Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have a well-defined safety profile based on data obtained from numerous clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting. Adverse events including risk of genital mycotic infection and volume depletion-related events are consistent with the mechanism of action of this drug class. However, several emergent (albeit infrequent) serious safety issues have also been reported. In their respective CVOTs, the proportion of patients with reported diabetic ketoacidosis was similar in empagliflozin or canagliflozin compared with their placebo groups, but it was higher for dapagliflozin. Canagliflozin may be associated with an increased risk of bone fracture and lower limb amputation; however, data are inconclusive. There is no evidence linking SGLT2 inhibitors with an increased risk of cancer, but these agents, particularly dapagliflozin, should be used with caution in patients with hematuria or a history of bladder cancer. Postmarketing reports of acute kidney injury have occurred in patients receiving SGLT2 inhibitors, and cases identified in recent CVOTs occurred with similar frequency in SGLT2 inhibitor and placebo groups. Common adverse events associated with SGLT2 inhibitors (such as genital infections or volume depletion) are generally mild and manageable by patients or by primary care physicians, and the risk of rare events (such as ketoacidosis) can be minimized by appropriate patient selection and early recognition of symptoms. When selecting treatment, it is important that clinicians weigh the known risks of SGLT2 inhibitors against their proven benefits, including the reduction of adverse cardiovascular and renal outcomes.

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“…33 Type 2 diabetes mellitus adversely effects bone metabolism and strength and increases the risk of fracture in affected individuals. 34…”

Section: Bone Fracturesmentioning

confidence: 99%

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors

McGill

Subramanian

2019

The American Journal of Cardiology

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“…Accordingly, the association between diabetes mellitus and bone health has long been a matter of debate. However, several studies have shown that diabetic bone is characterized by abnormal alterations in bone metabolism, decreased bone mineral content and density, increased fracture rate, and delayed fracture healing [13][14][15]. Furthermore, in diabetes mellitus, bone turnover is reduced or disrupted in parallel with increased risk of bone fractures, in which bone formation declines with reduced mineralization and bone cell number [12,16].…”

Section: Introductionmentioning

confidence: 99%

Coumarin Ameliorates Impaired Bone Turnover by Inhibiting the Formation of Advanced Glycation End Products in Diabetic Osteoblasts and Osteoclasts

et al. 2020

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Accumulating evidence demonstrates that the risk of osteoporotic fractures increases in patients with diabetes mellitus. Thus, diabetes-induced bone fragility has recently been recognized as a diabetic complication. As the fracture risk is independent of the reduction in bone mineral density, deterioration in bone quality may be the main cause of bone fragility. Coumarin exists naturally in many plants as phenylpropanoids and is present in tonka beans in significantly high concentrations. This study investigated whether coumarin ameliorated the impaired bone turnover and remodeling under diabetic condition. The in vitro study employed murine macrophage Raw 264.7 cells differentiated to multinucleated osteoclasts with receptor activator of nuclear factor-κΒ ligand (RANKL) in the presence of 33 mM glucose and 1–20 μM coumarin for five days. In addition, osteoblastic MC3T3-E1 cells were exposed to 33 mM glucose for up to 21 days in the presence of 1–20 μM coumarin. High glucose diminished tartrate-resistant acid phosphatase activity and bone resorption in RANKL-differentiated osteoclasts, accompanying a reduction of cathepsin K induction and actin ring formation. In contrast, coumarin reversed the defective osteoclastogenesis in diabetic osteoclasts. Furthermore, high glucose diminished alkaline phosphatase activity and collagen type 1 induction of osteoblasts, which was strongly enhanced by submicromolar levels of coumarin to diabetic cells. Furthermore, coumarin restored the induction of RANK and osteoprotegerin in osteoclasts and osteoblasts under glucotoxic condition, indicating a tight coupling of osteoclastogenesis and osteoblastogenesis. Coumarin ameliorated the impaired bone turnover and remodeling in diabetic osteoblasts and osteoclasts by suppressing the interaction between advanced glycation end product (AGE) and its receptor (RAGE). Therefore, coumarin may restore optimal bone turnover of osteoclasts and osteoblasts by disrupting the hyperglycemia-mediated AGE–RAGE interaction.

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“…43 The underlying mechanism of increased bone fragility in individuals with T2DM may involve hyperglycemia, insulinopenia, reduced level of insulin-like growth factor 1, adipokines, and cytokines affecting osteocyte, accumulation of advanced glycation end products facilitating cross-link with collagen, and late diabetic complications, such as DR and diabetic kidney disease (DKD), which may increase the risk of falling. 33,44 Furthermore, a number of observational studies have suggested the association between MVCs and an increased incidence of fracture. A study indicating that patients with T2DM with MVCs characterized by deteriorations in cortical bone 22 found that biochemical bone markers, including OC, P1NP, and β-CTX, were reduced in the patients with MVCs, which is mostly consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

“…BTMs are suggested to be useful indicators in monitoring treatment and diagnosing for secondary causes of osteoporosis 25 as well as independent predictors for osteoporosis [26][27][28] and fracture risk. 29,30 Although there are a number of studies reporting the relationships between bone metabolism, indicated by BTMs, and T2DM, [31][32][33] few studies have focused on the interrelationships between bone biochemical markers and DR, 34,35 in particular, and its severity. Additionally, these researches revealed conflicting and inconclusive results.…”

Section: Introductionmentioning

confidence: 99%

Low serum levels of bone turnover markers are associated with the presence and severity of diabetic retinopathy in patients with type 2 diabetes mellitus

Liu

Wang

et al. 2020

Journal of Diabetes

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Background: Accumulating evidence demonstrates an association of type 2 diabetes mellitus (T2DM) and its microvascular complications with increased fracture risk. In this study, we aimed to evaluate the relationships between serum concentrations of bone turnover markers and the presence and/or severity of diabetic retinopathy (DR) among patients with T2DM. Methods: A total of 285 patients with T2DM comprising 168 patients without DR and 117 patients with DR were enrolled in the cross-sectional study. In the latter group, patients were further divided into patients of mild and severe DR stages. The biochemical parameters and bone turnover markers were determined in all participants. Results: This study found that serum levels of procollagen type 1 N-terminal propeptide (P1NP), a bone formation marker, and the bone resorption marker serum β-cross-linked C-telopeptide of type I collagen (β-CTX) were more decreased in diabetic patients with DR than in those without DR, with differences remaining significant (P < .05) in multivariate linear regression models after adjustments for multiple confounding factors. Osteocalcin and β-CTX levels were further reduced along with the severity of DR among participants with DR. Moreover, multivariate logistic regression analysis revealed that lower serum levels of P1NP and β-CTX were associated with higher odds for the presence of DR, while β-CTX was associated with the severity of DR. Conclusion: Our results suggest that the development of DR might be involved in the progression of T2DM-induced deficits in bone formation and resorption or vice versa. Follow-up studies and further research are necessary to validate the associations and elucidate the underlying mechanisms. K E Y W O R D S bone turnover markers, diabetic retinopathy, type 2 diabetes mellitus Yaxin An and Simo Liu contributed equally to this study.

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Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties

Cited by 109 publications

References 182 publications

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors

Coumarin Ameliorates Impaired Bone Turnover by Inhibiting the Formation of Advanced Glycation End Products in Diabetic Osteoblasts and Osteoclasts

Low serum levels of bone turnover markers are associated with the presence and severity of diabetic retinopathy in patients with type 2 diabetes mellitus

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