Differences in the roles of types 1 and 2 diabetes in the susceptibility to the risk of fracture: a systematic review and meta-analysis

Background Diabetes mellitus (DM) causes excess risk of fracture at varied sites. Whereas, the difference between the roles of types 1 DM (T1DM) and 2 DM (T2DM) diabetes in the risk of fractures remains limited and inconclusive. We, therefore, conducted a meta-analysis to assess the differences for the associations of T1DM and T2DM with the risk of fractures. Methods We systematically searched PubMed, Embase, and the Cochrane library for eligible studies until May 2021. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the pooled effect estimates for the associations of T1DM and T2DM with the risk of fractures using the random-effects model. An indirect comparison results for the ratio of OR (ROR) with 95% CI were also applied to assess the difference between T1DM and T2DM with the risk of fractures. Results Twenty-two cohort studies involving a total of 6,484,851 individuals were selected for meta-analysis. We noted that T1DM was associated with an increased risk of all fractures (OR: 1.72; 95% CI 1.36–2.19; P < 0.001), and fractures at the hip (OR: 4.01; 95% CI 2.90–5.54; P < 0.001), upper arm (OR: 2.20; 95% CI 1.61–3.00; P < 0.001), ankle (OR: 1.97; 95% CI 1.24–3.14; P = 0.004), and vertebrae (OR: 2.18; 95% CI 1.85–2.57; P < 0.001). Moreover, T2DM induced excess risk to all fractures (OR: 1.19; 95% CI 1.09–1.31; P < 0.001), including fractures at the hip (OR: 1.25; 95% CI 1.15–1.35; P < 0.001), upper arm (OR: 1.42; 95% CI 1.20–1.67; P < 0.001), and ankle (OR: 1.15; 95% CI 1.01–1.31; P = 0.029). Furthermore, we noted that T1DM versus T2DM was associated with greater risk to all fractures (ROR: 1.45; 95% CI 1.12–1.87; P = 0.005), including fractures at the hip (ROR: 3.21; 95% CI 2.30–4.48; P < 0.001), upper arm (ROR: 1.55; 95% CI 1.09–2.20; P = 0.015), and ankle (ROR: 1.71; 95% CI 1.06–2.78; P = 0.029). Conclusions This study found that T1DM caused an excess risk to all fractures, including fractures at the hip, upper arm, and ankle than T2DM. Further studies should therefore be conducted to directly compare the differences between T1DM and T2DM with the risk of fractures at various sites. Supplementary Information The online version contains supplementary material available at 10.1186/s13098-021-00687-8.

diabetes-specific symptoms and microvascular complications [2,3]. Diabetes and its complications are also considered a global burden, therefore, reducing the disease burden of diabetes is an important goal of medical care societies and health policymakers [4,5]. Patients with diabetes are susceptible to excess risk of cardiovascular disease, neuropathy, nephropathy, retinopathy, and mortality [6]. Moreover, the rapidly increasing diabetes prevalence was also parallel with an increase in osteoporotic fractures [7]. Numerous studies have found a positive association of diabetes with the risk of fractures [8][9][10][11][12][13][14], and the potential reason for the association between diabetes and fractures included increased frequency of falling, cortical porosity, microvascular disease, and high levels of advanced glycation end-products [15][16][17]. The National Osteoporosis Foundation guidelines, therefore, suggested that screening for osteoporosis should be conducted for general women aged ≥ 65 years and men aged ≥ 70 years to prevent the morbidity and mortality related to fractures [18]. However, the strength of the association of type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) with the risk of fractures remains controversial. We, therefore, conducted a systematic review and meta-analysis of cohort studies to assess the differences between the associations of T1DM and T2DM with the risk of fracture at various sites. Moreover, whether study design and gender affected this difference was also evaluated.

