Effect of Diabetes on the Fracture Resistance of Bone

Original Paper


Diabetes increases the likelihood of suffering a fracture, and in the case of type 2 diabetes mellitus (T2D), low bone mass does not explain this loss in fracture resistance. Insulin contributes to the accrual of bone mass. As such, the elevated fracture risk among those with type 1 diabetes (T1D) could be due to a deficit in bone structure, especially if the diabetes is poorly controlled. Clinical studies involving computed tomography scans do suggest that low moment of inertia and low cross-sectional area of cortical bone accompany T1D. However, low bone mass does not typically accompany T2D, and fracture resistance arises from all the hierarchical levels comprising the organization of bone’s constituents. One consequence of diabetes, hyperglycemia, causes an increase in non-enzymatic collagen crosslinks, also known as advanced glycation end products (AGEs). Increases in AGEs within the bone matrix are strongly correlated with the age-related decrease in the ability of bone to dissipate energy during failure (toughness and fracture toughness). While elevated AGEs are associated with higher incidence of fracture, the mechanism by which non-enzymatic crosslinking lowers fracture resistance is not fully delineated. The general concept is that increases in AGEs within the matrix cause the collagen phase to become brittle, reducing the capacity of the tissue to resist the formation and propagation of microdamage. While certainly more research into the diabetic effects on fracture resistance is necessary before clear therapeutic options are identified, diabetes should be considered a problem of bone brittleness, not just one of low bone strength.


Bone quality Toughness Collagen crosslinks Strength Computed tomography Structure Architecture Biomechanics Brittleness Hyperglycemia 


  1. 1.
    Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care. 2001;24(7):1192–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, et al. Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab. 2006;91(9):3404–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Schwartz AV, Sellmeyer DE. Diabetes, fracture, and bone fragility. Curr Osteoporos Rep. 2007;5(3):105–11.PubMedCrossRefGoogle Scholar
  4. 4.
    Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166(5):495–505.PubMedCrossRefGoogle Scholar
  5. 5.
    Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int. 2009;84(1):45–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Lewiecki EM. Management of osteoporosis. Clin Mol Allergy. 2004;2(1):9.PubMedCrossRefGoogle Scholar
  7. 7.
    Atik OS, Gunal I, Korkusuz F. Burden of osteoporosis. Clin Orthop Relat Res. 2006;443:19–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int. 1997;7(5):407–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Thrailkill KM, Liu L, Wahl EC, Bunn RC, Perrien DS, Cockrell GE, et al. Bone formation is impaired in a model of type 1 diabetes. Diabetes. 2005;54(10):2875–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Lapcevic WA, French DD, Campbell RR. All-cause mortality rates of hip fractures treated in the VHA: do they differ from medicare facilities? J Am Med Dir Assoc. 2010;11(2):116–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Bass E, French DD, Bradham DD, Rubenstein LZ. Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann Epidemiol. 2007;17(7):514–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Tuominen JT, Impivaara O, Puukka P, Ronnemaa T. Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care. 1999;22(7):1196–200.PubMedCrossRefGoogle Scholar
  14. 14.
    Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M. Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporos Int. 2009;20(6):923–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Boehm HF, Eckstein F, Wunderer C, Kuhn V, Lochmueller EM, Schreiber K, et al. Improved performance of hip DXA using a novel region of interest in the upper part of the femoral neck: in vitro study using bone strength as a standard of reference. J Clin Densitom. 2005;8(4):488–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Muller ME, Webber CE, Bouxsein ML. Predicting the failure load of the distal radius. Osteoporos Int. 2003;14(4):345–52.PubMedCrossRefGoogle Scholar
  17. 17.
    Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res. 1992;7(2):137–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Buysschaert M, Cauwe F, Jamart J, Brichant C, De Coster P, Magnan A, et al. Proximal femur density in type 1 and 2 diabetic patients. Diabete Metab. 1992;18(1):32–7.PubMedGoogle Scholar
  19. 19.
    Hampson G, Evans C, Petitt RJ, Evans WD, Woodhead SJ, Peters JR, et al. Bone mineral density, collagen type 1 alpha 1 genotypes and bone turnover in premenopausal women with diabetes mellitus. Diabetologia. 1998;41(11):1314–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Schwartz AV. Diabetes mellitus: Does it affect bone? Calcif Tissue Int. 2003;73(6):515–9.PubMedCrossRefGoogle Scholar
  21. 21.
    de L II, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 2005;16(12):1713–20.CrossRefGoogle Scholar
  22. 22.
