Current Osteoporosis Reports

, Volume 14, Issue 6, pp 351–358 | Cite as

Bone Microarchitecture in Type 1 Diabetes: It Is Complicated

  • Hillary A. KeenanEmail author
  • Ernesto Maddaloni
Bone and Diabetes (A Schwartz and P Vestergaard, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Bone and Diabetes


Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of “bone quality,” rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health.


Bone quality Microarchitecture Type 1 diabetes Diabetes Complications Bone fragility 


Compliance with Ethical Standards

Conflict of Interest

Hillary A. Keenan and Ernesto Maddaloni declare that they have no conflict 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.

No animal or human studies were done for this manuscript. The authors were not authors on any of the papers referenced in this review.


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

  1. 1.
    Bass E, French DD, Bradham DD, Rubenstein LZ. Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann Epidemiol. 2007;17:514–9.CrossRefPubMedGoogle Scholar
  2. 2.•
    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. In this meta-analysis the most important studies evaluating risk of bone fractures in diabetes were evaluated, showing an higher and disproportionate risk of bone fractures in those with T1DM vs T2DM.CrossRefPubMedGoogle Scholar
  3. 3.
    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;166:495–505.CrossRefPubMedGoogle Scholar
  4. 4.
    Starup-Linde J, Vestergaard P. Management of endocrine disease: diabetes and osteoporosis: cause for concern? Eur J Endocrinol. 2015;173:R93–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Rakic V, Davis WA, Chubb SAP, Islam FMA, Prince RL, Davis TME. Bone mineral density and its determinants in diabetes: the fremantle diabetes study. Diabetologia. 2006;49:863–71.CrossRefPubMedGoogle Scholar
  6. 6.
    Weber G, Beccaria L, De’Angelis M, Mora S, Galli L, Cazzuffi MA, et al. Bone mass in young patients with type I diabetes. Bone Miner. 1990;8:23–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250–61.CrossRefPubMedGoogle Scholar
  8. 8.•
    Riggs BL, Melton Iii LJ, Robb RA, Camp JJ, Atkinson EJ, Peterson JM, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res. 2004;19:1945–54. A population-based study highlighted in this review because showing different bone composition in different sites.CrossRefPubMedGoogle Scholar
  9. 9.
    Donnelly E. Methods for assessing bone quality: a review. Clin Orthop Relat Res. 2011;469:2128–38.CrossRefPubMedGoogle Scholar
  10. 10.•
    Lettgen B, Hauffa B, Möhlmann C, Jeken C, Reiners C. Bone mineral density in children and adolescents with juvenile diabetes: selective measurement of bone mineral density of trabecular and cortical bone using peripheral quantitative computed tomography. Horm Res. 1995;43:173–5. One of the first papers evaluating bone in T1DM by pQCT. This study suggested the importance of using pQCT in diabetes and showed differences in Tb and Ct bone in adolescents affected by T1DM vs healthy controls.CrossRefPubMedGoogle Scholar
  11. 11.
    Heap J, Murray MA, Miller SC, Jalili T, Moyer-Mileur LJ. Alterations in bone characteristics associated with glycemic control in adolescents with type 1 diabetes mellitus. J Pediatr. 2004;144:56–62.CrossRefPubMedGoogle Scholar
  12. 12.
    Saha MT, Sievänen H, Salo MK, Tulokas S, Saha HH. Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporos Int. 2009;20:1401–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Roggen I, Gies I, Vanbesien J, Louis O, De Schepper J. Trabecular bone mineral density and bone geometry of the distal radius at completion of pubertal growth in childhood type 1 diabetes. Horm Res Pædiatr. 2013;79:68–74.CrossRefPubMedGoogle Scholar
  14. 14.
    Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA. Bone mineral acquisition in adolescents with type 1 diabetes. J Pediatr. 2004;145:662–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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;30:2046–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Roe TF, Mora S, Costin G, Kaufman F, Carlson ME, Gilsanz V. Vertebral bone density in insulin-dependent diabetic children. Metabolism. 1991;40:967–71.CrossRefPubMedGoogle Scholar
