Skeletal Health in Pediatric Inflammatory Bowel Disease

  • Francisco Sylvester


Bone Mineral Density Inflammatory Bowel Disease Bone Mass Osteoclast Differentiation Intestinal Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Seeman E, Delmas PD. Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 2006;354(21):2250–61.PubMedCrossRefGoogle Scholar
  2. 2.
    Kirschner BS, Sutton MM. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 1986;91(4):830–6.PubMedGoogle Scholar
  3. 3.
    Sylvester FA, Davis PM, Wyzga N, Hyams JS, Lerer T. Are activated T cells regulators of bone metabolism in children with Crohn disease? J Pediatr 2006;148(4):461–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Dresner-Pollak R, Karmeli F, Eliakim R, Ackerman Z, Rachmilewitz D. Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease. Am J Gastroenterol 2000;95(3):699–704.PubMedCrossRefGoogle Scholar
  5. 5.
    Sylvester FA. IBD and skeletal health: children are not small adults! Inflamm Bowel Dis 2005;11(11):1020–3.PubMedCrossRefGoogle Scholar
  6. 6.
    Bachrach LK. Osteoporosis and measurement of bone mass in children and adolescents. Endocrinol Metab Clin North Am 2005;34(3):521–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement 2000;17(1):1–45.Google Scholar
  8. 8.
    Lu PW, Briody JN, Ogle GD, Morley K, Humphries IR, Allen J, et al. Bone mineral density of total body, spine, and femoral neck in children and young adults: a cross-sectional and longitudinal study. J Bone Miner Res 1994;9(9):1451–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Seeman E. Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 2001;86(10):4576–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Herzog D, Bishop N, Glorieux F, Seidman EG. Interpretation of bone mineral density values in pediatric Crohn disease. Inflamm Bowel Dis 1998;4(4):261–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Stains JP, Civitelli R. Cell-to-cell interactions in bone. Biochem Biophys Res Commun 2005;328(3):721–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Parfitt AM, Travers R, Rauch F, Glorieux FH. Structural and cellular changes during bone growth in healthy children. Bone 2000;27(4):487–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Rauch F, Bailey DA, Baxter-Jones A, Mirwald R, Faulkner R. The ‘muscle-bone unit’ during the pubertal growth spurt. Bone 2004;34(5):771–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 2005;4(3):325–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Feng X. Regulatory roles and molecular signaling of TNF family members in osteoclasts. Gene 2005;350(1):1–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999;402(6759):304–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397(6717):315–23.PubMedCrossRefGoogle Scholar
  18. 18.
    Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003;111(8):1221–1230.PubMedCrossRefGoogle Scholar
  19. 19.
    Takayanagi H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med 2005;83(3):170–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999;25(3):255–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 2000;106(10):1229–37.PubMedCrossRefGoogle Scholar
  22. 22.
    Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-a induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106(12):1481–1488.PubMedGoogle Scholar
  23. 23.
    Zhang YH, Heulsmann A, Tondravi MM, Mukherjee A, Abu-Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem 2001;276(1):563–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ. TNFa Potently Activates Osteoclasts, through a Direct Action Independent of and Strongly Synergistic with RANKL. Endocrinology 2002;143(3):1108–1118.PubMedCrossRefGoogle Scholar
  25. 25.
    Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Natl Acad Sci U S A 2001;98(24):13960–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89(2):309–19.PubMedCrossRefGoogle Scholar
  27. 27.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12(9):1260–1268.PubMedGoogle Scholar
  28. 28.
    Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 1998;247(3):610–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 2002;416(6882):744–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Takai H, Kanematsu M, Yano K, Tsuda E, Higashio K, Ikeda K, et al. Transforming Growth Factor-b Stimulates the Production of Osteoprotegerin/Osteoclastogenesis Inhibitory Factor by Bone Marrow Stromal Cells. J Biol Chem 1998;273(42):27091–27096.PubMedCrossRefGoogle Scholar
  31. 31.
    Glass DA, 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005;8(5):751–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG. Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 2006;119(Pt 7):1283–96.PubMedCrossRefGoogle Scholar
  33. 33.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 2000;408(6812):600–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Sasaki H, Hou L, Belani A, Wang CY, Uchiyama T, Muller R, et al. IL-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol 2000;165(7):3626–30.PubMedGoogle Scholar
  35. 35.
    Owens JM, Gallagher AC, Chambers TJ. IL-10 modulates formation of osteoclasts in murine hemopoietic cultures. J Immunol 1996;157(2):936–40.PubMedGoogle Scholar
  36. 36.
    Horwood NJ, Elliott J, Martin TJ, Gillespie MT. IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro. J Immunol 2001;166(8):4915–21.PubMedGoogle Scholar
  37. 37.
