Skip to main content

Advertisement

Log in

Is Diabetic Skeletal Fragility Associated with Microvascular Complications in Bone?

  • Bone and Diabetes (A Schwartz and P Vestergaard, section editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The objective of this literature review is to determine whether there are indications that microvascular complications occur in diabetic bone. Evidence definitively linking diabetic skeletal fragility with microvascular complications in bone remains elusive.

Recent Findings

Circumstantial evidence, some recent and some lost to time, suggests that atherosclerotic vascular diseases such as peripheral arterial disease cause poor blood perfusion of bone and subsequent hypoxia and contribute to low bone density and high cortical porosity, patterns similar to some recently observed in diabetic subjects. Evidence also exists to suggest that potentially anti-angiogenic conditions, such as impaired vascular endothelial growth factor (VEGF) signaling, predominate in diabetic bone.

Summary

Microvascular complications may contribute, in part, to diabetic skeletal fragility but data supporting this interpretation are primarily circumstantial at this time. This review highlights gaps in our knowledge and hopefully spurs further discussions and research on this topic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Bonds DE 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.

    Article  CAS  PubMed  Google Scholar 

  2. Janghorbani M et al. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166(5):495–505.

    Article  PubMed  Google Scholar 

  3. Martinez-Laguna D et al. Incident type 2 diabetes and hip fracture risk: a population-based matched cohort study. Osteoporos Int. 2015;26(2):827–33.

    Article  CAS  PubMed  Google Scholar 

  4. Fan Y et al. Diabetes mellitus and risk of hip fractures: a meta-analysis. Osteoporos Int. 2016;27(1):219–28.

    Article  CAS  PubMed  Google Scholar 

  5. Looker AC, Eberhardt MS, Saydah SH. Diabetes and fracture risk in older U.S. adults. Bone. 2016;82:9–15.

    Article  PubMed  Google Scholar 

  6. Ottenbacher KJ et al. 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.

    Article  PubMed  Google Scholar 

  7. Kilpadi KL et al. Type 2 diabetes is associated with vertebral fractures in a sample of clinic- and hospital-based Latinos. J Immigr Minor Health. 2014;16(3):440–9.

    Article  CAS  PubMed  Google Scholar 

  8. American Diabetes Association. Fast facts. Data and statistics about diabetes, 2014.

  9. International Diabetes Federation. IDF Diabetes Atlas, 2015.

  10. Hernandez RK et al. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice Research Database. Acta Orthop. 2012;83(6):653–60.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Semel J et al. Predictors of outcome following hip fracture rehabilitation. PM&R. 2010;2(9):799–805.

  12. Reistetter TA et al. Diabetes comorbidity and age influence rehabilitation outcomes after hip fracture. Diabetes Care. 2011;34(6):1375–7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bass E, French DD, Bradham DD. A national perspective of Medicare expenditures for elderly veterans with hip fractures. J Am Med Dir Assoc. 2008;9(2):114–9.

    Article  PubMed  Google Scholar 

  14. Wilmot E, Idris I. Early onset type 2 diabetes: risk factors, clinical impact and management. Ther Adv Chronic Dis. 2014;5(6):234–44.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wilmot EG et al. Type 2 diabetes in younger adults: the emerging UK epidemic. Postgrad Med J. 2010;86(1022):711–8.

    Article  PubMed  Google Scholar 

  16. Kao WH et al. Type 2 diabetes is associated with increased bone mineral density in Mexican-American women. Arch Med Res. 2003;34(5):399–406.

    Article  PubMed  Google Scholar 

  17. Ma L et al. Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies. Eur J Epidemiol. 2012;27(5):319–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Prieto-Alhambra D et al. The association between fracture and obesity is site-dependent: a population-based study in postmenopausal women. J Bone Miner Res. 2012;27(2):294–300.

    Article  PubMed  Google Scholar 

  19. Schwartz AV 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yamamoto M, Sugimoto T. Advanced glycation end products, diabetes, and bone strength. Curr Osteoporos Rep. 2016;14(6):320–6.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bailey AJ, Paul RG, Knott L. Mechanisms of maturation and ageing of collagen. Mech Ageing Dev. 1998;106(1–2):1–56.

    Article  CAS  PubMed  Google Scholar 

  22. Vashishth D. Advanced glycation end-products and bone fractures. IBMS Bonekey. 2009;6(8):268–78.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2016;82:21–7.

