Uric acid to high-density lipoprotein cholesterol ratio and osteoporosis: evidence from the National Health and Nutrition Examination Survey

doi:10.21203/rs.3.rs-3969287/v1

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Uric acid to high-density lipoprotein cholesterol ratio and osteoporosis: evidence from the National Health and Nutrition Examination Survey

https://doi.org/10.21203/rs.3.rs-3969287/v1

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Background: Uric acid to high-density lipoprotein cholesterol ratio (UHR) was a novel indicator reflecting inflammatory and metabolic status. This study aimed to investigate the association between UHR and bone mineral density (BMD), as well as the risk of osteoporosis, in individuals aged 50 years and above.

Methods: This cross-sectional study included participants aged 50 and older from the National Health and Nutrition Examination Survey. Dual-energy X-ray absorptiometry (DXA) was employed to measure femoral neck BMD (FN-BMD). Furthermore, linear regression models were employed to examine the association between UHR and FN-BMD, while generalized additive models were used to assess the nonlinear relationship between UHR and FN-BMD. In addition, logistic regression models were employed to evaluate the association between UHR and the risk of osteoporosis.

Results: Finally, 2,963 adults were included in this study, with a mean age of 64.16 ± 8.92 years. The results of linear regression models revealed a positive association between UHR and FN-BMD with or without adjustment for covariates. Furthermore, the results of logistic regression models suggested that elevated UHR levels were associated with a decreased risk of osteoporosis with or without adjustment for covariates. Moreover, the results of subgroup analysis showed that the positive association between UHR and BMD was observed among individuals aged 65 and older but not those aged 50 to 64 after stratification by age, and interaction analyses for age showed significant differences after adjustment for all covariates.

Conclusions: Clinicians should be alert to the potential risk of osteoporosis among individuals with low UHR levels. UHR might serve as a risk indicator for osteoporosis.

Health sciences/Diseases

Health sciences/Pathogenesis

Health sciences/Risk factors

osteoporosis

uric acid

high-density lipoprotein cholesterol

bone mineral density

National Health and Nutrition Examination Survey

Osteoporosis is a systemic musculoskeletal disorder characterized by reduced bone mineral density (BMD) and deterioration of bone tissue microstructure [1]. A notable feature of osteoporosis is its high prevalence, with approximately one-third of women and one-fifth of men aged 50 and above at risk globally [2–4]. An epidemiological study conducted in China revealed a prevalence of osteoporosis of 5.0% among men and 20.6% among women aged 40 and above [5]. The continual aging of the population is anticipated to lead to a rise in the prevalence of osteoporosis [6, 7]. Moreover, osteoporosis is associated with substantial financial and societal burdens, with annual costs estimated at $17.9 billion in the United States (US) and £4 billion in the United Kingdom [8]. In addition, osteoporosis is linked to high rates of disability and mortality, particularly due to the serious complications of osteoporotic fractures, such as hip fractures, which significantly affect the health and quality of life of elderly individuals [9–11]. Therefore, early prevention of osteoporosis is a crucial focus of current research.

Exploring the risk factors and protective factors of diseases is currently an essential approach to search for early prevention measures. Osteoporosis, from a pathological viewpoint, encompasses a multifaceted pathogenic process involving bone metabolism, hormonal regulation, and immune modulation [1, 12]. Moreover, the etiology of osteoporosis is linked to a variety of factors [1, 12, 13]. Accumulating evidence has demonstrated that risk factors for osteoporosis encompass age, gender, menopausal status, race, physical activity levels, nutritional intake, and others [13, 14]. Furthermore, numerous studies have suggested that utilizing these risk factors to identify and predict the likelihood of developing osteoporosis is an efficacious method for early prevention and screening [15, 16]. Therefore, there is a growing emphasis on investigating the factors linked to osteoporosis in current research.

The uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR), a novel marker indicating metabolic and inflammatory conditions, has been linked to an increased risk of different illnesses in previous research and has been demonstrated to have the ability to serve as a predictor for several clinical outcomes [17–20]. Xie et al. discovered that high UHR levels were independently linked to the risk and severity of non-alcoholic fatty liver disease in the American population, with varying correlations based on gender [20]. Zhu et al. posited that elevated levels of UHR might serve as a cost-effective and dependable predictor for the onset of non-alcoholic fatty liver disease in non-obese individuals of Chinese exhibiting normal levels of blood lipids [21]. Furthermore, Yang and colleagues identified an association between elevated UHR levels and an increased likelihood of adverse cardiovascular events in individuals with chronic total occlusion of the coronary arteries [22]. Yang et al. revealed that the simultaneous presence of high UA and low HDL-C had a synergistic impact on risk stratification for patients with acute myocardial infarction [23]. These findings suggest that UHR may serve as a valuable and independent prognostic marker, supplementing traditional risk factors. However, the relationship between UHR and the risk of osteoporosis has not been definitively established. Further investigation into this association may aid in the identification of early predictive markers for osteoporosis.

