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Bone, Inflammation, and Inflammatory Bowel Disease

  • Epidemiology and Pathophysiology (Mone Zaidi and Jeffrey I. Mechanick, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Osteoporosis is a leading cause of morbidity in patients with inflammatory bowel disease (IBD). Bone loss is an early systemic process and occurs even before clinical disease manifests. Bone disease is attributed to vitamin D deficiency, steroid use, and/or systemic inflammation. In this review, we discuss the molecular pathways of bone loss mediated by inflammatory cytokines and other mediators. Further research will hopefully clarify the mechanisms of inflammation-induced bone loss in IBD and guide effective treatment modalities.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. EFFO and NOF. Who are candidates for prevention and treatment for osteoporosis? Osteoporos Int. 1997;7(1):1–6.

    Article  Google Scholar 

  2. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22:465.

    Article  PubMed  Google Scholar 

  3. Reid IR. Glucocorticoid osteoporosis - mechanisms and management. Eur J Endocrinol. 1997;137:209.

    Article  PubMed  CAS  Google Scholar 

  4. Pazianas M, Zaidi M, Subhani JM, Finch PJ, Ang L, Maxwell JD. Efferent loop small intestinal vitamin D receptor concentration and bone mineral density after Billroth II (Polya) gastrectomy in humans. Calcif Tissue Int. 2003;72(4):485–90.

    Article  PubMed  CAS  Google Scholar 

  5. Schulte C, Dignass AU, Mann K, Goebell H. Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease. Inflamm Bowel Dis. 1998;4(4):268–75.

    Article  PubMed  CAS  Google Scholar 

  6. Shen B, Remzi FH, Oikonomou IK, Lu H, Lashner BA, Hammel JP, et al. Risk factors for low bone mass in patients with ulcerative colitis following ileal pouch-anal anastomosis. Am J Gastroenterol. 2009;104(3):639–46.

    Article  PubMed  Google Scholar 

  7. Tignor AS, Wu BU, Whitlock TL, Lopez R, Repas K, Banks PA, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105(12):2680–6.

    Article  PubMed  Google Scholar 

  8. Ward LM, Rauch F, Matzinger MA, Benchimol EI, Boland M, Mack DR. Iliac bone histomorphometry in children with newly diagnosed inflammatory bowel disease. Osteoporos Int. 2010;21:331–7.

    Article  PubMed  CAS  Google Scholar 

  9. Turner J, Pellerin G, Mager D. Prevalence of metabolic bone disease in children with celiac disease is independent of symptoms at diagnosis. J Pediatr Gastroenterol Nutr. 2009;49(5):589–93.

    Article  PubMed  Google Scholar 

  10. •• Oostlander AE et al. Dutch Initiative on Crohn and Colitis (ICC). Histomorphometric analysis reveals reduced bone mass and bone formation in patients with quiescent Crohn’s disease. Gastroenterology. 2011;140(1): 116–23. This study identifies that bone loss occurs even before clinically significant bowel disease has occurred, implicating chronic inflammation as the earliest cause for metabolic bone disease in IBD.

    Article  PubMed  Google Scholar 

  11. Godfrey JD et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology. 2010;139(3):763–9.

    Article  PubMed  Google Scholar 

  12. Pazianas M, Butcher GP, Subhani JM, Finch PJ, Ang L, Collins C, et al. Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake. Osteoporos Int. 2005;16(1):56–63.

    Article  PubMed  CAS  Google Scholar 

  13. Weiss RJ, Wick MC, Ackermann PW, Montgomery SM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases—a case-control study with 53,108 patients with fracture. J Rheumatol. 2010;37(11):2247–50.

    Article  PubMed  Google Scholar 

  14. Ashcroft AJ et al. Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin. Immunity. 2003;19(6):849–61.

    Article  PubMed  CAS  Google Scholar 

  15. Moschen AR 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.

    Article  PubMed  CAS  Google Scholar 

  16. •• Miheller P et al. Changes of OPG and RANKL concentrations in Crohn’s disease after infliximab therapy. Inflamm Bowel Dis. 2007;13(11):1379–84. This study demonstrates that IBD treatment targeted at inflammatory cytokines can alter bone metabolism favorably, thereby establishing inflammation as a cause for bone loss.

    Article  PubMed  Google Scholar 

  17. Paganelli M et al. Inflammation is the main determinant of low bone mineral density in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2007;13(4):416–23.

    Article  PubMed  Google Scholar 

  18. Kumar S, Votta BJ, Rieman DJ, Badger AM, Gowen M, Lee JC. IL-1- and TNF-induced bone resorption is mediated by p38 mitogen activated protein kinase. J Cell Physiol. 2001;187(3):294–303.

    Article  PubMed  CAS  Google Scholar 

  19. Rovedatti L et al. Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut. 2009;58(12):1629–36.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Mahida YR, Wu K, Jewell DP. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn’s disease. Gut. 1989;30:835–8.

