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
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Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM) despite normal, or even increased, bone mineral density.
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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.
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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).
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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.
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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.
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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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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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Nature Reviews Endocrinology thanks P. Vestergaard, who co-reviewed with R. Viggers, A. Schwartz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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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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DOI: https://doi.org/10.1038/s41574-021-00555-5
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