This study sought to examine the correlation between UHR and bone mineral density (BMD), as well as the risk of osteoporosis, using data from the National Health and Nutrition Examination Survey (NHANES). Our hypothesis posited that increased UHR levels would be linked to higher BMD and a reduced risk of osteoporosis.

Study design and population

This cross-sectional study incorporated participants from the NHANES 2017-March 2020 cycle. NHANES is a biennial survey conducted by the National Center for Health Statistics (NCHS) to evaluate the health and nutritional status of the US population. All participants provided written informed consent, and the project received approval from the Institutional Review Board of the NCHS. Furthermore, the inclusion criteria for participants were as follows: (i) aged 50 and above, (ii) with complete BMD data, and (iii) with complete UHR data. In addition, individuals with missing data on covariates were excluded from the present study. Other details are provided on the NHANES website [24].

BMD measurement and osteoporosis

BMD was measured using dual-energy X-ray absorptiometry (DXA) examinations, in which the femoral neck BMD (FN-BMD) was selected as the outcome variable because FN-BMD has been demonstrated to be associated with the risk of hip fractures [25]. According to the results of BMD and the World Health Organization (WHO) criteria, a T-score of ≤-2.5 for FN-BMD was indicative of osteoporosis, in which the specific values were derived from previous studies (men: BMD ≤ 0.588 g/cm²; women: BMD ≤ 0.560 g/cm²) [26–28]. The comprehensive details on the methodology of BMD measurement are provided on the NHANES website [29].

UHR assessment

UHR was considered the exposure variable in this study. According to a previous study [18], the formula for calculating UHR is as follows: UHR (%) = UA (mg/dL) / HDL-C (mg/dL). Detailed UA and HDL-C measurement procedures can be found on the NHANES website [30].

Covariates

Given the potential for confounding variables to impact both the outcome and exposure variables, this study incorporated multiple covariates in the subsequent analyses. Finally, age, sex/menopausal status (post-menopausal women, pre-menopausal women, and men), race (non-Hispanic White, non-Hispanic Black, Mexican American, and other races), education level (under high school, high school or equivalent, above high school), body mass index (BMI) status (normal: BMI < 25 kg/m²; overweight: 25 ≤ BMI < 30 kg/m²; and obese: BMI ≥ 30 kg/m²), smoking status (never former, current), drinking status (never former, current), physical activity, vitamin D intake, calcium intake, milk product consumption (never, rarely, sometimes, often, varied), history of diabetes (yes, no), history of arthritis (yes, no), history of cancer (yes, no), history of fractures (yes, no), history of glucocorticoid use (yes, no), alanine aminotransferase (ALT) (U/L), aspartate aminotransferase (AST) (U/L), alkaline phosphatase (ALP) (IU/L), blood urea nitrogen (BUN) (mmol/L), serum creatinine (mg/dL), serum calcium (mg/dL), serum total cholesterol (TC) (mg/dL), serum triglycerides (TG) (mg/dL), serum HDL-C, serum UA (mg/dL) were included as potential covariates. Other details on assessment for covariates are provided on the NHANES website [24].

Statistical analysis

Baseline characteristics were reported as mean ± standard deviation (SD) for continuous variables and as n (%) for categorical variables. Additionally, differences in baseline characteristics among groups stratified by UHR were assessed using one-way analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. Moreover, linear regression models were utilized to explore the association between UHR and FN-BMD, while logistic regression models were employed to examine the association between UHR and the risk of osteoporosis. In addition, the nonlinear relationship between UHR and FN-BMD was determined using generalized additive models (GAM). Furthermore, subgroup analysis and interaction testing were conducted to assess the relationship between UHR and BMD, as well as the potential risk of osteoporosis, among various populations categorized by age, sex/menopausal status, race/ethnicity, and BMI. Ultimately, UHR values were converted from a continuous variable to a categorical variable (quartile 1 to quartile 4) (Q1-Q4) in order to examine the association between UHR and FN-BMD, as well as the risk of osteoporosis. Data analysis was conducted utilizing R software version 4.2.1 (https://cran.r-project.org/) and EmpowerStats version 2.0 (http://www.empowerstats.com). A significance level of P < 0.05 was established to ascertain statistical significance.

