The association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and bone mineral density in adult men: NHANES (2011-2018)

doi:10.21203/rs.3.rs-4881995/v1

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The association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and bone mineral density in adult men: NHANES (2011-2018)

https://doi.org/10.21203/rs.3.rs-4881995/v1

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Background The ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) represents a novel lipid marker. This study examined the correlation between NHHR and lumbar bone mineral density (BMD) in adult men.

Methods Data from the 2011 to 2018 National Health and Nutrition Examination Survey (NHANES) were utilized in this study, including 5,434 men aged 20-59 years. To analyze the relationship between NHHR and lumbar BMD, multivariate linear regression models and stratified analyses were employed. Fitted smoothing curves and threshold effect analysis were also applied to examine the nonlinear association of NHHR with lumbar BMD.

Results After adjusting for covariates, weighted multivariable linear regression models revealed a negative relationship between NHHR and lumbar BMD (β = -0.005, 95% CI: -0.008 to -0.002, P < 0.001). Subgroup analyses stratified by race, age, and BMI demonstrated this negative association in non-Hispanic black (β = -0.015, 95% CI: -0.025 to -0.005, P = 0.003) and other race (β = -0.006, 95% CI: -0.012 to -0.001, P = 0.013), participants aged 40-49 years (β = -0.011, 95% CI: -0.017 to -0.004, P = 0.001), BMI<25 (β = -0.009, 95% CI: -0.017 to -0.001, P= 0.022) and 25≤BMI<30 (β = -0.010, 95% CI: -0.015 to -0.005, P < 0.001). For the total cohort, other race individuals, and participants aged 30-39 years, a nonlinear relationship was explored with inflection points at 4.76, 5.00, and 2.83, respectively.

Conclusions In adult men aged 20 to 59 years, our research identified a negative relationship between NHHR and lumbar BMD. Among the overall cohort, as well as in other race individuals and participants aged 30-39 years, the relationship exhibited a nonlinear curve with inflection points at 4.76, 5.00, and 2.83, respectively. Consequently, NHHR measurement may serve as a sensitive biomarker for early osteoporosis detection and therapeutic guidance.

Health sciences/Diseases

Health sciences/Endocrinology

Health sciences/Medical research

Health sciences/Pathogenesis

NHANE

Lumbar BMD

Osteoporosis

NHHR

Osteoporosis is a systemic skeletal disease characterized by diminished bone mass and the deterioration of bone microarchitecture, leading to increased fragility and a substantially heightened risk of fractures [1, 2]. According to the International Osteoporosis Foundation, over 30% of women and more than 20% of men over the age of 50 suffer from osteoporosis or reduced bone mass, placing them at significant risk for fractures [3]. Concurrently, with the aging population, the incidence of osteoporosis continues to escalate [4]. Osteoporosis not only severely impacts patients' quality of life, resulting in serious consequences such as hip, spine, and wrist fractures, but also imposes a substantial economic burden and consumes significant healthcare resources [5, 6]. In addition to senile osteoporosis and postmenopausal osteoporosis, reduced bone mass in adult men and women is a significant concern and may represent an intervenable stage [7, 8]. Bone loss is influenced by multiple factors, including genetics, age, environment, and lifestyle, and is closely linked to lipid metabolism [9, 10]. Therefore, to mitigate the high prevalence and mortality associated with osteoporosis, it is essential to identify and manage modifiable factors contributing to the condition.

The roles of various lipoproteins in cardiovascular diseases have been extensively investigated, underscoring their significant impact on atherosclerosis and related conditions [11]. Recent studies exploring the relationship between lipoproteins and osteoporosis have elucidated the intricate associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). The pathogenic role of LDL-C in atherosclerosis is well-established [12]. Previous literature has demonstrated a negative correlation between LDL-C and bone mineral density (BMD) [13]. In contrast, other studies have shown that HDL-C is positively correlated with bone density, highlighting its potential protective role in bone health [14]. However, some studies indicate a negative correlation or no correlation between HDL-C levels and BMD [15, 16]. Furthermore, fluctuations in triglyceride and total cholesterol levels are closely associated with BMD, although the findings from different research studies have been incongruous [15, 17].

In recent years, the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has emerged as a novel comprehensive indicator, reflecting the overall status of lipid metabolism. It may offer superior predictive value for cardiovascular diseases and osteoporosis compared to traditional single lipid markers [18]. However, the relationship between NHHR and BMD in adult men remains unexplored. Therefore, this study aimed to evaluate the relationship between NHHR and BMD in adult men, using data from the National Health and Nutrition Examination Survey (NHANES) 2011–2018. We hypothesized that NHHR is negatively related to lumbar BMD.

