In the present study, the prevalence of osteoporosis, bone metabolism marker levels, and risk factors for developing low BMD were analyzed in healthy old male patients and those with T2DM for a relatively long diabetic duration (10.5 ± 6.1
y). Significant differences in the prevalence of low BMD and T score measurements at the lumbar spine and femur, risk of developing low BMD and fracture, bone formation and resorption markers, and other markers known to affect bone metabolism were observed between the two groups. Finally, BMD of total spine (L1–L4) and hip was positively correlated with BMI and negatively correlated with age, duration of diabetes, and 24
h urinary albumin.
Patients with type 1 diabetes (T1DM) often have lower BMD as compared with healthy subjects, likely as a result of insulin deficiency [10
]. However, conflicting studies regarding the association between osteoporosis and T2DM have been reported. Whereas some studies reported a higher prevalence of osteoporosis among individuals with T2DM [15
] even despite BMD [19
], others have observed no differences in BMD between T1DM, T2DM, and control subjects [19
]. Alternatively, another study reported that T2DM was a protective factor for osteoporosis [20
]. In the present study, the prevalence of low BMD was 59.4% and 24.0% in the T2DM and control groups, respectively, which was similar to that reported by Xia et al. [15
]. In addition, most T score and BMD measurements at the lumbar spine and femur in the T2DM group were significantly lower than observed in the control groups, even after adjusting for systolic blood pressure, cigarette smoking, and intake of daily dietary staple foods. This coincided with an increased incidence of osteopenia or osteoporosis in the T2DM group. Moreover, the risk of developing low bone mass for the T2DM patients analyzed was 4.583-fold higher than in the control group. These results suggest that T2DM itself may be a risk factor for low bone mass and are similar to those of Sta and Li-Yu [21
], who reported a prevalence of T2DM in subjects with osteoporosis of 22.4% compared to 19.1% in those with normal BMD. The conflicting results in patients with T2DM are likely due to the pathogenetic complexity of the condition [9
], including differences in the duration, severity, and treatment as well as different methods used to measure BMD [22
]. In addition, the investigated populations varied in age, BMI, gender, insulin levels, and duration of disease, which might also result in the contradictory results of previous studies [23
Although the relationship between osteoporosis and T2DM remains to be fully elucidated, patients with T1DM or T2DM are at greater risk of fractures due to decreased BMD [24
]. Interestingly, a high BMI is associated with increased BMD and has been shown to be a protective factor against the risk of osteoporosis and fracture in some studies [25
]. However, Xu et al. [14
] reported a positive correlation between weight as well as BMI with BMD in Chinese male patients with T2DM. The results of this study are in agreement with results of a meta-analysis that found that BMI as a predictor of BMD also holds true in patients with T2DM [28
]. In the present study, the risk of fracture for the T2DM group was 2.561-fold higher than that of the control subjects. Lower BMD and impaired bone formation may be caused by insulinopenia and hyperglycemia associated with T2DM [22
], which is consistent with the high levels of FPB, PBG, and HbA1
C and reduced T score and BMD observed in the T2DM group.
In the present study, the T score measured at the femoral neck showed the greatest difference between the two groups, which is similar to the Health ABC Study that reported an association between T2DM and rapid bone loss at the femoral neck [29
]. The femoral neck may be more vulnerable to the metabolic alterations characteristic of T2DM, as cortical and cancellous bone may be differently affected by insulin, glucose, BMI, sex steroids, and parathyroid hormone [18
The present study assessed the BMD of both the hip and spine (L1–L4). Although the reference site is traditionally the hip, combining the BMD results at more than one region from a single scan significantly increases fracture risk prediction [30
]. Moreover, osteoporotic vertebral fractures may be accompanied with osteopenia or even normal peripheral BMD in some cases, possibly because trabecular bone in the spine has a higher turn-over rate than cortical bone in the periphery [31
Although osteoporosis is asymptomatic until fracture, fractures are often undetectable and misdiagnosed, and few studies have assessed the related symptoms of osteoporosis. The duration of arthralgia and age of first fracture were similar between groups in the present study; however, the T2DM group had a significantly longer duration of lumbago and back pain, which might be due to the high incidence of osteopenia and osteoporosis. Because patients with diabetes are less sensitive to pain due to diabetic neuropathy, the pain associated with osteoporosis and the duration of arthralgia maybe more significant in this population. In Rasul et al. work [32
], old male patients with diabetes and polyneuropathy experienced higher bone turnover than those without polyneuropathy, suggesting that prevention or treatment of polyneuropathy might reduce osteoporosis and fracture in T2DM.