Selection of the study population

A total of 15,560 participants from the NHANES 2017-March 2020 were included in this study. Furthermore, exclusions were made for participants below 50 years of age and those with missing data on BMD, UHR, or covariates. Finally, a total of 2,963 participants aged 50 and older were included in the final analysis. The detailed flowchart illustrating the inclusion and exclusion process can be found in Fig. 1.

Baseline characteristics

A total of 2,963 adults were included in this study, with a mean age of 64.16 ± 8.92 years. The mean of HDL-C level was 54.59 ± 16.28 mg/dL, and the mean of UA level was 5.53 ± 1.46 mg/dL. Among the participants, 27.81% were post-menopausal women, 18.93% were pre-menopausal women, and 53.26% were males. After converting UHR from a continuous variable to a categorical variable, there were significant differences among UHR groups in FN-BMD and the proportion of individuals with osteoporosis (P < 0.001). Specifically, participants with higher UHR levels showed higher BMD values and a lower proportion of individuals with osteoporosis than those with lower UHR levels. The detailed information on baseline characteristics is listed in Table 1.

Table 1

Baseline characteristics of study population
Characteristics	Total	UHR (Q1)	UHR (Q2)	UHR (Q3)	UHR (Q4)	P-value
	N = 2,963	N = 739	N = 742	N = 740	N = 742
Age (years)	64.16 ± 8.92	63.91 ± 9.08	63.82 ± 8.84	64.42 ± 9.03	64.46 ± 8.71	0.372
Sex/menopausal status, n (%)						< 0.001
Post-menopausal women	824 (27.81%)	337 (45.60%)	242 (32.61%)	168 (22.70%)	77 (10.38%)
Pre-menopausal women	561 (18.93%)	227 (30.72%)	153 (20.62%)	112 (15.14%)	69 (9.30%)
Men	1578 (53.26%)	175 (23.68%)	347 (46.77%)	460 (62.16%)	596 (80.32%)
Race, n (%)						0.062
Non-Hispanic White	1209 (40.80%)	320 (43.30%)	288 (38.81%)	313 (42.30%)	288 (38.81%)
Non-Hispanic Black	731 (24.67%)	168 (22.73%)	194 (26.15%)	197 (26.62%)	172 (23.18%)
Mexican American	283 (9.55%)	59 (7.98%)	74 (9.97%)	74 (10.00%)	76 (10.24%)
Other races	740 (24.97%)	192 (25.98%)	186 (25.07%)	156 (21.08%)	206 (27.76%)
Education level, n (%)						< 0.001
Under high school	535 (18.06%)	101 (13.67%)	130 (17.52%)	142 (19.19%)	162 (21.83%)
High school or equivalent	738 (24.91%)	170 (23.00%)	197 (26.55%)	184 (24.86%)	187 (25.20%)
Above high school	1690 (57.04%)	468 (63.33%)	415 (55.93%)	414 (55.95%)	393 (52.96%)
BMI status, n (%)						< 0.001
Normal BMI	690 (23.29%)	302 (40.87%)	171 (23.05%)	139 (18.78%)	78 (10.51%)
Overweight	1119 (37.77%)	283 (38.29%)	295 (39.76%)	273 (36.89%)	268 (36.12%)
Obesity	1154 (38.95%)	154 (20.84%)	276 (37.20%)	328 (44.32%)	396 (53.37%)
Smoking status, n (%)						< 0.001
Never	1571 (53.02%)	445 (60.22%)	405 (54.58%)	370 (50.00%)	351 (47.30%)
Former	931 (31.42%)	190 (25.71%)	209 (28.17%)	237 (32.03%)	295 (39.76%)
Currently	461 (15.56%)	104 (14.07%)	128 (17.25%)	133 (17.97%)	96 (12.94%)
Drinking status, n (%)						0.101
Never	269 (9.08%)	74 (10.01%)	70 (9.43%)	70 (9.46%)	55 (7.41%)
Former	788 (26.59%)	183 (24.76%)	187 (25.20%)	190 (25.68%)	228 (30.73%)
Currently	1906 (64.33%)	482 (65.22%)	485 (65.36%)	480 (64.86%)	459 (61.86%)
Physical activity (h/day)	10.81 ± 17.88	10.01 ± 17.17	11.89 ± 19.64	10.93 ± 17.47	10.39 ± 17.11	0.202
