CHD is caused by the insufficient blood supply to the heart due to coronary atherosclerosis, which seriously endangers human health. With increasing age, a series of changes occur in the human body. Previous epidemiological studies have shown a significant relationship between CHD and osteoporosis, and the “bone-vascular axis” concept has further deepened their relationship(6). The physiological and pathological changes of bone and blood vessels are inseparable. Marcovitz et al. (7)reported the correlation between coronary artery stenosis and BMD for the first time and adopted dichotomy with coronary artery stenosis ≥ 50% as the grouping standard. The BMD of the group with coronary artery stenosis ≥ 50% was significantly lower than that of those with <50% stenosis. Subsequently, more scholars were involved in the relevant research work. However, the research results of different scholars might be different due to variations in selected patients, regional differences, different measuring sites, and many other reasons. Moreover, most scholars have adopted dichotomy to conduct research without revealing the overall situation of lesions. This study quantitatively evaluated the severity of CHD and explored the relationship between CHD and osteoporosis in a more comprehensive and in-depth manner.
Basic characteristics of population and CHD
There were many traditional risk factors for CHD in the past. However, new risk factors have emerged with the continuous change in the social environment and the development of various studies. In this study, we selected age, gender, hypertension, diabetes, BMI, heart rate, smoking, drinking, TG, TC, LDL, and HDL as the basic indicators. The comparison between the CHD and non-CHD groups demonstrated statistically significant differences in age, gender, hypertension, diabetes, BMI, smoking, and drinking. The binary logistic regression analysis showed that age, gender, BMI, hypertension, diabetes, smoking, and drinking were closely related to CHD. The older the age, the more serious the degeneration of the body organs. The decreased elasticity of blood vessels, endothelial damage, and various metabolic diseases can synergistically lead to coronary atherosclerosis. Hypertension can increase the pressure load on the vascular wall, damage the vascular endothelium, and destroy the balance of various physiological metabolism, thus leading to coronary atherosclerosis(8). Vasculopathy in diabetes is a long-term chronic process. Elevated blood glucose causes oxidative stress and produces many free radicals to destroy vascular endothelium, generating a series of chain reactions to induce coronary atherosclerosis(9). Both long-term smoking and drinking can cause vascular endothelial damage, and drinking is often accompanied by a high-fat diet, which can induce coronary atherosclerosis under the combined action of all aspects(10, 11). Furthermore, CHD has a high mortality rate.
A more comprehensive exploration and understanding of its high-risk factors are conducive to early prevention and treatment. These indicators also act as risk factors for osteoporosis. Some scholars believe that the relationship between osteoporosis and CHD lies in the fact that they have many common risk factors. There was no statistically significant difference in heart rate, TG, TC, LDL, and HDL. However, our results differed from the previous results in that dyslipidemia was a high-risk factor for CHD. The reason might be related to the long-term use of lipid-lowering drugs in some subjects. The limitation of this study was that the selected subjects were old, and most had a long medication history for various metabolic diseases and related glucose-lowering and lipid-lowering treatments. The effects and correlations of the above drugs were not included in the statistical analysis.
BMD and CHD
The BMD of the CHD group was significantly lower than that of the non-CHD group. Pearson correlation analysis showed that the BMDs of the lumbar spine and femur were negatively correlated with the modified Gensini score and Agatston score. Specifically, the lower the BMD, the more severe the osteoporosis, and the modified Gensini score and Agatston score are higher. The modified Gensini score is vital evidence for evaluating the severity of coronary atherosclerosis, which is an overall assessment of different parts and segments of the coronary artery and different degrees of stenosis from 1% to 100%. Compared with the “dichotomy,” which takes the stenosis degree ≥ 50% as the grouping threshold, it can provide a more detailed description of the degree of coronary artery stenosis. Compared with the modified Gensini score, which focuses on assessing the degree of vascular stenosis, the Agatston score is more inclined to assess the vascular wall condition. The Agatston score can reasonably evaluate the plaque load of the coronary artery and calculate the size of the calcification. Both scores were used as the criteria for quantitative evaluation of the severity of coronary artery disease in this study. With the reduction of BMD, the complexity of coronary artery atherosclerosis also increases. Binary logistic analysis showed that osteoporosis was an independent risk factor for CHD. The growth and metabolism of bone are inseparable from the function of blood vessels. The physiological mechanism between osteoporosis and the progression of vascular atherosclerosis is very complex. Many studies have explored the mechanism between them. Bone metabolism regulation and vascular atherosclerosis have the same physiological factors, including cathepsins, vitamins, and hormones. There are common signal pathways between them as well: 1. RANKL-RANK-OPG pathway is an essential pathway in bone metabolism, which affects bone metabolism by regulating the differentiation and activity of osteoclasts(5). This pathway is also expressed in blood vessels and can affect the transformation process of smooth muscle cells to osteoid cells(12); 2. the Wnt/β-catenin pathway is vital for bone metabolism, which affects bone metabolism by regulating the differentiation and activity of osteoblasts(13). At the same time, this pathway has also been found to play an important role in the transformation process of smooth muscle cells to osteoblasts (14); 3. Sclerostin is secreted by osteocytes and can regulate bone function. Recently, sclerostin has been found to be expressed in smooth muscle cells of blood vessels with atherosclerosis(15); 4. Pro-inflammatory cytokines can cause atherosclerosis and enhance osteoclast activity, thereby leading to bone loss(16); 5. Parathyroid hormone has dual effects on bone absorption and production(17) and can also promote the mineralization of blood vessel walls by inhibiting intracellular signal transduction(18); 6. Fibroblast growth factor affects bone metabolism and atherosclerosis by regulating calcium and phosphorus metabolism(19, 20). There is no clear consensus on the correlation between BMD of different parts and CHD, but the results of this study showed that the sensitivity of femur BMD was higher than that of lumbar BMD when compared to the correlation with modified Gensini score and Agatston score. Some scholars(21) believed that the dual-energy X-ray could be affected by the calcification and degeneration of the adjacent aorta when measuring BMD of the lumbar spine, resulting in an error in the measurement value. Bagger et al.(22) believed that this result is affected by the blood supply of various parts. The blood supply of the lumbar spine is bilateral, while that of the femur is unilateral. Therefore, the change in bone density of the femur is more sensitive, which also reveals the close relationship between bone metabolism and blood vessels from another perspective. Reducing blood supply to the bone terminal end caused by coronary atherosclerosis is essential in reducing BMD, which may be a mechanism of the relationship between osteoporosis and CHD.
