Cardiovascular disease is a risk factor for osteoporosis: a case-control study in Chinese women

Background: Osteoporosis and cardiovascular disease (CVD) are age-related diseases. According to some studies, patients with CVD have a higher risk of bone loss. This retrospective study intended to reveal the correlation between osteoporosis and CVD in Chinese women. Although epidemiological evidence has provided evidence of the relationship between the two, it lacks clinical data in southeast China. Methods: The 2873 participants completed the baseline survey from January 2007 to October 2019, and 2496 were included in this retrospective study. We divided all subjects into the osteoporosis group and the non-osteoporosis group based on their bone mineral density. Dual-energy x-ray absorptiometry (DXA) was used to examine bone mineral density. The general information came from the questionnaire survey and medical records. Results: According to the criterion, the osteoporosis group had 799 subjects, with a mean age of 64.19 years. The non-osteoporosis group had 1697 subjects, with a mean age of 61.03 years. Subjects in the osteoporosis group had a signicantly higher prevalence of hypertension and coronary heart disease. Besides, there was a higher probability of drinking tea and drinking milk in the osteoporosis group. In correlation analysis, the occurrence of osteoporosis correlated positively with hypertension and coronary heart disease. Logistic regression analysis showed that the odds of osteoporosis was high if participants had hypertension, coronary heart disease, or drank tea and drank milk. Conclusions: This study indicated that patients with osteoporosis had a higher prevalence of CVD in Chinese women, and CVD is one of the hazard factors for osteoporosis.


Background
Osteoporosis is a skeletal disease accompanied by low bone mass and deterioration in bone microarchitecture, leading to increased bone fragility and risk of fractures [1]. Cardiovascular disease (CVD) is mainly caused by arteriosclerosis, including coronary heart disease, hypertension, cerebral infarction, and other vascular diseases. Osteoporosis and CVD are common clinical diseases. With the lifestyle changes and the aging of the population, the incidence has increased signi cantly and seriously threatens the physical and mental health of the elderly.
It was previously thought that the two were independent of each other, but epidemiological studies have proved the correlation between them [2,3]. In recent years, with the further study of the relationship between osteoporosis and CVD, it has been con rmed that they have similar risk factors in the elderly, especially in postmenopausal women. Age, smoking, lack of physical exercise, vitamin D de ciency, and diabetes mellitus were considered the common risk factors for osteoporosis and CVD [4][5][6]. Some studies have indicated that patients with CVD have a higher risk of bone loss. Besides, individuals with low bone mass have higher mortality from CVD [7]. The possible link between CVD and osteoporosis urges us to analyze correlation and identify a common pathological basis. The similar pathogenesis of vascular calci cation and bone mineralization involves oxidative stress, in ammation, and lipid metabolism [8,9].
Similarly, genetic research also provides evidence for the connection between the two. The deletion of speci c genes in mice and mutation of critical genes in humans can lead to vascular calci cation and early osteoporosis [12]. The research on the relationship between the two is bene cial to prevention and treatment. Speci cally, the clinical evaluation of CVD patients should consider the measurement of bone mineral density. Also, patients with osteoporosis should undergo the examination of the electrocardiogram or Doppler ultrasound. This also has great signi cance in treating the two diseases [5].
Epidemiology provides the most direct and considerable evidence for the relationship. The different methods and populations that have been studied so far limit the reliability of the results [13]. Some clinical studies have been reported in some areas of China [14][15][16]. However, given the relatively small sample size included, it is di cult to re ect the overall situation. This retrospective study focuses on postmenopausal women in Fuzhou over 12 years, involving nearly three thousand participants, which can represent, to a certain extent, the prevalence of osteoporosis in southeastern China. It also provides extensive sample data for further investigating the relationship between osteoporosis and CVD in Chinese women.

Study Population
This retrospective study was carried out from January 2007 to October 2019 with participants from Fuzhou, capital of Fujian Province. All participants were investigated in the department of osteoporosis of the Fujian Academy of Chinese Medical Sciences. The 2873 participants accepted the questionnaire survey, and 2496 of them aged between 41 and 90 were included in this study. All subjects could provide complete medical records and sign informed consent independently.
The data required for the study came from the questionnaire survey. General information, such as age, height, weight, blood pressure, menarche age, menopausal age, past medical history, personal lifestyle, were collected and carefully lled in the uni ed form by the trained physicians. The height and weight were measured without shoes, and then the body mass index (BMI) was calculated.
All participants were excluded if they had hyperparathyroidism, diabetes, rheumatoid arthritis, and other endocrine and immune diseases that affect bone metabolism. Patients with severe liver and kidney and hematopoietic diseases and malignant tumors were also excluded. Further, none of the subjects had received osteoporosis treatment or other known drugs that affect bone metabolism. All potential subjects had complete data records. The written consent was necessary for all participants.
The diagnostic of osteoporosis was based on T score in the lumbar spine or femoral neck. T score £ -2.5 is osteoporosis; osteopenia is diagnosed as -2.5 < T score < -1.0; T score ³ -1.0 is normal [17]. All subjects were divided into the osteoporosis group and non-osteoporosis group according to their T score. Cardiovascular diseases were de ned by asking participants at the rst visit and checking relevant medical records if they had suffered from brain infarction, coronary heart disease, and hypertension. Lifestyle habits were de ned as activities that participants perform every day.
Bone mineral density measurement Dual-energy X-ray absorptiometry (DXA) (Discovery W, Hologic Inc, USA) was used to measure bone mineral density (BMD) of the lumbar spine and left femoral neck. The T score was calculated according to the reference range of the instrument manufacturer. The inspection was performed daily by the same professional physician. The coe cient of variation (CV) for repeated measurements is approximately 1.0%.