    Article  CAS  PubMed  Google Scholar 

  24. Vashishth D et al. Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone. 2001;28(2):195–201.

    Article  CAS  PubMed  Google Scholar 

  25. Farr, J.N., et al., In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res, 2013;29(4):787–95.

  26. Rubin MR et al. Advanced glycation endproducts and bone material properties in type 1 diabetic mice. PLoS One. 2016;11(5), e0154700.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Poundarik AA et al. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. 2015;52:120–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Viguet-Carrin S et al. An in vitro model to test the contribution of advanced glycation end products to bone biomechanical properties. Bone. 2008;42(1):139–49.

    Article  CAS  PubMed  Google Scholar 

  29. Hofmann B et al. Relationship between cardiac tissue glycation and skin autofluoresence in patients with coronary artery disease. Diab and Metabol. 2014;41(5):410–5.

  30. Fessel G et al. Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness. PLoS One. 2014;9(11), e110948.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Saito M 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(10):1514–23.

    Article  CAS  PubMed  Google Scholar 

  32. Ivers RQ et al. Diabetes and risk of fracture: The Blue Mountains Eye Study. Diabetes Care. 2001;24(7):1198–203.

    Article  CAS  PubMed  Google Scholar 

  33. Viegas M et al. Prevalence of osteoporosis and vertebral fractures in postmenopausal women with type 2 diabetes mellitus and their relationship with duration of the disease and chronic complications. J Diabetes Complications. 2011;25(4):216–21.

    Article  PubMed  Google Scholar 

  34. • Burghardt AJ 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. This is the first paper to show that diabetic bone tissue is characterized by cortical porosity.

  35. Patsch JM et al. Increased cortical porosity in type 2 diabetic postmenopausal women with fragility fractures. J Bone Miner Res. 2013;28(2):313–24.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Heilmeier U et al. Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics. Osteoporos Int. 2016;27(9):2791–802.

    Article  CAS  PubMed  Google Scholar 

  37. • Lim Y et al. Association of bone mineral density and diabetic retinopathy in diabetic subjects: the 2008–2011 Korea National Health and Nutrition Examination Survey. Osteoporos Int. 2016;27(7):2249–57. This paper reports on a large epidemiological study showing that low BMD in diabetic women is associated with a long disease duration and diabetic retinopathy.

  38. • Thompson B, Towler DA. Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol. 2012;8(9):529–43. This is an excellent review of the complex interactions of the bone-vascular axis.

  39. Zelzer E et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development. 2002;129(8):1893–904.

    CAS  PubMed  Google Scholar 

  40. Maes C et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002;111(1–2):61–73.

    Article  CAS  PubMed  Google Scholar 

  41. • Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest. 2016;126(2):509–26. This study comprehensively reports on the roles of osteoblast-expressed VEGF-A in a bone healing model. It provides compelling new information on its autocrine and paracrine effects in bone healing.

  42. Street J et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99(15):9656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang Y et al. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007;117(6):1616–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. •• Prisby RD et al. Aging reduces skeletal blood flow, endothelium-dependent vasodilation, and NO bioavailability in rats. J Bone Miner Res. 2007;22(8):1280–8. A seminal paper showing that skeletal blood flow decreases with age and provides evidence that diminished vasodilation resulting from limited nitric oxide availability is a root cause.

  45. McCarthy I. The physiology of bone blood flow: a review. J Bone Joint Surg Am. 2006;88 (Suppl 3):4–9.

  46. Cowin SC, Cardoso L. Blood and interstitial flow in the hierarchical pore space architecture of bone tissue. J Biomech. 2015;48(5):842–54.

    Article  PubMed  Google Scholar 

  47. •• Brookes M. The vascular reaction of tubular bone to ischaemia in peripheral occulusive vascular disease. J Bone Joint Surg (Br). 1960;42(1):110–25. This histological study of human tibiae was one of the first to report that atherosclerotic disease was associated with dramatic changes in bone structure, most likely due to poor blood perfusion. The patterns revealed by Brookes are similar to those observed in diabetic patients with and without vascular disease.

  48. Tanko LB et al. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res. 2005;20(11):1912–20.

    Article  PubMed  Google Scholar 

  49. • Matsumoto T et al. Three-dimensional cortical bone microstructure in a rat model of hypoxia-induced growth retardation. Calcif Tissue Int. 2011;88(1):54–62. This paper shows that hypoxia in long bones results in structural changes such as cortical porosity that results from efforts to revascularize the bone tissue. This work corroborates Brookes’ early work in an experimental animal model.

  50. Hackam DG, Anand SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA. 2003;290(7):932–40.

    Article  PubMed  Google Scholar 

  51. Brookes M. Sequelae of experimental partial ischaemia in long bones of the rabbit. J Anat. 1960;94(Pt 4):552–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015;116(9):1509–26.

    Article  CAS  PubMed  Google Scholar 

  53. Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289):1257–64.

