Current Osteoporosis Reports

, Volume 12, Issue 2, pp 181–188 | Cite as

Diabetes, Collagen, and Bone Quality

  • Mitsuru SaitoEmail author
  • Yoshikuni Kida
  • Soki Kato
  • Keishi Marumo
Biomechanics (M Silva and P Zysset, Section Editors)


Diabetes increases risk of fracture, although type 2 diabetes is characterized by normal or high bone mineral density (BMD) compared with the patients without diabetes. The fracture risk of type 1 diabetes as well as type 2 diabetes increases beyond an explained by a decrease of BMD. Thus, diabetes may reduce bone strength without change in BMD. Whole bone strength is determined by bone density, structure, and quality, which encompass the micro-structural and tissue material properties. Recent literature showed that diabetes reduces bone material properties rather than BMD. Collagen intermolecular cross-linking plays an important role in the expression of bone strength. Collagen cross-links can be divided into beneficial enzymatic immature divalent and mature trivalent cross-links and disadvantageous nonenzymatic cross-links (Advanced glycation end products: AGEs) induced by glycation and oxidation. The formation pathway and biological function are quite different. Not only hyperglycemia, but also oxidative stress induces the reduction in enzymatic cross-links and the formation of AGEs. In this review, we describe the mechanism of low bone quality in diabetes and the usefulness of the measurement of plasma or urinary level of AGEs for estimation of fracture risk.


Diabetes Bone quality Collagen Cross-links Advanced glycation end products Pentosidine Homocysteine Fracture risk 