    Nagata N, Kitaura H, Yoshida N, Nakayama K. Inhibition of RANKL-induced osteoclast formation in mouse bone marrow cells by IL-12: involvement of IFN-[gamma] possibly induced from non-T cell population. Bone 2003;33(4):721–732.PubMedCrossRefGoogle Scholar
  38. 38.
    Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000;103(1):41–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95(11):1046–57.PubMedCrossRefGoogle Scholar
  40. 40.
    Sandberg WJ, Yndestad A, Oie E, Smith C, Ueland T, Ovchinnikova O, et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 2006;26(4):857–63.PubMedCrossRefGoogle Scholar
  41. 41.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390(6656):175–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Williamson E, Bilsborough JM, Viney JL. Regulation of mucosal dendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol 2002;169(7):3606–12.PubMedGoogle Scholar
  43. 43.
    Yun TJ, Chaudhary PM, Shu GL, Frazer JK, Ewings MK, Schwartz SM, et al. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol 1998;161(11):6113–21.PubMedGoogle Scholar
  44. 44.
    Theill LE, Boyle WJ, Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002;20:795–823.Google Scholar
  45. 45.
    Bernstein CN, Sargent M, Leslie WD. Serum osteoprotegerin is increased in Crohn disease: a population-based case control study. Inflamm Bowel Dis 2005;11(4):325–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Moschen AR, Kaser A, Enrich B, Ludwiczek O, Gabriel M, Obrist P, et al. The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss. Gut 2005;54(4):479–87.PubMedCrossRefGoogle Scholar
  47. 47.
    Franchimont N, Reenaers C, Lambert C, Belaiche J, Bours V, Malaise M, et al. Increased expression of receptor activator of NF-kappa B ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn disease patients. Clin Exp Immunol 2004;138(3):491–498.PubMedCrossRefGoogle Scholar
  48. 48.
    Canalis E. The fate of circulating osteoblasts. N Engl J Med 2005;352(19):2014–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000;141(7):2674–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Difedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, et al. Tumor Necrosis Factor alpha Blockade Restores Growth Hormone Signaling in Murine Colitis. Gastroenterology 2005;128(5):1278–1291.PubMedCrossRefGoogle Scholar
  51. 51.
    Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, et al. Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006;281(7):4326–33.PubMedCrossRefGoogle Scholar
  52. 52.
    Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells. J Leukoc Biol 2005;77(3):388–399.PubMedCrossRefGoogle Scholar
  53. 53.
    Franchimont N, Putzeys V, Collette J, Vermeire S, Rutgeerts P, De Vos M, et al. Rapid improvement of bone metabolism after infliximab treatment in Crohn disease. Alimentary Pharmacology and Therapeutics 2004;20(6):607–614.PubMedCrossRefGoogle Scholar
  54. 54.
    Ryan BM, Russel MG, Schurgers L, Wichers M, Sijbrandij J, Stockbrugger RW, et al. Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn disease: a prospective study. Aliment Pharmacol Ther 2004;20(8):851–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Bernstein M, Irwin S, Greenberg GR. Maintenance infliximab treatment is associated with improved bone mineral density in Crohn disease. Am J Gastroenterol 2005;100(9):2031–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Weitzmann MN, Cenci S, Rifas L, Haug J, Dipersio J, Pacifici R. T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms. J Bone Miner Res 2001;16(2):328–37.PubMedCrossRefGoogle Scholar
  57. 57.
    Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res 2005;40(4):287–93.PubMedCrossRefGoogle Scholar
  58. 58.
    Roggia C, Tamone C, Cenci S, Pacifici R, Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med 2004;95(2):125–32.PubMedGoogle Scholar
  59. 59.
    Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006;116(5):1186–1194.PubMedCrossRefGoogle Scholar
  60. 60.
    Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996;111(5):1263–71.PubMedCrossRefGoogle Scholar
  61. 61.
    Dresner-Pollak R, Gelb N, Rachmilewitz D, Karmeli F, Weinreb M. Interleukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones. Gastroenterology 2004;127(3):792–801.PubMedCrossRefGoogle Scholar
  62. 62.
    Ashcroft AJ, Cruickshank SM, Croucher PI, Perry MJ, Rollinson S, Lippitt JM, et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity 2003;19(6):849–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Byrne FR, Morony S, Warmington K, Geng Z, Brown HL, Flores SA, et al. CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin. Gut 2005;54(1):78–86.PubMedCrossRefGoogle Scholar
  64. 64.
    Issenman RM, Atkinson SA, Radoja C, Webber CE. Spinal Bone Mass During The First Two Years of Treatment in Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr 1996.Google Scholar
  65. 65.
