Our study investigated the relationship between folate levels and osteoporosis, in the US population, over the last decade. Due to folate’s unique properties and functions, it has always played an irreplaceable role in organisms. Recent studies have shown that folate may regulate lipid metabolism and oxidative stress reaction, activate AMP-activated protein kinase (AMPK) pathway, and reduce high-fat diet induced osteoporosis. Additionally, it has also been found that B vitamins and folate supplements can improve BMD [13, 20]. All these suggest that folate may affect bone formation.
In this study, age, sex, hypertension and physical activity can influence the occurrence of osteoporosis, which is consistent with existing studies [21]. However, the incidence of osteoporosis was not higher in diabetic than in non-diabetic (P < 0.001). Studies have found that BMD increases in diabetic patients, although the risk of fracture is increased eventually, this is related to the duration of diabetes and complications [22–23], and more research needs to be conducted.
Folate concentration was significantly lower in the osteoporosis group than in the non-osteoporosis group (P < 0.001). For further study, we divided folate into low, medium, and high grades. In men, the risk of osteoporosis with moderate and high folate levels was significantly higher than the low folate levels, and the higher the folate level, the higher the risk, suggesting that folate may affect the formation of bone, and high folate levels may have an inhibitory effect. In age stratification, between the ages of 50 to 70, medium and high levels of folate showed to have a higher risk of osteoporosis than lower levels. After adjusting for covariates, such as gender, no significant difference was found in the results, which may be related to female hormones. Women will experience menopause at about 50 years old, and the loss of estrogen after menopause will lead to bone loss [24], increasing the occurrence of overall osteoporosis. No association between folate and osteoporosis was found in the group older than 70 years. It was considered that the decreased secretion of hormones in older individuals can stimulate osteoclasts and inhibit osteoblasts [25], accompanied by the decline of organ function and physical activity, resulting in bone decline, which will affect the occurrence of osteoporosis. In racial stratification, except for the multi-ethnic minorities, other races have an increased risk of osteoporosis with the increase of folate levels. This shows that folate is associated with osteoporosis, however the relationship between different races needs further investigation.
Considering that folate levels do not show a simple linear relationship with osteoporosis, we used RCS to describe it. In the total population, with the increase of folate concentration, the risk of osteoporosis gradually decreased, reaching the lowest point at 25nmol/L, and then there was a J-shaped relationship between the two. In the stratified analysis, the images were similar among the subgroups of men and women, aged 50–70. Folate levels lower than 50nmol/L seems to have a protective factor against osteoporosis, while levels higher 50nmol/L seems to be a risk factor, which gives us a reference for the possible prevention of osteoporosis. This is similar to a study by Stanley et al., who found that both high and low folate levels increase cardiovascular mortality in hypertensive individuals [26].
The United States is a large folate supplement distributor. Since the 1990s, the government has implemented adding folate to flour and grain to improve people's folate levels. The implementation of folate policy has also played a role in reducing the occurrence of several diseases. In 2018, the United States stopped implementing the policy of adding folate, causing speculation. Some studies have found that excessive folate does not bring benefits, however increases cardiovascular events and all-cause mortality [27–28]. Professor Evans points out that high serum folate is associated with an increased risk of death in adults with diabetes in a 15- year study [29]. The current explanation is that excessive folate may increase the level of unbound folate and increase the degradation of folate [30], and also control biological methylation and nucleotide synthesis, thus damaging DNA integrity [31]. Moreover, excessive intake of natural folate will not cause poisoning, while long-term high dose of synthetic folate intake will produce a large amount of unmetabolized folate, which may reduce the cytotoxicity of its natural killer cells [32]. It may also affect the absorption of other nutrients or mask the symptoms of vitamin B12 deficiency [33].
According to our knowledge, our study is the first to reveal the relationship between folate and osteoporosis, and to determine the cut-off point of folate concentration to prevent osteoporosis. The NHANES database had an abundant amount of representative population data, which provided a large number of samples to support our research. At the same time, there were some limitations. Dietary intake is an important factor affecting folate levels. There is currently insufficient data regarding this, thus we cannot report on the statistically relevant variables. Additionally, the article is a cross-sectional study, it cannot reveal the prognostic relationship between folate and osteoporosis.
In summary, the concentration of folate can affect the occurrence of osteoporosis. Low levels of folate can play a protective role, while high levels folate can be a risk factor. The ascertain the specific folate cut-off point further studies need to be conducted.