  17. 17.••
    Shanbhogue VV, Hansen S, Frost M, Jørgensen NR, Hermann AP, Henriksen JE, et al. Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with type 1 diabetes mellitus. J Bone Miner Res. 2015;30:2188–99. This paper compares bone microarchitecture, strength, and remodeling in those with type 1 diabetes, with and without small vessel complications to matched control groups using HR-pQCT. While no differences were found in bone metrics between individuals with type 1 diabetes without microvascular complications and controls, significant differences were found in both the trabecular and cortical aspects of those with complications and their matched controls. The authors suggest the presence of complications is associated with increased frailty in those with type 1 diabetes.CrossRefPubMedGoogle Scholar
  18. 18.••
    Starup-Linde J, Lykkeboe S, Gregersen S, Hauge E-M, Langdahl BL, Handberg A, et al. Bone structure and predictors of fracture in type 1 and type 2 diabetes. J Clin Endocrinol Metab 2016;101:928–936. In a population from an outpatient clinic, differences in the bone density of those with type 1 and type 2 diabetes were found at the hip and in stiffness of the tibia in adjusted models. These factors were both increased in those with type 2 diabetes. Of interest, was that those with the highest levels of sclerostin, in the third tertile, were found to have the lowest risk of fracture, putting this protein forward as potential marker of frailty.Google Scholar
  19. 19.••
    Neumann T, Lodes S, Kästner B, Lehmann T, Hans D, Lamy O, et al. Trabecular bone score in type 1 diabetes—a cross-sectional study. Osteoporos Int. 2016;27:127–33. Trabecular bone score as an estimate of bone microarchitecture significantly differentiated those with fracture amongst those with type 1 diabetes, whereas BMD of the lumbar spine did not. These data, as the TBS is based on the trabecular assessment, suggest that trabecular deficit is responsible for fracture risk in those with type 1 diabetes. The authors suggest TBS may provide an added benefit to BMD in determining who among those with type 1 diabetes is at increased risk for frailty fracture.CrossRefPubMedGoogle Scholar
  20. 20.
    Armas LAG, Akhter MP, Drincic A, Recker RR. Trabecular bone histomorphometry in humans with type 1 diabetes mellitus. Bone. 2012;50:91–6.CrossRefPubMedGoogle Scholar
  21. 21.••
    Abdalrahaman N, McComb C, Foster JE, McLean J, Lindsay RS, McClure J, et al. Deficits in trabecular bone microarchitecture in young women with type 1 diabetes mellitus. J Bone Miner Res. 2015;30:1386–93. This study provides an examination of tibial microarchitecture and vertebral marrow adiposity in female young adults with type 1 diabetes. The findings indicate lower levels of IGF-1 and ALS may be associated with deficits in tibial trabecular microarchitecture. Importantly, this paper also shows evidence of an association of proliferative diabetic retinopathy with skeletal health.CrossRefPubMedGoogle Scholar
  22. 22.
    Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol (Chicago, Ill 1960). 1984;102:527–32.CrossRefGoogle Scholar
  23. 23.
    Perkins BA, Krolewski AS. Early nephropathy in type 1 diabetes: a new perspective on who will and who will not progress. Curr Diab Rep. 2005;5:455–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, Lachin JM, White NH, Hainsworth DP, Sun W, Cleary PA, et al. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes. 2015;64:631–42.CrossRefGoogle Scholar
  25. 25.
    Montalcini T, Gallotti P, Coppola A, Zambianchi V, Fodaro M, Galliera E, et al. Association between low C-peptide and low lumbar bone mineral density in postmenopausal women without diabetes. Osteoporos Int. 2015;26:1639–46.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142:309–19.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis—from clinical observation towards molecular understanding. Osteoporos Int. 2007;18:251–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V. Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab. 2004;89:4246–53.CrossRefPubMedGoogle Scholar
  29. 29.•
    Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O’Donnell CJ, Wilson PW. Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int. 2001;68:271–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–50.CrossRefPubMedGoogle Scholar
  31. 31.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Aiello LP, Wong JS. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl. 2000;77:S113–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab Elsevier Inc. 2013;17:20–33.CrossRefGoogle Scholar
  34. 34.••
    Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest. 2016;126:509–26. Little research has been done on the regulation of endothelial cells (CD45+) and VEGF excretion by osteoblasts. This paper demonstrates that this may play a role in the bone-vascular axis, using evidence through flox models of the VEGFR.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Street J, Bao M, de Guzman L, Bunting S, Peale FV, Ferrara N, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002;99:9656–61.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Jacobsen KA, Al-Aql ZS, Wan C, Fitch JL, Stapleton SN, Mason ZD, et al. Bone formation during distraction osteogenesis is dependent on both VEGFR1 and VEGFR2 signaling. J Bone Miner Res. 2008;23:596–609.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chakravarthy H, Beli E, Navitskaya S, O’Reilly S, Wang Q, Kady N, et al. Imbalances in mobilization and activation of pro-inflammatory and vascular reparative bone marrow-derived cells in diabetic retinopathy. PLoS One. 2016;11, e0146829.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    de Oliveira RA, Barreto FC, Mendes M, dos Reis LM, Castro JH, Britto ZML, et al. Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease. Kidney Int. 2015;87:1039–45.CrossRefPubMedGoogle Scholar
  39. 39.
    Lima EM, Goodman WG, Kuizon BD, Gales B, Emerick A, Goldin J, et al. Bone density measurements in pediatric patients with renal osteodystrophy. Pediatr Nephrol. 2003;18:554–9.PubMedGoogle Scholar
  40. 40.
    Andress DL. Adynamic bone in patients with chronic kidney disease. Kidney Int. 2008;73:1345–54.CrossRefPubMedGoogle Scholar
  41. 41.
    Thalassinos NC, Hadjiyanni P, Tzanela M, Alevizaki C, Philokiprou D. Calcium metabolism in diabetes mellitus: effect of improved blood glucose control. Diabet Med. 1993;10:341–4.CrossRefPubMedGoogle Scholar
  42. 42.
    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;84:45–55.CrossRefPubMedGoogle Scholar
  43. 43.
    Prisby R, Guignandon A, Vanden-Bossche A, Mac-Way F, Linossier M-T, Thomas M, et al. Intermittent PTH(1–84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res. 2011;26:2583–96.CrossRefPubMedGoogle Scholar
  44. 44.
    Lim Y, Chun S, Lee JH, Baek KH, Lee WK, Yim H-W, 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.Google Scholar
  45. 45.
    Tesfaye S, Boulton AJM, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Qin W, Bauman WA, Cardozo CP. Evolving concepts in neurogenic osteoporosis. Curr Osteoporos Rep. 2010;8:212–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Tanaka K, Hirai T, Kodama D, Kondo H, Hamamura K, Togari A. α1B-Adrenoceptor signalling regulates bone formation through the up-regulation of CCAAT/enhancer-binding protein δ expression in osteoblasts. Br J Pharmacol. 2016;173:1058–69.CrossRefPubMedGoogle Scholar
  48. 48.
    Hirai T, Tanaka K, Togari A. β-adrenergic receptor signaling regulates Ptgs2 by driving circadian gene expression in osteoblasts. J Cell Sci. 2014;127:3711–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Bonnet N, Brunet-Imbault B, Arlettaz A, Horcajada MN, Collomp K, Benhamou CL, et al. Alteration of trabecular bone under chronic beta2 agonists treatment. Med Sci Sports Exerc. 2005;37:1493–501.CrossRefPubMedGoogle Scholar
  50. 50.
    Swift JM, Swift SN, Allen MR, Bloomfield SA. Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse. PLoS One. 2014;9, e106904.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bonnet N, Benhamou CL, Brunet-Imbault B, Arlettaz A, Horcajada MN, Richard O, et al. Severe bone alterations under beta2 agonist treatments: bone mass, microarchitecture and strength analyses in female rats. Bone. 2005;37:622–33.CrossRefPubMedGoogle Scholar
