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Mechanisms of diabetes mellitus-induced bone fragility

Key Points

  • Patients with type 1 diabetes mellitus or type 2 diabetes mellitus (T2DM) have an increased risk of fractures; BMD underestimates this risk in individuals with T2DM, making risk assessment challenging

  • Patients with diabetes mellitus with long-term disease, poor glycaemic control, β-cell failure and who receive insulin treatment are at the highest risk of fractures

  • Low bone turnover, accumulation of advanced glycation endproducts, micro and macro-architecture alterations and tissue material damage lead to abnormal biomechanical properties and impair bone strength

  • Other determinants of bone fragility include inflammation, oxidative stress, adipokine alterations, WNT dysregulation and increased marrow fat

  • Complications of diabetes mellitus, such as neuropathy, poor balance, sarcopenia, vision impairment and frequent hypoglycaemic events, increase the risk of falls and risk of fracture; preventive measures are advised, especially in patients taking insulin

  • Use of thiazolidinediones, or some SGLT2 inhibitors might contribute to increased fracture risk; antidiabetic medications with good bone safety profiles such as metformin, GLP1analogues or DPP4 inhibitors are preferred

Abstract

The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.

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Figure 1: Mechanisms underlying bone loss and fractures in type 2diabetes mellitus.
Figure 2: Cellular and molecular mechanisms of bone diseases in diabetes mellitus.

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Acknowledgements

The authors acknowledge the support of the other members of the CSA IOF Bone and Diabetes Working Group: K. Akesson, M. S. M. Ardawi, C. Cooper, R. Eastell, G. El Hajj Fuleihan, S. Hough, R. Josse, D. Kendler, M. Kraenzlin, W. Leslie, M. Massi Benedetti, A. Mithal and A. Suzuki.

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N.N. and D.D.P. researched data for the article. N.N., M.C., B.A., A.V.S. and S.L.F. made substantial contributions to discussions of the content. N.N., M.C., B.A., A.V.S. and S.L.F. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Nicola Napoli.

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N.N. has served as a consultant for Amgen and Takeda. A.V.S is a consultant for Amgen and Jansen. The other authors declare no competing interests.

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Napoli, N., Chandran, M., Pierroz, D. et al. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13, 208–219 (2017). https://doi.org/10.1038/nrendo.2016.153

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