Vitamin D intake (mcg/day)	0.39 ± 1.41	0.49 ± 1.70	0.37 ± 1.05	0.41 ± 1.75	0.29 ± 0.92	0.048
Calcium intake (mcg/day)	13.14 ± 8.65	15.31 ± 9.75	13.80 ± 8.92	12.11 ± 7.70	11.34 ± 7.53	< 0.001
Milk product consumption, n (%)						0.425
Never	672 (22.68%)	191 (25.85%)	156 (21.02%)	160 (21.62%)	165 (22.24%)
Rarely	595 (20.08%)	149 (20.16%)	139 (18.73%)	145 (19.59%)	162 (21.83%)
Sometimes	797 (26.90%)	186 (25.17%)	209 (28.17%)	211 (28.51%)	191 (25.74%)
Often	895 (30.21%)	211 (28.55%)	237 (31.94%)	223 (30.14%)	224 (30.19%)
Varied	4 (0.13%)	2 (0.27%)	1 (0.13%)	1 (0.14%)	0 (0.00%)
History of hypertension, n (%)						< 0.001
Yes	1587 (53.56%)	335 (45.33%)	363 (48.92%)	417 (56.35%)	472 (63.61%)
No	1376 (46.44%)	404 (54.67%)	379 (51.08%)	323 (43.65%)	270 (36.39%)
History of diabetes, n (%)						< 0.001
Yes	660 (22.27%)	98 (13.26%)	142 (19.14%)	189 (25.54%)	231 (31.13%)
No	2303 (77.73%)	641 (86.74%)	600 (80.86%)	551 (74.46%)	511 (68.87%)
History of arthritis, n (%)						0.380
Yes	1319 (44.52%)	344 (46.55%)	338 (45.55%)	315 (42.57%)	322 (43.40%)
No	1644 (55.48%)	395 (53.45%)	404 (54.45%)	425 (57.43%)	420 (56.60%)
History of cancer, n (%)						0.504
Yes	487 (16.44%)	123 (16.64%)	109 (14.69%)	126 (17.03%)	129 (17.39%)
No	2476 (83.56%)	616 (83.36%)	633 (85.31%)	614 (82.97%)	613 (82.61%)
History of fractures, n (%)						0.781
Yes	427 (14.41%)	100 (13.53%)	113 (15.23%)	110 (14.86%)	104 (14.02%)
No	2536 (85.59%)	639 (86.47%)	629 (84.77%)	630 (85.14%)	638 (85.98%)
History of glucocorticoid use, n (%)						0.679
Yes	211 (7.12%)	48 (6.50%)	56 (7.55%)	58 (7.84%)	49 (6.60%)
No	2752 (92.88%)	691 (93.50%)	686 (92.45%)	682 (92.16%)	693 (93.40%)
Alanine aminotransferase (U/L)	21.70 ± 14.82	19.61 ± 13.04	20.83 ± 14.17	22.01 ± 17.44	24.36 ± 13.85	< 0.001
Aspartate aminotransferase (U/L)	22.18 ± 11.70	22.27 ± 11.20	21.61 ± 9.91	21.80 ± 13.67	23.05 ± 11.69	0.082
Alkaline phosphatase (IU/L)	81.80 ± 25.64	81.36 ± 25.93	82.25 ± 26.85	82.02 ± 26.45	81.59 ± 23.22	0.909
Blood urea nitrogen (mmol/L)	16.52 ± 6.15	15.06 ± 5.10	15.55 ± 4.81	16.78 ± 5.71	18.70 ± 7.85	< 0.001
Serum Creatinine (mg/dL)	0.95 ± 0.42	0.82 ± 0.41	0.90 ± 0.43	0.96 ± 0.38	1.11 ± 0.40	< 0.001
Serum Calcium (mg/dL)	9.31 ± 0.39	9.33 ± 0.38	9.29 ± 0.39	9.31 ± 0.38	9.29 ± 0.41	0.213
Total cholesterol (mg/dL)	190.64 ± 43.77	203.09 ± 39.92	194.77 ± 42.66	183.96 ± 43.19	180.75 ± 45.59	< 0.001
Triglyceride (mg/dL)	143.88 ± 98.51	101.37 ± 45.25	127.92 ± 62.72	146.48 ± 74.88	199.57 ± 148.52	< 0.001
HDL-C (mg/dL)	54.59 ± 16.28	72.76 ± 16.09	57.21 ± 9.94	48.46 ± 8.20	40.00 ± 7.03	< 0.001
UA (mg/dL)	5.53 ± 1.46	4.15 ± 0.87	5.14 ± 0.91	5.82 ± 0.97	7.03 ± 1.25	< 0.001
Femur neck BMD (g/cm²)	0.77 ± 0.15	0.72 ± 0.14	0.77 ± 0.15	0.79 ± 0.15	0.82 ± 0.14	< 0.001
Bone status, n (%)						< 0.001
Non-osteoporosis	2780 (93.82%)	657 (88.90%)	695 (93.67%)	704 (95.14%)	724 (97.57%)
Osteoporosis	183 (6.18%)	82 (11.10%)	47 (6.33%)	36 (4.86%)	18 (2.43%)
Normal BMI < 25 kg/m², overweight 25 ≤ BMI < 30 kg/m², obesity BMI ≥ 30 kg/m².
BMD, bone mineral density; BMI, body mass index, HDL-C, high-density lipoprotein cholesterol; UA, uric acid; UHR, uric acid to high-density lipoprotein cholesterol ratio.

