Wallace WHB, Crofton PM, Wardhaugh B, Magowan R, Kelnar CJH 1999 Short-term changes in lower leg length in children treated for acute lymphoblastic leukaemia. J Pediatr Endocrinol Metab 12: 75–80
Gilsanz V, Carlson ME, Roe TF, Ortega JA 1990 Osteoporosis after cranial irradiation for acute lymphoblastic leukemia. J Pediatr 117: 238–244
Hoorweg-Nijman JJG, Kardos G, Roos JC, van Dijk HJ, Netelenbos C, Popp-Snijders C, de Ridder CM, Delemarre-van de Waal HA 1999 Bone mineral density and markers of bone turnover in young adult survivors of childhood lymphoblastic leukaemia. Clin Endocrinol 50: 237–244
Warner JT, Evans WD, Webb DK, Bell W, Gregory JW 1999 Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45: 544–551
Atkinson SA, Fraher L, Gundberg CM, Andrew M, Pai M, Barr RD 1989 Mineral homeostasis and bone mass in children treated for acute lymphoblastic leukemia. J Pediatr 114: 793
Halton JM, Atkinson SA, Fraher L, Webber C, Gill GJ, Dawson S, Barr RD 1996 Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukaemia. J Bone Miner Res 11: 1774–1783
Arikoski P, Komulainen J, Riikonen P, Voutilainen R, Knip M, Kröger H 1999 Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study. J Clin Endocrinol Metab 84: 3174–3181
Crofton PM, Kelnar CJH 1998 Bone and collagen markers in paediatric practice. Int J Clin Pract 52: 557–565
Rosen CJ, Donahue LR, Hunter SJ 1994 Insulin-like growth factors and bone: the osteoporosis connection. Proc Soc Exp Biol Med 206: 83–102
Ferry RJ, Cerri RW, Cohen P 1999 Insulin-like growth factor binding proteins: new proteins, new functions. Horm Res 51: 53–67
Kelly KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG 1996 Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 28: 619–637
Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, Kelnar CJH, Wallace WHB 1998 Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukaemia. J Clin Endocrinol Metab 83: 3121–3129
Crofton PM, Ahmed SF, Wade JC, Elmlinger MW, Ranke MB, Kelnar CJH, Wallace WHB 1999 Effects of a third intensification block of chemotherapy on bone and collagen turnover, insulin-like growth factor I, its binding proteins and short-term growth in children with acute lymphoblastic leukaemia. Eur J Cancer 35: 960–967
Ahmed SF, Wallace WHB, Kelnar CJH 1995 Knemometry in childhood: a study to compare the precision of two different techniques. Ann Hum Biol 22: 247–252
Melkko J, Niemi S, Risteli L, Risteli J 1990 Radioimmunoassay of the carboxyterminal propeptide of human type I procollagen. Clin Chem 36: 1328–1332
Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L 1993 Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 39: 635–640
Risteli J, Niemi S, Trivedi P, Mäentausta O, Mowat AP, Risteli L 1988 Rapid equilibrium radioimmunoassay for the amino-terminal propeptide of human type III procollagen. Clin Chem 34: 715–718
Peaston RT, Cooper J 1986 Affinity electrophoresis of alkaline phosphatase isoenzymes. Clin Chem 32: 235–236
Blum WF, Breier BH Radioimmunoassay for IGFs and IGFBPs 1994 Growth Regul 4 ( Suppl 1): 11–19
Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel JH, Bierich JR 1990 A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70: 1292–1297
Elmlinger MW, Wimmer K, Biemer E, Blum WF, Ranke MB, Dannecker GE 1996 Insulin-like growth factor binding protein 2 (IGFBP-2) is differentially expressed in leukaemic T- and B-cell lines. Growth Regul 6: 152–157
Crofton PM 1992 Wheat-germ lectin affinity electrophoresis for alkaline phosphatase isoforms in children: age-dependent reference ranges and changes in liver and bone disease. Clin Chem 38: 663–670
Blum WF 1996 Insulin-like growth factors and their binding proteins. In: MB Ranke (ed) Diagnostics of Endocrine Function in Children and Adolescents. JA Barth, Edition J&J, Heidelberg, pp 190–218