    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(4):427–44.PubMedCrossRefGoogle Scholar
  23. 23.
    Wallace C, Reiber GE, LeMaster J, Smith DG, Sullivan K, Hayes S, et al. Incidence of falls, risk factors for falls, and fall-related fractures in individuals with diabetes and a prior foot ulcer. Diabetes Care. 2002;25(11):1983–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care. 2002;25(10):1749–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Forsen L, Meyer HE, Midthjell K, Edna TH. Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia. 1999;42(8):920–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, et al. Older women with diabetes have an increased risk of fracture: a Prospective Study. J Clin Endocrinol Metab. 2001;86(1):32–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Ottenbacher KJ, Ostir GV, Peek MK, Goodwin JS, Markides KS. Diabetes mellitus as a risk factor for hip fracture in Mexican American older adults. J Gerontol A Biol Sci Med Sci. 2002;57(10):M648–53.PubMedCrossRefGoogle Scholar
  28. 28.
    De Laet CE, Van Hout BA, Burger H, Weel AE, Hofman A, Pols HA. Hip fracture prediction in elderly men and women: validation in the Rotterdam study. J Bone Miner Res. 1998;13(10):1587–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12(12):989–95.PubMedCrossRefGoogle Scholar
  30. 30.
    Pressman AR, Lo JC, Chandra M, Ettinger B. Methods for assessing fracture risk prediction models: experience with FRAX in a large integrated health care delivery system. J Clin Densitom. 2011;14(4):407–15. doi:10.1016/j.jocd.2011.06.006.PubMedCrossRefGoogle Scholar
  31. 31.
    Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. Jama. 2011;305(21):2184–92. doi:10.1001/jama.2011.715.PubMedCrossRefGoogle Scholar
  32. 32.
    Giangregorio L, Leslie W, Lix L, Johansson H, Oden A, McCloskey E, et al. FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res. 2011;. doi:10.1002/jbmr.556.Google Scholar
  33. 33.
    Rho JY, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92–102.PubMedCrossRefGoogle Scholar
  34. 34.
    Gupta HS, Zioupos P. Fracture of bone tissue: the ‘hows’ and the ‘whys’. Med Eng Phys. 2008;30(10):1209–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Ritchie RO. How does human bone resist fracture? Ann N Y Acad Sci. 2010;1192:72–80. doi:10.1111/j.1749-6632.2009.05232.x.PubMedCrossRefGoogle Scholar
  36. 36.
    Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone. 1993;14(4):595–608.PubMedCrossRefGoogle Scholar
  37. 37.
    Martin RB. Determinants of the mechanical properties of bones. J Biomech. 1991;24(Suppl 1):79–88.PubMedCrossRefGoogle Scholar
  38. 38.
    Teo JC, Si-Hoe KM, Keh JE, Teoh SH. Relationship between CT intensity, micro-architecture and mechanical properties of porcine vertebral cancellous bone. Clin Biomech (Bristol, Avon). 2006;21(3):235–44. doi:10.1016/j.clinbiomech.2005.11.001.CrossRefGoogle Scholar
  39. 39.
    Zysset PK. A review of morphology-elasticity relationships in human trabecular bone: theories and experiments. J Biomech. 2003;36(10):1469–85.PubMedCrossRefGoogle Scholar
  40. 40.
    Garrison JG, Slaboch CL, Niebur GL. Density and architecture have greater effects on the toughness of trabecular bone than damage. Bone. 2009;44(5):924–9. doi:10.1016/j.bone.2008.12.030.PubMedCrossRefGoogle Scholar
  41. 41.
    Shi X, Liu XS, Wang X, Guo XE, Niebur GL. Type and orientation of yielded trabeculae during overloading of trabecular bone along orthogonal directions. J Biomech. 2010;43(13):2460–6. doi:10.1016/j.jbiomech.2010.05.032.PubMedCrossRefGoogle Scholar
  42. 42.
    Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000;27(5):687–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Yerramshetty JS, Akkus O. The associations between mineral crystallinity and the mechanical properties of human cortical bone. Bone. 2008;42(3):476–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Martin RB, Lau ST, Mathews PV, Gibson VA, Stover SM. Collagen fiber organization is related to mechanical properties and remodeling in equine bone. A comparison of two methods. J Biomech. 1996;29(12):1515–21.PubMedGoogle Scholar
  45. 45.
