Inflammatory Bowel Diseases and Skeletal Health

  • Francisco Sylvester


Bone and muscle constitute a functional unit, which is essential for locomotion. The muscle-bone unit is frequently affected by inflammatory bowel disease (IBD) and in children especially by Crohn disease. Muscle mass is significantly reduced (cachexia) at diagnosis in children with Crohn disease. These deficits persist despite adequate clinical response to anti-inflammatory therapy and catch-up weight gain. Bone mass and bone architecture are both compromised in pediatric Crohn disease. Linear growth and bone modeling and remodeling are all affected. As a result, bones are shorter. Osteoclasts expand the bone marrow cavity of long bones, while osteoblasts do not expand the periosteal envelope at the same rate, producing a thinner cortex. The cortical bone density is however augmented, probably due to inhibited bone remodeling. Trabecular bone mass may be reduced secondary to decreased bone formation. These changes in IBD can affect bone and muscle by multiple mechanisms including malnutrition (resulting in deficits of macro- and micronutrients), inflammatory cytokines and activated T cells, inhibition of sex steroids and insulin-like growth factor 1, and inactivity. In addition, corticosteroids can directly cause muscle loss, inhibit bone formation, and indirectly increase bone resorption. Antitumor necrosis factor-α and exclusive enteral nutrition on the other hand can reconstitute linear growth and bone modeling and remodeling. In this chapter, we discussed in detail the muscle-bone phenotype in human IBD and animal models of IBD. We also present possible mechanisms by which IBD affects the muscle-bone unit and some options to ensure the achievement of peak bone mass in children with IBD.


Crohn disease Ulcerative colitis Inflammatory bowel disease Children Sarcopenia Cachexia Bone mineral density Pediatric osteoporosis 


  1. 1.
    Seeman E. Bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19(3):219–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Sylvester FA, Gordon CM, Thayu M, Burnham JM, Denson LA, Essers J, et al. Report of the CCFA pediatric bone, growth and muscle health workshop, New York City, November 11-12, 2011, with updates. Inflamm Bowel Dis. 2013;19(13):2919–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Bellido T. Osteocyte-driven bone remodeling. Calcif Tissue Int. 2014;94(1):25–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Sylvester FA, Wyzga N, Hyams JS, Davis PM, Lerer T, Vance K, et al. Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13(1):42–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Wang Q, Seeman E. Skeletal growth and peak bone strength. Best Pract Res Clin Endocrinol Metab. 2008;22(5):687–700.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang Q, Wang XF, Iuliano-Burns S, Ghasem-Zadeh A, Zebaze R, Seeman E. Rapid growth produces transient cortical weakness: a risk factor for metaphyseal fractures during puberty. J Bone Miner Res. 2010;25(7):1521–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang Q, Ghasem-Zadeh A, Wang XF, Iuliano-Burns S, Seeman E. Trabecular bone of growth plate origin influences both trabecular and cortical morphology in adulthood. J Bone Miner Res. 2011;26(7):1577–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Ohlsson C, Darelid A, Nilsson M, Melin J, Mellstrom D, Lorentzon M. Cortical consolidation due to increased mineralization and endosteal contraction in young adult men: a five-year longitudinal study. J Clin Endocrinol Metab. 2011;96(7):2262–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Walsh JS, Paggiosi MA, Eastell R. Cortical consolidation of the radius and tibia in young men and women. J Clin Endocrinol Metab. 2012;97(9):3342–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Black DM, Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med. 2016;374(3):254–62.PubMedCrossRefGoogle Scholar
  11. 11.
    Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267–76.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bala Y, Seeman E. Bone’s material constituents and their contribution to bone strength in health, disease, and treatment. Calcif Tissue Int. 2015;97(3):308–26.PubMedCrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014;20(8):833–46.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Nemoto Y, Kanai T, Makita S, Okamoto R, Totsuka T, Takeda K, et al. Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis. Gastroenterology. 2007;132(1):176–89.PubMedCrossRefGoogle Scholar
  16. 16.
    Ciucci T, Ibanez L, Boucoiran A, Birgy-Barelli E, Pene J, Abou-Ezzi G, et al. Bone marrow Th17 TNFalpha cells induce osteoclast differentiation, and link bone destruction to IBD. Gut. 2015;64(7):1072–81.PubMedCrossRefGoogle Scholar
  17. 17.
