Association Between Dietary Selenium Intake and Bone Mineral Density: A Cross-sectional Study Using National Health and Nutrition Examination Survey

Abstract

Assessments of whether dietary selenium intake is related to bone health are scarce, with few relevant studies limited by its small sample. The aim of present study was to investigated the association between dietary selenium intake and bone mineral density (BMD) levels in different sites, including total femur, femur neck, trochanter and intertrochanter in femur and lumbar spine in the National Health and Nutrition Examination Survey (NHANES) database. Generalized linear models for the association between dietary selenium intake and BMD and generalized additive model for the dose-response relationship were used. A total of 21939 participants were included, and the mean age was 40.68 ± 22.42 years, and 51.28% were male. In multivariable adjustment model, participants had highest quintiles of dietary selenium intake (Q5) were associated with increased BMD levels in total femur (β=0.014, 95CI%: 0.008, 0.020, P＜0.001), femur neck (β=0.010, 95CI%: 0.004, 0.016, P=0.001), trochanter (β=0.011, 95CI%: 0.005, 0.017, P＜0.001), intertrochanter (β=0.017, 95CI%: 0.010, 0.025, P＜0.001) and lumbar spine (β=0.013, 95CI%: 0.005, 0.020, P＜0.001) compared with those in quintiles 1 (Q1). The dose-response relationship showed the inverted U-shape relationship between dietary selenium relationship and BMD levels (P for non-linearity ＜0.05). Participants tended to have increased levels of BMD as the dietary selenium intake increased when dietary selenium was below the turning point, and then a negative relation was observed when dietary was higher than the turning point. Our study indicated that higher dietary selenium intake was associated with increased BMD levels in total femur, femur neck, trochanter, intertrochanter, and lumbar spine, and these relationships were nonlinear. Future high-quality, prospective longitudinal studies are needed to confirm these findings.

Introduction

Osteoporosis is a systemic bone disease that is common worldwide. Approximately 10.2 million people aged 50 years and over had osteoporosis in 2010 in the US, and the number is expected to reach 13.5 million by 2030 [1, 2]. Osteoporosis, characterized by reduced bone mass, low bone mineral density (BMD), and bone microstructure deterioration [3, 4], increases the risk of all-cause mortality, including cardiovascular- and cancer-related mortality [5–7]. The etiology of reduced bone mass and the development of osteoporosis is related to multiple factors, including genetic, environmental, and dietary factors [8, 9]. Furthermore, oxidative stress has been implicated as a causative factor for many disease states, including the diminished BMD in osteoporosis. Therefore, including antioxidant-rich whole plant foods in the diet and adopting lifestyle modifications to maintain appropriate antioxidant levels may increase BMD and reduce the risk of brittleness-related fractures [10].

The element selenium is an essential micronutrient that forms the so-called “selenoproteins” when incorporated into the polypeptide chain of proteins. Selenoproteins and Se-dependent enzymes are involved in many crucial biological mechanisms, such as antioxidant and anti-inflammatory pathways [11, 12], intracellular redox regulation [13], and thyroid hormone metabolism [14]. A previous observational study demonstrated that the serum Se concentration was positively associated with bone outcomes, including BMD and fracture risk [15]. In a cross-sectional study, the relationship between serum selenium and the risk of osteoporosis-related fracture was nonlinear, but a strong positive correlation was evident between osteoporosis-related fracture risk and relatively high selenium exposure [16]. At present, few studies have examined the effects of dietary selenium intake on bone health, and those that have are limited by small sample sizes.

One study suggested that antioxidant intake, including Se, β-carotene, vitamin C, and vitamin E, was inversely associated with the risk of osteoporotic hip fracture in an older population of smokers [17]. However, a prospective population-based cohort study indicated that sodium selenite supplementation did not affect bone turnover markers or physical performance in postmenopausal women with osteopenia [18].

This study investigated the association between dietary selenium intake and BMD in various bones, including the femur, femur neck, trochanter and intertrochanter in the femur, and lumbar spine. Data on dietary intake was drawn from the cross-sectional National Health and Nutrition Examination Survey (NHANES). We examined the nonlinear dose–response association between dietary selenium intake and BMD.

Methods

The protocol of the present study was approved by the Institutional Review Board of the National Center for Health Statistics in United States. All participants gave their written informed consent. All authors declared that all methods in this study were carried out in accordance with relevant guidelines and regulations.

