Investigating the risk of bone fractures in elderly patients with type 2 diabetes mellitus: a retrospective study

Background Elderly patients with type 2 diabetes mellitus (T2DM) experience fractures more frequently than elderly individuals without diabetes. Fractures requiring hospitalization greatly affect quality of life, and although elderly patients with T2DM have several risk factors associated with fractures, only a few studies have evaluated these in detail in the Asian population. We conducted a retrospective study of elderly patients with T2DM for evaluating factors associated with fracture risk. Methods We conducted a retrospective study using electronic medical records (EMR) of patients aged ≥65 years with T2DM who were admitted to a public general medical institute in central Tokyo, Japan. We evaluated factors associated with fractures necessitating hospitalization in elderly patients with T2DM characteristics and hypoglycemic agent use. Factors associated with fracture risk were identified using multivariable logistic regression analysis. Results A total of 2,112 elderly patients (age ≥ 65 years) with T2DM were analyzed. Among them, 69 (3.3%) patients had been hospitalized for fractures. Factors associated with fractures were female sex (OR, 3.46), eGFR < 60 ml / min / 1.73 m2 (OR, 0.55), and thiazolidine use (OR, 4.28). Further, a separate analysis based on sex revealed that the use of thiazolidines was significantly associated with fracture risk in both sexes. Conclusions In elderly patients with T2DM, the key factor associated with fractures was the use of thiazolidines in both males and females. In this study, the use of thiazolidines was newly identified as a factor which increased the risk of fractures requiring hospitalization in elderly males. The study findings should be considered when hypoglycemic agents are selected for treating elderly patients with T2DM. Information bias, selection bias, and the effect of concomitant drugs may be the underlying reasons for why eGFR < 60 mL / min / 1.73 m2 reduced the fracture risk. However, details are unknown, and additional investigations are needed.


Background
The worldwide prevalence of diabetes has been on the rise, and Japan ranks among the top 10 countries in terms of the number of elderly patients with diabetes. Moreover, the increasing proportion of the elderly in Japan includes the diabetic population. Decreased bone mass and pathological aging put elderly patients at risk for bone fractures, which reportedly negatively affect activities of daily living (ADLs); in challenging and serious cases, such fractures increase the risk of mortality [1][2][3]. A study on patients aged ≥55 years who were hospitalized for fractures demonstrated that 7.4% of the patients were discharged with medical care services and 53.2% were transferred to another medical facility [4]. Thus, fractures requiring hospitalization for elderly patients have a significant effect on their quality of life (QOL). Patients with type 2 diabetes mellitus (T2DM) are at a higher risk of bone fractures than individuals without diabetes, regardless of bone density [5,6].
In Japan, the frequently used hypoglycemic agents comprise seven oral drugs and two injectable drugs, acting via nine different mechanisms. Among these agents, the only family of agents that has a clear correlation with risk of fractures is the thiazolidine (TZD) family, which has been found to increase the risk of bone fractures in females [7][8][9][10]. Although reports have also implicated other types of drugs in the occurrence of bone fractures [10], no consensus has been reached. Elderly patients with T2DM have various risk factors associated with fractures, but few studies have evaluated these in detail in the Asian population. The aim of the present study was to investigate the relationship between patient background, hypoglycemic agents, and risk factors in elderly patients with T2DM in Japan.

Subjects
We conducted a retrospective study using electronic medical records (EMR) of patients aged ≥65 years with T2DM mellitus who were admitted to Tokyo Saiseikai Central Hospital, which is a public general medical institute in central Tokyo, Japan. Data from January 2014 to January 2016 were used for analyses.
The inclusion criteria were (1) age ≥ 65 years, (2) a diagnosis of T2DM (ICD-10 code E11) or diabetes (ICD-10 code E14), and (3) inpatient status. The exclusion criteria were (1) a diagnosis of type 1 diabetes or no diagnosis of diabetes, (2) age < 65 years, (3) outpatient status, or (4) hospitalized ≥2 times within the study period. Data regarding patient characteristics and medicines used were recorded on the first day of hospitalization.
On the basis of the blood glucose target levels recommended by the Japanese Diabetes guidelines for patients with diabetes, the cutoff value for HbA1c was < 7.0 and that for BMI was < 25 kg/m 2 .

Statistical analysis
Patient characteristics were tabulated as mean values plus or minus the standard deviation. Continuous variables were analyzed using unpaired t-test. Nominal variables were compared using χ 2 test. Logistic regression was used for identifying which factors affect the incidence of fractures, using fractures necessitating hospitalization as the target variable. Univariate analysis was performed using explanatory variables including patient characteristics, hypoglycemic agent usage, and dosing of SU, glinides, BG, TZD, αGI, SGLT2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonist, and insulin. Explanatory variables with a significance of p < 0.2 were extracted using univariate analysis, and odds ratios (ORs) [at 95% confidence interval (CI)] were calculated using multivariate analysis. Because bone fracture incidence differs between males and females [11], the patients were separately analyzed on the basis of sex using the same method as described above for each subgroup. All statistical analyses were performed using the software Stata version 10 (stata corp, TX USA), and the statistical significance threshold was set at < 5%.
Ethics approval: This study was conducted in accordance with ethical guidelines for medical and health research involving human subjects. The ethics board of the Tokyo Saiseikai Central Hospital approved the study (control number, 27-51).