    Nemoto Y, Kanai T, Takahara M, Oshima S, Nakamura T, Okamoto R, et al. Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells. Gut. 2013;62(8):1142–52.PubMedCrossRefGoogle Scholar
  18. 18.
    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
  19. 19.
    Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 2004;64(22):8451–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Tokoyoda K, Zehentmeier S, Hegazy AN, Albrecht I, Grun JR, Lohning M, et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity. 2009;30(5):721–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Rauch F. The dynamics of bone structure development during pubertal growth. J Musculoskelet Neuronal Interact. 2012;12(1):1–6.PubMedGoogle Scholar
  22. 22.
    Bianchi ML, Baim S, Bishop NJ, Gordon CM, Hans DB, Langman CB, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol. 2010;25(1):37–47.PubMedCrossRefGoogle Scholar
  23. 23.
    Ikeda K, Takeshita S. The role of osteoclast differentiation and function in skeletal homeostasis. J Biochem. 2016;159(1):1–8.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    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
  26. 26.
    Watanabe Y, Namba A, Aida Y, Honda K, Tanaka H, Suzuki N, et al. IL-1beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes. Mediators Inflamm. 2009;2009:308596.PubMedCrossRefGoogle Scholar
  27. 27.
    Hoshino A, Iimura T, Ueha S, Hanada S, Maruoka Y, Mayahara M, et al. Deficiency of chemokine receptor CCR1 causes osteopenia due to impaired functions of osteoclasts and osteoblasts. J Biol Chem. 2010;285(37):28826–37.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Mun SH, Ko NY, Kim HS, Kim JW, Kim DK, Kim AR, et al. Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes. Cell Mol Life Sci. 2010;67:3883–92.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Gilbert LC, Chen H, Lu X, Nanes MS. Chronic low dose tumor necrosis factor-alpha (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. Bone. 2013;56(1):174–83.PubMedCrossRefGoogle Scholar
  30. 30.
    Ota K, Quint P, Weivoda MM, Ruan M, Pederson L, Westendorf JJ, et al. Transforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors. Bone. 2013;57:68–75.PubMedCrossRefGoogle Scholar
  31. 31.
    Humphrey MB, Nakamura MC. A comprehensive review of immunoreceptor regulation of osteoclasts. Clin Rev Allergy Immunol. 2016;51:48–58.PubMedCrossRefGoogle Scholar
  32. 32.
    McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Dore RK, Cohen SB, Lane NE, Palmer W, Shergy W, Zhou L, et al. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis. 2010;69(5):872–5.PubMedCrossRefGoogle Scholar
  34. 34.
    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
  35. 35.
    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):1260–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    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
  37. 37.
    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
  38. 38.
    Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, et al. Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res. 2001;16(10):1787–94.PubMedCrossRefGoogle Scholar
  39. 39.
    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
  40. 40.
    Moverare-Skrtic S, Henning P, Liu X, Nagano K, Saito H, Borjesson AE, et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med. 2014;20(11):1279–88.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012;18(3):405–12.PubMedCrossRefGoogle Scholar
  42. 42.
    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
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Park-Min KH, Ji JD, Antoniv T, Reid AC, Silver RB, Humphrey MB, et al. IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol. 2009;183(4):2444–55.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yoshimatsu M, Kitaura H, Fujimura Y, Eguchi T, Kohara H, Morita Y, et al. IL-12 inhibits TNF-alpha induced osteoclastogenesis via a T cell-independent mechanism in vivo. Bone. 2009;45(5):1010–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Kitaura H, Fujimura Y, Yoshimatsu M, Kohara H, Morita Y, Aonuma T, et al. IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-alpha-mediated osteoclastogenesis of bone marrow cells. Calcif Tissue Int. 2011;89(1):65–73.PubMedCrossRefGoogle Scholar
  47. 47.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203(12):2673–82.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, et al. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-alpha antibodies. J Bone Miner Res. 2014;29(9):1981–92.PubMedCrossRefGoogle Scholar
  49. 49.
    Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell. 2008;132(5):794–806.PubMedCrossRefGoogle Scholar
  50. 50.