    Article  CAS  PubMed  Google Scholar 

  54. Simard E et al. Receptor for advanced glycation end-products signaling interferes with the vascular smooth muscle cell contractile phenotype and function. PLoS One. 2015;10(8), e0128881.

    Article  PubMed  PubMed Central  Google Scholar 

  55. •• Shanbhogue VV et al. Compromised cortical bone compartment in type 2 diabetes mellitus patients with microvascular disease. Eur J Endocrinol. 2016;174(2):115–24. This paper is very important because it demonstrates with high-resolution CT imaging that cortical porosity is associated with a microvascular disease diagnosis.

  56. Yu EW et al. Defects in cortical microarchitecture among African-American women with type 2 diabetes. Osteoporos Int. 2015;26(2):673–9.

    Article  CAS  PubMed  Google Scholar 

  57. Paccou J et al. Bone microarchitecture in men and women with diabetes: the importance of cortical porosity. Calcif Tissue Int. 2016;98(5):465–73.

    Article  CAS  PubMed  Google Scholar 

  58. Chen YW et al. High prevalence of lower extremity peripheral artery disease in type 2 diabetes patients with proliferative diabetic retinopathy. PLoS One. 2015;10(3), e0122022.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Oikawa A et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol. 2010;30(3):498–508.

    Article  CAS  PubMed  Google Scholar 

  60. Spinetti G et al. Global remodeling of the vascular stem cell niche in bone marrow of diabetic patients: implication of the microRNA-155/FOXO3a signaling pathway. Circ Res. 2013;112(3):510–22.

    Article  CAS  PubMed  Google Scholar 

  61. Orlandi A et al. Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice. Basic Res Cardiol. 2010;105(6):703–12.

    Article  CAS  PubMed  Google Scholar 

  62. Tepper OM et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106(22):2781–6.

    Article  PubMed  Google Scholar 

  63. Costa PZ, Soares R. Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci. 2013;92(22):1037–45.

    Article  CAS  PubMed  Google Scholar 

  64. Roca F et al. Glycation: the angiogenic paradox in aging and age-related disorders and diseases. Ageing Res Rev. 2014;15:146–60.

    Article  CAS  PubMed  Google Scholar 

  65. Simo R et al. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev. 2006;2(1):71–98.

    Article  CAS  PubMed  Google Scholar 

  66. Neufeld G et al. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):9–22.

    CAS  PubMed  Google Scholar 

  67. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438(7070):937–45.

    Article  CAS  PubMed  Google Scholar 

  68. Clarkin CE, Gerstenfeld LC. VEGF and bone cell signalling: an essential vessel for communication? Cell Biochem Funct. 2013;31(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  69. Wang S et al. Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7. Proc Natl Acad Sci U S A. 2008;105(22):7738–43.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Grover TR et al. Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol-3-kinase-nitric oxide pathway in the late-gestation ovine fetus. Pediatr Res. 2002;52(6):907–12.

    Article  CAS  PubMed  Google Scholar 

  71. Chen XL et al. VEGF-induced vascular permeability is mediated by FAK. Dev Cell. 2012;22(1):146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.

    Article  CAS  PubMed  Google Scholar 

  73. Barleon B et al. Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors. Angiogenesis. 2001;4(2):143–54.

    Article  CAS  PubMed  Google Scholar 

  74. Saito T et al. VEGF-A induces its negative regulator, soluble form of VEGFR-1, by modulating its alternative splicing. FEBS Lett. 2013;587(14):2179–85.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang F et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci U S A. 2009;106(15):6152–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ray PS, Fox PL. A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity. EMBO J. 2007;26(14):3360–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ben-Av P et al. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett. 1995;372(1):83–7.

    Article  CAS  PubMed  Google Scholar 

  78. Ishida A et al. Expression of vascular endothelial growth factor receptors in smooth muscle cells. J Cell Physiol. 2001;188(3):359–68.

    Article  CAS  PubMed  Google Scholar 

  79. Deckers MM et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology. 2000;141(5):1667–74.

    Article  CAS  PubMed  Google Scholar 

  80. Prasadam I et al. Osteocyte-induced angiogenesis via VEGF-MAPK-dependent pathways in endothelial cells. Mol Cell Biochem. 2014;386(1–2):15–25.

    Article  CAS  PubMed  Google Scholar 

  81. Cheung WY et al. Osteocyte apoptosis is mechanically regulated and induces angiogenesis in vitro. J Orthop Res. 2011;29(4):523–30.