Compliance with Ethics Guidelines

Conflict of Interest

M. Saito, Y. Kida, S. Kato, and K. Marumo declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta-analysis. Osteoporos Int. 2007;18:427–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Burr DB. Bone quality: understanding what matters. Review. J Musculoskelet Neuronal Interact. 2004;4:184–6.PubMedGoogle Scholar
  3. 3.
    Satio M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Review. Osteoporos Int. 2010;21:195–214.CrossRefGoogle Scholar
  4. 4.••
    Sroga GE, Vashishth D. Effects of bone matrix proteins on fracture and fragility in osteoporosis. Review. Curr Osteoporos Rep. 2012;10:141–50. Review of roles of collagen and noncollagenous proteins in bone.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Viguet-Carrin S, Garnero P, Delmas PD. The role of collagen in bone strength. Review. Osteoporos Int. 2006;17:319–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Robins SP, Bailey AJ. The chemistry of the collagen cross-links. Characterization of the products of reduction of skin, tendon and bone with sodium cyanoborohydride. Biochem J. 1977;163:339–46.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Uzawa K, Grzesik WJ, Nishiura T, et al. Differential expression of human lysyl hydroxylase genes, lysine hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro. J Bone Miner Res. 1999;14:1272–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Satio M, Soshi S, Tanaka T, et al. Intensity-related differences in collagen post-translational modification in MC3T3-E1 osteoblasts after exposure to low and high intensity pulsed ultrasound. Bone. 2004;35:644–55.CrossRefGoogle Scholar
  9. 9.
    Pornprasertsuk S, Duarte WR, Mochida Y, et al. Overexpression of lysyl hydroxylase-2b leads to defective collagen fibrillogenesis and matrix mineralization. J Bone Miner Res. 2005;20:81–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Eyre DR, Paz A, Gallop PM, et al. Cross-linking in collagen and elastin. Annu Rev Biochem. 1984;53:717–48.PubMedCrossRefGoogle Scholar
  11. 11.
    Satio M, Marumo K, Fujii K, et al. Single column high—performance liquid chromatographic—fluorescence detection of immature, mature and senescent cross-links of collagen. Anal Biochem. 1997;253:26–32.CrossRefGoogle Scholar
  12. 12.
    Yamauchi M, Katz EP. The post-translational chemistry and molecular packing of mineralizing tendon collagens. Connect Tissue Res. 1993;29:81–98.PubMedCrossRefGoogle Scholar
  13. 13.
    Eyre DR, Dickson IR, Ness KV, et al. Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues. Biochem J. 1988;252:495–500.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Kuboki Y, Kudo A, Mizuno M, et al. Time-dependent changes of collagen cross-links and their precursors in the culture of osteogenic cells. Calcif Tissue Int. 1992;50:473–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Satio M, Soshi S, Fujii K. Effect of hyper- and microgravity on collagen post-translational controls of MC3T3-E1 osteoblasts. J Bone Miner Res. 2003;18:1695–705.CrossRefGoogle Scholar
  16. 16.•
    Kato S, Saito M, Funasaki H, et al. Distinctive collagen maturation process in fibroblasts derived from rabbit anterior cruciate ligament, medial collateral ligament, and patellar tendon in vitro. Knee Surg Sports Traumatol Arthrosc. 2013. In vitro study for exploring the relationship between lysyl oxidase, lysine hydroxylase, and enzymatic cross-link formation. Google Scholar
  17. 17.
    Maruhashi T, Kii I, Saito M, et al. Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase. J Biol Chem. 2010;285:13294–303.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Atsawasuwan P, Mochida Y, Parisuthiman D, et al. Expression of lysyl oxidase isoforms in MC3T3-E1 osteoblastic cells. Biochem Biophys Res Commun. 2005;327:1042–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Bird TA, Levene CI. Lysyl oxidase: evidence that pyridoxal phosphate is a co-factor. Biochem Biophys Res Commun. 1982;108:1172–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Wang SX, Mure M, Medzihradszky KF, et al. A cross-linked co-factor in lysyl oxidase: redox function for amino acid side chains. Science. 1996;273:1078–84.PubMedCrossRefGoogle Scholar
  21. 21.
    Fujii K, Kajiwara T, Kurosu H, et al. Effect of vitamin B6 deficiency on the cross-link formation of collagen. FEBS Lett. 1979;97:193–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Satio M, Fujii K, Mori Y, et al. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. 2006;17:1514–23.CrossRefGoogle Scholar
  23. 23.
    Feres-Filho EJ, Choi YJ, Han X, et al. Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells. J Biol Chem. 1995;270:30797–803.PubMedCrossRefGoogle Scholar
  24. 24.
    Hong HH, Uzel MI, Duan C, et al. Regulation of lysyl oxidase, collagen, and connective tissue growth factor by TGF-beta1 and detection in human gingiva. Lab Invest. 1999;79:1655–67.PubMedGoogle Scholar
  25. 25.
    Reiser K, Summers P, Medrano JF, et al. Effects of elevated circulating IGF-1 on the extracellular matrix in high-growth C57BL/6J mice. Am J Physiol. 1996;271:R696–703.PubMedGoogle Scholar
  26. 26.