    Kim HS, Kim DK, Kim AR, Mun SH, Lee SK, Kim JH, et al. Fyn positively regulates the activation of DAP12 and FcRgamma-mediated costimulatory signals by RANKL during osteoclastogenesis. Cell Signal. 2012;24(6):1306–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Kim H, Kim T, Jeong BC, Cho IT, Han D, Takegahara N, et al. Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Cell Metab. 2013;17(2):249–60.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Decker CE, Yang Z, Rimer R, Park-Min KH, Macaubas C, Mellins ED, et al. Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass. Proc Natl Acad Sci U S A. 2015;112(51):15654–9.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12(6):657–64.PubMedCrossRefGoogle Scholar
  54. 54.
    Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SE, Wakkach A, Blin-Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med. 2012;209(3):537–49.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    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
  56. 56.
    Roysland R, Masson S, Omland T, Milani V, Bjerre M, Flyvbjerg A, et al. Prognostic value of osteoprotegerin in chronic heart failure: the GISSI-HF trial. Am Heart J. 2010;160(2):286–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Montagnana M, Lippi G, Danese E, Guidi GC. The role of osteoprotegerin in cardiovascular disease. Ann Med. 2013;45(3):254–64.PubMedCrossRefGoogle Scholar
  58. 58.
    Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front Immunol. 2014;5:511.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    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
  60. 60.
    Summers deLuca L, Gommerman JL. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol. 2012;12(5):339–51.PubMedGoogle Scholar
  61. 61.
    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
  62. 62.
    Chino T, Draves KE, Clark EA. Regulation of dendritic cell survival and cytokine production by osteoprotegerin. J Leukoc Biol. 2009;86(4):933–40.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Jones D, Glimcher LH, Aliprantis AO. Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection. J Clin Invest. 2011;121(7):2534–42.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Nahidi L, Leach ST, Sidler MA, Levin A, Lemberg DA, Day AS. Osteoprotegerin in pediatric Crohn’s disease and the effects of exclusive enteral nutrition. Inflamm Bowel Dis. 2011;17(2):516–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Franchimont N, Reenaers C, Lambert C, Belaiche J, Bours V, Malaise M, et al. Increased expression of receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin in the colon of Crohn’s disease patients. Clin Exp Immunol. 2004;138(3):491–8.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Arijs I, Li K, Toedter G, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009;58:1612–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Sylvester FA, Turner D, Draghi 2nd A, Uuosoe K, McLernon R, Koproske K, et al. Fecal osteoprotegerin may guide the introduction of second-line therapy in hospitalized children with ulcerative colitis. Inflamm Bowel Dis. 2011;17(8):1726–30.PubMedCrossRefGoogle Scholar
  70. 70.
    Abdallah BM, Jafari A, Zaher W, Qiu W, Kassem M. Skeletal (stromal) stem cells: an update on intracellular signaling pathways controlling osteoblast differentiation. Bone. 2015;70:28–36.PubMedCrossRefGoogle Scholar
  71. 71.
    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
  72. 72.
    Difedele LM, He J, Bonkowski EL, Han X, Held MA, Bohan A, et al. Tumor necrosis factor-a blockade restores growth hormone signaling in murine colitis. Gastroenterology. 2005;128(5):1278–91.PubMedCrossRefGoogle Scholar
  73. 73.
    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
  74. 74.
    Yamazaki M, Fukushima H, Shin M, Katagiri T, Doi T, Takahashi T, et al. Tumor necrosis factor alpha represses bone morphogenetic protein (BMP) signaling by interfering with the DNA binding of Smads through the activation of NF-kappaB. J Biol Chem. 2009;284(51):35987–95.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lee HL, Yi T, Woo KM, Ryoo HM, Kim GS, Baek JH. Msx2 mediates the inhibitory action of TNF-alpha on osteoblast differentiation. Exp Mol Med. 2010;42(6):437–45.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-a-induced genes in bone cells. J Leukoc Biol. 2005;77(3):388–99.PubMedCrossRefGoogle Scholar
  77. 77.
    Uno JK, Kolek OI, Hines ER, Xu H, Timmermann BN, Kiela PR, et al. The role of tumor necrosis factor-a in down-regulation of osteoblast Phex gene expression in experimental murine colitis. Gastroenterology. 2006;131(2):497–509.PubMedCrossRefGoogle Scholar
  78. 78.