Data sources, search strategy, and selection criteria
The Meta-analysis Of Observational Studies in Epidemiology protocol was used to conduct and report this systematic review and meta-analysis [19]. On the basis of this protocol, cohort studies that investigated the role of T1DM or T2DM with the risk of fractures were eligible in our study. The databases of PubMed, Embase, and the Cochrane library were searched for eligible studies from their inception up to May 2021. The following terms were used as medical subject headings or text words: ("diabetes" OR "diabetes mellitus" OR "glucose" OR "glycated hemoglobin") AND ("fractures, spontaneous" OR "osteoporotic fractures" OR "fractures, compression" OR "fracture"). The reference lists of potentially relevant articles were also manually reviewed for additional new eligible studies.
The literature search and study selection were conducted independently by 2 reviewers, and face-to-face discussions were used to settle disagreements until a consensus was reached. A study was included if they fulfilled the following inclusion criteria: (1) Study design: prospective or retrospective cohort studies; (2) Participants: general population; (3) Exposure and control:   T1DM, T2DM, and non-DM population; (4) Outcome:  all fracture, or fractures at hip, distal forearm, upper  arm, ankle, and vertebrae; and (5) all the studies should  have reported the effect estimates for the role of T1DM or T2DM with the risk of fractures. This study did not contain any human or life participants, therefore, ethics approval and informed consent were not applicable.

Data collection and quality assessment
Information from included studies contained the first author or study group's name, publication year, region, study design, sample size and number of DM, mean age, male proportion, smoking proportion, body mass index (BMI), DM type, follow-up duration, adjusted factors, and reported effect estimates. The quality of the individual studies were also assessed using the Newcastle-Ottawa Scale (NOS), which is widely used for assessing the quality of observational studies in a meta-analysis. The scoring system for each study ranged from 0-9 [20]. Studies having between 7 and 9 stars were regarded as high-quality. Data extraction and quality assessment were also independently performed by 2 reviewers, and any inconsistency was resolved and adjudicated by an additional reviewer during reading of the full-text of studies.

Statistical analysis
The role of T1DM and T2DM in the risk of fractures was calculated based on the effect estimates (relative risk, hazard ratio, or odds ratio [OR]) using the 95% confidence intervals (CIs) in individual studies. The pooled OR was also calculated using the random-effects models, which considered the underlying variations across included studies [21,22]. Then, the OR ratio (ROR) with a 95% CI was estimated on the basis of specific ORs, and 95% CIs were taken for T1DM and T2DM studies having risk of fractures [23]. Heterogeneity for each investigated outcome was also assessed using the I 2 and Q statistic, and significant heterogeneity was defined as I 2 > 50.0% or P < 0.10 [24,25]. Subgroup analyses for the differences of T1DM and T2DM with the risk of fractures were also assessed on the basis of the study design, and gender. Similarly, publication bias was evaluated as well using qualitative and quantitative methods, including funnel plots, Egger, and Begg tests [26,27]. The 2-sided inspection level for pooled results was adopted, and statistical significance was set at P < 0.05. Also, all the analyses in our study were performed using the STATA (version 10.0; STATA Corporation, College Station, TX, USA) software.

Literature search
A total of 9873 articles were identified from initial electronic searches, and 5621 articles were retained after

All fracture
The studies assessing the role of T1DM and T2DM in the risk of all fractures were reported in studies 4 and 12 studies, respectively (Fig. 2). We noted that both T1DM  (Table 3). Also, no significant publication bias to all fractures was observed (P-value for Egger: 0.075; P-value for Begg: 0.535; Additional file 1).

Hip fracture
The studies that reported the role of T1DM and T2DM in hip fracture risk were studies 9 and 19, respectively (Fig. 3) Table 2). Also, subgroup analyses found that a significant difference between T1DM and T2DM was associated with the risk of hip fracture in all subgroups (Table 3). In contrast, the Begg test did not find any significant publication bias for hip fracture (P = 0.856), while the Egger-test found significant publication bias (P < 0.001) (Additional file 1).

Distal forearm fracture
The studies that reported the role of T1DM and T2DM in distal forearm fracture risk were studies 2 and 9, respectively (Fig. 4). We noted that T1DM

Upper arm fracture
The studies that reported the role of T1DM and T2DM in upper arm fracture risk were studies 2 and 7, respectively (Fig. 5). A summary of the results indicated that T1DM    13:84 significant publication bias to upper arm fracture (P-value for Egger: 0.117; P-value for Begg: 0.837; Additional file 1).