Study population

We used the data from NHANES, which is a population-based cross-sectional survey designed to assess the health, nutritional status, and potential risk factors of the civilian, noninstitutionalized population of the US. The consecutive surveys are conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control (CDC) via in-person interviews, physical examinations and laboratory tests in a mobile examination center (MEC). Approximately, 5000 individuals at 15 geographic sites are selected by a multistage, stratified probability sampling design every 2 years. NHANES was approved by the National Center for Health Statistics Institutional Review Board, and each participants provided written informed consent. We extracted and aggregated data from four cycles of NHANES (2005–2010, 2013-2014). Participants with missing information on dietary selenium intake and BMD were excluded. Lastly, data on 21 939 participants were available for analysis of total femur, femur neck, trochanter and intertrochanter in femur, and 18 116 participants were available for analysis of lumbar spine. The detailed description of the NHANES was published elsewhere[6,19].

Assessment of dietary selenium intake

Dietary selenium intake and other food components, including dietary fiber and calcium intake were obtained from 24-hour dietary recall interviews which was conducted in the Mobile Examination Center (MEC). During the interview, participants were asked to recall the details of food and beverages consumed in 24-hours period before the interview. For each participant, nutrient intake from each food or beverage were estimated. The dietary selenium intake was calculated as microgram per day (μg/day).

Bone mineral density measurement 

BMD measurement was obtained using the method of dual-energy x-ray absorptiometry (DXA) with Hologic QDR 4500A fan-beam densitometers (Hologic Inc., Bedford, MA, USA)[6], which is an internationally accepted standard-of-care screening tool used to assess fragility-fracture risk[20]. The DXA examinations were administered by trained and certified radiology technologists. DXA scans were administered to eligible survey participants 8 years of age and older. Pregnant female, self-reported history of radiographic contrast material in the past 7 days, and measured weighted over 300 pounds were ineligible for the DXA examination.

Other covariates

The covariates involved age (years), sex (male and female), race (non-Hispanic white, non-Hispanic black, Mexican American, or other race/ethnicity), education (under high school, high school, or above high school), and family income (Under $20,000, $20,000-55000, or $20,000 and over) were obtained from in-person household interviews. Body mass index (BMI) was calculated as weight divided by height squared (kg/m²), and was classified into underweight (＜18.5 kg/m²), normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (≥30 kg/m²). Furthermore, leisure time physical activity (＜500 MET/week, 500-999 MET/week, or ≥1000 MET/week), smoke status (yes or no), alcohol use (yes or no), diabetes (yes or no), and hypertension (yes or no) were ascertained using questionnaires, which were self-reported by the participants.

Statistical analysis

Descriptive characteristics were summarized using means ± standard deviation (SD) for continuous variables and proportions for categorical variables. Data analyses accounted for the masked variance and used the recommended weighting methodology. Dietary selenium intake was divided into quintiles, and the differences between quintiles of selenium in participants characteristics were determined using one-way ANOVA or χ2 tests. We used generalized linear models to assess the association between dietary selenium intake and BMD. Three models were used in current analysis: model 1 was crude model without adjustment for potential confounders; model 2 was adjusted for age and sex; model 3 was further adjusted for race, education, family income, body mass index, leisure time physical activity, smoke status, alcohol use, dietary fiber intake, calcium intake, diabetes, and hypertension. We also assess the dose-response relationship between dietary selenium intake and BMD by using a generalized additive model (GAM). Moreover, to test the robustness of our findings, we used subgroup analysis by age (<50 vs. ≥50 years) and sex. All statistical analysis were performed using R software (version 3.5.3) and EmpowerStats (R) (www.empowerstats.com, X&Y solutions, Inc. Boston MA). Statistical significance was indicated by a two-sided P value <0.05.

Results

Characteristics of the participants included in present study are shown in Table 1. Of the 21939 participants, the mean age was 40.68 ± 22.42 years, and 51.28% were male. Approximately, 43% of participants were non-Hispanic white, and 44.54% of participants had education level less than high school. Compare with participants in quintiles 1 (Q1), those in higher quintiles (Q2-Q5) tended to be younger, male, non-Hispanic white, and have higher educated, higher family income, more smoke and alcohol use, more leisure time physical activity, dietary fiber and calcium intake, and lower prevalence of diabetes and hypertension.