    Majewski PM, Thurston RD, Ramalingam R, Kiela PR, Ghishan FK. Cooperative role of NF-{kappa}B 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.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Jang WG, Jeong BC, Kim EJ, Choi H, Oh SH, Kim DK, et al. Cyclic AMP Response Element-binding Protein H (CREBH) mediates the inhibitory actions of tumor necrosis factor alpha in osteoblast differentiation by stimulating Smad1 degradation. J Biol Chem. 2015;290(21):13556–66.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefGoogle Scholar
  81. 81.
    Griffin LM, Thayu M, Baldassano RN, DeBoer MD, Zemel BS, Denburg MR, et al. Improvements in bone density and structure during anti-TNF-alpha therapy in pediatric Crohn’s disease. J Clin Endocrinol Metab. 2015;100(7):2630–9.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Calvi LM. Osteolineage cells and regulation of the hematopoietic stem cell. Best Pract Res Clin Haematol. 2013;26(3):249–52.PubMedCrossRefGoogle Scholar
  83. 83.
    Pacifici R. T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci. 2016;1364:11–24.PubMedCrossRefGoogle Scholar
  84. 84.
    Takayanagi H. Osteoimmunology in 2014: two-faced immunology-from osteogenesis to bone resorption. Nat Rev Rheumatol. 2015;11(2):74–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998;160(7):3513–21.PubMedGoogle Scholar
  86. 86.
    Adamopoulos IE, Chao CC, Geissler R, Laface D, Blumenschein W, Iwakura Y, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Res Ther. 2010;12(1):R29.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Li JY, D'Amelio P, Robinson J, Walker LD, Vaccaro C, Luo T, et al. IL-17A is increased in humans with primary hyperparathyroidism and mediates PTH-induced bone loss in mice. Cell Metab. 2015;22(5):799–810.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015;112(22):7061–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Pacifici R. Role of T cells in ovariectomy induced bone loss–revisited. J Bone Miner Res. 2012;27(2):231–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387:156–67.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kelchtermans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P. Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis. 2009;68(5):744–50.PubMedCrossRefGoogle Scholar
  94. 94.
    Terauchi M, Li JY, Bedi B, Baek KH, Tawfeek H, Galley S, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 2009;10(3):229–40.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Pappalardo A, Thompson K. Novel immunostimulatory effects of osteoclasts and macrophages on human gammadelta T cells. Bone. 2015;71:180–8.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood. 2010;116(2):210–7.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kiesel JR, Buchwald ZS, Aurora R. Cross-presentation by osteoclasts induces FoxP3 in CD8+ T cells. J Immunol. 2009;182(9):5477–87.PubMedCrossRefGoogle Scholar
  98. 98.
    Buchwald ZS, Kiesel JR, DiPaolo R, Pagadala MS, Aurora R. Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. PLoS One. 2012;7(6):e38199.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Buchwald ZS, Yang C, Nellore S, Shashkova EV, Davis JL, Cline A, et al. A bone anabolic effect of RANKL in a murine model of osteoporosis mediated through FoxP3+ CD8 T cells. J Bone Miner Res. 2015;30(8):1508–22.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J, Martinez-Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503(7475):272–6.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Cao SS. Endoplasmic reticulum stress and unfolded protein response in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:636–44.PubMedCrossRefGoogle Scholar
  103. 103.
    Wu Y, Yang M, Fan J, Peng Y, Deng L, Ding Y, et al. Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis. Cell Death Dis. 2014;5:e1464.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Murakami T, Saito A, Hino S, Kondo S, Kanemoto S, Chihara K, et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol. 2009;11(10):1205–11.PubMedCrossRefGoogle Scholar
  105. 105.
    Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, et al. Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011;286(6):4809–18.PubMedCrossRefGoogle Scholar
  106. 106.
    Tohmonda T, Miyauchi Y, Ghosh R, Yoda M, Uchikawa S, Takito J, et al. The IRE1alpha-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep. 2011;12(5):451–7.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Tohmonda T, Yoda M, Mizuochi H, Morioka H, Matsumoto M, Urano F, et al. The IRE1alpha-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis. J Biol Chem. 2013;288(3):1691–5.PubMedCrossRefGoogle Scholar
  108. 108.
    Tohmonda T, Yoda M, Iwawaki T, Matsumoto M, Nakamura M, Mikoshiba K, et al. IRE1alpha/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis. J Clin Invest. 2015;125(8):3269–79.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Cao SS, Luo KL, Shi L. Endoplasmic reticulum stress interacts with inflammation in human diseases. J Cell Physiol. 2016;231(2):288–94.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kneissel M, Luong-Nguyen NH, Baptist M, Cortesi R, Zumstein-Mecker S, Kossida S, et al. Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone. 2004;35(5):1144–56.PubMedCrossRefGoogle Scholar
  111. 111.