    Article  PubMed  Google Scholar 

  82. Al-Dujaili SA et al. Apoptotic osteocytes regulate osteoclast precursor recruitment and differentiation in vitro. J Cell Biochem. 2011;112(9):2412–23.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang Q et al. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem. 2008;283(19):13491–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang Q et al. VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and beta3-integrin. Matrix Biol. 2008;27(7):589–99.

    Article  PubMed  Google Scholar 

  85. Makino N et al. High serum TNF-alpha level in Type 2 diabetic patients with microangiopathy is associated with eNOS down-regulation and apoptosis in endothelial cells. J Diabetes Complications. 2005;19(6):347–55.

    Article  PubMed  Google Scholar 

  86. Ai-Aql ZS et al. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res. 2008;87(2):107–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Botusan IR et al. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008;105(49):19426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. • Thangarajah H et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A. 2009;106(32):13505–10. This paper reports that hyperglycemia impairs the transactivation of hypoxia-inducible factor 1 alpha (HIF-1α). This may be the mechanism that causes decreased VEGF-A expression in osteoblasts exposed to chronic hyperglycemia.

  89. •• Botolin S, McCabe LR. Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem. 2006;99(2):411–24. Seminal paper that demonstrates the impact of chronic hyperglycemia on osteoblasts. One outcome is decreased VEGF-A expression, thus diminishing the pro-angiogenic potential of the bone microenvironment.

  90. Coe LM et al. The bone marrow microenvironment contributes to type I diabetes induced osteoblast death. J Cell Physiol. 2011;226(2):477–83.

    Article  CAS  PubMed  Google Scholar 

  91. Rashid G et al. Effect of advanced glycation end-products on gene expression and synthesis of TNF-alpha and endothelial nitric oxide synthase by endothelial cells. Kidney Int. 2004;66(3):1099–106.

    Article  CAS  PubMed  Google Scholar 

  92. Vestergaard P, Rejnmark L, Mosekilde L. Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int. 2011;88(3):209–14.

    Article  CAS  PubMed  Google Scholar 

  93. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.

    Article  CAS  PubMed  Google Scholar 

  94. Esser N et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141–50.

    Article  CAS  PubMed  Google Scholar 

  95. Sharma R et al. Caspase-2 maintains bone homeostasis by inducing apoptosis of oxidatively-damaged osteoclasts. PloS one. 2014;9(4):e93696.

  96. Dhindsa S et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33(6):1186–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kapoor D et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154(6):899–906.

    Article  CAS  PubMed  Google Scholar 

  98. Manavalan JS et al. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(9):3240–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Movahed A et al. Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism. J Bone Miner Metab. 2012;30(6):683–91.

    Article  CAS  PubMed  Google Scholar 

  100. Ardawi MS et al. Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes. Bone. 2013;56(2):355–62.

    Article  CAS  PubMed  Google Scholar 

  101. Alikhani M et al. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2007;40(2):345–53.

    Article  CAS  PubMed  Google Scholar 

  102. Zhang Y, Yang JH. Activation of the PI3K/Akt pathway by oxidative stress mediates high glucose-induced increase of adipogenic differentiation in primary rat osteoblasts. J Cell Biochem. 2013;114(11):2595–602.

    Article  CAS  PubMed  Google Scholar 

  103. Yeap BB et al. Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men. J Clin Endocrinol Metab. 2015;100(1):63–71.

    Article  CAS  PubMed  Google Scholar 

  104. Yamamoto M et al. Decreased PTH levels accompanied by low bone formation are associated with vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2012;97(4):1277–84.

    Article  CAS  PubMed  Google Scholar 

  105. O’Sullivan EP et al. Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status. Thromb Res. 2010;126(6):e423–7.

    Article  PubMed  Google Scholar 

  106. Niu Y et al. Association of plasma osteoprotegerin levels with the severity of lower extremity arterial disease in patients with type 2 diabetes. BMC Cardiovasc Disord. 2015;15:86.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yamamoto 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(3):1013–9.

    Article  CAS  PubMed  Google Scholar 

  108. Leslie WD et al. Biphasic fracture risk in diabetes: a population-based study. Bone. 2007;40(6):1595–601.

    Article  PubMed  Google Scholar 

  109. Melton 3rd LJ et al. A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab. 2008;93(12):4804–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Roberto Jose Fajardo.

Ethics declarations

Conflict of Interest

Roberto Fajardo reports grants from AO Spine Foundation, N.A. and the NIH (R01AR064244-04S1) during the conduct of the study.

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.

Additional information

This article is part of the Topical Collection on Bone and Diabetes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fajardo, R.J. Is Diabetic Skeletal Fragility Associated with Microvascular Complications in Bone?. Curr Osteoporos Rep 15, 1–8 (2017). https://doi.org/10.1007/s11914-017-0341-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-017-0341-8

Keywords

Navigation