Statistical analysis
EpiDate 2 was used to enter and proofread data repeatedly, and SPSS 23.0(IBM, NY, USA) software was used to conduct all analyses. The results were expressed as average standard deviation or quantity (percentage). The t-test or Mann-Whitney U test was used for continuous variables. The chi-square test was used for the difference in frequency. Pearson or Spearman correlation analysis was used for univariate analyses of disease risk factors. Logistic regression analysis was con rmed with osteoporosis as dependent variables to evaluate the factors affecting osteoporosis. All the insigni cant in uencing factors were excluded from the analysis using the forward stepwise method. In all analyses, P < 0.05 suggested statistical signi cance.

Results
Characteristics of subjects between the osteoporosis group and non-osteoporosis group.
After excluding 377 participants who did not meet the criteria, 2496 subjects were included in the study.
There were 799 people in the osteoporosis group and 1697 people in the non-osteoporosis group. The age of the osteoporosis group was between 47 and 85, with 64.19±6.68 years. The age of the nonosteoporosis group was between 41 and 85, with 61.03±6.82 years. Statistically, the age and menarche age of subjects who suffered from osteoporosis were signi cantly older than those who did not, and the menopause age was more advanced. They also had a lower height and lighter weight (P < 0.001).
Besides, The BMD of the osteoporosis group was signi cantly lower than the non-osteoporosis group (P < 0.001) ( Table 1). Abbreviations: NA not applicable, BMI body mass index, BMD bone mineral density, SD standard deviation Comparison of in uencing factors between the osteoporosis group and non-osteoporosis group.
Comparing the in uencing factors between the two groups indicated that patients in the osteoporosis group had a higher prevalence of hypertension and coronary heart disease (P < 0.05). Besides, there was a higher probability of drinking tea and drinking milk in the osteoporosis group (P < 0.05) ( Table 2). In correlation analysis, the occurrence of osteoporosis correlated positively with age, menarche age, drinking tea, drinking milk, hypertension, and coronary heart disease (r > 0, P < 0.05) but negatively with height, weight, BMI, and menopause age (r < 0, P < 0.05), whereas smoking, drinking coffee, hyperlipidemia, and cerebral infarction did not. The age, weight, BMI, drinking tea, drinking milk, and hyperlipidemia was positively related to hypertension (r > 0, P < 0.05), while the height and femoral neck BMD were negatively related to hypertension (r < 0, P < 0.05). Similarly, the femoral neck BMD was also negatively associated with coronary heart disease (r < 0, P < 0.05) while the age and menarche age were positively associated with coronary heart disease (r > 0, P < 0.05). The results also indicated that the risk of cerebral infarction increased with age. Besides, there were strong correlations between hypertension, coronary heart disease, and cerebral infarction (r > 0, P < 0.01) ( Table 3). Logistic regression analysis with osteoporosis as a dependent variable.
Taking osteoporosis as the dependent variable, we conducted a two-class logistic regression analysis. After adjusting the confounding factors such as age, height, weight, menarche age, menopause age, drinking tea, and drinking milk, the result showed that hypertension and coronary heart disease were signi cant in uencing factors for osteoporosis (P < 0.05). The increased age, menarche age, and the occurrence of hypertension, coronary heart disease, drinking tea, drinking milk were related to the increased risk of osteoporosis. The adjusted OR of suffering from osteoporosis was1.280 for participants with hypertension compared to those without hypertension and 1.503 for participants when suffering from coronary heart disease. Moreover, lower height, lighter weight, and earlier menopause may also be related to the increased risk of osteoporosis (Table 4).

