Umbrella review protocol type 2 diabetes mellitus and fracture risk

Abstract

BACKGROUND

Type 2 diabetes mellitus (T2DM) represents a major global public health challenge, with projections indicating that the number of affected individuals could reach 853 million by 2050. While microvascular and macrovascular complications in diabetic patients are well-documented, there is a growing focus on skeletal involvement, particularly diabetic osteoporosis. Traditionally, the increased fracture risk in T2DM has been attributed to mechanisms like the accumulation of advanced glycation end products and oxidative stress. However, emerging evidence suggests that T2DM patients may experience compensatory skeletal adaptations, such as increases in bone density, which complicate the relationship between T2DM and fracture risk. This study utilizes an umbrella meta-analysis to systematically assess the association between T2DM and fracture risk, aiming to clarify existing controversies in the literature.

AIM

To thoroughly evaluate the association between T2DM and fracture risks at various anatomical sites, including overall fractures, hip fractures, and non-vertebral fractures. The goal is to provide an evidence-based foundation for developing individualized fracture management strategies in clinical practice.

METHODS

Conducted in accordance with PRISMA guidelines, this umbrella meta-analysis involved a systematic literature search across the PubMed, Web of Science, and EMBASE databases up to October 1, 2025. The search aimed to identify meta-analyses that evaluated the association between T2DM and fracture risk. Inclusion criteria were limited to studies involving T2DM patients, with fracture risk as the outcome measure, expressed as relative risk (RR) and 95% confidence intervals (CIs). The methodological quality of the studies was assessed using the AMSTAR 2 tool. Statistical analyses employed either fixed-effects or random-effects models based on I² heterogeneity statistics, and sensitivity analyses were performed to confirm the robustness of the findings.

RESULTS

A total of 16 studies were included in the analysis. The findings revealed a significant association between T2DM and an increased risk of total fractures (RR = 1.23, 95%CI: 1.17-1.28), with low heterogeneity observed (I² = 44.8%). Site-specific analyses showed heterogeneous associations: Increased risks were identified for non-vertebral fractures (RR = 1.22, 95%CI: 1.18-1.27), ankle fractures (RR = 1.43, 95%CI: 1.21-1.64), and upper arm fractures (RR = 1.43, 95%CI: 1.21-1.64). Conversely, the risk of hip fractures was significantly reduced (RR = 0.80, 95%CI: 0.72-0.89), although this result exhibited considerable heterogeneity (I² = 94.9%). No significant associations were found for vertebral or humeral fractures. Sensitivity analyses confirmed the robustness of the hip fracture outcome after excluding outliers. A forest plot for total fractures visually illustrated a consistent trend toward increased risk. Furthermore, funnel plot analysis indicated mild publication bias, which did not compromise the primary conclusions. The observed heterogeneity in the hip fracture analysis was mainly due to specific study deviations.

CONCLUSION

T2DM shows a heterogeneous association with fracture risk, highlighting the need for the development of site-specific clinical strategies. The reduced risk of hip fractures may indicate compensatory skeletal adaptation, while the increased risk at other sites is linked to diabetic complications like neuropathy. Future research should focus on large-scale cohort studies, inclusive of ethnic diversity, and the optimization of risk prediction tools to improve fracture prevention and management in T2DM patients.

Keywords: Type 2 diabetes mellitus; Fracture risk; Umbrella meta-analysis; Bone fragility; Heterogeneity

Core Tip: This umbrella review reveals the complex, site-specific relationship between type 2 diabetes mellitus (T2DM) and fracture risk. Contrary to the elevated risk for overall, non-vertebral, and ankle fractures, T2DM was associated with a significantly reduced risk of hip fracture. This paradoxical finding challenges conventional views and may be attributed to skeletal compensatory adaptations in T2DM, such as adaptive increases in bone density. The study underscores the necessity of moving beyond a generalized fracture risk assessment and developing individualized, site-specific prevention and management strategies for patients with T2DM.