    Ozasa H, Tominaga T, Nishimura T, et al. Lysyl oxidase activity in the mouse uterine cervix is physiologically regulated by estrogen. Endocrinology. 1981;109:618–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Sanada H, Shikata J, Hamamoto H. Changes in collagen cross-linking and lysyl oxidase by estrogen. Biochim Biophys Acta. 1978;541:408–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Satio M, Marumo K, Soshi S, et al. Raloxifene ameliorates detrimental enzymatic and non-enzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int. 2010;21:655–66.Google Scholar
  29. 29.
    Nagaoka H, Mochida Y, Atsawasuwan P, et al. 1, 25(OH), 2D3 regulates collagen quality in an osteoblastic cell culture system. Biochem Biophys Res Commun. 2008;377:674–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Saito M, Shiraishi A, Ito M, et al. Comparison of effects of alfacalcidol and alendronate on mechanical properties and bone collagen cross-links of callus in the fracture repair rat model. Bone. 2010;46:1170–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Saito M, Marumo K, Ushiku C, et al. Effects of alfacalcidol on mechanical properties and collagen cross-links of the femoral diaphysis in glucocorticoid-treated rats. Calcif Tissue Int. 2011;88:314–24.PubMedCrossRefGoogle Scholar
  32. 32.
    Feres-Filho EJ, Menassa GB, Han X, et al. Regulation of lysyl oxidase by basic fibroblast growth factor in osteoblastic MC3T3-E1 cells. J Biol Chem. 1996;271:6411–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Satio M, Fujii K, Tanaka T, et al. Effect of low- and high-intensity pulsed ultrasound on collagen post-translational modifications in MC3T3-E1 osteoblasts. Calcif Tissue Int. 2004;75:384–95.CrossRefGoogle Scholar
  34. 34.
    Rodriguez C, Alcudia JF, Martinez-Gonzalez J, et al. Lysyl oxidase (LOX) down-regulation by TNFalpha: a new mechanism underlying TNFalpha-induced endothelial dysfunction. Atherosclerosis. 2008;196:558–64.PubMedCrossRefGoogle Scholar
  35. 35.
    Turecek C, Fratzl-Zelman N, Rumpler M, et al. Collagen cross-linking influences osteoblastic differentiation. Calcif Tissue Int. 2008;82:392–400.PubMedCrossRefGoogle Scholar
  36. 36.•
    Thaler R, Agsten M, Spitzer S, et al. Homocysteine suppresses the expression of the collagen cross-linker lysyl oxidase involving IL-6, Fli1, and epigenetic DNA methylation. J Biol Chem. 2011;286:5578–88. In vitro study for exploring the roles of homocysteine on lysyl oxidase expression.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Thaler R, Spitzer S, Rumpler M, et al. Differential effects of homocysteine and beta aminopropionitrile on preosteoblastic MC3T3-E1 cells. Bone. 2010;46:703–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kang HA, Trelstad RL. A collagen defect in homocystinuria. J Clin Invest. 1973;52:2571–8.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.••
    Yang J, Hu X, et al. Homocysteine level and risk of fracture: a meta-analysis and systematic review. Bone. 2012;51:376–82. Reports clinical results of mildly elevated plasma homocysteine on fracture risk. PubMedCrossRefGoogle Scholar
  40. 40.
    Blouin S, Thaler HW, Korninger C, et al. Bone matrix quality and plasma homocysteine levels. Bone. 2009;44:959–64.PubMedCrossRefGoogle Scholar
  41. 41.
    Satiod M, Fujii K, Soshi S, et al. Degree of mineralization-related collagen cross-linking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int. 2006;79:160–8.CrossRefGoogle Scholar
  42. 42.
    McLean RR, Hannan MT. B vitamins, homocysteine, and bone disease: epidemiology and pathophysiology. Curr Osteoporos Rep. 2007;5:112–9.PubMedCrossRefGoogle Scholar
  43. 43.•
    Ebesunun MO, Obajobi EO. Elevated plasma homocysteine in type 2 diabetes mellitus: a risk factor for cardiovascular diseases. Pan Afr Med J. 2012;12:48. Reports clinical results of mildly elevated plasma homocysteine in diabetes.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Fujii K, Kuboki Y, Sasaki S. Aging of human bone and cartilage collagen: changes in the reducible cross-links and their precursors. Gerontology. 1976;22:363–70.PubMedCrossRefGoogle Scholar
  45. 45.
    Saito M. Age-related changes in biochemical characteristics of collagen from human weight-bearing and non-weight-bearing bone. Tokyo Jikeikai Med J. 1999;114:327–37. Available at: Scholar
  46. 46.
    Banse X, Sims TJ, et al. Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res. 2002;17:1621–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Brady JD, Robins SP. Structural characterization of pyrrolic cross-links in collagen using a biotinylated Ehrlich's reagent. J Biol Chem. 2001;276:18812–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Kuypers R, Tyler M, Kurth LB, et al. Identification of the loci of the collagen-associated Ehrlich chromogenic in type I collagen confirms its role as a trivalent cross-link. Biochem J. 1992;283:129–36.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Hanson DA, Eyre DR. Molecular site specificity of pyridinoline and pyrrole cross-links in type I collagen of human bone. J Biol Chem. 1996;271:26508–16.PubMedCrossRefGoogle Scholar
  50. 50.•
    Saito M, Marumo K, Uhsiku C, et al. Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1–34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys. Osteoporos Int. 2011;22:2373–83. Use of monkey OVX model to explore the contribution of collagen cross-link formation to bone strength and the effects of teriparatide treatment on bone strength.PubMedCrossRefGoogle Scholar
