This cross-sectional study was conducted to clarify the relationship between fibrinogen and total BMD by performing multivariate linear regression analysis on NHANES data from 1999 to 2002. Our study primarily showed that fibrinogen levels were negatively associated with total BMD in most postmenopausal women aged 50 years and older. However, this association varies by race. To the best of our knowledge, the relationship between fibrinogen and total BMD in postmenopausal women is still poorly studied and the mechanism of the negative association is unclear.

Chronic inflammation has been identified as a predisposing factor for progressive bone loss [8, 9]. People with significantly higher levels of inflammatory cytokines than healthy individuals are more prone to osteoporosis, and accumulation of inflammatory cytokines can mediate oxidative stress injury, promote osteoclast proliferation, and increase bone resorption, leading to osteoporosis [10, 11]. Inflammation is usually accompanied by elevated levels of pro-inflammatory mediators such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6) and their markers, reflecting destructive and degenerative processes in tissues [12]. These peripheral blood biomarkers, have been used to monitor disease states and assess treatment outcomes [13]. It is becoming clear that fibrinogen appears to be one of the predisposing factors for low-grade chronic inflammation. In addition to the role of fibrin in coagulation, excessive deposition of fibrin in the tissue matrix can lead to increased local inflammation. In an experimental animal study, it was found that severe osteoporosis, which is fibrinogen-dependent, disorders of bone remodeling units with fibrinogen-mediated osteoclast activation occurred in mice defective in the fibrinogen gene [14]. However, a study by Cole et al. [7] found impaired fibrinolysis due to fibrinogen deficiency, leading to persistent fibrin deposition, resulting in premature skeletal aging and growth retardation. Increased fibrinogen promotes osteoclast activation, and fibrinogen regulates actin organization through its effects on osteoclast morphology; it not only increases actin organization and enhances bone resorption, but also promotes the formation of M-CSF and RANKL-induced bone resorption, and it alone induces bone resorption in vitro [15]. Thus, maintenance and development of the skeletal vascular system require adequate fibrinolytic activity to prevent premature skeletal aging and developmental retardation. Past studies have typically explored the effects of estrogen or inflammation on bone density alone, and there is no evidence that estrogen may contribute to osteoporosis by affecting inflammation levels [16]. Postmenopausal women will experience an increase in inflammatory cytokines due to a decrease in estrogen, which will cause excessive osteoclast production and bone resorption [17, 18]. Our study suggests that fibrinogen is negatively associated with total BMD. Fibrinogen deposition may increase the risk of bone loss by promoting chronic inflammation providing a new direction for research on the mechanisms of osteoporosis.

Interestingly, relatively high levels of fibrinogen have been found to be associated with lower BMD only in Non-Hispanic White and Mexican American postmenopausal women. This may be related to dietary habits and body fat distribution in different races, especially ectopic and visceral fat [9]. Some experimental animal studies have found that high-fat diet-induced obesity increases the deleterious effects of estrogen deficiency on bone in a mouse model of postmenopausal women, and that obesity and estrogen deficiency may affect inflammation levels leading to increased bone fragility [19]. The higher fat intake in the modern diet has led to a higher proportion of polyunsaturated fatty acids (PUFA), resulting in low-grade chronic inflammation (LGCI), which promotes the development of many chronic diseases, including obesity and osteoporosis [20]. Therefore, osteoporosis is also considered to be a chronic inflammatory disease [21]. Fibrinogen has rarely been used as a predictor of changes in bone mineral density. In previous studies, evidence for a direct correlation between fibrinogen and total BMD is very limited. Therefore, we conducted this study. In the present study we found a negative correlation between fibrinogen and total BMD. If serum fibrinogen concentration is used as a routine indicator in clinical investigations, it would be clinically relevant for most patients to assess the risk of reduced bone mineral density based on these findings.

However, there are some shortcomings in our study. First, because the present study was a cross-sectional study, it was difficult to determine whether there was a causal relationship between fibrinogen and bone mineral density. Second, other confounding factors not included in the present study may also lead to bias. Therefore, we need to conduct a longitudinal study with a large sample to determine the relationship between fibrinogen and bone mineral density in postmenopausal women (Fig. 1, 2, 3).

The association between fibrinogen and total BMD. Each black dot represents a sample. Age, race, dietary intake within 24 h (protein, fat and dietary fiber), body mass index, poverty to income ratio, total cholesterol, total protein, blood urea nitrogen, phosphorus, and serum calcium were adjusted. The red curve is a smooth curve fitting to the scatter diagram, representing the relationship between total BMD and fibrinogen level

The association between fibrinogen and total BMD. The solid arcs indicate the smoothed curve fit between the variables. The blue bars represent the fitted 95% confidence intervals. Age, race, dietary intake within 24 h (protein, fat and dietary fiber), body mass index, poverty to income ratio, total cholesterol, total protein, blood urea nitrogen, phosphorus, and serum calcium were adjusted

The association between fibrinogen and total BMD stratified by race. Age, dietary intake within 24 h (protein, fat and dietary fiber), body mass index, poverty to income ratio, total cholesterol, total protein, blood urea nitrogen, phosphorus, and serum calcium were adjusted