Covariates screening

Covariates with a P-value < 0.1 in univariate linear regression analysis (outcome: FN-BMD) were selected for subsequent analysis. Finally, all covariates except for education level, milk product consumption, history of arthritis, BUN, and TG were included in the subsequent analysis. For detailed participant information, please refer to Supplementary Table S1. The presence of multicollinearity between UHR and the included covariates was assessed through the variance inflation factor (VIF) values, with a VIF > 5 indicating multicollinearity. Based on the VIF values, there was no multicollinearity between UHR and the included covariates. Other detailed information is listed in Supplementary Table S2.

Association between UHR and BMD

The results of linear regression models indicated that UHR was positively associated with FN-BMD among individuals aged 50 and older with or without adjustments for covariates. Furthermore, the results of the subgroup analysis found that positive associations between UHR and FN-BMD were observed in individuals aged 65 and above, whites, those with normal BMI, and obese participants after adjustment for all covariates. In addition, the results of interaction analysis showed significant age differences (but not for other stratification factors) after adjustment for all covariates. Detailed data are provided in Table 2. Finally, the results of nonlinear fitting indicated that FN-BMD increased with an increase in UHR values. The specific results are shown in Fig. 2.

Table 2

Association between UHR and FN-BMD
Population	Model1			Model2			Model3
	β (95% CI)	P-value	P interaction	β (95% CI)	P-value	P interaction	β (95% CI)	P-value	P interaction
Overall	0.0065 (0.0055, 0.0075)	<0.0001	-	0.0014 (0.0004, 0.0024)	0.0044	-	0.0014 (0.0004, 0.0024)	0.0051	-
Age ^a			0.5020			0.0168			0.0331
50–64 years	0.0064 (0.0051, 0.0078)	<0.0001		0.0004 (-0.0010,0.0018)	0.5589		0.0010 (-0.0004,0.0024)	0.1649
65 years and older	0.0071 (0.0057, 0.0086)	<0.0001		0.0023 (0.0009, 0.0038)	0.0014		0.0022 (0.0007, 0.0036)	0.0040
Sex/menopausal status ^b			0.1002			0.8037			0.6346
Post-menopausal women	0.0060 (0.0037, 0.0082)	<0.0001		0.0019 (-0.0002,0.0040)	0.0802		0.0018 (-0.0005,0.0042)	0.1185
Pre-menopausal women	0.0027 (0.0006, 0.0048)	0.0139		0.0018 (-0.0001,0.0037)	0.0587		0.0018 (-0.0001,0.0037)	0.0605
Men	0.0034 (0.0020, 0.0048)	0.0001		0.0013 (-0.0001,0.0027)	0.0659		0.0013 (-0.0001,0.0027)	0.0698
Race/ethnicity ^c			0.4820			0.3536			0.3386
Non-Hispanic White	0.0062 (0.0048, 0.0076)	<0.0001		0.0016 (0.0002, 0.0031)	0.0245		0.0016 (0.0001, 0.0030)	0.0366
Non-Hispanic Black	0.0063 (0.0041, 0.0085)	<0.0001		0.0019 (-0.0004,0.0041)	0.1028		0.0020 (-0.0003,0.0044)	0.0829
Mexican American	0.0044 (0.0013, 0.0076)	0.0062		0.0009 (-0.0025,0.0042)	0.6145		0.0013 (-0.0024,0.0049)	0.4980
Other races	0.0075 (0.0057, 0.0094)	<0.0001		0.0005 (-0.0014,0.0025)	0.5987		0.0002 (-0.0018,0.0023)	0.8243
BMI ^d			0.2530			0.3621			0.3058
Normal BMI	0.0061 (0.0040, 0.0083)	<0.0001		0.0019 (-0.0002,0.0041)	0.0734		0.0024 (0.0002, 0.0046)	0.0360
Overweight	0.0043 (0.0026, 0.0061)	0.0001		0.0002 (-0.0016,0.0020)	0.8313		0.0004 (-0.0015,0.0022)	0.7067
Obesity	0.0038 (0.0023, 0.0053)	0.0659		0.0019 (0.0005, 0.0033)	0.0087		0.0018 (0.0004, 0.0033)	0.0154
Model 1: no covariates were adjusted; Model 2: age, sex/menopausal status, race/ethnicity, and BMI were adjusted; Model 3: all covariates were adjusted.
^a age was not adjusted.
^b sex/menopausal status was not adjusted.
^c race/ethnicity was not adjusted.
^d BMI was not adjusted.
BMD, bone mineral density; BMI body mass index; FN, femoral neck; UHR, uric acid to high-density lipoprotein cholesterol ratio.