Study population and inclusion criteria

The NHANES is a national program in the United States designed to provide objective statistics on health issues and address emerging public health concerns among the general public. The National Center for Health Statistics’ Institutional Review Board approved the survey methodologies, and informed consent was obtained from all participants [19]. Our analysis utilized data from 2011 to 2018, encompassing four cycles of the NHANES datasets, including a total of 39,156 participants. The exclusion criteria were: (1) females (n = 19,848), (2) participants younger than 20 years or older than 59 years (n = 12,155), (3) individuals with missing NHHR (n = 719) and BMD data (n = 836), and (4) those with missing covariate data (n = 164). Ultimately, 5,434 participants were included in our analysis (Fig. 1).

NHHR exposure assessment

In this study, NHHR, defined as the ratio of non-HDL-C to HDL-C, was utilized as the exposure variable. Using blood samples obtained from fasting individuals, non-HDL-C is determined by deducting HDL-C from TC [20, 21]. An automated biochemical analyzer performed enzymatic testing to assess TC and HDL-C levels.

BMD measurements

Total lumbar BMD was used as an outcome variable in this analysis, calculated as the mean of measurements obtained from the first to the fourth lumbar vertebra. Dual-energy X-ray absorptiometry is a widely utilized technology for evaluating BMD, owing to its efficiency, simplicity, and minimal radiation exposure [22]. Dual-energy X-ray absorptiometry was performed using a Hologic QDR 4500A device and Apex software version 3.2 by qualified radiology technologists to assess lumbar BMD.

Covariates definitions

Multivariate models included variables that might confound the relationship between NHHR and lumbar BMD. The analysis incorporated the following covariates: age, race, educational level, marital status, smoking history, drinking history, moderate work activity, hypertension, diabetes, ratio of family income to poverty (PIR), body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum calcium, serum phosphorus, total protein, blood urea nitrogen, serum uric acid, TC, HDL-C, TG, LDL-C, and lumbar BMD. Categories "other Hispanic" and "other multiracial race" from the original NHANES data were combined into the variable "other race" to reduce sample size bias. Smoking, drinking, moderate work activity, hypertension, and diabetes were assessed via questionnaires: "Have you smoked at least 100 cigarettes in your lifetime?", “Have you ever had 4/5 or more drinks every day?”, "Does moderate-intensity activity cause slight increases in breathing or heart rate?", "Has a doctor ever diagnosed you with diabetes?", and "Has a doctor ever diagnosed you with high blood pressure?" Comprehensive details on these covariates can be accessed on the NHANES website (https://www.cdc.gov/nchs/nhanes/).

Statistical analysis

All assessments incorporated NHANES sampling weights. The present study used the mean ± standard deviation to represent continuous variables and percentages for categorical variables. Participant characteristics were divided into quartiles based on NHHR levels. To compare differences between participant characteristics, weighted Student's t-tests were used for continuous variables and weighted chi-square tests for categorical variables. Weighted multivariate linear regression analyses were conducted to explore the relationship between NHHR and lumbar BMD using three distinct models. Model 1 was unadjusted. Model 2 adjusted for age and race. Model 3 adjusted for age, race, educational level, marital status, smoking, drinking, moderate work activity, hypertension, diabetes, PIR, BMI, ALT, AST, serum calcium, serum phosphorus, total protein, blood urea nitrogen, and serum uric acid. For subgroup analysis, stratified multivariate regression analysis was also performed. Moreover, nonlinear associations were assessed using weighted smooth curve fitting and threshold effect analysis. A two-piecewise linear regression model was utilized to determine the inflection point. All analyses were conducted using R (http://www.R-project.org, The R Foundation) and EmpowerStats software (http://www.empowerstats.com, X&Y Solutions, Inc., Boston, MA), with statistical significance set at P < 0.05.

Participants characteristics

The weighted characteristics of participants were divided into quartiles based on NHHR levels (Q1: 0.36–2.21; Q2: 2.22–3.06; Q3: 3.07–4.12; Q4: 4.13-27.00), as depicted in Table 1. This study included 5,434 participants aged 20 to 59 years, with a mean age of 38.98 ± 11.68 years, of whom 61.61% were non-Hispanic white. Most participants had an education level above high school (61.45%) and were married (51.81%). The prevalence of smoking, drinking, hypertension, and diabetes among participants were 46.62%, 21.10%, 23.44%, and 5.91%, respectively. Our study revealed significant differences in baseline characteristics between the NHHR quartiles. Participants in the highest NHHR quartile were predominantly non-Hispanic white, with elevated BMI, ALT, AST, serum uric acid, and TC, and reduced PIR and lumbar BMD compared to those in the lower quartiles.