  51. 51.
    Vashishth D. The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep. 2007;5:62–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang X, Shen X, Li X, et al. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31:1–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Viguet-Carrin S, Farlay D, Bala Y, et al. An in vitro model to test the contribution of advanced glycation end products to bone biomechanical properties. Bone. 2008;42:139–49.PubMedCrossRefGoogle Scholar
  54. 54.
    Satio M, Fujii K, Soshi S, et al. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int. 2006;17:986–95.CrossRefGoogle Scholar
  55. 55.
    Satio M, Mori S, Mahsiba T, et al. Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs. Osteoporos Int. 2008;19:1343–54.CrossRefGoogle Scholar
  56. 56.
    Dong XN, Qin A, et al. In situ accumulation of advanced glycation end products (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone. 2011;49:174–83.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Nakamura K, Nakazawa Y, Ienaga K, et al. Acid-stable fluorescent advanced glycation end products: vesperlysines A, B, and C are formed as cross-linked products in the Maillard reaction between lysine or proteins with glucose. Biochem Biophys Res Commun. 1997;232:227–30.PubMedCrossRefGoogle Scholar
  58. 58.
    Sims TJ, Rasmussen LM, Oxlund H, et al. The role of glycation cross-links in diabetic vascular stiffening. Diabetologia. 1996;39:946–51.PubMedCrossRefGoogle Scholar
  59. 59.
    Sell DR, Biemel KM, Reihl O, et al. Glucosepane is a major protein cross-link of the senescent human extracellular matrix. Relationship with diabetes. J Biol Chem. 2005;280:12310–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Viguet-Carrin S, Gineyts E, Bertholon C, et al. Simple and sensitive method for quantification of fluorescent enzymatic mature and senescent cross-links of collagen in bone hydrolysate using single-column high performance liquid chromatography. J Chromatogr B Anal Technol Biomed Life Sci. 2009;877:1–7.CrossRefGoogle Scholar
  61. 61.
    Robins SP, Bailey AJ. Age-related changes in collagen: the identification of reducible lysine-carbohydrate condensation products. Biochem Biophys Res Commun. 1972;48:76–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Monnier VM, Sell DR, Dai Z, et al. The role of the Amadori product in the complications of diabetes. Ann N Y Acad Sci. 2008;1126:81–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Brennan M. Changes in solubility, non-enzymatic glycation, and fluorescence of collagen in tail tendons from diabetic rats. J Biol Chem. 1989;264:20947–52.PubMedGoogle Scholar
  64. 64.
    Sanguineti R, Storace D, Monacelli F, et al. Pentosidine effects on human osteoblasts in vitro. Ann N Y Acad Sci. 2008;1126:166–72.PubMedCrossRefGoogle Scholar
  65. 65.••
    Khosravi R, Sodek KL, Faibish M, et al. Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone. 2014;58:33–41. In vitro study for exploring the roles of AGEs on lysyl oxidase expression.PubMedCrossRefGoogle Scholar
  66. 66.••
    Tanaka K, Yamaguchi T, Kaji H, et al. Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress. Biochem Biophys Res Commun. 2013;438:463–7. In vitro study for exploring the roles of AGEs on cellular dysfunction.PubMedCrossRefGoogle Scholar
  67. 67.
    Ogawa N, Yamaguchi T, Yanao T, et al. The combination of high glucose and advanced glycation end-products (AGEs) inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs. Horm Metab Res. 2007;39:871–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Mercer N, Ahmed H, Etcheverry SB, et al. Regulation of advanced glycation end product (AGE) receptors and apoptosis by AGEs in osteoblast-like cells. Mol Cell Biochem. 2007;306:87–94.PubMedCrossRefGoogle Scholar
  69. 69.•
    Li G, Xu J, Li Z. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling. Biochem Biophys Res Commun. 2012;423:684–9. In vitro study for exploring the roles of AGEs on cellular dysfunction.PubMedCrossRefGoogle Scholar
  70. 70.
    Cortizo AM, Lettieri MG, Barrio DA, et al. Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Mol Cell Biochem. 2003;250:1–10.PubMedCrossRefGoogle Scholar
  71. 71.•
    Cui S, Xiong F, Hong Y, et al. APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner. J Bone Miner Res. 2011;26:1084–98. In vitro study for exploring the roles of AGEs on osteoclast activation.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Zhou Z, Han JY, Xi CX, et al. HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res. 2008;23:1084–96.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Miyata T, Notoya K, Yoshida K, et al. Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J Am Soc Nephrol. 1997;8:260–70.PubMedGoogle Scholar
  74. 74.••
    Mitome J, Yamamoto H, Saito M, et al. Non-enzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Calcif Tissue Int. 2011;88:521–9. Human biopsy data from the patients with chronic renal failure.PubMedCrossRefGoogle Scholar
  75. 75.
    Valcourt U, Merle B, Gineyts E, et al. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem. 2007;282:5691–703.PubMedCrossRefGoogle Scholar
