Characteristics of Bone Metabolism in Postmenopausal Women With Newly Diagnosed Type 2 Diabetes Mellitus

Huijuan Li; Yuhua Wen; Peipei Liu; Liya Zhang; Xiaoya Zhang; Yichen Liu; Bin Ma; Haidong Kuang; Jianxin Wang; Lige Song


Clin Endocrinol. 2021;95(3):430-438. 

In This Article


Our results confirmed that T2DM individuals had higher areal BMD and decreased bone formation even when they were diagnosed as T2DM for the first time which excluded the interference of diabetic duration and anti-diabetic drugs. Low bone turnover has been found as the feature of bone metabolism in T2DM patients.[7] But, in this study, we found bone resorption markers remained at the same level in the newly diagnosed T2DM group which meant decreased bone formation could be the primary pathophysiology during the early stage of T2DM.

Consistent with most previous studies,[8,9] we found lower levels of P1NP and OC in T2DM. In contrast, both ALP and BALP were found to be relatively higher in T2DM. A former study that enrolled twenty patients diagnosed with T2DM found out a higher level of ALP in T2DM, and it had a positive association with diabetes mellitus duration.[22] BALP is the bone-derived isoform synthesized by osteoblast in the early period of differentiation. A former study revealed that the level of BALP was increased in T2DM compared with healthy controls although the difference was not statistically significant.[23] As for bone resorption status, both TRACP-5b and CTX had no significant differences between postmenopausal women with T2DM and non-diabetic patients, according to our results. A cross-sectional study enrolled 237 type 2 diabetic postmenopausal women, and 93 healthy controls also showed no difference of CTX between the two groups.[9] And, a previous study confirmed that PTH was lower in the T2DM group.[13]

According to an in vitro study, chronic hyperglycaemia could have a direct inhibitory effect on osteoblast function through modulating gene expression in type 1 diabetic mice, and the level of OC was also found to be decreased.[24] And the accumulation of advanced glycosylation end-products (AGEs) caused by increased glucose exposure in T2DM could potentially interfere with osteoblast differentiation[25] and thus decreased the level of P1NP.[26] High glucose-induced reactive oxygen species (ROS) production could also suppress the expression level of OC in primary osteoblasts.[27] And the result from some observational studies showed that HbA1C was inversely correlated with OC.[11] Meanwhile, OC plays a vital role in both glucose and bone metabolism. Uncarboxylated osteocalcin released from bone matrix to peripheral blood circulation can bind to its receptor in pancreatic β-cells and therefore induce cell proliferation and increase the synthesis and secretion of insulin[28] helping maintain normal glucose metabolism. And the impaired glucose metabolism may in turn suppress the level of OC. After adjusting for other potential factors, HbA1c was inversely correlated with OC in both T2DM group and control group.

Alkaline phosphatase activity in osteoblast was increased under high ROS condition induced by high glucose.[27] A previous study using mouse osteoblasts demonstrated that the expression of BALP was increased under chronic hyperglycaemia while the expression of OC was decreased.[24] In contrast to BALP, OC is expressed in the late period of differentiation. A clinical study from Japanese also figured out that the serum OC/BALP ratio was negatively correlated with HbA1c in male patients with T2DM.[29] And another case-control study further confirmed that OC/BALP ratio was decreased in T2DM cases.[23] Therefore, prolonged hyperglycaemia can bring harm to osteoblastic maturation, bone formation and mineralization eventually. The low bone formation and high mineralization may suggest that the bone becomes hypermineralized in patients with T2DM, which can explain the paradox of high BMD but low bone strength.[30]

Diabetes-enhanced inflammation such as higher level of IL-17 can promote bone resorption.[31] And in T2DM rodent models including TallyHo mice and Zucker Diabetic Fatty rats, bone resorption level mostly appears to be elevated, as evidenced by increased serum CTX, TRACP and osteoclasts histological numbers.[32] However, clinical studies had different results. The resorption markers of T2DM were found to be lower,[8,10] higher[12,13] or no difference.[9] These conflicting results may due to the different genetic background, diabetic duration and metabolic status between patients from various studies. Although in this study, patients with newly diagnosed T2DM showed normal bone resorption level, the effects of diabetes on bone might have already appeared and gradually developed as the disease progressed.

High concentrations of glucose can directly suppress the secretion of PTH from cultured bovine parathyroid cells.[33] And PTH secretion was significantly inhibited when human parathyroid cells were incubated with AGEs for 48 hours.[34] In response to vitamin D deficiency, the PTH secretion was reported to be significantly attenuated in patients with T2DM.[35] Postmenopausal women with T2DM had lower PTH levels, although both Ca and P levels were not significantly different from their controls and kept in the normal range in our study. In addition to glucose level, we suspect that other endocrine changes occurring in T2DM may also have pathophysiological effects on PTH secretion requiring more investigations. Also, the decreased PTH level may be one of the important reasons leading to the reduction in bone turnover in patients with T2DM.

The present study has some strengths. We select patients with newly diagnosed T2DM. Those patients have a shorter duration of T2DM and usually have no diabetic complications. Therefore, the interference of anti-diabetic drug, diabetic duration and complication can be avoided. Besides, our testing covers almost all bone turnover markers, including TRACP-5b and BALP which may be ignored in previous studies. However, it still has some limitations. First, it is a cross-sectional study, so the cause-and-effect relationships cannot be fully established. Further prospective research focussing on the same topic is warranted. Second, our study lacks the detection of AGE level. Hence, we are unable to evaluate the effect of AGE on bone metabolism directly. Third, we did not measure the blood concentration of uncarboxylated OC, so we could not further analyse the relationship between glucose metabolism and OC.

In conclusion, bone turnover in T2DM can be affected by metabolic and endocrine alterations in diabetes. Patients with T2DM may have a lower level of bone formation and impaired osteoblastic maturation, which may be mainly attributed by hyperglycaemia. Postmenopausal women diagnosed as T2DM for the first time are at risk of abnormal bone metabolism, which needs more attention. Furthermore, physicians should intervene early to avoid diabetic osteoporosis and fragile fractures.