While the current published literature demonstrates significant association between the serum sclerostin and CTRP3 with osteosclerosis, little is known about the additional impact of T2DM on these biomarkers. In our study, we demonstrated that the presence of T2DM in osteoporotic/osteopenic women led to further reduction in the serum CTRP3 than the presence of osteoporosis again. The serum CTRP3 was negatively correlated with higher degrees of osteoporosis/osteopenia- as indicated by BMD- as well as markers of insulin resistance and glycemic control. On the other hand, serum sclerostin exhibited further upregulation in patients with combined T2DM and osteoporosis/osteopenia than osteoporosis/osteopenia only; the biomarker was positively correlated with higher degrees of osteoporosis- as indicated by BMD- as well as markers of insulin resistance and glycemic control. The multivariate regression analysis demonstrated that serum CTRP3 and sclerostin were independent predictors of T2DM in women with osteoporosis/osteopenia.
CTRP3, a member of adipocytokines-related family, is a critical regulator of many cellular processes that mediate metabolism, development, and inflammation. A cumulative body of evidence indicated that dysregulation of serum CTRP3 levels is a constant feature of many metabolic disorders, including diabetes and obesity (20–22). Recently, an emerging evidence highlighted a significant role of serum CTRP3 in regulation of bone hemostasis; the role of CTRP3 in regulation of bone structure appears to stem from its ability to maintain normal turnover of chondrocytes and cartilaginous structure through regulation of ERK1/2 and PI3K pathways (27,28). Thus, authors has linked downregulation of serum CTRP3 to defective bone metabolism and features of osteoporosis (29). On the other hand, the association between CTRP3 and T2DM is well-established with reported decline in serum CTRP3 levels among cases with insulin resistance and poor glycemic control(24). Therefore, we hypothesized that serum CTRP3 can be used as a biomarker for detection of early osteoporosis in patients with T2DM patients. Our analysis demonstrated that the serum CTRP3 exhibited higher decline in the setting of combined T2DM and osteoporosis than osteoporosis alone. The serum CTRP3 was independent predictors of T2DM in women with osteoporosis and correlated significantly with metabolic parameters. To our knowledge, this is the first report that addressed the impact of T2DM on serum CTRP3 among women with osteoporosis. Nonetheless, the association between serum CTRP3 and osteoporosis or T2DM alone were reported previously. For example, Xu and colleagues (25) reported significant decline in serum CTRP3 among postmenopausal women with osteoporosis. Other reports showed significant decline in serum CTRP3 among patients with T2DM and diabetic nephropathy (30,31).
Sclerostin is usually secreted by osteocytes and late osteoblasts to mediate physiological bone metabolism (10). The changes in the levels of circulating sclerostin may reflect the changes in bone activity, making it a biomarker for the diagnosis and prognosis of osteoporosis (11). On the other hand, previous animal models demonstrated high expression of sclerostin gene, SOST, in the setting of T2DM(32). Thus, it is logical to assume higher degree of dysregulated levels of sclerostin in patients with combined T2DM and osteoporosis. We found that serum sclerostin was higher in patients with combined T2DM and osteoporosis than osteoporosis only; the biomarker was positively correlated with higher degrees of osteoporosis- as indicated by BMD- as well as markers of insulin resistance and glycemic control. Similar to our findings, Wang and colleagues(33) showed that the combination of T2DM and osteoporosis led to higher increase in serum sclerostin than osteoporosis alone; moreover, serum sclerostin correlated with BMD parameters, HbA1c, and serum glucose level. Likewise, García-Martín and colleagues(34) found positive correlation between with higher severity of osteoporosis, HOMA-IR, and serum insulin.
Despite the novelty of the present study, we acknowledge the presence of some methodological limitations. The cross-sectional nature of the present study limits the validity of the observed associations and further long-term studies are still needed to confirm the sequential role of T2DM on osteoporosis biomarkers. In addition, the lack of pre-planned samples size calculation and being a single-center experience are additional limitations of the present study.
In conclusion, the present study provides a novel evidence about the impact of T2DM on osteoporosis biomarkers, serum CTRP3 and sclerostin. The results indicated that women with combined T2DM and osteoporosis/osteopenia exhibited more dysregulation in both biomarkers than women with osteoporosis/osteopenia. alone. Thus, serum CTRP3 and sclerostin can be used as biomarkers for early detection of osteoporosis in diabetic patients. Further experiments are warranted to confirm our findings and to understand the mechanistic processes behind the additional impact of T2DM on the osteoporosis biomarkers. In addition, further investigations about the link between adipose tissue and bone hemostasis are recommended.