The unadjusted and multivariable adjusted associations between dietary selenium intake and BMD, including total femur, femur neck, trochanter, intertrochanter and lumbar spine are shown in Table 2. In crude model, compared with the lowest quintiles of dietary selenium intake, higher dietary selenium intake was linked with increased BMD levels (all P-trend < 0.001). After adjustment for potential confounders, the results were also consistent. In multivariable model, participants had highest quintiles of dietary selenium intake (Q5) were associated with increased BMD levels in total femur (β = 0.014, 95CI%: 0.008, 0.020, P<0.001), femur neck (β = 0.010, 95CI%: 0.004, 0.016, P = 0.001), trochanter (β = 0.011, 95CI%: 0.005, 0.017, P<0.001), intertrochanter (β = 0.017, 95CI%: 0.010, 0.025, P<0.001) and lumbar spine (β = 0.013, 95CI%: 0.005, 0.020, P<0.001) compared with those in quintiles 1 (Q1).

We further used GAM to examine the dose-response association, and found the inverted U-shape association between dietary selenium intake and BMD levels (Fig. 1). Overall, participants tended to have increased levels of BMD as the dietary selenium intake increased when dietary selenium intake was below the turning point, and then the BMD decrease as the dietary selenium intake increased when dietary selenium intake was higher than the turning point. Furthermore, we used a log likelihood ratio test showed the significant differences between linear model to and segmented regression model, indicating that the associations between dietary selenium intake and BMD levels of total femur (P < 0.001), femur neck (P = 0.003), trochanter (P = 0.005), intertrochanter (P < 0.001), and lumbar spine (P = 0.004) were non-linear.

In the subgroups stratified by age, the highest quintiles of dietary selenium intake were positively associated with increased BMD levels in total femur, femur neck, trochanter, intertrochanter, and lumbar spine (Table 3). By contrast, no statistical associations were observed between highest quintiles of dietary selenium intake and BMD level in female.

Discussion

We analyzed data from a large-scale nationally representative population-based cross-sectional study (NHANES) and determined that higher dietary selenium intake was associated with increased BMD in the femur, femur neck, trochanter, intertrochanter, and lumbar spine, and the effect remained consistent across various age groups and genders. Furthermore, the results from the generalized additive model suggested a nonlinear inverted U-shape association between dietary selenium intake and BMD.

Severe Se deficiency is associated with Keshan disease, an endemic osteoarticular cardiomyopathy that is characterized by the selective necrosis of articular and growth plate chondrocytes [21]. Bone has the second-highest proportion of selenium (16%) in the body, only exceeded by skeletal muscles (27.5%) [22]. Few studies have examined the association between dietary selenium intake and bone health, leading to inconsistent epidemiological results. One study demonstrated that dietary selenium supplementation did not attenuate mammary tumorigenesis–mediated bone loss in a male mouse breast cancer model [23]. A recent randomized double-blinded controlled study by Walsh et al. reported that 200 µg/day selenite supplementation did not affect the musculoskeletal health of postmenopausal women [24]. However, in the present study, a higher dietary selenium intake did result in increased BMD. In line with our findings, a cross-sectional study that included 6267 participants demonstrated that compared with those in the lowest quartile of dietary selenium intake, those belonging to the fourth quartile exhibited a lower odds ratio for osteoporosis (OR: 0.47, 95% CI: 0.31–0.73) [25]. Zhang et al. observed that Se intake was negatively associated with the risk of osteoporotic hip fracture [17].

The biological mechanisms responsible for the effects of Se intake on BMD are uncertain. A previous study demonstrated that changes in the redox state can alter the bone remodeling process, which allows continuous bone regeneration through the coordination of the three major types of bone cells: osteoclasts, osteoblasts, and osteocytes [26]. Changes in reactive oxygen species (ROS) and/or antioxidant systems may be involved in the pathogenesis of bone loss. Osteoblast and osteocyte apoptosis induced by ROS leads to osteoclast formation and inhibits mineralization and osteogenesis. Excessive osteocyte apoptosis is associated with oxidative stress that leads to imbalanced osteoclast formation, which results in increased bone remodeling and bone loss [26–28]. Moreover, Se plays a crucial role in antioxidant, immunological, and anti-inflammatory processes. The physiological function of the essential micronutrient Se is mainly mediated by selenoproteins [29], which have antioxidant activities and are known to maintain the redox cell balance, protect against oxidative stress caused by ROS, and regulate inflammation and osteocyte proliferation and differentiation [30]. Furthermore, it has been reported that interleukin-6 (IL-6) and other cytokines play a crucial role in the pathogenesis of osteoporosis [31]. Therefore, the anti-inflammatory effect of Se may be partly mediated by inhibiting the activity of IL-6 and cytokines [32, 25]. Another potential mechanism linking Se to bone health is the relationship of Se-dependent glutathione peroxidase to thyroid protection [33]. Therefore, Se deficiency may increase the level of thyroid hormone in the blood, leading to accelerated bone loss and osteoporosis [34].

