To the best of our knowledge, this is a relatively large-sample study in a Chinese community with complete markers of bone metabolism and a large Chinese cross-sectional study that investigates the associations of T2DM and BMD, BTMs, and osteoporosis fracture in postmenopausal women. In our study, we found a negative correlation between FPG and BTMs and speculated that lower levels of P1NP and CTX may be associated with an increased fracture risk in patients with type 2 diabetes. We hypothesized that the underlying mechanism might be that hyperglycemia leads to bone marrow alterations and damaged differentiation potential, which changes bone metabolism, resulting in reduced bone turnover, poor bone quality, and ultimately fractures.
The effect of T2DM on BMD remains controversial, although fracture risk significantly increases in patients with T2DM. Epidemiological surveys show that in patients with type 1 diabetes, BMD is reduced, bone mass decreases and the incidence of osteoporosis ranges from 48–72%[20]. BMD is increased, decreased or unchanged for patients with T2DM. These results have been reported in both domestic and foreign literature. In our study, there was a significant increase in BMD in patients with type 2 diabetes, which was consistent with other studies[9, 21]. This further confirms that BMD may be an inappropriate tool for assessing the risk of bone loss and fracture in patients with type 2 diabetes. For patients with diabetes, T value greater than − 2.5 may be required as a cut-off value for osteoporosis diagnosis.
Recent studies have shown that osteoporosis fracture is one of the complications of diabetes in the skeletal system, but the specific mechanism is not clear[22, 23]. The higher incidence of fractures in the diabetic population may be associated with specific complications of diabetes, including peripheral neuropathy, impaired visual, postural hypotension, hypoglycemic attacks, and vascular disease. The deficiency of this article is that there is no additional detailed information about the specific types of fracture observed. Therefore, it is difficult to further clarify the causal relationship between diabetes and osteoporosis fractures.
BTMs are considered independent diagnostic and prognostic indicators or as a supplementary index to BMD for osteoporosis fractures. Previous studies of bone turnover markers in diabetes have been limited and controversial, but most scholars have agreed that BTMs might be an important link between bone metabolism and glucose metabolism. Wang J[14] analyzed three BTMs in the Chinese population. The levels of N-terminal osteocalcin (N-MID), type 1 collagen N-terminal peptide (PINP) and type 1 collagen carboxyl-terminal peptide (CTX) were significantly decreased in the T2DM groups compared to the controls (P < 0.01), revealing that BTMs are highly associated with T2DM, insulin sensitivity and beta cell function. Reyes-García R[24] showed lower levels of bone resorption markers and PTH-i compared with the levels of controls. The lower the bone metabolism is, the higher the incidence of fracture.
In our study, women with T2DM showed lower bone turnover compared with N-DM controls. These results also supported the above findings. Multiple regression analysis showed that both PINP and CTX were affected by fasting blood glucose. The higher the levels of FBG were, the lower the levels of PINP and CTX. This finding suggests that postmenopausal T2DM patients with increased FBG have decreased bone formation, bone resorption, and overall bone turnover. In this study, there was a lack of data on the course of diabetes, diabetes treatment plans, blood glucose control, glycosylated hemoglobin and other more accurate data. There are too many factors affecting FBG, which alone may be insufficient.
Advanced glycosylation end products (AGEs), stable cross-linking products, are formed by a series of nonenzymatic reactions between glucose and protein and are significantly increased in individuals with T2DM. AGEs affect attachment to the collagen matrix and interfere with the development of osteoblasts[25, 26]. AGEs may also decrease bone resorption by altering the structural integrity of matrix proteins and inhibiting osteoclastic differentiation. In postmenopausal T2DM patients with increased fasting glucose, both formation and bone resorption were decreased, and the level of overall bone transformation was decreased. RANKL is an agonist that regulates important aspects of osteoclasts, such as differentiation, fusion, survival, activation, and apoptosis[27]. Hyperglycemia has been shown to inhibit the above pathway mediated by RANKL and could induce low bone turnover[28]. Although there is no significant reduction in BMD in patients with T2DM, another factor that may contribute to the increase in fractures is microstructural abnormalities. Increased cortical porosity is a key determinant of bone fragility[29]. In a recent community study, T2DM and elevated fasting glucose levels resulted in unfavorable cortical microarchitecture at the distal tibial cortex[30]. This may indicate that the weakening of bone biomechanics is beyond the range of BMD measurements and that there may be significant microscopic contributors to osteoporosis fracture. Thus, BTMs may be a more sensitive alternative to BMD in assessing fracture risk in patients with diabetes.
Our study has some limitations. First, in our cross-sectional study, we only observed an association between BTMs and glucose metabolism, not a causal relationship. Further forward-looking and biomechanical studies are needed to confirm other potential associations. Second, FBG is only a temporary phenomenon, and there are too many factors influencing it. We need a more stable long-term indicator, such as glycosylated hemoglobin or glycosylated plasma protein, to further explore the relationship between blood glucose and bone metabolism. Third, a few subjects with diabetes may have T1DM as we could not distinguish between type 1 and type 2 diabetes. Fourth, we lack data on the relationship between BTMs and glucose metabolism in premenopausal women, which may be different from the population included in this study. According to previous data, the level of sex hormone can affect bone metabolism[15]. This means that we truly need to explore this issue further in different populations.
In conclusion, postmenopausal women with T2DM had lower levels of BTMs than controls, which reflected a lower bone turnover. Hyperglycemia in postmenopausal T2DM patients may affect bone metabolism by inhibiting osteoblast differentiation, promoting osteoblast apoptosis, and generating AGEs. The study suggested that actively controlling blood glucose may help maintain bone turnover balance and improve bone mass, thereby reducing the risk of fracture. The detection of BTMs in patients with type 2 diabetes can predict the risk of diabetes complicated with osteoporosis earlier than BMD, which is convenient for early intervention and treatment.