  76. 76.
    Silva MJ, Brodt MD, Lynch MA, et al. Type 1 diabetes in young rats leads to progressive trabecular bone loss, cessation of cortical bone growth, and diminished whole bone strength and fatigue life. J Bone Miner Res. 2009;24:1618–27.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Okazaki R, Totsuka Y, Hamano K, et al. Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab. 1997;82:2915–20.PubMedGoogle Scholar
  78. 78.
    McCarthy AD, Etcheverry SB, Bruzzone L, et al. Non-enzymatic glycation of a type I collagen matrix: effect on osteoblastic development and oxidative stress. BMC Cell Biol. 2001;2:16.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.••
    Nojiri H, Saita Y, Saito M, et al. Cytoplasmic superoxide causes bone fragility due to low turnover osteoporosis with impaired collagen cross-links. J Bone Miner Res. 2011;26:2682–94. Oxidative stress in SOD knockout mice induces bone collagen cross-link abnormality.PubMedCrossRefGoogle Scholar
  80. 80.
    Ventura E, Durant R, Jaussent A, et al. Homocysteine and inflammation as main determinants of oxidative stress in the elderly. Free Radic Biol Med. 2009;46:737–44.PubMedCrossRefGoogle Scholar
  81. 81.•
    Leslie WD, Rubin MR, Schwarz AV, et al. Type 2 diabetes and bone. Review. J Bone Miner Res. 2012;27:2231–7. Review from mainly clinical studies in fracture risk of diabetes.PubMedCrossRefGoogle Scholar
  82. 82.••
    Hammond MA, Gallant MA, Burr DB, et al. Nanoscale changes in collagen are reflected in physical and mechanical properties of bone at the microscale in diabetic rats. Bone. 2013;60C:26–32. Using diabetic rat model to explore the collagen alignment in bone.Google Scholar
  83. 83.
    Oxlund H, Barckman M, Ortoft G, et al. Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone. 1995;17:365S–71.PubMedGoogle Scholar
  84. 84.
    Opsahl W, Zeronian H, Ellison M, et al. Role of copper in collagen cross-linking and its influence on selected mechanical properties of chick bone and tendon. J Nutr. 1982;112:708–16.PubMedGoogle Scholar
  85. 85.
    Garnero P, Borel O, Gineyts E, et al. Extracellular post-translational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone. Bone. 2006;38:300–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Viguet-Carrin S, Roux JP, Arlot ME, et al. Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae. Bone. 2006;39:1073–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Vashishth D, Gibson GJ, Khoury JI, et al. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28:195–201.PubMedCrossRefGoogle Scholar
  88. 88.
    Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone. 2007;40:1144–51.PubMedCrossRefGoogle Scholar
  89. 89.
    Tomasek JJ, Meyers SW, Basinger JB, et al. Diabetic and age-related enhancement of collagen-linked fluorescence in cortical bones of rats. Life Sci. 1994;55:855–61.PubMedCrossRefGoogle Scholar
  90. 90.
    Odetti P, Rossi S, Monacelli F, et al. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005;1043:710–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Sugiyama S, Miyata T, Ueda Y, et al. Plasma levels of pentosidine in diabetic patients: an advanced glycation end product. J Am Soc Nephrol. 1998;9:1681–8.PubMedGoogle Scholar
  92. 92.
    Takahashi M, Ohishi T, Aoshima H, et al. The Maillard protein cross-link pentosidine in urine from diabetic patients. Diabetologia. 1993;36:664–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Yamamoto M, Yamaguchi T, Yamauchi M, et al. Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes Care. 2009;32:2263–8.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Yamamoto M, Yamaguchi T, Yamauchi M, et al. Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2008;93:1013–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Schwartz AV, Garnero P, Hillier TA, et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab. 2009;94:2380–6.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Shiraki M, Kuroda T, Tanaka S, et al. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab. 2008;26:93–100.PubMedCrossRefGoogle Scholar
  97. 97.
    Shiraki M, Urano T, Kuroda T, et al. The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fracture. J Bone Miner Metab. 2008;26:595–602.PubMedCrossRefGoogle Scholar
  98. 98.
    Tanaka S, Kuroda T, Saito M, et al. Urinary pentosidine improves risk classification using fracture risk assessment tools for postmenopausal women. J Bone Miner Res. 2011;26:2778–84.PubMedCrossRefGoogle Scholar
  99. 99.••
    Schwartz AV, Vittinghoff E, Bauer DC, et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA. 2011;305:2184–92. Usefulness of the combination of FRAX and the estimation of diabetes on fracture risk assessment.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Satio M, Fujii K, Soshi S, et al. Effects of vitamin B6 and Vitamin K2 on bone mechanical properties and collagen cross-links in spontaneously diabetic WBN/Kob rats. J Bone Miner Res. 2005;(Suppl):SU420.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mitsuru Saito
    • 1
    Email author
  • Yoshikuni Kida
    • 1
  • Soki Kato
    • 1
  • Keishi Marumo
    • 1
  1. 1.Department of Orthopaedic SurgeryJikei University School of MedicineTokyoJapan

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