    Zhao Y, Chen G, Zhang W, Xu N, Zhu JY, Jia J, et al. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1alpha/BNIP3 signaling pathway. J Cell Physiol. 2012;227(2):639–48.PubMedCrossRefGoogle Scholar
  112. 112.
    Sambandam Y, Townsend MT, Pierce JJ, Lipman CM, Haque A, Bateman TA, et al. Microgravity control of autophagy modulates osteoclastogenesis. Bone. 2014;61:125–31.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Liu F, Fang F, Yuan H, Yang D, Chen Y, Williams L, et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J Bone Miner Res. 2013;28(11):2414–30.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Pantovic A, Krstic A, Janjetovic K, Kocic J, Harhaji-Trajkovic L, Bugarski D, et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone. 2013;52(1):524–31.PubMedCrossRefGoogle Scholar
  115. 115.
    Nollet M, Santucci-Darmanin S, Breuil V, Al-Sahlanee R, Cros C, Topi M, et al. Autophagy in osteoblasts is involved in mineralization and bone homeostasis. Autophagy. 2014;10(11):1965–77.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Zhang L, Guo YF, Liu YZ, Liu YJ, Xiong DH, Liu XG, et al. Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. J Bone Miner Res. 2010;25(7):1572–80.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Van bezooijen RL, Farih-Sips HC, Papapoulos SE, Lowik CW. Interleukin-17: a new bone acting cytokine in vitro. J Bone Miner Res. 1999;14(9):1513–21.PubMedCrossRefGoogle Scholar
  118. 118.
    Yago T, Nanke Y, Ichikawa N, Kobashigawa T, Mogi M, Kamatani N, et al. IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17. J Cell Biochem. 2009;108(4):947–55.PubMedCrossRefGoogle Scholar
  119. 119.
    Balani D, Aeberli D, Hofstetter W, Seitz M. Interleukin-17A stimulates granulocyte-macrophage colony-stimulating factor release by murine osteoblasts in the presence of 1,25-dihydroxyvitamin D(3) and inhibits murine osteoclast development in vitro. Arthritis Rheum. 2013;65(2):436–46.PubMedCrossRefGoogle Scholar
  120. 120.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103(9):1345–52.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, et al. Induction of osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells. 2012;30(4):762–72.PubMedCrossRefGoogle Scholar
  122. 122.
    Jimenez-Dalmaroni MJ, Gerswhin ME, Adamopoulos IE. The critical role of toll-like receptors–From microbial recognition to autoimmunity: a comprehensive review. Autoimmun Rev. 2016;15(1):1–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Takami M, Kim N, Rho J, Choi Y. Stimulation by toll-like receptors inhibits osteoclast differentiation. J Immunol. 2002;169(3):1516–23.PubMedCrossRefGoogle Scholar
  124. 124.
    Zou W, Bar-Shavit Z. Dual modulation of osteoclast differentiation by lipopolysaccharide. J Bone Miner Res. 2002;17(7):1211–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Zou W, Schwartz H, Endres S, Hartmann G, Bar-Shavit Z. CpG oligonucleotides: novel regulators of osteoclast differentiation. FASEB J. 2002;16(3):274–82.PubMedCrossRefGoogle Scholar
  126. 126.
    Krisher T, Bar-Shavit Z. Regulation of osteoclastogenesis by integrated signals from toll-like receptors. J Cell Biochem. 2014;115(12):2146–54.PubMedCrossRefGoogle Scholar
  127. 127.
    Sjogren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res Off J Am Soc Bone Miner Res. 2012;27(6):1357–67.CrossRefGoogle Scholar
  128. 128.
    Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014;229:1822–30.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Zhang J, Motyl KJ, Irwin R, MacDougald OA, Britton RA, McCabe LR. Loss of Bone and Wnt10b Expression in Male Type 1 Diabetic Mice Is Blocked by the Probiotic Lactobacillus reuteri. Endocrinology. 2015;156(9):3169–82.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    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
  131. 131.
    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
  132. 132.