Association between NHHR and BMD

The findings of the multivariate regression analysis are presented in Table 2. In Model 1, with no covariates adjusted, lumbar BMD was negatively correlated with NHHR (β = -0.008, 95% CI: -0.011 to -0.006, P < 0.001). This inverse association remained significant after adjusting for confounders in both Model 2 (β = -0.005, 95% CI: -0.008 to -0.003, P < 0.001) and Model 3 (β = -0.005, 95% CI: -0.008 to -0.002, P < 0.001). In the fully adjusted Model 3, participants in the highest NHHR quartile had a 0.029 g/cm² lower lumbar BMD compared to those in the lowest NHHR quartile after NHHR was converted from a continuous to a quartile variable.

Subgroup analysis

Subgroup analyses stratified by race, age, BMI, hypertension, and diabetes are presented in Table 2. In Model 3, the data indicated a negative correlation between NHHR and lumbar BMD exclusively in non-Hispanic black (β = -0.015, 95% CI: -0.025 to -0.005, P = 0.003) and other race (β = -0.006, 95% CI: -0.012 to -0.001, P = 0.013) participants, with no significant association observed in Mexican American or non-Hispanic white groups. Age-stratified results revealed a negative relationship between NHHR and lumbar BMD in participants aged 40–49 years (β = -0.011, 95% CI: -0.017 to -0.004, P = 0.001). Among the three BMI groups, a significant negative correlation existed in the BMI < 25 range (β = -0.009, 95% CI: -0.017 to -0.001, P = 0.022) and the 25 ≤ BMI < 30 range (β = -0.010, 95% CI: -0.015 to -0.005, P < 0.001).

A nonlinear correlation between NHHR and BMD

Figures 2, 3, and 4 depict smooth curve fits and generalized additive models that were utilized to define the nonlinear connection between NHHR and lumbar BMD. Employing a two-piecewise linear regression model, the association between NHHR and lumbar BMD illustrated a nonlinear relationship, with an inflection point at 4.76 (Table 3). In the other race group, this relationship followed a reverse-L curve, with an inflection point at 5.00 (Table 4). Similarly, the relationship between NHHR and lumbar BMD in participants aged 30–39 years also followed a reverse-L curve, with an inflection point at 2.83 for NHHR (Table 5).

This study initially explored the relationship between NHHR and BMD in adult men. Our multivariate linear regression analyses revealed a negative correlation between NHHR and lumbar BMD. Curve fitting and threshold effect analyses indicated a nonlinear relationship between the variables, with an inflection point at 4.76. Specifically, in the other race group and participants aged 30–39 years, we discovered a nonlinear relationship between NHHR and lumbar BMD, with inflection points at 5.00 and 2.83, respectively.

Despite the absence of direct evidence on the role of NHHR in osteoporosis, extensive research has explored the relationship between HDL-C, LDL-C, and TC with osteoporosis [17, 23, 24]. Recent studies have revealed that LDL-C is negatively associated with lumbar spine BMD in postmenopausal women when LDL-C levels are below 3.52 mmol/L [25]. Xiao et al. further demonstrated that elevated LDL-C levels are linked to reduced lumbar spine BMD, indicating a detrimental impact of LDL-C on bone health [23]. High LDL-C levels may impair osteoblast function and enhance osteoclast activity, leading to decreased bone mass. LDL-C and its oxidized form (ox-LDL) can activate osteoclasts, promoting bone resorption and further decreasing BMD [26, 27]. Similarly, numerous studies have shown that higher cholesterol levels are associated with an increased risk of lower BMD or osteoporosis [28, 29]. Cao et al. reported a significant negative association between total cholesterol and total BMD in US adults after adjusting for age, BMI, smoking, and alcohol consumption [30]. Potential mechanisms may include systemic inflammation and oxidative stress induced by high cholesterol levels, disrupting bone metabolism balance by increasing bone resorption and decreasing bone formation [31].

