Osteoporosis is an important health problem for postmenopausal women. In order to evaluate and prevent OP, more and more evaluation tools have emerged and developed. In 2008, the FRAX released by the World Health Organization Cooperation Center in Sheffield, UK, is the most widely used tool to assess bone health. However, with the deepening of research in the field of OP, more and more risk factors have been found. Riancho JA et al.[35] found that the change of KL was closely related to BMD in postmenopausal women. As far as we know, there are few studies on Klotho and the development of OP, and further studies are needed to reveal the relationship between them.
In this study, our results indicate that Klotho is an independent protective factor for postmenopausal women with OP (OR 0.561(0.339–0.925), P = 0.023). Compared with the quartile with the lowest Klotho level, the risk of OP in the highest quartile is reduced by 69.2%. The RCS results show that when the serum Klotho level is higher than 824.09pg/ml, this protective effect is more obvious. Subgroup analysis shows that when all variables are adjusted, the P for trend is significant, indicating that the OP incidence in participants drops more significantly with the same extent increase in BMD. Compared with previous studies, our study confirm that age and body type are independent influencing factors of OP.
Our research has reached a similar conclusion with Kužmová Z et al.[25] and Baldan A et al.[26], that is, Klotho is a protein that protects bones. Klotho can reduce the incidence of OP, which means that it can promote the stability of bone trabecular structure and reduce the incidence of osteoporotic fractures. However, our results are inconsistent with those of De-la-O A et al.[27] Considering that they studied a specific age group, and they included both men and women, in addition, sedentary may also be one of the influencing factors. In addition, Neyra JA et al.[36] mentioned that Klotho can inhibit the expression of bone FGF-23 in healthy people, while in CKD people, low Klotho will promote the production of bone FGF-23. Therefore, Klotho may have different functions in different health states.
Calcium and phosphate are essential trace elements for human bone structure. Imai M et al.[37] observed that Klotho protein inhibited expression of 25(OH)VitD3 1α-hydroxylase in kidney cells in vitro, which is the key enzyme for VitD3 activation. The deficiency of Klotho will hinder the activation of VitD. Additionally, Grabner A et al.[38] found that Klotho deficient mice showed a high expression phenotype of FGF-23, although this might be a feedback mechanism of the body. Several studies have shown that FGF-23 reduces the serum VitD3 level by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25-(OH)2D[18, 21, 39, 40]. Lacking of VitD3 leads to inhibition of intestinal calcium absorption, while the deficit of calcium salt and phosphate will lead to bone calcification disorder, resulting in decreased bone density.
FGF-23 is a key hormone regulator of calcium metabolism, phosphate and vitamin D. Its physiological functions include maintaining bone health and systemic mineral balance[18, 41]. FGF-23 is mainly secreted by osteoblasts in bone tissue and responds to the increase of phosphate and calcium load, calcitriol, parathyroid hormone (PTH) and bone remodeling. When bone remodeling occurs, osteoblasts will secrete FGF-23 by binding to FGFR1-Klotho in proximal and distal tubules of kidney, and then FGF-23 ligand-receptor complex activates PLCγ/calcineurin/NFAT or FRS2α/Ras/MAPK downstream cascade signals, thus promoting the renal phosphate reabsorption and decreasing urinary phosphate excretion. At the same time, the parathyroid gland also expresses FGFR, and the combination of ligand and receptor is to inhibit the secretion of PTH. Both of these pathways promote bone formation and reduce bone degradation. Klotho is a mediator when FGF-23 binding to its receptor and increases the affinity of these FGFR selectively to FGF-23[42]. The deficiency of Klotho will lead to the impairment of phosphorus reabsorption in the kidney and secondary hyperparathyroidism, which will lead to bone formation disorder.
Klotho was originally considered as an aging related protein. Knockout of KL will lead to the reduction of life span[43]. A defect in KL expression will lead to premature aging syndrome[12]. It is generally recognized that OP has a strong negative correlation with age, and OP is also a manifestation of aging. Our study shows that the lack of Klotho is related to the occurrence of OP. Therefore, Klotho can explain part of mechanisms in the occurrence of age-related OP.
To our best knowledge, this study is the first to use a national sample to explore the relationship between OP and Klotho. NHANES collects a large, multi-ethnic, representative population of the United States, which enhances the statistical effectiveness of the research and provides more convincing results. In addition, we fully adjusts the potential confounding factors when exploring the relationship between OP and Klotho level, which makes the research results more accurate. However, our research also has some limitations. Firstly, NHANES database has collected the information of VitD and PTH, but the determined form of vitD is not VitD3 that produces biological activity but VitD2, and there is no PTH survey data in the collected years. Unfortunately, FGF-23 has not been collected in NHANES. Secondly, NHANES is a cross-sectional study, therefore, it is difficult to determine the relationship between temporal and causative. Moreover, due to no response to the NHANES survey and the missing values of some variables, there may be bios in exclude participants from the analysis. This requires some longitudinal studies with serial serum Klotho measurements should address temporality. Thirdly, due to the differences between races, the accuracy of the model still needs additional evaluation when the result applied to races in other countries or regions.
In conclusion, we found in a nationally representative sample that serum Klotho was negatively correlated with the prevalence of OP, and the higher the serum Klotho level, the more obvious the protective effect. We propose a protective factor for OP, which can provide guidance for research on diagnosis and risk assessment of OP.