    Oxlund H, Barckman M, Ortoft G, Andreassen TT. Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone. 1995;17(4 Suppl):365S–71S.PubMedGoogle Scholar
  46. 46.
    Muir P, Johnson KA, Ruaux-Mason CP. In vivo matrix microdamage in a naturally occurring canine fatigue fracture. Bone. 1999;25(5):571–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Kaeding CC, Najarian RG. Stress fractures: classification and management. Phys Sportsmed. 2010;38(3):45–54. doi:10.3810/psm.2010.10.1807.PubMedCrossRefGoogle Scholar
  48. 48.
    Jones BH, Harris JM, Vinh TN, Rubin C. Exercise-induced stress fractures and stress reactions of bone: epidemiology, etiology, and classification. Exerc Sport Sci Rev. 1989;17:379–422.PubMedGoogle Scholar
  49. 49.
    Chantelau E, Richter A, Schmidt-Grigoriadis P, Scherbaum WA. The diabetic Charcot foot: MRI discloses bone stress injury as trigger mechanism of neuroarthropathy. Exp Clin Endocrinol Diabetes. 2006;114(3):118–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Mori S, Burr DB. Increased intracortical remodeling following fatigue damage. Bone. 1993;14(2):103–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Burr DB, Martin RB, Schaffler MB, Radin EL. Bone remodeling in response to in vivo fatigue microdamage. J Biomech. 1985;18:189–200.PubMedCrossRefGoogle Scholar
  52. 52.
    Schaffler MB, Choi K, Milgrom C. Aging and matrix microdamage accumulation in human compact bone. Bone. 1995;17(6):521–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone. 1997;20(4):375–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Zioupos P. Accumulation of in vivo fatigue microdamage and its relation to biomechanical properties in ageing human cortical bone. J Microsc. 2001;201(Pt 2):270–8.CrossRefGoogle Scholar
  55. 55.
    Zioupos P. Accumulation of in vivo fatigue microdamage and its relation to biomechanical properties in ageing human cortical bone. J Microsc. 2001;201(2):270–8.CrossRefGoogle Scholar
  56. 56.
    Yeni YN, Brown CU, Wang Z, Norman TL. The influence of bone morphology on fracture toughness of the human femur and tibia. Bone. 1997;21(5):453–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Yeni YN, Brown CU, Norman TL. Influence of bone composition and apparent density on fracture toughness of the human femur and tibia. Bone. 1998;22(1):79–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Zioupos P, Currey JD, Hamer AJ. The role of collagen in the declining mechanical properties of aging human cortical bone. J Biomed Mater Res. 1999;45(2):108–16.PubMedCrossRefGoogle Scholar
  59. 59.
    Wang XD, Masilamani NS, Mabrey JD, Alder ME, Agrawal CM. Changes in the fracture toughness of bone may not be reflected in its mineral density, porosity, and tensile properties. Bone. 1998;23(1):67–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Issa C, Zantout MS, Azar ST. Osteoporosis in men with diabetes mellitus. J Osteoporos. 2011;2011:651867. doi:10.4061/2011/651867.PubMedGoogle Scholar
  61. 61.
    Wongdee K, Charoenphandhu N. Osteoporosis in diabetes mellitus: possible cellular and molecular mechanisms. World J Diabetes. 2011;2(3):41–8. doi:10.4239/wjd.v2.i3.41.PubMedCrossRefGoogle Scholar
  62. 62.
    Burstein AH, Reilly DT, Martens M. Aging of bone tissue: mechanical properties. J Bone Joint Surg Am. 1976;58(1):82–6.PubMedGoogle Scholar
  63. 63.
    McCalden RW, McGeough JA, Barker MB, Court-Brown CM. Age-related changes in the tensile properties of cortical bone. The relative importance of changes in porosity, mineralization, and microstructure. J Bone Joint Surg Am. 1993;75(8):1193–205.PubMedGoogle Scholar
  64. 64.
    Zioupos P, Currey JD, Hamer AJ. The role of collagen in the declining mechanical properties of aging human cortical bone. J Biomed Mater Res. 1999;45(2):108–16.PubMedCrossRefGoogle Scholar
  65. 65.
