Abstract
Aims
Previous studies have suggested that selenium as a trace element is involved in bone health, but findings related to the specific effect of selenium on bone health remain inconclusive. Thus, we performed a meta-analysis by including all the relevant studies to elucidate the association between selenium status (dietary intake or serum selenium) and bone health indicators (bone mineral density (BMD), osteoporosis (OP), or fracture).
Methods
PubMed, Embase, and Cochrane Library were systematically searched to retrieve relevant articles published before 15 November 2022. Studies focusing on the correlation between selenium and BMD, OP, or fracture were included. Effect sizes included regression coefficient (β), weighted mean difference (WMD), and odds ratio (OR). According to heterogeneity, the fixed-effect or random-effect model was used to assess the association between selenium and bone health.
Results
From 748 non-duplicate publications, 19 studies were included. We found a significantly positive association between dietary selenium intake (β = 0.04, 95% confidence interval (CI) 0.00 to 0.07, p = 0.029) as well as serum selenium (β = 0.13, 95% CI 0.00 to 0.26, p = 0.046) and BMD. Consistently, those with higher selenium intake had a lower risk of OP (OR = 0.47, 95% CI 0.31 to 0.72, p = 0.001), and patients with OP had a significantly lower level of serum selenium than healthy controls (WMD = -2.01, 95% CI -3.91 to -0.12, p = 0.037). High dietary selenium intake was associated with a lower risk of hip fracture (OR = 0.44, 95% CI 0.37 to 0.52, p < 0.001).
Conclusion
Selenium was positively associated with BMD and inversely associated with OP; dietary selenium intake was negatively associated with hip fracture. The causality and therapeutic effect of selenium on OP needs to be investigated in future studies.
Cite this article: Bone Joint Res 2023;12(7):423–432.
Article focus
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Evaluate whether selenium status (dietary intake and serum selenium) is a protective factor of bone health.
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The primary outcomes of interest were bone mineral density (BMD), osteoporosis (OP) incidence, and fracture.
Key messages
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Compared with those who had lower dietary selenium intake and lower serum selenium, subjects with higher dietary selenium intake and higher serum selenium had higher BMD.
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Higher dietary selenium intake was associated with a lower risk of OP. Compared with healthy controls, OP patients had lower serum selenium.
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High selenium intake was associated with a lower risk of hip fracture.
Strengths and limitations
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This is the first meta-analysis focusing on the potential association between selenium and bone health.
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Including 19 studies that reported different outcomes of bone health (eight for BMD, eight for OP, and seven for fracture), we provided results based on a large sample covering 69,672 subjects.
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Heterogeneity was detected across the studies in certain analyses, while subgroup and sensitivity analyses were not conducted due to the relatively small number of studies.
Introduction
Bone health plays a pivotal role in the quality of life and ability to self-care, and its degradation is observed in diseases such as osteoporosis (OP) and osteoporotic fracture.1,2 OP is characterized by reduced bone mineral density (BMD) and deterioration of bone microarchitecture, and results in increased bone fragility and risk of fracture,3 leading to mobility limitations, chronic disability, and reduced quality of life.4,5 This condition was estimated to affect more than 10 million older adults in the USA,6 and the prevalence of OP was 20.6% among women aged 40 years or older in China.7 With an ageing population, it is predicted that OP-related healthcare burdens will increase rapidly.8 Multiple environmental and genetic factors play a role in OP,9-11 but there is still an urgent need to determine more modifiable potential risk factors for OP.
Selenium is a trace element that has multiple and complex effects on human health.12,13 Selenium status was reported to be associated with various disorders such as cardiovascular disease, type 2 diabetes mellitus, infertility, and neurological disease.14-16 The major source of human selenium is the food chain; geographical variation significantly influences the selenium content and availability in foods, therefore leading to an uneven geographical distribution of selenium-associated diseases.17,18
As bones contain the second-highest proportion of selenium in the body,19 the effects of selenium on bone health have been evaluated in both preclinical and clinical studies.20,21 Yet, the results of these clinical studies are inconclusive. Meta-analysis can combine the results of multiple scientific studies to obtain a comprehensive estimate. However, no such study had been performed to assess the associations of selenium with BMD, OP, and fracture. We conducted a meta-analysis involving all eligible studies to fill this information gap.