Bone metabolic markers and CHD
In the synthesis and catabolism of bone tissue, many metabolites are produced and distributed in bone, blood, or other body fluids in different concentrations and structures, which affects bone remodeling and reconstruction by regulating the endocrine of bone metabolism. They can also maintain internal environment stability by mediating multiple links of human metabolism. We selected some markers of bone metabolism, including Ca, P, OC, and CTX. Ca and P constitute the basic framework of bone and are the basic raw materials of bone formation and the products of release from bone absorption. The process of coronary calcification has many connections with the process of bone metabolism. Osteoporosis patients have disordered bone metabolism and complex calcium and phosphorus metabolism changes. Some scholars believe bone loss shares the same physiological process with calcium salt deposition on the vascular wall(5). The abnormal activity of osteoblasts and osteoclasts in osteoporosis patients and the metabolic disorder and abnormal deposition of calcium and phosphorus could lead to accelerated vascular wall calcification. Among them, type I collagen secreted by osteoblasts and calcified vascular cells(23) is the main component of matrix vesicles, enriching calcium ions and promoting the deposition of calcium salts on the vascular wall. Type I collagen can promote the oxidative modification of LDL and accelerate coronary artery calcification. In addition, type I collagen can accelerate the transformation of monocyte to macrophages to absorb more lipids, and it can also directly increase calcium invasion, leading to coronary artery calcification. NF-kB and RANK/RANKL(24) can activate osteoclasts, aggravate the course of osteoporosis, and promote the occurrence of coronary calcification (Figure 2). Some scholars put forward the “calcification paradox” concept and believed that artery calcification was associated with bone turnover disorders and bone mass loss, thus promoting coronary atherosclerosis formation(25). Some patients with osteoporosis and decreased blood calcium take calcium supplements without a prescription. However, calcium has a significant effect on the cardiovascular system. Some studies have shown that calcium supplementation may increase the risk of cardiovascular disease, and calcium intake is positively correlated with the rate of coronary artery calcification and negatively correlated with insulin resistance and blood pressure(26). Calcium can affect the contractile activity of the myocardium by acting on the calcium-sensitive receptors distributed on cardiomyocytes. Therefore, long-term accumulation of calcium impacts the cardiovascular system. Scholars(27) conducted a multi-ethnic study and found that long-term and moderate calcium supplementation would not increase the risk of coronary atherosclerosis. However, excessive calcium supplementation (700mg/day) would lead to a 22% increase in the risk of coronary atherosclerosis. This study showed no significant difference in Ca and P between the CHD and non-CHD groups. OC and CTX, the markers of bone turnover, can reflect the metabolic state of bone, the biochemical products of bone cell activity, and bone matrix metabolism level and provide dynamic information about bone. Hence, it is a reasonable research direction to explore the relationship between osteoporosis and coronary atherosclerosis by observing the dynamics of bone turnover markers. OC is a bone formation marker, and CTX is a bone resorption marker. The previous research results of many scholars were inconsistent. They believed there was a negative correlation or no correlation between bone turnover markers and coronary artery atherosclerosis. This study showed no significant difference in OC and CTX between CHD and non-CHD groups. Some scholars have speculated that OC can improve vascular endothelial function and reduce the risk of coronary atherosclerosis by affecting certain inflammatory factors. However, this mechanism is unclear, and the results need further confirmation. The OC components in the blood are complex, including carboxylated osteocalcin (cOC), uncarboxylated osteocalcin (ucOC), and various osteocalcin segments. The biological activities of different types of components are different. This study failed to determine the composition of OC separately for detailed research, which may be why the results of this study differ from those of some previous studies. Montalcini et al.(28) believed that a high bone turnover rate was positively correlated with coronary atherosclerosis, indicating that it is worth observing the relationship between bone turnover markers and CHD, and more accurate and detailed measurements are needed.
Limitations of the study
The limitations of this study were as follows. It is a cross-sectional study and cannot clarify the causal relationship. Since bone metabolic markers are affected not only by the bone turnover system but also by the cardiovascular system and other factors, this study cannot calculate statistical differences in bone metabolic markers.