    Harris L, Senagore P, Young VB, McCabe LR. Inflammatory bowel disease causes reversible suppression of osteoblast and chondrocyte function in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296(5):G1020–9.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Issenman RM, Atkinson SA, Radoja C, Fraher L. Longitudinal assessment of growth, mineral metabolism, and bone mass in pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr. 1993;17(4):401–6.PubMedCrossRefGoogle Scholar
  135. 135.
    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
  136. 136.
    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
  137. 137.
    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.Google Scholar
  138. 138.
    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
  139. 139.
    Bourges O, Dorgeret S, Alberti C, Hugot JP, Sebag G, Cezard JP. Low bone mineral density in children with Crohn’s disease. Arch Pediatr. 2004;11(7):800–6.PubMedCrossRefGoogle Scholar
  140. 140.
    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
  141. 141.
    Semeao EJ, Jawad AF, Zemel BS, Neiswender KM, Piccoli DA, Stallings VA. Bone mineral density in children and young adults with Crohn’s disease. Inflamm Bowel Dis. 1999;5(3):161–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Dubner SE, Shults J, Baldassano RN, Zemel BS, Thayu M, Burnham JM, et al. Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn’s disease. Gastroenterology. 2009;136(1):123–30.PubMedCrossRefGoogle Scholar
  143. 143.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Tsampalieros A, Berkenstock MK, Zemel BS, Griffin L, Shults J, Burnham JM, et al. Changes in trabecular bone density in incident pediatric Crohn’s disease: a comparison of imaging methods. Osteoporos Int. 2014;25(7):1875–83.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Schmidt S, Mellstrom D, Norjavaara E, Sundh V, Saalman R. Longitudinal assessment of bone mineral density in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2012;55(5):511–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Neu CM, Manz F, Rauch F, Merkel A, Schoenau E. Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography. Bone. 2001;28(2):227–32.PubMedCrossRefGoogle Scholar
  147. 147.
    Werkstetter KJ, Pozza SB, Filipiak-Pittroff B, Schatz SB, Prell C, Bufler P, et al. Long-term development of bone geometry and muscle in pediatric inflammatory bowel disease. Am J Gastroenterol. 2011;106(5):988–98.PubMedCrossRefGoogle Scholar
  148. 148.
    Thayu M, Shults J, Burnham JM, Zemel BS, Baldassano RN, Leonard MB. Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn’s disease. Inflamm Bowel Dis. 2007;13(9):1121–8.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Sylvester FA, Leopold S, Lincoln M, Hyams JS, Griffiths AM, Lerer T. A two-year longitudinal study of persistent lean tissue deficits in children with Crohn’s disease. Clin Gastroenterol Hepatol. 2009;7(4):452–5.PubMedCrossRefGoogle Scholar
  150. 150.
    Laakso S, Valta H, Verkasalo M, Toiviainen-Salo S, Makitie O. Compromised peak bone mass in patients with inflammatory bowel disease – a prospective study. J Pediatr. 2014;164(6):1436–43.e1.PubMedCrossRefGoogle Scholar
  151. 151.
    Pappa H, Thayu M, Sylvester F, Leonard M, Zemel B, Gordon C. Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2011;53(1):11–25.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    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.PubMedCrossRefGoogle Scholar
  153. 153.
    Bechtold S, Alberer M, Arenz T, Putzker S, Filipiak-Pittroff B, Schwarz HP, et al. Reduced muscle mass and bone size in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(2):216–25.PubMedCrossRefGoogle Scholar
  154. 154.
    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
  155. 155.
    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
  156. 156.
    Sylvester FA, Wyzga N, Hyams JS, Gronowicz GA. Effect of Crohn’s disease on bone metabolism in vitro: a role for interleukin-6. J Bone Miner Res. 2002;17(4):695–702.PubMedCrossRefGoogle Scholar
  157. 157.
    Laurent MR, Dubois V, Claessens F, Verschueren SM, Vanderschueren D, Gielen E, et al. Muscle-bone interactions: from experimental models to the clinic? A critical update. Mol Cell Endocrinol. 2016;432:14–36.PubMedCrossRefGoogle Scholar
  158. 158.
    Thayu M, Denson LA, Shults J, Zemel BS, Burnham JM, Baldassano RN, et al. Determinants of changes in linear growth and body composition in incident pediatric Crohn’s disease. Gastroenterology. 2010;139:430–8.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Werkstetter KJ, Ullrich J, Schatz SB, Prell C, Koletzko B, Koletzko S. Lean body mass, physical activity and quality of life in paediatric patients with inflammatory bowel disease and in healthy controls. J Crohns Colitis. 2012;6:665–73.PubMedCrossRefGoogle Scholar
  160. 160.
    Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: Basic science and clinical review. World J Gastroenterol WJG. 2014;20(17):4934–47.PubMedCrossRefGoogle Scholar
  161. 161.
    Meeker S, Seamons A, Maggio-Price L, Paik J. Protective links between vitamin D, inflammatory bowel disease and colon cancer. World J Gastroenterol. 2016;22(3):933–48.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Prosnitz AR, Leonard MB, Shults J, Zemel BS, Hollis BW, Denson LA, et al. Changes in vitamin D and parathyroid hormone metabolism in incident pediatric Crohn’s disease. Inflamm Bowel Dis. 2013;19(1):45–53.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Middleton JP, Bhagavathula AP, Gaye B, Alvarez JA, Huang CS, Sauer CG, et al. Vitamin D status and bone mineral density in African American children with Crohn disease. J Pediatr Gastroenterol Nutr. 2013;57(5):587–93.PubMedCrossRefGoogle Scholar
  164. 164.
    Nowak JK, Grzybowska-Chlebowczyk U, Landowski P, Szaflarska-Poplawska A, Klincewicz B, Adamczak D, et al. Prevalence and correlates of vitamin K deficiency in children with inflammatory bowel disease. Sci Rep. 2014;4:4768.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Nakajima S, Iijima H, Egawa S, Shinzaki S, Kondo J, Inoue T, et al. Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition. 2011;27(10):1023–8.PubMedCrossRefGoogle Scholar
  166. 166.
    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.PubMedCrossRefGoogle Scholar
  167. 167.
    Loftus EJ, Crowson CS, Sandborn WJ, Tremaine WJ, O'Fallon WM, Melton 3rd LJ. Long-term fracture risk in patients with Crohn’s disease: a population-based study in Olmsted County, Minnesota. Gastroenterology. 2002;123(2):468–75.PubMedCrossRefGoogle Scholar
  168. 168.
    Persad R, Jaffer I, Issenman RM. The prevalence of long bone fractures in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2006;43(5):597–602.PubMedCrossRefGoogle Scholar
  169. 169.
    Kappelman MD, Galanko JA, Porter CQ, Sandler RS. Risk of diagnosed fractures in children with inflammatory bowel diseases. Inflamm Bowel Dis. 2011;17:1125–30.PubMedCrossRefGoogle Scholar
  170. 170.
    Siffledeen JS, Siminoski K, Jen H, Fedorak RN. Vertebral fractures and role of low bone mineral density in Crohn’s disease. Clin Gastroenterol Hepatol. 2007;5(6):721–8.PubMedCrossRefGoogle Scholar
  171. 171.
    Semeao EJ, Stallings VA, Peck SN, Piccoli DA. Vertebral compression fractures in pediatric patients with Crohn’s disease. Gastroenterology. 1997;112(5):1710–3.PubMedCrossRefGoogle Scholar
  172. 172.
    Tsampalieros A, Lam CK, Spencer JC, Thayu M, Shults J, Zemel BS, et al. Long-term inflammation and glucocorticoid therapy impair skeletal modeling during growth in childhood Crohn disease. J Clin Endocrinol Metab. 2013;98(8):3438–45.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Al-Shaar L, Mneimneh R, Nabulsi M, Maalouf J, Fuleihan GH. Vitamin D3 dose requirement to raise 25-hydroxyvitamin D to desirable levels in adolescents: results from a randomized controlled trial. J Bone Miner Res. 2014;29(4):944–51.PubMedCrossRefGoogle Scholar
  174. 174.
    Werkstetter KJ, Schatz SB, Alberer M, Filipiak-Pittroff B, Koletzko S. Influence of exclusive enteral nutrition therapy on bone density and geometry in newly diagnosed pediatric Crohn’s disease patients. Ann Nutr Metab. 2013;63(1–2):10–6.PubMedCrossRefGoogle Scholar
  175. 175.
    Bernstein CN, Targownik LE, Leslie WD. What is the role for bisphosphonates in IBD? Gut. 2014;63(9):1369–70.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.The University of North Carolina at Chapel HillChapel HillUSA

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