Although BMD as measured by DEXA is the best predictive and prognostic measure of osteoporosis, a comprehensive risk assessment for osteoporosis beyond BMD measurements should be undertaken in patients with diabetes [33
]. Analysis of bone metabolism markers along with BMD is considered to improve fracture prediction, particularly those associated with bone turnover [34
], which has the added advantage of independently revealing fracture risk [30
]. Diabetic osteopenia is characterized by low bone turnover, resulting from osteoblast deficiency and subsequent reduced bone formation accompanied by normal bone resorption [22
]. In addition, the systemic changes associated with diabetes, including inflammation, advanced glycation end-product accumulation, and reactive oxygen species generation, may also affect bone remodeling [19
]. In this study, both the markers of bone formation and resorption were significantly lower in the T2DM, which is indicative of low-bone-turn-over osteoporosis. These results also suggest that T2DM can affect bone resorption.
The proposed reasons for diabetes-associated bone loss include calcium, phosphorus, magnesium, and trace element deficiency originating from poor blood glucose control, hypoinsulinemia, and chronic complication of diabetes [38
]. Since, in this study, the patients with T2DM had generally well-controlled disease, the influence of poorly-controlled T2DM on bone health could not be determined. However, previous studies have reported conflicting results regarding the influence of glycemic control on BMD [40
]. In addition, a recent study suggested that T2DM and osteoporosis were etiologically related through the actions of osteocalcin and adiponectin [42
]. In the present study, significantly increased PTH and calcitonin and decreased serum calcium levels were observed in the T2DM group, which was similar to those in Inzerillo and Epstein [39
]. However, the clinical significance of these differences remains to be determined as all were within the normal range.
Osteoporosis in men is often due to secondary causes in addition to advancing age, including hypogonadism, smoking, chronic obstructive pulmonary disease, glucocorticoid therapy, and androgen deprivation therapy for prostate cancer, and alcohol abuse [3
]. Meier et al. [43
] reported that testosterone levels could also predict risk of fracture. In the present study, the testosterone levels of both groups were within the normal range. Because bone loss accelerates after the age of 70 years, and rapid bone loss is more common with deficient testosterone levels [44
], differences in the age of the study population may account for the differential effects of testosterone levels. In addition to testosterone, serum levels of 25-hydroxyvitamin D3
mmol/L) were associated with an increased risk of hip fracture in men and women older than 65 years [45
]. However, no differences in 25-hydroxyvitamin D3
levels were observed between the groups in our study, which is similar to a previous report [42
], and suggests that altered 25-hydroxyvitamin D3
levels are not a major reason for bone loss.
IGF-1 can also stimulate osteoblast growth and the formation of bone matrix [46
]. In men, trabecular bone loss is associated with changes in IGF-1 signaling [47
]. Furthermore, high blood glucose level can inhibit the synthesis and release of IGF-1 [48
]. IGF-1 levels were significantly lower in the T2DM group analyzed in the present study. However, its predictive value has yet to be determined.
Many lifestyle factors can influence bone metabolism, and the negative effects of smoking, lower calcium consumption, and physical inactivity on osteoporosis have been reported [49
]. However, Anaforoglu et al. [23
] reported no such effects. In the present study, there were fewer smokers and alcohol drinkers in the T2DM group; this group also consumed less daily dietary staple food and more individuals were physically active although no difference in duration of being physically active was observed.
BMD of hip and total spine (L1–L4) was positively correlated with duration of physically active and BMI, indicating a protective effect of BMI, which is similar to a previous study [20
]. BMD of total hip was also positively correlated with waist-to-hip ratio and negatively associated with TC and LDL-C. The reasons for these associations remain unclear and require further analysis.
The present study has limitations. The sample size was relatively small, particularly in the T2DM group due to the strict inclusion and exclusion criteria. Further large-scale, prospective studies to assess diabetes-associated changes in BMD and its determinants are needed.
In conclusion, in old male patients with T2DM, altered bone formation and resorption may result in their increased risk of low BMD and subsequent low-bone-turn-over osteoporosis. Assessing of the markers of bone metabolism along with BMD and patient and lifestyle characteristics may help determine bone status in this population and contribute to the prevention and intervention of osteoporosis.