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  • Review Article
  • Published:

Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus

Abstract

Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.

Key points

  • Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM) despite normal, or even increased, bone mineral density.

  • Clinical studies have revealed that the two most consistent alterations in bone quality in patients with T2DM are impaired bone material properties and increased cortical porosity.

  • These abnormalities seem to be linked, at least in part, to accumulation of advanced glycation end products (leading to impaired bone material properties) and microvascular disease (leading to increased cortical porosity).

  • Evidence from the past few years also indicates that T2DM, at least in mice, is associated with accelerated skeletal ageing and increased accumulation of senescent cells, in bone as well as in other tissues.

  • Current strategies for fracture prevention in patients with T2DM include minimizing exposure to diabetes mellitus drugs that increase fracture risk and use of osteoporosis medications shown to be effective in patients without diabetes mellitus.

  • Further studies are needed to evaluate the efficacy of osteoporosis medications specifically in patients with T2DM and to develop new drugs targeting the mechanisms potentially driving skeletal fragility in patients with T2DM.

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Fig. 1: Age-adjusted and sex-adjusted incidence of fractures based on the number of hypoglycaemic episodes and baseline HbA1c in a cohort of Japanese patients with T2DM.
Fig. 2: Bone turnover is reduced in patients with T2DM.
Fig. 3: A working model for the pathogenesis of skeletal fragility and increased fracture risk in patients with T2DM.
Fig. 4: Accelerated osteocyte senescence in T2DM.
Fig. 5: Emerging pathophysiological mechanisms at the nexus of complications related to T2DM, including skeletal fragility.

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Acknowledgements

The authors acknowledge the support of NIH grants AG062413 (S.K., J.N.F.), AG004875 (S.K., D.G.M.), AR027065 (S.K.), AR070241 (J.N.F.), AG065868 (J.N.F., S.K.), AG063707 (D.G.M.) and AR068275 (D.G.M.).

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Khosla, S., Samakkarnthai, P., Monroe, D.G. et al. Update on the pathogenesis and treatment of skeletal fragility in type 2 diabetes mellitus. Nat Rev Endocrinol 17, 685–697 (2021). https://doi.org/10.1038/s41574-021-00555-5

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