Discussion
The present study found that female sex and TZD use are significant risk factors for bone fractures requiring hospitalization, and that an eGFR of < 60 mL / min / 1.73 m 2 is associated with reduced fracture risk. Separate analysis of male and female patient characteristics revealed that TZD use is a risk factor for both sexes.
When estrogen levels decrease at menopause (at approximately 50 years of age), there is a significant accompanying decrease in bone mass, which progresses toward bone loss and osteoporosis [12]. Because the mean age of the females in the present study was 78.1 ± 7.6 years, and because 64.4% of the patients were aged ≥75 years, it was assumed that many of the females had gone through menopause approximately 20 years ago, and that their risk of bone fractures (relative to males) had increased via the same mechanism as in non-diabetic patients.
In the present study, an eGFR < 60 mL / min / 1.73 m 2 was associated with a decreased risk of fractures and an OR of 0.55. Although chronic kidney disease (CKD) can cause bone fragility independent of other factors, the risk of bone fractures reportedly further increased with disease progression as a result of renal osteodystrophy caused by secondary hyperparathyroidism [13]. However, whether decreased kidney function increases the risk of bone fractures remains to be clarified; some researchers have reported that it does [14,15], while others have reported that it does not [16,17]. Administering activated vitamin D3 and calcium carbonate to patients with secondary hyperparathyroidism induced by decreased renal

inhibitors), TZD (thiazolidines), αGI (α-glucosidase inhibitors), BG (biguanides), SU (sulfonylureas), DPP-4 inhibitors (dipeptidyl peptidase 4 inhibitors), GLP-1 receptor agonist (glucagon-like peptide-1 receptor agonist)
function may reduce the risk of fractures, and further investigation of the effects is warranted. In terms of the relationship between glycemic control state and bone fracture risk, the risk of bone fractures reportedly increase with higher HbA1c levels [18]. Although HbA1c level was stratified and analyzed in this study, a significant reduction in fracture risk was not observed. Because bone turnover markers improve in the short term by controlling blood sugar [19], fracture risk may be correlated with the state of glycemic control. However, the ACCORD BONE ancillary study found that the risk of fractures was not improved in an intensive glycemic control group [20]. Therefore, good glycemic control in the short term may not be sufficient for reducing the risk of fractures. However, there was insufficient data in the present study to show the effect of glycemic control on fracture risk over a fixed duration, because only the HbA1c value targeted for investigation were used and no subsequent observations were made.
Odds ratios obtained in the present study suggest that TZD use significantly increases the odds of fractures in males (OR, 4.70), females (OR, 4.71), and overall (OR, 4.28). The relationship between T2DM use and the risk of fractures is complex, because the risk of fractures is not only affected by complications and patient characteristics, but also by treatments used in glucose level management. Several studies have reported that TZD use increases the risk of fractures in females, especially in postmenopausal females [21,22]. This provides an explanation for why the rate of TZD use was significantly lower in females than in males. The use of TZD reportedly increases the risk of fracture in males aged ≥50 years with type 2 diabetes [23]. Because the study population involved patients aged ≥65 years, it can be concluded that use of TZD increased the risk of fracture. After 2011, when administration of the TZD pioglitazone was reportedly associated with bladder cancer [24], treatments with TZD were initiated with proper care. Therefore, many of the subjects in the present study were administered TZDs before 2011, and the increased OR in males may have resulted from the long-term TZD administration and because TZDs tend to be administered to patients with a prolonged history of morbidity.
Our study had several important limitations. First, it was a retrospective study conducted at a single      institution and using electronic medical records (EHR); therefore, information and selection biases that may have affected results could not be eliminated. Second, patients with bone fractures who did not require hospitalization were excluded; thus, the study population may have been biased toward more severe cases being selected. Third, because TZDs promote weight gain, they were more likely to be administered (in light of their obesogenic properties) to non-overweight, low-BMI patients already at risk of fractures, which may have influenced the increased fracture risk associated with TZD use. Fourth, as this was a cross-sectional study, it was not possible to examine the effect of the length of administration period of diabetes drugs on fracture risk. Finally, because this study did not use data collected for research purposes, it lacks data regarding renal function, such as albuminuria, and information regarding Vitamin D3 and calcium preparations used for advanced renal dysfunction. Therefore, a detailed study stratifying kidney function could not be conducted.

Conclusions
In elderly patients with T2DM, the key factor associated with fractures was TZD use in both males and females. The present study also showed that TZD use increases risk of bone fractures necessitating hospitalization in males. These results may need to be considered while selecting hypoglycemic agents for treating elderly patients with T2DM. Information bias, selection bias, and the effect of concomitant drugs may be the underlying reasons for why eGFR < 60 mL / min / 1.73 m 2 reduced the fracture risk. However, details are unknown, and additional investigations are needed.