Association between UHR and osteoporosis risk

The results of logistic regression analysis indicated that UHR was negatively associated with the risk of osteoporosis among individuals aged 50 and older with or without adjustments for covariates. Furthermore, the results of subgroup analysis found that the negative associations between UHR and the risk of osteoporosis were observed in men, whites, blacks, those with normal BMI, and obese participants. The results of the interaction analysis suggested that there were no significant interactions detected after adjustment for covariates. Detailed data are provided in Table 3.

Table 3

Association between UHR and the risk of osteoporosis
Population	Model 1			Model 2			Model 3
	OR (95% CI)	P-value	P interaction	OR (95% CI)	P-value	P interaction	OR (95% CI)	P-value	P interaction
Overall	0.8670 (0.8323, 0.9032)	< 0.0001	-	0.9347 (0.8931, 0.9783)	0.0037	-	0.9148 (0.8716, 0.9602)	0.0003	-
Age ^a			0.3849			0.8686			0.8600
50–64 years	0.8349 (0.7716, 0.9034)	0.0001		0.9503 (0.8731, 1.0343)	0.2379		0.9072 (0.8254, 0.9972)	0.0437
65 years and older	0.8697 (0.8281, 0.9133)	< 0.0001		0.9337 (0.8852, 0.9849)	0.0119		0.9233 (0.8728, 0.9767)	0.0054
Sex/menopausal status ^b			0.6869			0.7163			0.9477
Post-menopausal women	0.8902 (0.8248, 0.9607)	0.0028		0.9594 (0.8840, 1.0412)	0.3211		0.9082 (0.8203, 1.0057)	0.0641
Pre-menopausal women	0.9225 (0.8483, 1.0032)	0.0595		0.9443 (0.8684, 1.0268)	0.1801		0.9137 (0.8295, 1.0064)	0.0673
Men	0.8795 (0.8210, 0.9421)	0.0003		0.9028 (0.8384, 0.9722)	0.0068		0.9080 (0.8417, 0.9794)	0.0125
Race/ethnicity ^c			0.2837			0.2353			0.2237
Non-Hispanic White	0.8926 (0.8509, 0.9364)	0.0001		0.9412 (0.8915, 0.9936)	0.0285		0.9196 (0.8676, 0.9747)	0.0048
Non-Hispanic Black	0.7877 (0.6654, 0.9324)	0.0055		0.8397 (0.7012, 1.0055)	0.0574		0.7977 (0.6397, 0.9949)	0.0449
Mexican American	0.8634 (0.6998, 1.0654)	0.1708		0.8922 (0.6847, 1.1626)	0.3984		0.0005 (0.0000, Inf)	0.9985
Other races	0.8245 (0.7481, 0.9087)	0.0001		0.9292 (0.8311, 1.0390)	0.1977		0.9273 (0.8156, 1.0542)	0.2489
BMI ^d			0.9420			0.9311			0.8375
Normal BMI	0.9050 (0.8505, 0.9630)	0.0016		0.9472 (0.8842, 1.0147)	0.1227		0.9151 (0.8460, 0.9899)	0.0269
Overweight	0.9153 (0.8496, 0.9860)	0.0198		0.9391 (0.8639, 1.0209)	0.1403		0.9342 (0.8521, 1.0242)	0.1469
Obesity	0.8978 (0.8266, 0.9751)	0.0105		0.9036 (0.8255, 0.9891)	0.0280		0.8872 (0.8041, 0.9789)	0.0171
Model 1: no covariates were adjusted; Model 2: age, sex/menopausal status, race/ethnicity, and BMI were adjusted; Model 3: all covariates were adjusted.
^a age was not adjusted.
^b sex/menopausal status was not adjusted.
^c race/ethnicity was not adjusted.
^d BMI was not adjusted.
BMI, body mass index; CI, confidence interval; OR, odds ratio; UHR, uric acid to high-density lipoprotein cholesterol ratio.