    Nyman JS, Roy A, Tyler JH, Acuna RL, Gayle HJ, Wang X. Age-related factors affecting the postyield energy dissipation of human cortical bone. J Orthop Res. 2007;25(5):646–55.PubMedCrossRefGoogle Scholar
  66. 66.
    Zioupos P, Currey JD. Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone. 1998;22(1):57–66.PubMedCrossRefGoogle Scholar
  67. 67.
    Nalla RK, Kruzic JJ, Kinney JH, Ritchie RO. Effect of aging on the toughness of human cortical bone: evaluation by R-curves. Bone. 2004;35(6):1240–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Koester KJ, Barth HD, Ritchie RO. Effect of aging on the transverse toughness of human cortical bone: evaluation by R-curves. J Mech Behav Biomed Mater. 2011;4(7):1504–13. doi:10.1016/j.jmbbm.2011.05.020.PubMedCrossRefGoogle Scholar
  69. 69.
    Zioupos P, Wang XT, Currey JD. The accumulation of fatigue microdamage in human cortical bone of two different ages in vitro. Clin Biomech (Bristol, Avon). 1996;11(7):365–75.CrossRefGoogle Scholar
  70. 70.
    Diab T, Sit S, Kim D, Rho J, Vashishth D. Age-dependent fatigue behaviour of human cortical bone. Eur J Morphol. 2005;42(1–2):53–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Zioupos P, Gresle M, Winwood K. Fatigue strength of human cortical bone: Age, physical, and material heterogeneity effects. J Biomed Mater Res A. 2007;86(3):627–36.Google Scholar
  72. 72.
    Kruzic JJ, Ritchie RO. Fatigue of mineralized tissues: cortical bone and dentin. J Mech Behav Biomed Mater. 2008;1(1):3–17.PubMedCrossRefGoogle Scholar
  73. 73.
    Carter DR, Hayes WC, Schurman DJ. Fatigue life of compact bone–II. Effects of microstructure and density. J Biomech. 1976;9(4):211–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Fleischli JG, Laughlin TJ, Athanasiou K, Lanctot DR, Lavery L, Wang X, et al. Effect of diabetes mellitus on the material properties of the distal tibia. J Am Podiatr Med Assoc. 2006;96(2):91–5.PubMedGoogle Scholar
  75. 75.
    Fleischli JG, Laughlin TJ, Lavery LA, Shah B, Lanctot D, Agrawal CM, et al. The effects of diabetes mellitus on the material properties of human metatarsal bones. J Foot Ankle Surg. 1998;37(3):195–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Saha MT, Sievanen H, Salo MK, Tulokas S, Saha HH. Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporos Int. 2009;20(8):1401–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Bechtold S, Putzker S, Bonfig W, Fuchs O, Dirlenbach I, Schwarz HP. Bone size normalizes with age in children and adolescents with type 1 diabetes. Diabetes Care. 2007;30(8):2046–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Melton LJ 3rd, Riggs BL, Leibson CL, Achenbach SJ, Camp JJ, Bouxsein ML, et al. A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab. 2008;93(12):4804–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Petit MA, Paudel ML, Taylor BC, Hughes JM, Strotmeyer ES, Schwartz AV et al. Bone mass and strength in older men with type 2 diabetes: The Osteoporotic Fractures in Men Study. J Bone Miner Res. 2010;25(2):285–91.Google Scholar
  80. 80.
    Register TC, Lenchik L, Hsu FC, Lohman KK, Freedman BI, Bowden DW, et al. Type 2 diabetes is not independently associated with spinal trabecular volumetric bone mineral density measured by QCT in the Diabetes Heart Study. Bone. 2006;39(3):628–33. doi:10.1016/j.bone.2006.03.003.PubMedCrossRefGoogle Scholar
  81. 81.
    Shu A, Yin MT, Stein E, Cremers S, Dworakowski E, Ives R, et al. Bone structure and turnover in type 2 diabetes mellitus. Osteoporos Int. 2011;. doi:10.1007/s00198-011-1595-0.Google Scholar
  82. 82.
    Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95(11):5045–55. doi:10.1210/jc.2010-0226.PubMedCrossRefGoogle Scholar
  83. 83.
    Sell DR, Monnier VM. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989;264(36):21597–602.PubMedGoogle Scholar
  84. 84.