  52. 52.
    Lind M, Svensson A-M, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371:1972–82.CrossRefPubMedGoogle Scholar
  53. 53.
    Rodriguez BL, Dabelea D, Liese AD, Fujimoto W, Waitzfelder B, Liu L, et al. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245–51.e1.CrossRefPubMedGoogle Scholar
  54. 54.
    Orchard TJ, Stevens LK, Forrest KY, Fuller JH. Cardiovascular disease in insulin dependent diabetes mellitus: similar rates but different risk factors in the US compared with Europe. Int J Epidemiol. 1998;27:976–83.CrossRefPubMedGoogle Scholar
  55. 55.
    de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2014;37:2843–63.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Valsania P, Zarich SW, Kowalchuk GJ, Kosinski E, Warram JH, Krolewski AS. Severity of coronary artery disease in young patients with insulin-dependent diabetes mellitus. Am Heart J. 1991;122:695–700.CrossRefPubMedGoogle Scholar
  57. 57.
    Pajunen P, Taskinen MR, Nieminen MS, Syvänne M. Angiographic severity and extent of coronary artery disease in patients with type 1 diabetes mellitus. Am J Cardiol. 2000;86:1080–5.CrossRefPubMedGoogle Scholar
  58. 58.
    Larsen JR, Tsunoda T, Tuzcu EM, Schoenhagen P, Brekke M, Arnesen H, et al. Intracoronary ultrasound examinations reveal significantly more advanced coronary atherosclerosis in people with type 1 diabetes than in age- and sex-matched non-diabetic controls. Diab Vasc Dis Res. 2007;4:62–5.CrossRefPubMedGoogle Scholar
  59. 59.
    The DCCT Research Group. Lipid and lipoprotein levels in patients with IDDM diabetes control and complication. Trial experience. Diabetes Care. 1992;15:886–94.CrossRefGoogle Scholar
  60. 60.
    Anagnostis P, Karagiannis A, Kakafika AI, Tziomalos K, Athyros VG, Mikhailidis DP. Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities? Osteoporos Int. 2009;20:197–207.CrossRefPubMedGoogle Scholar
  61. 61.
    Sennerby U, Farahmand B, Ahlbom A, Ljunghall S, Michaëlsson K. Cardiovascular diseases and future risk of hip fracture in women. Osteoporos Int. 2007;18:1355–62.CrossRefPubMedGoogle Scholar
  62. 62.
    Bagger YZ, Tankó LB, Alexandersen P, Qin G, Christiansen C. Radiographic measure of aorta calcification is a site-specific predictor of bone loss and fracture risk at the hip. J Intern Med. 2006;259:598–605.CrossRefPubMedGoogle Scholar
  63. 63.
    Arnett TR, Gibbons DC, Utting JC, Orriss IR, Hoebertz A, Rosendaal M, et al. Hypoxia is a major stimulator of osteoclast formation and bone resorption. J Cell Physiol. 2003;196:2–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Arnett TR. Acidosis, hypoxia and bone. Arch Biochem Biophys. 2010;503:103–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Reeve J, Arlot M, Wootton R, Edouard C, Tellez M, Hesp R, et al. Skeletal blood flow, iliac histomorphometry, and strontium kinetics in osteoporosis: a relationship between blood flow and corrected apposition rate. J Clin Endocrinol Metab. 1988;66:1124–31.CrossRefPubMedGoogle Scholar
  66. 66.
    Marenzana M, Arnett TR. The key role of the blood supply to bone. Bone Res. 2013;1:203–15.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Collins TC, Ewing SK, Diem SJ, Taylor BC, Orwoll ES, Cummings SR, et al. Peripheral arterial disease is associated with higher rates of hip bone loss and increased fracture risk in older men. Circulation. 2009;119:2305–12.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lampropoulos CE, Papaioannou I, D’Cruz DP. Osteoporosis—a risk factor for cardiovascular disease? Nat Rev Rheumatol. 2012;8:587–98.CrossRefPubMedGoogle Scholar
  69. 69.
    Thompson B, Towler DA. Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol. 2012;8:529–43.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sprini D, Rini GB, Di Stefano L, Cianferotti L, Napoli N. Correlation between osteoporosis and cardiovascular disease. Clin Cases Miner Bone Metab. 2014;1:117–9.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Research Division, Joslin Diabetes Center, Harvard Medical SchoolBostonUSA
  2. 2.Department of Medicine, Unit of Endocrinology and DiabetesUniversity Campus Bio-Medico of RomeRomeItaly

Personalised recommendations