Sensitivity analysis

When UHR was transformed from a continuous variable into a categorical variable (Q1 to Q4), the results of linear regression results indicated that individuals with the highest UHR levels (Q4) exhibited higher FN-BMD than those with the lowest UHR levels (Q1). Moreover, the results of logistic regression analysis suggested that individuals with higher UHR levels (Q3 and Q4) showed a lower risk of osteoporosis than those with the lowest UHR level (Q1). The specifical results are listed in Table 4.

Table 4

Association between UHR (Q1 to Q4) and FN-BMD (and the risk of osteoporosis)
Outcome	Subgroup	Model1		Model2		Model3
		β/OR (95% CI)	P-value	β/OR (95% CI)	P-value	β/OR (95% CI)	P-value
FN-BMD	UHR (Q1)	Reference (0)	-	Reference (0)	-	Reference (0)	-
	UHR (Q2)	0.0464 (0.0318, 0.0611)	< 0.0001	0.0057 (-0.0074, 0.0188)	0.3952	0.0079 (-0.0051, 0.0209)	0.2356
	UHR (Q3)	0.0690 (0.0543, 0.0836)	< 0.0001	0.0112 (-0.0024, 0.0249)	0.1070	0.0126 (-0.0012, 0.0263)	0.0728
	UHR (Q4)	0.0967 (0.0821, 0.1113)	< 0.0001	0.0164 (0.0017, 0.0311)	0.0285	0.0180 (0.0031, 0.0328)	0.0181
Non-osteoporosis vs. Osteoporosis	UHR (Q1)	Reference (1)	-	Reference (1)	-	Reference (1)	-
	UHR (Q2)	0.5418 (0.3727, 0.7877)	0.0013	0.8622 (0.5712, 1.3015)	0.4805	0.7868 (0.5158, 1.2002)	0.2657
	UHR (Q3)	0.4097 (0.2730, 0.6149)	0.0001	0.7240 (0.4571, 1.1467)	0.1687	0.6094 (0.3782, 0.9821)	0.0419
	UHR (Q4)	0.1992 (0.1183, 0.3354)	< 0.0001	0.4678 (0.2586, 0.8461)	0.0120	0.3948 (0.2137, 0.7296)	0.0030
Model 1: no covariates were adjusted; Model 2: age, sex/menopausal status, race/ethnicity, and BMI were adjusted; Model 3: all covariates were adjusted.
BMD, bone mineral density; CI, confidence interval; FN, femoral neck; OR, odds ratio; UHR, uric acid to high-density lipoprotein cholesterol ratio.

The escalating incidence of osteoporosis among middle-aged and elderly individuals, leading to a notable decline in quality of life for older adults, has elevated osteoporosis to a recognized global public health issue [1, 12]. This cross-sectional study observed that UHR showed a positive association with FN-BMD and a negative association with osteoporosis risk in individuals aged 50 and older. Furthermore, the results of subgroup analyses revealed that the positive association between UHR and FN-BMD was observed in individuals aged 65 and older but not those aged 50–64 years, and the results of interaction analysis showed significant age differences after adjustment for all covariates.

This study identified a positive association between UHR and BMD, and individuals with high UHR levels were associated with a reduced risk of osteoporosis. Previous research has reported a positive association between UA levels and BMD [31–34]. For instance, Jin et al. observed a positive association between UA and BMD males aged 50 and above [33]. Xu et al. found that serum UA levels were positively associated with BMD among patients diagnosed with osteoporosis [34]. Yao et al. demonstrated a positive correlation between UA and lumbar spine BMD in elderly individuals [35]. However, the relationship between HDL-C and BMD is a topic of debate, as numerous studies have suggested a negative correlation between HDL-C and BMD [36, 37]. Tang et al. observed a negative association between HDL-C and BMD in individuals aged 20 and above [36]. Wang et al. identified a negative correlation between HDL-C levels and total BMD in male adolescents aged 12 to 19, specifically in non-black and non-Mexican populations [37]. In contrast, Xie et al. posited that a positive correlation between HDL-C and lumbar spine BMD was observed in individuals aged 20 to 59 years in their study [38]. The aforementioned findings may contribute to the observed positive association between UHR and BMD. Nevertheless, further investigations with larger sample sizes are necessary to elucidate the relationship between UHR and BMD more comprehensively.