    Harpavat M, Greenspan SL, O’Brien C, Chang CC, Bowen A, Keljo DJ. Altered bone mass in children at diagnosis of Crohn disease: a pilot study. J Pediatr Gastroenterol Nutr 2005;40(3):295–300.PubMedCrossRefGoogle Scholar
  66. 66.
    Ahmed SF, Horrocks IA, Patterson T, Zaidi S, Ling SC, McGrogan P, et al. Bone mineral assessment by dual energy X-ray absorptiometry in children with inflammatory bowel disease: evaluation by age or bone area. J Pediatr Gastroenterol Nutr 2004;38(3):276–80.PubMedCrossRefGoogle Scholar
  67. 67.
    Croucher PI, Vedi S, Motley RJ, Garrahan NJ, Stanton MR, Compston JE. Reduced bone formation in patients with osteoporosis associated with inflammatory bowel disease. Osteoporos Int 1993;3(5):236–41.PubMedCrossRefGoogle Scholar
  68. 68.
    Hyams JS, Wyzga N, Kreutzer DL, Justinich CJ, Gronowicz GA. Alterations in bone metabolism in children with inflammatory bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr 1997;24(3):289–95.PubMedCrossRefGoogle Scholar
  69. 69.
    Varghese S, Wyzga N, Griffiths AM, Sylvester FA. Effects of serum from children with newly diagnosed Crohn disease on primary cultures of rat osteoblasts. J Pediatr Gastroenterol Nutr 2002;35(5):641–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Sylvester FA, Wyzga N, Hyams JS, Gronowicz GA. Effect of Crohn disease on bone metabolism in vitro: a role for interleukin-6. J Bone Miner Res 2002;17(4):695–702.PubMedCrossRefGoogle Scholar
  71. 71.
    Burnham JM, Shults J, Semeao E, Foster B, Zemel BS, Stallings VA, et al. Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res 2004;19(12):1961–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Burnham JM, Shults J, Semeao E, Foster BJ, Zemel BS, Stallings VA, et al. Body-composition alterations consistent with cachexia in children and young adults with Crohn disease. Am J Clin Nutr 2005;82(2):413–420.PubMedGoogle Scholar
  73. 73.
    Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81(3):353–73.PubMedGoogle Scholar
  74. 74.
    Sentongo TA, Semaeo EJ, Stettler N, Piccoli DA, Stallings VA, Zemel BS. Vitamin D status in children, adolescents, and young adults with Crohn disease. Am J Clin Nutr 2002;76(5):1077–81.PubMedGoogle Scholar
  75. 75.
    Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med 2000;133(10):795–9.PubMedGoogle Scholar
  76. 76.
    Loftus EV, Jr., Crowson CS, Sandborn WJ, Tremaine WJ, O’Fallon WM, Melton LJ, 3rd. Long-term fracture risk in patients with Crohn disease: a population-based study in Olmsted County, Minnesota. Gastroenterology 2002;123(2):468–75.PubMedCrossRefGoogle Scholar
  77. 77.
    Klaus J, Armbrecht G, Steinkamp M, Bruckel J, Rieber A, Adler G, et al. High prevalence of osteoporotic vertebral fractures in patients with Crohn disease. Gut 2002;51(5):654–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression fractures in pediatric patients with Crohn disease. Gastroenterology 1997;112(5):1710–3.PubMedCrossRefGoogle Scholar
  79. 79.
    Gupta A, Paski S, Issenman R, Webber C. Lumbar spine bone mineral density at diagnosis and during follow-up in children with IBD. J Clin Densitom 2004;7(3):290–5.PubMedCrossRefGoogle Scholar
  80. 80.
    van der Sluis IM, de Ridder MA, Boot AM, Krenning EP, de Muinck Keizer-Schrama SM. Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults. Arch Dis Child 2002;87(4):341–7; discussion 341–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Bourges O, Dorgeret S, Alberti C, Hugot JP, Sebag G, Cezard JP. [Low bone mineral density in children with Crohn disease]. Arch Pediatr 2004;11(7):800–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, Wilkinson AA. Bone densitometry in Canadian children 8–17 years of Age. Calcif Tissue Int 1996;59(5):344–51.PubMedCrossRefGoogle Scholar
  83. 83.
    Scheer K, Kratzsch J, Deutscher J, Gelbrich G, Borte G, Kiess W. Bone metabolism in 53 children and adolescents with chronic inflammatory bowel disease. Klin Padiatr 2004;216(2):62–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Semeao EJ, Jawad AF, Zemel BS, Neiswender KM, Piccoli DA, Stallings VA. Bone mineral density in children and young adults with Crohn disease. Inflamm Bowel Dis 1999;5(3):161–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Boot AM, Bouquet J, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut 1998;42(2):188–94.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Francisco Sylvester
    • 1
  1. 1.Connecticut Childrens Medical CenterHartfordUSA

Personalised recommendations