Discussion
With the continuous extension of life expectancy, the incidence of CVD and osteoporosis is increasing. More evidence shows that there are common risk factors and similar pathological mechanisms between the two [18]. In this retrospective study, we found that among all the women who met the criteria, there were 799 cases of osteoporosis, with a prevalence rate of 32.01%, which was similar to that reported in other literature [19,20]. Among the 799 patients, 174 suffered from hypertension, and 54 suffered from coronary heart disease. The prevalence was signi cantly higher than that of non-osteoporosis. This illustrates that CVD may increase the risk of osteoporosis, which is consistent with previous studies [21][22][23]. In correlation analysis, advanced age, later menarche, earlier menopause, and lower height may also be associated with this risk. To further adjust the factors causing this increased risk, we conducted a multivariate regression analysis and found that hypertension and coronary heart disease were related to the increased risk of osteoporosis. This indicates a signi cant correlation between CVD and osteoporosis, and CVD is one of the hazard factors for osteoporosis, suggesting that fracture and CVD prevention should be considered in the clinic. According to the results, drinking tea and milk also increased the risk of osteoporosis, which was inconsistent with previous studies. This may be because we didn't record the duration and amount of drinking milk and tea.
Some studies have reported that low BMD, as a hazard factor for cardiovascular events, is superior to traditional risk factors in predicting disease development, such as hyperlipidemia and smoking [24,25]. The lower BMD and increased bone loss rates were also related to an increased risk of CVD in the Chinese cohort [26]. Interestingly, a study showed a favorable relationship between reduced risk of cardiovascular disease and BMD [27]. Another study followed 6872 men and women for 5.7 years, and 196 developed myocardial infarction during this period. The result revealed that low hip BMD was a hazard factor for infarction [28]. In this study, we analyzed the in uencing factors of CVD and found that age, weight, BMI, drinking tea, drinking milk, and hyperlipidemia were positively related to hypertension while the height and femoral neck BMD were negatively associated with hypertension. Similarly, the femoral neck BMD was also negatively correlated with coronary heart disease. This shows that low femoral neck BMD is one of the risk factors for CVD, which is consistent with the reported results.
Osteoporosis and CVD are common age-related diseases. As shown in the results, the risk of osteoporosis, hypertension, coronary heart disease, and cerebral infarction increased with age. Changes in estrogen levels caused by menopause or aging can directly affect blood vessel wall and bone metabolism [15]. Bones and blood vessels are considered to be important targets for estrogen. Estrogen can improve the function of endothelial cells and vascular smooth muscle cells, and inhibit platelet aggregation and the response of blood vessels to injury [29,30]. Similarly, estrogen in serum can reduce the number and activity of osteoclasts and inhibit bone resorption. The decrease in estrogen results in increased bone resorption [31][32][33]. Besides, the reduction may lead to an increase in proin ammatory cytokines. The proin ammatory cytokines were related to bone loss and severe arteriosclerosis [34,35].
As we know, oxidative stress increases with age, further leading to the production of oxidized lipids. The oxidative stress is involved in bone resorption by inducing osteoclast differentiation and inhibiting osteoblast differentiation and leads to vascular calci cation because of the damage to endothelial cells [36][37][38]. Moreover, vascular endothelial cells may accelerate the differentiation of adipose stem cells into osteoblasts by secreting BMP [39]. Other matrix proteins are also found in bone tissue and vascular matrix. Angiogenesis and bone formation can be coupled through unique vascular forms and pathways [40,41]. The decrease in blood supply is easy to lead to atherosclerosis, which may affect blood circulation in bone and further damage bone metabolism, leading to osteoporosis [42]. The latest biological factors (sclerostin, broblast growth factor-23) are also related to atherosclerosis and bone metabolism [5]. These studies can explain the common pathological mechanism of age-related osteoporosis and CVD.
The limitation of this study is a single-center retrospective study with poor homogeneity, many confounding factors, and low evidence. Second, it is di cult to get the causal relationship between in uencing factors and osteoporosis, so a prospective cohort study should be considered in the next step. Third, the information related to cardiovascular disease comes from medical records rather than immediate examination. Further research needs to be done based on this study.

Conclusion
In short, this observational study indicated the correlation between osteoporosis and cardiovascular disease in Chinese women. Based on the results, cardiovascular assessment should be considered in patients with osteoporosis to prevent adverse events. This further supports the view that there is a biological link between the two.
Abbreviations CVD: cardiovascular disease; BMP: bone morphogenetic proteins; OPG: osteoprotegerin; MPG: matrix protein Gla; TNF-a: tumor necrosis factor-alpha; BMD: bone mineral density; DXA: dual-energy X-ray absorptiometry; CV: coe cient of variation; NA: not applicable; BMI: body mass index; SD: standard deviation; SE: standard error; OR odds ratio; C.I.: con dence interval Declarations (2018R1035-4, 2018R1035-7). The funding body has no speci c restrictions in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials
The datasets generated during and analysed during the current study are not publicly available due to the protection of personal information but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate All methods were carried out in accordance with the Declaration of Helsinki. This retrospective study performed using the date from questionnaire survey. All participants signed informed consent to obtain necessary personal information when receiving free BMD measurement.