Crofton PM, Wade JC, Taylor MRH, Holland CV 1997 Serum concentrations of the carboxyterminal propeptide of type I procollagen, the aminoterminal propeptide of type III procollagen, the cross-linked carboxyterminal telopeptide of type I collagen and their interrelationships in schoolchildren. Clin Chem 43: 1577–1581
Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM, Preece MA 1995 Cross-sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 73: 17–24
Crofton PM 1988 What is the cause of benign transient hyperphosphataaemia? A study of 35 cases. Clin Chem 34: 335–340
Sorva R, Kivivuori S-M, Turpeinen M, Marttinen E, Risteli J, Risteli L, Sorva A, Siimes MA 1997 Very low rate of type I collagen synthesis and degradation in newly diagnosed children with acute lymphoblastic leukemia. Bone 20: 139–143
May KP, West SG, McDermott MT, Huffer WE 1994 The effect of low-dose methotrexate on bone metabolism and histomorphometry in rats. Arthritis Rheum 37: 201–206
Moëll C, Garwicz S 1995 High-dose methotrexate causes short-term suppression of growth in rabbits. Acta Paediatr 84: 1237–1240
Wheeler DL, Vander Griend RA, Wronski TJ, Miller GJ, Keith EE, Graves JE 1995 The short- and long-term effects of methotrexate on the rat skeleton. Bone 16: 215–221
Nesbit M, Krivit W, Heyn R, Sharp H 1976 Acute and chronic effects of methotrexate on hepatic, pulmonary, and skeletal systems. Cancer 37: 1048–1054
Risteli J, Sogaard H, Oikarinen A, Risteli L, Karvonen J, Zachariae H 1988 Aminoterminal propeptide of type III procollagen in methotrexate-induced liver fibrosis and cirrhosis. Br J Dermatol 119: 321–325
Mohnike KL, Kluba U, Mittler U, Aumann V, Vorwerk P, Blum WF 1996 Serum levels of insulin-like growth factor-I, -II and insulin-like growth factor binding proteins -2 and -3 in children with acute lymphoblastic leukaemia. Eur J Pediatr 155: 81–86
Müller HL, Oh Y, Lehrnbecher T, Blum WF, Rosenfeld RG 1994 Insulin-like growth factor-binding protein-2 concentrations in cerebrospinal fluid and serum of children with malignant solid tumors or acute leukemia. J Clin Endocrinol Metab 79: 428–434
Kanety H, Madjar Y, Levi J, Papa MZ, Pariente C, Goldwasser B, Karsik A 1993 Serum insulin-like growth factor-binding protein-2 (IGFBP-2) level is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 77: 229–233
Lee DY, Kim SJ, Lee YC 1999 Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients. J Korean Med Sci 14: 401–404
Acknowledgements
The authors thank K. Schmitt for expert technical assistance. We are also grateful to R. Magowan and B. Wardhaugh for their contributions to the anthropometric measurements and for their help in coordinating sample collection. Finally, we would like to thank Dr. P. Shaw for assistance in retrieving data from case notes and Dr. A. Thomas at the Royal Hospital for Sick Children, Edinburgh for allowing her patients to be studied.
Author information
Authors and Affiliations
Additional information
This work was supported by Serono Laboratories (UK), the Child Growth Foundation, and the Jennifer Fund.
Rights and permissions
About this article
Cite this article
Crofton, P., Ahmed, S., Wade, J. et al. Bone Turnover and Growth During and After Continuing Chemotherapy in Children with Acute Lymphoblastic Leukemia. Pediatr Res 48, 490–496 (2000). https://doi.org/10.1203/00006450-200010000-00012
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200010000-00012
This article is cited by
-
The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies
Bone Research (2023)
-
Bone Turnover Markers in Children: From Laboratory Challenges to Clinical Interpretation
Calcified Tissue International (2022)
-
IGFBP2: integrative hub of developmental and oncogenic signaling network
Oncogene (2020)
-
Physical therapy and chiropractic use among childhood cancer survivors with chronic disease: impact on health-related quality of life
Journal of Cancer Survivorship (2011)