    Zieman S, Kass D. Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail. 2004;10(3):144–9. quiz 50-1.PubMedCrossRefGoogle Scholar
  85. 85.
    Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone. 2002;31(1):1–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Tomasek JJ, Meyers SW, Basinger JB, Green DT, Shew RL. Diabetic and age-related enhancement of collagen-linked fluorescence in cortical bones of rats. Life Sci. 1994;55(11):855–61.PubMedCrossRefGoogle Scholar
  87. 87.
    Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone. 2007;40(4):1144–51.PubMedCrossRefGoogle Scholar
  88. 88.
    Monnier VM, Mustata GT, Biemel KL, Reihl O, Lederer MO, Zhenyu D, et al. Cross-linking of the extracellular matrix by the maillard reaction in aging and diabetes: an update on “a puzzle nearing resolution”. Ann N Y Acad Sci. 2005;1043:533–44.PubMedCrossRefGoogle Scholar
  89. 89.
    Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21(2):195–214.Google Scholar
  90. 90.
    Shiraki M, Kuroda T, Tanaka S, Saito M, Fukunaga M, Nakamura T. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab. 2008;26(1):93–100.PubMedCrossRefGoogle Scholar
  91. 91.
    Gineyts E, Munoz F, Bertholon C, Sornay-Rendu E, Chapurlat R. Urinary levels of pentosidine and the risk of fracture in postmenopausal women: the OFELY study. Osteoporos Int. 2010;21(2):243–50.Google Scholar
  92. 92.
    Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(7):2380–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. 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(3):1013–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Saito M, Fujii K, Soshi S, Tanaka T. 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(7):986–95.PubMedCrossRefGoogle Scholar
  95. 95.
    Nyman JS, Ni Q, Nicolella DP, Wang X. Measurements of mobile and bound water by nuclear magnetic resonance correlate with mechanical properties of bone. Bone. 2008;42(1):193–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28(2):195–201.PubMedCrossRefGoogle Scholar
  97. 97.
    Viguet-Carrin S, Farlay D, Bala Y, Munoz F, Bouxsein ML, Delmas PD. An in vitro model to test the contribution of advanced glycation end products to bone biomechanical properties. Bone. 2008;42(1):139–49.PubMedCrossRefGoogle Scholar
  98. 98.
    Reddy GK. Glucose-mediated in vitro glycation modulates biomechanical integrity of the soft tissues but not hard tissues. J Orthop Res. 2003;21(4):738–43.PubMedCrossRefGoogle Scholar
  99. 99.
    Gupta HS, Seto J, Wagermaier W, Zaslansky P, Boesecke P, Fratzl P. Cooperative deformation of mineral and collagen in bone at the nanoscale. Proc Natl Acad Sci USA. 2006;103(47):17741–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Dong XN, Almer JD, Wang X. Post-yield nanomechanics of human cortical bone in compression using synchrotron X-ray scattering techniques. J Biomech. 2011;44(4):676–82. doi:10.1016/j.jbiomech.2010.11.003.PubMedCrossRefGoogle Scholar
  101. 101.
    Zimmermann EA, Schaible E, Bale H, Barth HD, Tang SY, Reichert P, et al. Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales. Proc Natl Acad Sci USA. 2011;108(35):14416–21. doi:10.1073/pnas.1107966108.PubMedCrossRefGoogle Scholar
  102. 102.
    Chan KS, Chan CK, Nicolella DP. Relating crack-tip deformation to mineralization and fracture resistance in human femur cortical bone. Bone. 2009;45(3):427–34. doi:10.1016/j.bone.2009.01.468.PubMedCrossRefGoogle Scholar
  103. 103.
    Hernberg CA. The bone structure in alloxan-induced diabetes mellitus in rats. Acta Med Scand. 1952;142(4):274–83.PubMedCrossRefGoogle Scholar
  104. 104.
    Nyman JS, Even JL, Jo CH, Herbert EG, Murry MR, Cockrell GE, et al. Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone. 2011;48(4):733–40. doi:10.1016/j.bone.2010.12.016.PubMedCrossRefGoogle Scholar
  105. 105.
    Dixit PK, Ekstrom RA. Decreased breaking strength of diabetic rat bone and its improvement by insulin treatment. Calcif Tissue Int. 1980;32(3):195–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Einhorn TA, Boskey AL, Gundberg CM, Vigorita VJ, Devlin VJ, Beyer MM. The mineral and mechanical properties of bone in chronic experimental diabetes. J Orthop Res. 1988;6(3):317–23.PubMedCrossRefGoogle Scholar
  107. 107.