The current study found a positive correlation between UHR and FN-BMD in individuals aged 65 and older, but not in those aged 50 to 64. This discrepancy may be attributed to several factors. The prevalence of osteoporosis varies among different age groups, with a notable increase in incidence as age increases [1, 7, 12]. Additionally, age was identified as a significant independent factor influencing BMD [1, 6, 12]. Furthermore, it is important to note that the sample size of individuals with osteoporosis in the 50–64 age group was relatively small (N = 56) in this study. Therefore, further research is needed to thoroughly elucidate these age-related differences.

The main findings of this study might have implications for future investigation. The novel inflammation and metabolic indicator UHR, which is a composite of UA and HDL-C, has been linked to various clinical conditions including hypertension, diabetes, metabolic syndrome, and non-alcoholic fatty liver disease [18, 39–41]. To the best of our knowledge, we firstly investigated the association between UHR and BMD, as well as the risk of osteoporosis. Importantly, we found that UHR values were negatively associated with osteoporosis risk. Therefore, UHR could serve as a novel indicator for identifying and predicting osteoporosis risk. Furthermore, the study revealed that the correlation between UHR and FN-BMD was only significant in individuals aged 65 and above, as opposed to those aged 50 to 64. Additionally, the findings from the interaction analysis indicated significant age-related differences following the adjustment for covariates. While the underlying reasons for these age disparities remain unclear, it is imperative to take into account such variations in age when utilizing UHR as a marker for identifying or predicting osteoporosis risk.

This study has some limitations, as follows. First, due to the cross-sectional design of the present study, we could not make interpretations of causality between UHR and osteoporosis. Second, some covariates in the study were collected using self-reported questionnaires, which might introduce recall bias. Third, the sample size of participants with osteoporosis in the present study was relatively small. Additional studies with large sample sizes are needed to investigate the relationship between UHR and osteoporosis risk further. Finally, as the participants in our study were exclusively from the United States, the current findings may not be applicable to other countries.

Clinicians should be alert to the potential risk of osteoporosis among individuals with low UHR levels. UHR might serve as a risk indicator for osteoporosis.

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ANOVA

analysis of variance

AST

aspartate aminotransferase

BMD

bone mineral density

BMI

body mass index

BUN

blood urea nitrogen

DXA

dual-energy X-ray absorptiometry

FN-BMD

femoral neck BMD

GAM

generalized additive model

HDL-C

high-density lipoprotein cholesterol

NHANES

National Health and Nutrition Examination Survey

NCHS

National Center for Health Statistics

standard deviation

total cholesterol

triglycerides

uric acid

UHR

uric acid to high-density lipoprotein cholesterol ratio

VIF

variance inflation factor.

Ethics approval and consent to participate

The NHANES was granted approval by the NCHS ethics review board. All participants from the NHANES were duly provided with and acknowledged the informed consent.

Consent for publication

Not applicable.

Availability of data and materials

The datasets obtained and analyzed in the present study are publicly available on the NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm).

Competing interests

The authors declare that they have no conflict of interest.

Funding

No Funding.

Authors' contributions

ZL and YT have contributed equally to this work. ZL: Conceptualization, Formal analysis, Data Curation, Writing- Original Draft, Writing- Review & Editing; YT: Conceptualization, Methodology, Validation, Writing- Original Draft, Writing- Review & Editing; YS: Software, Data Curation, Visualization, Writing- Review & Editing; ML: Validation, Writing- Review & Editing; MC: Software, Writing- Review & Editing; XP: Investigation, Writing- Review & Editing; ZH: Conceptualization, Writing - Review & Editing, Supervision; JH: Conceptualization, Methodology, Writing - Review & Editing, Supervision.

Acknowledgements

None.

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No competing interests reported.

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Uric acid to high-density lipoprotein cholesterol ratio and osteoporosis: evidence from the National Health and Nutrition Examination Survey

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Abstract

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Background

Methods

Study design and population

BMD measurement and osteoporosis

UHR assessment

Covariates

Statistical analysis

Results

Selection of the study population

Baseline characteristics

Covariates screening

Association between UHR and BMD

Association between UHR and osteoporosis risk

Sensitivity analysis

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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