Conversely, HDL-C is renowned for its role in reverse cholesterol transport, which can reduce the risk of cardiovascular disease and osteoporosis [24, 32]. Some studies suggest a positive correlation between high HDL-C levels and higher BMD, indicating a protective effect on bone health. For instance, Zolfaroli et al. found HDL-C positively associated with BMD at both the lumbar spine and femoral neck in postmenopausal women [14]. HDL-C may mitigate the production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), reducing inflammatory damage to bone tissue [33]. Additionally, HDL-C decreases oxidative stress, protecting osteoblasts from free radical damage and supporting bone formation and maintenance [34]. However, other studies have reported that HDL-C is either negatively correlated with BMD or shows no association, suggesting complex mechanisms through which HDL-C influences bone density. Hussain et al. found that higher HDL-C levels are associated with lower BMD, independent of common fracture risk factors [10]. Two cross-sectional surveys in China revealed a negative relationship between HDL-C and BMD, suggesting a potential adverse impact on bone health [35, 36]. Furthermore, another cross-sectional study found no association between HDL-C levels and osteoporosis in various locations [15]. The heterogeneity among studies, potentially arising from differences in study designs, sampling methodologies, confounding variables, and racial distribution, may explain these conflicting results.

Our research, after adjusting for covariates, indicates that a higher NHHR is significantly associated with lower BMD in adult men aged 20–59 years according to weighted multiple linear regression models. In line with the STROBE statement, we performed a subgroup analysis to identify specific groups exhibiting varied trends [37]. Among the total cohort, other race individuals, and participants aged 30–39 years, we discovered a nonlinear relationship with inflection points at 4.76, 5.00, and 2.83, respectively. Considering this relationship, regulating NHHR by lowering LDL-C and TG levels while maintaining or increasing HDL-C levels could offer a more comprehensive approach to preventing and treating osteoporosis.

Strengths and limitations

The study has several strengths. First, it is the first to explore the relationship between NHHR and lumbar BMD in American adult men, utilizing a nationally representative sample that reflects the general American population. Second, it suggests that NHHR may serve as a novel marker for bone health, highlighting the role of lipid metabolism disorders in bone loss mechanisms. Third, the use of multivariate linear regression, stratified analyses, smooth curve fitting, and threshold effect analysis, adjusted for numerous confounders, enhances the reliability of the results. However, the study has limitations. First, the sample is restricted to American men aged 20–59 years, and the relevance of the NHHR-BMD relationship to other populations or ethnicities remains uncertain due to genetic, environmental, and cultural differences, necessitating further mechanistic research and large-scale prospective studies. Additionally, the cross-sectional design limits the ability to establish causality between NHHR levels and BMD. Second, despite adjusting for many confounders, potential factors may still impact the outcomes. Third, the cross-sectional nature of the study restricts the ability to determine causality between NHHR and lumbar BMD in adult men. Therefore, further prospective clinical and basic research is needed to validate causal inferences.

In adult men aged 20 to 59 years, our research identified a negative relationship between NHHR and lumbar BMD. Across the overall cohort, as well as among other race individuals and participants aged 30–39 years, the relationship followed a reverse-L curve with inflection points at 4.76, 5.00, and 2.83, respectively. NHHR measurement may serve as a novel biomarker for the early detection and prevention of osteoporosis.

NHANES National Health and Nutrition Examination Survey

DXA dual-energy X-ray absorptiometry

PIR Ratio of family income to poverty

BMI Body mass index

ALT Alanine aminotransferase

AST Aspartate aminotransferase

TC Total cholesterol

HDL-C High-density lipoprotein cholesterol

TG Triglyceride

LDL-C Low-density lipoprotein cholesterol

BMD Bone mineral density

Acknowledgments

We acknowledge the data from the National Health and Nutrition Examination Survey (NHANES).

Author contributions

Z.S. performed and interpreted statistics and also drafted the initial manuscript. Y.Y. was responsible for data collection and statistical analysis. P.L. designed the study and revised the manuscript. All authors read and approved the final manuscript.

Funding

This research did not receive direct funding from any third-party donor or funding institution, whether public, commercial, or non-profit.

Data availability

The dataset that was analyzed in this study is publicly available at NHANES: https://www.cdc.gov/nchs/nhanes/.

Ethics approval and consent to participate

This study involving human participants was reviewed and approved by the Ethics Review Board of the National Center for Health Statistics. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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The association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio and bone mineral density in adult men: NHANES (2011-2018)

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Abstract

Figures

Introduction

Materials and methods

Study population and inclusion criteria

NHHR exposure assessment

BMD measurements

Covariates definitions

Statistical analysis

Results

Participants characteristics

Association between NHHR and BMD

Subgroup analysis

A nonlinear correlation between NHHR and BMD

Discussion

Strengths and limitations

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

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