Methods
Protocol and registration
This study was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).22 The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) network (CRD42019147188). Preplanned methods have been detailed when necessary.23
Search strategy
The search was undertaken using the PubMed, Embase, and Cochrane Library databases from inception to 15 November 2022. Key terminology related to selenium (including dietary selenium intake and serum selenium) and bone health (including BMD, OP, and osteoporotic fracture) were used to synthesize the search strategy (Supplementary Table i). The search terms were adapted for different databases accordingly. No restriction was imposed, and non-English written papers were translated. HX and NW independently screened the titles and abstracts. References of the finally included studies were manually reviewed.
Eligibility criteria
Eligibility screening was based on the following inclusion criteria: 1) either interventional or observational studies in humans, including randomized controlled trials (RCTs), case-control studies, cross-sectional studies, and cohort studies; 2) studies using dietary selenium intake or monitoring serum selenium levels; 3) the primary outcome included BMD value, OP (diagnosed based on the World Health Organization (WHO) criteria) and the prevalence or incidence of osteoporotic fracture; and 4) studies reporting the association of selenium with BMD value, OP, or fracture. The exclusion criteria were: 1) animal studies; 2) case reports, meeting abstracts, comments, and reviews; and 3) missing data of interest.
Quality assessment
Methodological quality was assessed by ZY and JW independently. Agreement between them was determined using Cohen’s Kappa value and disagreements were resolved by discussion. The Newcastle-Ottawa Scale (NOS),24 and the adapted NOS for cross-sectional studies, were used for observational studies.25 The NOS considers three domains, including selection, comparability, and outcome. A study with a score > 7 has high quality, 4 to 6 has moderate quality, and < 4 has low quality. The quality of RCT was rated by the Cochrane risk of bias assessment tool.
Data extraction
The following data were extracted by HX and NW independently using a standardized collection form: publication information (i.e. author, year of publication); study information (i.e. country, study type, study setting); demographic information (i.e. age and sex); exposure information (i.e. dietary selenium intake or serum selenium level); and outcome information (i.e. BMD, prevalence or incidence of OP or fracture). Effect sizes (β, mean difference (MD), odds ratio (OR), or relative risk (RR)) were extracted directly if available, or calculated from the relevant data in the original studies. The data of median and interquartile range were converted to mean and standard deviation (SD) using verified formulae, which were distribution-free of the underlying data.26 If overall effect sizes were reported, these effect sizes would be extracted. For studies reporting effect sizes by subgroups (e.g. age, sex, BMI, smoking status, alcohol use), the estimates were pooled before conducting meta-analysis. For studies reporting multiple statistical models, the model with the most adjusted variable was extracted.
Statistical analysis
We estimated association between selenium and bone health using the inverse-variant method. Effect sizes were reported as β, WMD, or OR with 95% CI. For studies reporting βs from multiple linear regression models,27-31 βs were pooled as previously described.32 The heterogeneity of the included studies was assessed using Cochrane’s Q test and I2 statistics, where p > 0.05 for Q statistics and I2 value < 50% suggested statistical homogeneity. If the included studies were homogeneous, the fixed-effect model would be used to pool the data; otherwise, the random-effect model would be used instead. Sensitivity analysis was used to assess the stability of results and the impact of every single study on the pooled estimates. Publication bias would be examined by conducting Egger’s test with funnel plot where feasible.33 All statistical analyses were performed using Stata software (version 12.0; StataCorp, USA) and Comprehensive Meta-Analysis (version 3.3.0; Biostat, USA).
Results
Literature search and characteristics of included studies
After the removal of duplicates, the preliminary literature search yielded 748 articles from PubMed, Embase, and Cochrane Library databases. Eventually, 19 studies covering a total of 69,672 subjects met our inclusion criteria (Figure 1).27-31,34-47 Of these studies, 18 were observational studies (eight had a cross-sectional design, seven had a case-control design, and three had a prospective design), except for one RCT. Across the included studies, the number of participants ranged from 60 to 21,939, while the mean age varied from 39.4 to 75.8 years, with mean selenium intake ranging from 41.2 to 154.4 μg/d or mean serum selenium level ranging from 66.7 to 131.1 μg/l (Table I and Table II). All the observational studies had a NOS score ≥ 4, namely moderate- to high-quality scores. The risk of bias was high for the RCT because of missing outcome data, as it did not include all participants in the analysis (Supplementary Figure a). The agreement between two authors reached a kappa value of 0.902, and the overall results are shown in Supplementary Tables ii to iv.