    Reddy GK, Stehno-Bittel L, Hamade S, Enwemeka CS. The biomechanical integrity of bone in experimental diabetes. Diabetes Res Clin Pract. 2001;54(1):1–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Zhang SQ, Chen GH, Lu WL, Zhang Q. Effects on the bones of vanadyl acetylacetonate by oral administration: a comparison study in diabetic rats. J Bone Miner Metab. 2007;25(5):293–301.PubMedCrossRefGoogle Scholar
  109. 109.
    Silva MJ, Brodt MD, Lynch MA, McKenzie JA, Tanouye KM, Nyman JS, 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(9):1618–27.PubMedCrossRefGoogle Scholar
  110. 110.
    Silva MJ, Brodt MD, Lynch MA, McKenzie JA, Tanouye KM, Nyman JS, 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(9):1618–27. doi:10.1359/jbmr.090316.PubMedCrossRefGoogle Scholar
  111. 111.
    Facchini DM, Yuen VG, Battell ML, McNeill JH, Grynpas MD. The effects of vanadium treatment on bone in diabetic and non-diabetic rats. Bone. 2006;38(3):368–77.PubMedCrossRefGoogle Scholar
  112. 112.
    Prisby RD, Swift JM, Bloomfield SA, Hogan HA, Delp MD. Altered bone mass, geometry and mechanical properties during the development and progression of type 2 diabetes in the Zucker diabetic fatty rat. J Endocrinol. 2008;199(3):379–88.PubMedCrossRefGoogle Scholar
  113. 113.
    Reinwald S, Peterson RG, Allen MR, Burr DB. Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models. Am J Physiol Endocrinol Metab. 2009;296(4):E765–74.PubMedCrossRefGoogle Scholar
  114. 114.
    Ahmad T, Ohlsson C, Saaf M, Ostenson CG, Kreicbergs A. Skeletal changes in type-2 diabetic Goto-Kakizaki rats. J Endocrinol. 2003;178(1):111–6.PubMedCrossRefGoogle Scholar
  115. 115.
    Saito M, Fujii K, Mori Y, Marumo K. 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(10):1514–23.PubMedCrossRefGoogle Scholar
  116. 116.
    Vestergaard P, Rejnmark L, Mosekilde L. Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int. 2011;88(3):209–14. doi:10.1007/s00223-010-9450-4.PubMedCrossRefGoogle Scholar
  117. 117.
    Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR, et al. Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia. 2001;44(11):2032–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Selby PL, Young MJ, Boulton AJ. Bisphosphonates: a new treatment for diabetic Charcot neuroarthropathy? Diabet Med. 1994;11(1):28–31.PubMedCrossRefGoogle Scholar
  119. 119.
    Pakarinen TK, Laine HJ, Maenpaa H, Mattila P, Lahtela J. The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: a pilot randomized controlled trial. Diabetes Care. 2011;34(7):1514–6. doi:10.2337/dc11-0396.PubMedCrossRefGoogle Scholar
  120. 120.
    Game FL, Catlow R, Jones GR, Edmonds ME, Jude EB, Rayman G, et al. Audit of acute Charcot’s disease in the UK: the CDUK Study. Diabetologia. 2011;. doi:10.1007/s00125-011-2354-7.PubMedGoogle Scholar
  121. 121.
    Zhang L, Liu Y, Wang D, Zhao X, Qiu Z, Ji H, et al. Bone biomechanical and histomorphometrical investment in type 2 diabetic Goto-Kakizaki rats. Acta Diabetol. 2009;46(2):119–26.PubMedCrossRefGoogle Scholar
  122. 122.
    Kawashima Y, Fritton JC, Yakar S, Epstein S, Schaffler MB, Jepsen KJ, et al. Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis. Bone. 2009;44(4):648–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Veterans AffairsTennessee Valley Healthcare SystemNashvilleUSA
  2. 2.Department of Orthopaedics and RehabilitationMedical Center East, Vanderbilt UniversityNashvilleUSA
  3. 3.Vanderbilt Center for Bone BiologyVanderbilt UniversityNashvilleUSA
  4. 4.Department of Biomedical EngineeringVanderbilt UniversityNashvilleUSA

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