In the present cross-sectional study that included 1500 patients aged ≥ 18 years old with T2DM, the serum osteocalcin level was significantly higher in women aged ༞50 years old compared with women aged ≤ 50 years old. However, this was lower in men aged ༞50 years old compared with men ≤ 50 years old. The circulating levels of osteocalcin were negatively associated with FBG and HbA1C in women and men aged ≤ 50 years, positively associated with fasting insulin levels in men aged ≤ 50 years old and women aged ༞50 years old, and negatively related to TG levels only in men aged ≤ 50 years old. In the binary logistic regression analysis, we suggested that serum osteocalcin levels were associated with multiple cardiovascular risk factors according to age and sex, including overweight/obesity, high HbA1C, high FBG, high TG, MetS, and LDL-C, after adjusting for potential confounding variables.
Osteocalcin is a marker of bone turnover, and its circulating concentration changes according to bone turnover rate with aging(19). In our present study, the serum levels of osteocalcin changed with age in men and women, but there were some differences, as follows. Serum osteocalcin levels were inversely correlated with age in men (r = -0.142, p < 0.0001) but positively correlated with age in women (r = 0.279, p < 0.0001, data not shown). Furthermore, the average levels of serum osteocalcin were significantly higher in men than in women. By contrast, the serum osteocalcin levels were significantly lower in women aged ≤ 50 years old than in men aged ≤ 50 years old, but these were higher in women aged ༞50 years old than in men aged ༞50 years old. Thus, consistent with previous observations, variables in bone turnover rate lead to age- and sex-specific differences in circulating osteocalcin concentration(14, 20).
Considering the influence of bone metabolism on glucose homeostasis, it could be speculated that serum osteocalcin is associated with glucose metabolism(7, 21). Some recent studies suggested that serum osteocalcin levels are associated with glucose metabolism markers, but the results were inconsistent(22, 23). In the present study, there were significant associations between circulating concentrations of osteocalcin and glucose control in men and women. The data revealed that serum osteocalcin levels are negatively associated with HbA1c and FBG and positively related to serum insulin levels. However, other clinical studies have shown that no associations exist between circulating osteocalcin and markers of glucose metabolism(23, 24). In most previous studies that explored the association between osteocalcin and glucose metabolism, the investigations were conducted in a specific group, such as older men or postmenopausal women(25). The difference in bone turnover rates among specific individuals may affect the association between circulating osteocalcin and glucose homeostasis.
A negative correlation was found between serum osteocalcin levels and BMI and the prevalence of being overweight/obese only in men aged ༞50 years old, in accordance with previous studies, but these associations disappeared in women aged ༞50 years old whose bone turnover rate increased and serum osteocalcin levels markedly elevated(16, 26). Bone formation and resorption occur continuously throughout life, and the bone turnover rate varies according to age and sex. In women, this rate is maintained at a relatively stable level (low level) until menopause. Then, it dramatically increases with increased bone loss(27). However, the pattern is obviously different in men. Bone turnover rate increases at 20 years old to build a peak bone mass and declines slightly after 50 years in men. Thereafter, the serum osteocalcin concentration remains at a stable level in older men(28). Thus, the serum osteocalcin level in men does not show dramatic changes in old age as in women aged 50 years old.
Previous study suggested that no relationship exists between osteocalcin and lipid metabolism in T2D(29). In the present study, the serum osteocalcin levels showed a negative correlation with high TG and low HDL-C risk in men aged ≤ 50 years old after adjusting for the other variables. In addition, serum osteocalcin levels showed a negative correlation with MetS risk only in men aged ≤ 50 years old. However, these associations disappeared in women and men aged ༞50 years old. The significant relationship between serum osteocalcin levels and dyslipidemia and MetS risk in men aged ≤ 50 years old is a finding that differs from the results of previous studies(25). The results confirmed the influence of serum osteocalcin on lipid metabolism through a sex-specific approach. Given these discrepant findings, we can speculate that the serum osteocalcin level in postmenopausal women is more influenced by bone turnover rate than other factors(25). This finding should be considered when evaluating the association of serum osteocalcin and lipid metabolism.
Bone is an endocrine organ that can affect multiple physiological processes through the secretion of hormones(30). Accumulating evidence supports the idea that osteocalcin has a protective role in cardiometabolic health, and a decrease in serum osteocalcin contributes to the development of cardiometabolic diseases, partly through its involvement in glucose and lipid homeostasis(31, 32). Decreased osteocalcin levels are associated with impaired glucose and lipid metabolism(33, 34). Furthermore, the present study suggested that lower serum osteocalcin levels were significantly associated with high cardiometabolic risk status in individuals aged ≤ 50 years old regardless of sex. Thus, serum osteocalcin levels were associated with glucose and lipid homeostasis, and cardiometabolic risk should be interpreted according to age and sex. Recent research suggested the presence of a complex crosstalk between bone and other metabolic and cardiovascular tissues(6, 35). However, the potential mechanism of pathophysiological underlying serum osteocalcin’s effect on cardiometabolic health should be further explored in the future.