    Article  PubMed  CAS  Google Scholar 

  22. Nemetz A, Tóth M, García-González MA, Zágoni T, Fehér J, Peña AS, et al. Allelic variation at the interleukin 1beta gene is associated with decreased bone mass in patients with inflammatory bowel diseases. Gut. 2001;49(5):644–9.

    Article  PubMed  CAS  Google Scholar 

  23. Kusugami K et al. Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Dig Dis Sci. 1995;40(5):949–59.

    Article  PubMed  CAS  Google Scholar 

  24. Shen C, Landers CJ, Derkowski C, Elson CO, Targan SR. Enhanced CBir1- specific innate and adaptive immune responses in Crohn’s disease. Inflamm Bowel Dis. 2008;14(12):1641–51.

    Article  PubMed  Google Scholar 

  25. Targan SR, Landers CJ, Yang H, et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology. 2005;128:2020–8.

    Article  PubMed  CAS  Google Scholar 

  26. Axmann R, Böhm C, Krönke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks OC formation in vitro and in vivo. Arthritis Rheum. 2009;60(9):2747–56.

    Article  PubMed  CAS  Google Scholar 

  27. Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum. 2010;62(1):33–43.

    Article  PubMed  CAS  Google Scholar 

  28. Li J et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA. 2000;97:1566–71.

    Article  PubMed  CAS  Google Scholar 

  29. Fuller K, Murphy C, Kirstein B, Fox SW, Chambers TJ. TNFα potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology. 2002;143:1108–18.

    Article  PubMed  CAS  Google Scholar 

  30. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF-α induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000;106:1481–8.

    Article  PubMed  CAS  Google Scholar 

  31. Friedman MS, Oyserman SM, Hankenson KD. Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. J Biol Chem. 2009;284(21):14117–25.

    Article  PubMed  CAS  Google Scholar 

  32. Thayu M, Leonard MB, Hyams JS, Crandall WV, Kugathasan S, Otley AR, et al. Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn’s disease: results of the REACH study. Clin Gastroenterol Hepatol. 2008;6(12):1378–84.

    Article  PubMed  CAS  Google Scholar 

  33. • Bernstein M, Irwin S, Greenberg GR. Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease. Am J Gastroenterol. 2005;100(9):2031–5. This study corroborates inflammation as a major cause of bone disease in IBD, and its reversal with blocking TNF-α with infliximab.

    Article  PubMed  CAS  Google Scholar 

  34. Pazianas M, Rhim AD, Weinberg AM, Su C, Lichtenstein GR. The effect of anti-TNF-alpha therapy on spinal bone mineral density in patients with Crohn’s disease. Ann N Y Acad Sci. 2006;1068:543–56.

    Article  PubMed  CAS  Google Scholar 

  35. Wong SC, Smyth A, McNeill E, Galloway PJ, Hassan K, McGrogan P, et al. The growth hormone insulin-like growth factor 1 axis in children and adolescents with inflammatory bowel disease and growth retardation. Clin Endocrinol (Oxf). 2010;73(2):220–8.

    CAS  Google Scholar 

  36. Eivindson M, Grønbaek H, Flyvbjerg A, Frystyk J, Zimmermann-Nielsen E, Dahlerup JF. The insulin-like growth factor (IGF)-system in active ulcerative colitis and Crohn’s disease: relations to disease activity and corticosteroid treatment. Growth Horm IGF Res. 2007;17(1):33–40.

    Article  PubMed  CAS  Google Scholar 

  37. Street ME et al. Relationships between serum IGF-1, IGFBP-2, interleukin-1beta and interleukin-6 in inflammatory bowel disease. Horm Res. 2004;61(4):159–64.

    Article  PubMed  CAS  Google Scholar 

  38. Corkins MR, Gohil AD, Fitzgerald JF. The insulin-like growth factor axis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2003;36(2):228–34.

    Article  PubMed  CAS  Google Scholar 

  39. Ballinger A. Fundamental mechanisms of growth failure in inflammatory bowel disease. Horm Res. 2002;58 Suppl 1:7–10.

    Article  PubMed  CAS  Google Scholar 

  40. Wolf M, Bohm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha inhibit growth hormone stimulation of Insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol. 1996;135729–737.

  41. Sarzi-Puttini P, Atzeni F, Schölmerich J, Cutolo M, Straub RH. Anti-TNF antibody treatment improves glucocorticoid induced insulin-like growth factor 1 (IGF1) resistance without influencing myoglobin and IGF1 binding proteins 1 and 3. Ann Rheum Dis. 2006;65(3):301–5.

    Article  PubMed  CAS  Google Scholar 

  42. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet. 1995;11(2):130–6.

    Google Scholar 

  43. •• Majewski PM, Thurston RD, Ramalingam R, Kiela PR, Ghishan FK. Cooperative role of NF-κB and poly(ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts. J Biol Chem. 2010;285(45):34828–38. This study identifies another mechanism by which TNF mediates bone loss in IBD, and implicates NF-κB and PARP-1 in the same, raising the possibility of therapeutic intervention.

