This cross-sectional study with 10,983 adult Americans showed for the first time that increased UHR levels are highly correlated with the risk of osteoporosis. The statistical study showed that even after controlling for every variable in the classification model, there was still a negative connection between lumbar BMD and UHR.This correlation was somewhat unstable in the subgroups of body mass index less than 25, age greater than 50, and diabetes mellitus, but otherwise remained consistent in all other subgroups. Furthermore, an L-shaped association with an inflection point of 2.97 was observed between UHR and lumbar BMD using threshold effect analysis and smoothed curve fitting. For every unit rise in UHR, BMD fell by 1% up until this inflection point, after which the association ceased to be statistically significant.
Two prevalent health issues among the elderly population that present a number of dangers and difficulties are osteoporosis and atherosclerosis. Not only may they have detrimental effects on one's health individually, but they may also compound one another's effects[23]. The new inflammatory marker known as UHR is used to measure the extent of atherosclerosis. The association between blood uric acid, HDL-C, and osteoporosis has been discussed in the news, despite the fact that prior research have not examined the relevance of the UHR in osteoporosis.The new inflammatory marker known as UHR is used to measure the extent of atherosclerosis. Although previous studies have not investigated the significance of UHR in osteoporosis, discussions of the relationship between blood uric acid and HDL-C and osteoporosis have been reported repeatedly. Higher SUA levels were shown to be independently linked to lower lumbar spine bone mineral density in healthy Chinese postmenopausal women in a longitudinal follow-up investigation.[24]. In a cross-sectional study of 275 obese patients, lumbar BMD was inversely associated with hyperuricemia in obese men[25]. Another cross-sectional study of 7,320 adolescents aged 12–19 found that in female adolescents, higher sUA levels may have adverse effects on bone health[26]. In addition, a cross-sectional study of 667 postmenopausal women showed a favourable association between HDL levels and BMD of the lumbar spine and femoral neck[27].These aforementioned findings indirectly validate our experimental results. However, some researchers have opposing opinions in the role of uric acid on osteoporosis. Serum uric acid was found to be positively associated with lumbar spine bone density in a cross-sectional study that included 6,254 American men[28]. Furthermore, after examining 5,074 patients in The Rotterdam Study, researchers came to the conclusion that elevated SUA levels guarded against bone loss[29]. Additionally, using animal tests, the researchers found that there were no variations in bone density or bulk density between normovolemic control animals and hyperuricemic rats[30]. There is also disagreement about the relationship between HDL and osteoporosis. For example, in a cross-sectional study, high HDL-C levels were found to affect bone loss in a Chinese population aged 20 to 80 years, with obese men having the most severe bone loss[31]. Interpretation of the aforementioned controversial studies may be attributed to differences in basic participant characteristics, race, age, and assessment of osteoporosis. Thus, with the UHR novel inflammatory index, the current study provides new evidence to deepen the understanding of the association between uric acid and lipid levels and osteoporosis risk.
The current cross-sectional investigation showed that UHR and BMD had a nonlinear negative connection in the U.S. population by multivariate linear regression as well as smoothed curve fitting. Understanding the underlying mechanisms between lipid and uric acid status and osteoporosis may help to explain the present work. Reactive oxygen species (ROS) are produced by oxidative stress, which is a separate risk factor for bone metabolism. These ROS disrupt intraosseous homeostasis and accelerate the development of osteoporosis by reducing bone formation in osteoblasts and osteoclasts and promoting bone resorption in osteoclasts[32]. The last byproduct of purine breakdown in the liver is UA[33], At healthy concentrations, UA is thought to be a potent endogenous antioxidant that scavenges singlet oxygen radicals, hydroxyl alone (.OH), and peroxyl alone (RO2). It can scavenge up to 60% of the blood serum's free radical scavenging ability[34], In addition, in vitro experiments conducted by an investigator found that UA inhibits osteoclastogenesis and reduces intracellular ROS levels in osteoclast precursors in mice[35], and thus UA prevents oxidative stress-associated bone loss and osteoporosis. Another study observed a negative correlation between sUA levels and type I collagen preprotein N-terminal (PINP) and type I collagen β-cross-linked c-terminal peptide (β-CTX) in postmenopausal women[35].PINP and β-CTX are markers that reflect bone formation and represent osteoblast activity. Bone formation and resorption are closely related to the process of bone conversion, and sUA was negatively correlated with bone formation markers, suggesting that sUA reduces bone conversion and thus bone loss, a finding also corroborated by previous cross-sectional studies[37, 38]. However, in hyperuricemia or gouty arthritis, the role of UA in bone metabolism switches and it becomes a source of oxidative stress instead. When the concentration of uric acid in the blood exceeds its solubility limit, uric acid precipitates out of the fluid and forms urate (mainly monosodium urate, MSU) crystals.The urate crystals are recognized and phagocytosed by induced phagocytosis of NLRP3 inflammatory vesicles, and after release of various inflammatory factors such as Interleukin-1β(IL-1β), Tumor necrosis factor-α༈TNF-α༉, and Interleukin-1༈IL-6༉[39–41], inflammatory cells are recruited, mainly neutrophils, into the joint space, which exacerbating the local inflammatory environment. These inflammatory factors not only lead to acute inflammatory responses such as gout, but also have long-term effects on bone tissue. Because receptor activator of nuclear factor κ b ligand (RANKL) signaling and IL-1, a significant bone resorption activator, work together to support the growth and development of osteoclast progenitor cells[42], By raising RANK expression in osteoblasts, which triggers RANKL downstream pathways in osteoclasts, including activation of nuclear factor kappa light chain enhancer (NF-κB), JNK, and p38 in B cells, and enhancement of bone resorption by osteoclasts, IL-6 plays a beneficial indirect role in osteoclast differentiation[43]. One of the main players in the pathophysiology of inflammation, tumor necrosis factor-α (TNF-α), stimulates the expression of M-CSF on stromal cells and RANKL in macrophages and bone marrow stromal cells.The mechanism by which TNF-α promotes osteoblast differentiation and activity is through the RANKL and M-CSF production[44]. Furthermore, some research has highlighted the potential harm that UA may cause to the metabolism of vitamin D. This can directly lower 1α-hydroxylase activity in the kidney's proximal tubules, which lowers the body's concentration of 1,25-dihydroxyvitamin D3 (also known as active vitamin D, or 1,25(OH)2D), aggravating bone loss and raising the risk of fractures[45]. By altering the metabolism of vitamin D, excessive uric acid can also indirectly cause raised PTH levels. Prolonged high PTH levels can also cause a preponderance of osteoclast activity, which upsets the balance of bone metabolism and results in bone loss[46].In addition, the PI3K/Akt and MAPK/ERK signaling pathways are essential for the control of bone metabolism. HDL activates the PI3K/Akt pathway via the SR-BI receptor, which promotes the proliferation of osteoblasts and prevents apoptosis, and promotes the activity of Runx2, which further enhances osteoblast differentiation and mineralization. Activation of the MAPK/ERK signaling pathway promotes the proliferation of osteoblasts and the synthesis of bone matrix components (e.g., collagen) by osteoblasts, thereby promoting bone formation and mineralization. Therefore, HDL plays an important role in the signaling events that affect osteoblast development, specialization, and osteogenic activity[47]. Furthermore, in bone marrow adipose tissue, PPARγ and CEBPa are important regulators of adipocyte development. The main protein component of HDL cholesterol, apolipoprotein A1, can be deficient in, which is equal to having lower HDL levels. This deficiency can raise the expression of CEBPa and PPARγ, which can alter the population of bone precursor cells, increase the development of adipocytes, and reduce the generation of osteoblasts[48].