Although limited data confirm the effects of dietary selenium supplementation on bone health, the accumulated evidence indicates a positive association between circulating Se concentrations and bone outcomes. A population-based cohort study conducted in five European cities demonstrated that higher Se levels were associated with increased hip BMD and decreased bone formation at the beginning of the research [15]. Other studies have indicated that Se deficiency can hinder bone growth and alter bone metabolism [35, 36]. In a survey conducted in the United States, increased serum Se concentrations were associated with increased femur BMD, decreased Fracture Risk Assessment Tool (FRAX) scores, and a reduced history of bone fractures [37]. A study, that used plasma Se and selenoprotein P as biomarkers demonstrated that an increase in Se content was associated with an increase in BMD in the lumbar spine and hip in European postmenopausal women [38]. In addition, low hair selenium levels have been reported to be associated with low lumbar and femoral BMD values in Korean adults [39]. The finding of a positive correlation between dietary selenium intake and blood selenium concentration [40, 41] suggests that Se supplementation may positively influence bone health in selenium -deficient patients.

Some observational studies have reported a U-shape relationship between serum Se and the risk of diabetes, coronary heart disease, anemia, and all-cause mortality [40, 42–44]. Data from NHANES Ⅲ indicate an inverse association between serum Se and all-cause mortality at low selenium levels (< 130 ng/mL) and a modest increase in mortality at high Se levels (> 150 ng/mL) [45]. Similar to the findings of these studies, the results of our study indicate a positive relationship between dietary selenium intake and BMD when dietary selenium intake is below a certain threshold and a negative relationship when dietary selenium intake is higher than that threshold. This may be because selenium is an essential element with a narrow safety margin, and higher concentrations often lead to toxicity [42]. Furthermore, the regulation of selenium levels in the body mainly depends on its excretion rather than absorption. When dietary selenium intake is high enough to optimize the levels of selenium protein, any further intake is completely offset by excreta, allowing for only a slight increase in systemic selenium [46].

The present study has several strengths. To our knowledge, this is the first study to assess the nonlinear relationship between dietary selenium intake and BMD in the femur, femur neck, trochanter, intertrochanter, and lumbar spine. Our study was based on a large nationally representative survey, and BMD was measured in a reliable independent lab using established methods. Moreover, we adjusted numerous potentially confounding factors, including socioeconomic, lifestyle, and nutrient intake factors. Our study also has some limitations. First, as a cross-sectional study, inferring a causal association between dietary selenium intake and BMD is challenging. Second, we did not assess the association between dietary selenium intake and the risk of osteoporosis because of the limitations of the original data. Furthermore, bone remodeling is a continuous physiological process that entails bone resorption by osteoclasts and bone formation by osteoblasts. Future high-quality, prospective longitudinal studies are required to confirm the findings of this study.

In summary, our study suggests that higher dietary selenium intake is associated with increased BMD in the femur, femur neck, trochanter, intertrochanter, and lumbar spine. Furthermore, this study identified an inverted U-shape relationship between dietary selenium intake and BMD. Future high-quality, prospective longitudinal studies are required to confirm these findings.

Conclusion

In summary, our study suggests that higher dietary selenium intake was associated with increased BMD levels in total femur, femur neck, trochanter, intertrochanter, and lumbar spine. Furthermore, the inverted U-shape relationship between dietary selenium intake and BMD levels were observed. Future high-quality, prospective longitudinal studies are needed to confirm these causalities.

Declarations

Acknowledgements We thank the third National Health and Nutrition Examination Survey for the permission for use of the data of the NHANES 2005–2010, 2013-2014.

Authors' contributions GX analyzed and interpreted the data, and was a major contributor in writing the manuscript. RL was the main contributor in the revising the contents of the original report. All authors read and approved the final manuscript.

Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Availability of data and materials The datasets analyzed during the current study are available in the website of the NHANES: https://www.cdc.gov/nchs/index.htm.

Compliance with Ethical Standards

Ethics approval and consent to participate This study was approved by the Institutional Review Board of the National Center for Health Statistics. All participants gave their written informed consent. All authors declared that all methods in this study were carried out in accordance with relevant guidelines and regulations.

Consent for Publication The authors consent the publication.

Code Availability Not applicable.

Conflict of Interest The authors declare no competing interests.

Code Availability Not applicable.

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