    Article  PubMed  CAS  Google Scholar 

  44. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(12):1502–6.

    Article  PubMed  CAS  Google Scholar 

  45. Uno JK, Kolek OI, Hines ER, Xu H, Timmermann BN, Kiela PR, et al. The role of tumor necrosis factor alpha in down-regulation of osteoblast Phex gene expression in experimental murine colitis. Gastroenterology. 2006;131(2):497–509.

    Article  PubMed  CAS  Google Scholar 

  46. • Ung VY, Foshaug RR, MacFarlane SM, Churchill TA, Doyle JS, Sydora BC, Fedorak RN. Oral administration of curcumin emulsified in carboxymethyl cellulose has a potent anti-inflammatory effect in the IL-10 gene-deficient mouse model of IBD. Dig Dis Sci. 2010;55(5):1272–7. This study identifies curcumin as anti-inflammatory in colitis, and further elucidates pathways of inflammation-mediated bone loss.

    Article  PubMed  CAS  Google Scholar 

  47. Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem. 2009;322(1–2):127–35.

    Article  PubMed  CAS  Google Scholar 

  48. Venkataranganna MV, Rafiq M, Gopumadhavan S, Peer G, Babu UV, Mitra SK. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzene- induced colitis through down-regulation of NFkappa-B and iNOS. World J Gastroenterol. 2007;13(7):1103–7.

    PubMed  CAS  Google Scholar 

  49. Camacho-Barquero L, Villegas I, Sánchez-Calvo JM, Talero E, Sánchez-Fidalgo S, Motilva V, et al. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol. 2007;7(3):333–42.

    Article  PubMed  CAS  Google Scholar 

  50. Xiao ZS, Crenshaw M, Guo R, Nesbitt T, Drezner MK, Quarles LD. Intrinsic mineralization defect in Hyp mouse osteoblasts. Am J Physiol. 1998;275(4 Pt 1):E700–8.

    PubMed  CAS  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. •• Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R, Guan K, Krebsbach PH, Wang CY. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009;15(6):682–9. This study implicates NF-κB in bone loss and identifies it as a point of therapeutic intervention.

    Article  PubMed  CAS  Google Scholar 

  54. Jochum W, David JP, Elliott C, Wutz A, Plenk Jr H, Matsuo K, et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med. 2000;6(9):980–4.

    Article  PubMed  CAS  Google Scholar 

  55. Eferl R, Hoebertz A, Schilling AF, Rath M, Karreth F, Kenner L, et al. The Fos-related antigen Fra-1 is an activator of bone matrix formation. EMBO J. 2004;23(14):2789–99.

    Article  PubMed  CAS  Google Scholar 

  56. •• Thurston RD, Larmonier CB, Majewski PM, Ramalingam R, Midura-Kiela M, Laubitz D, Vandewalle A, Besselsen DG, Mühlbauer M, Jobin C, Kiela PR, Ghishan FK. Tumor necrosis factor and interferon-gamma down-regulate Klotho in mice with colitis. Gastroenterology. 2010;138(4):1384–94, 1394. This study identifies the role of Klotho, a novel pathway, in inflammation-mediated bone loss in IBD.

  57. Maekawa Y, Ishikawa K, Yasuda O, Oguro R, Hanasaki H, Kida I, et al. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009;35(3):341–6.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

MA and SA would like to thank Ankit Amin (MS) and Anastasia Floros (MS) for their inputs in the preparation of figure.

Disclosure

Conflicts of interest: M. Agrawal: none; S. Arora: none; J. Li: none; R. Rahmani: none; L. Sun: none; A.F. Steinlauf: none; J.I. Mechanick: has been a consultant for Abbott Nutrition and Nestle Nutrition; has received grant support from Select Medical Corp.; has received honoraria from Abbott Nutrtion and Nestle Nutrition; has received payment for development of educational presentations including service on speakers’ bureaus from Abbott Nutrition; and has received travel/accommodations expenses covered or reimbursed by Abbott Nutrition and Nestle Nutrition; M. Zaidi: has been a consultant for Amgen, Procter & Gamble, Roche and Genentech, GlaxoSmithKline, Warner Chilcott, and Novartis; has given expert testimony for Bowman and Brooke, Simes, and VEnables; has two patents on FSH and TSH, only if they mature into a drug, from Mount Sinai School of Medicine; has received payment for development of educational presentations including service on speakers’ bureaus from CME Education LLC and also various CME prams at academic institutions.

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Agrawal, M., Arora, S., Li, J. et al. Bone, Inflammation, and Inflammatory Bowel Disease. Curr Osteoporos Rep 9, 251–257 (2011). https://doi.org/10.1007/s11914-011-0077-9

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  • DOI: https://doi.org/10.1007/s11914-011-0077-9

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