Vertebrae fracture
The studies that reported the role of T1DM and T2DM in vertebrae fracture risk were studies 1 and 8, respectively (Fig. 7). We noted that T1DM was associated with an increased risk of vertebrae fracture (OR: 2.18; 95%CI 1.85-2.57; P < 0.001), whereas no significant association of T2DM in vertebrae fracture risk (OR: 1.45; 95%CI 0.82-2.56; P = 0.200) was observed. Also, no significant heterogeneity for the role of T2DM (I 2 = 98.5%; P < 0.001) was reported. Furthermore, the association between the risk of vertebrae fracture in T1DM and T2DM patients, respectively, was notstatistically significant (ROR: 1.50; 95%CI 0.83-2.72; P = 0.177; Table 2). Also, no significant publication bias existed in relation to vertebrae fracture (P-value for Egger: 0.267; P-value for Begg: 1.000; Additional file 1).  [51]. However, these studies focused on the risk of hip fracture between T1DM and T2DM patients, but did not compare the strength of T1DM and T2DM with the risk of fracture at various sites. Therefore, this study was conducted to update the knowledge about discrepancies in fracture risk between T1DM and T2DM patients. From this study, it was also found both T1DM and T2DM patients was associated with an increased risk of fractures at most sites. Moreover, the risk of all fractures, including fractures at the hip, upper arm, and ankle in T1DM patients was significantly higher than in T2DM patients. This observation proposes a potential role of T1DM in skeletal fragility, including deficits in bone mineral density, bone geometry, bone microarchitecture, and biomechanical properties [52][53][54]. Furthermore, the role of T2DM in the risk of fracture is proposed to be because of lower levels of bone turnover markers with reduced bone formation [55,56]. Additionally, patients with T1DM were associated with an increased risk of all fractures, hip, upper arm, and ankle fractures than those with T2DM. The potential reason for this observation is proposed to be that T2DM patients presented higher body weight and BMI than those with T1DM patients, while the fracture in T2DM patients was due to sustained higher traumatic load and soft-tissue energy absorption in obese patients [50]. Finally, the changes in body mineral density in T1DM and T2DM patients differed, which caused the observed varying fracture risk [51].
Subgroup analyses found significant differences that existed between T1DM and T2DM patients, resulting in the risk of all fractures, including hip fracture in most of the subgroups. The risk of all fractures between T1DM and T2DM patients were not also observed in the studies that focused on males and females. This observation is because of (1) the all-fracture risk between T1DM and T2DM that was balanced by fracture at other sites. Therefore, T1DM and T2DM did not affect the risk of distal forearm; (2) the imbalance characteristics between T1DM and T2DM patients, which affected the risk of fractures; and (3) the adjusted factors between T1DM and T2DM that differed, thereby affecting the risk of fracture.
The limitations of this study should be acknowledged. First, this study contained both prospective and retrospective cohort studies, and the selection or recall biases is proposed to be biases on the risk of fracture. Second, the difference between T1DM and T2DM associated with the risk of fractures at varied sites was based on indirect comparison evidence, and various adjusted factors resulted in the risk of fractures. Third, the role of T1DM in the risk of fracture was reported in a smaller number of included studies, and the power to detect potential differences affected the comparison results. Fourth, subgroup analyses were conducted based on study design and gender, but the differences based on other characteristics were not conducted. Fifth, the severity of DM was not addressed, which is proposed to play an important role in subsequent fracture risk. Finally, inherent limitations for meta-analysis of published articles, including inevitable publication bias and the restricted detailed analyses also posed a limitation to this study.

Conclusions
This study found that T1DM and T2DM induced excess risk of fractures at most sites. Moreover, T1DM patients were associated with an increased risk of all fractures, including fractures at the hip, upper arm, and ankle than T2DM patients. Further, large-scale prospective studies should thus be conducted to directly compare the differences between T1DM and T2DM patients with their risk of fracture at various sites.