Fig. 1
The selection process of included studies.
Table I.
Characteristics of included studies reporting dietary selenium intake.
| Study | Location | Mean age, yrs | Sex | Participants, n | Design | Mean selenium intake, μg/d |
Outcome | BMD instrument | BMD or fracture site | Quality score |
|---|---|---|---|---|---|---|---|---|---|---|
| Grili et al41 2022 | Brazil | 66.8 | Female | 124 | Cross-sectional | 154.4 | Osteoporosis | DXA | Lumber spine and femur | 8 |
| Rivas et al27 2012 | Spain | - | Female | 280 | Cross-sectional | 75.8 | BMD | DXA | Calcaneous | 6 |
| Sun et al39 2014 | China | 70.9 | Male and female | 1,452 | Case-control | 44.7 | Fracture | - | Hip | 5 |
| Walsh et al42 2021 | UK | 65.9 | Female | 120 | RCT | - | BMD | DXA | Spine and hip | High risk of bias |
| Wang et al38 2019 | China | 52.2 | Male and female | 6,267 | Cross-sectional | 43.5 | Osteoporosis | Radiological absorptiometry system | Middle phalanges of the second to fourth fingers | 6 |
| Wolf et al28 2005 | USA | 63.2 | Female | 11,068 | Cross-sectional | 85.9 | BMD | DXA | Total body, lumbar spine, and total hip | 7 |
| Wu et al29 2020 | USA | - | Male and female | 2,983 | Cross-sectional | 101.5 | BMD and fracture | DXA | Spine and femur | 8 |
| Xue and Liu37 2022 | USA | 40.68 | Male and female | 21,939 | Cross-sectional | N/A | BMD | DXA | Total body, lumbar spine, and hip | 7 |
| Zhang et al35 2006 | USA | 75.8 | Male and female | 1,215 | Case-control | 105.7 | Fracture | - | Hip | 7 |
| Zhang et al43 2021 | China | 42.4 | Male and female | 17,150 | Cohort | 41.2 | Fracture | - | Total body | 5 |
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BMD, bone mineral density; DXA, dual energy X-ray absorptiometry; N/A, not available; RCT, randomized controlled trial.
Table II.
Characteristics of included studies reporting serum selenium.
| Study | Location | Mean age, yrs | Sex | Participants, n | Design | Mean serum selenium, μg/l |
Outcome | BMD instrument | BMD or fracture site | Quality score |
|---|---|---|---|---|---|---|---|---|---|---|
| Al-E-Ahmad et al34 2018 | India | 67.2 | Male and female | 180 | Case-control | 57.6 | Osteoporosis | DXA | Spine and femur | 7 |
| Arikan et al45 2011 | Turkey | 54.7 | Male and female | 70 | Case-control | 66.7 | Osteoporosis | DXA | Lumbar spine, femoral neck, trochanter, Ward’s triangle, and total hip | 5 |
| Beukhof et al47 2016 | Netherlands | 77 | Male | 387 | Cross-sectional | 91.9 | BMD | DXA | Femoral neck, trochanter, Ward’s triangle | 7 |
| Galvez-Fernandez et al36 2021 | Spain | 48.7 | Male and female | 1,365 | Cohort | 84.7 | Fracture | Radiograph, CT scan, or nuclear magnetic resonance | Hip, humerus, and Colle’s fracture | 6 |
| Hoeg et al31 2012 | Europe | 67.8 | Female | 2,374 | Cohort | 94.3 | Osteoporosis and fracture | DXA | Lumbar spine, femoral neck | 8 |
| Kul et al46 2021 | Turkey | 64.8 | Female | 75 | Case-control | 261.2 | Osteoporosis | DXA | Lumbar vertebrae, femoral neck | 6 |
| Wang et al40 2015 | China | 65.5 | Male | 60 | Case-control | 129.8 | Osteoporosis | DXA | Lumbar spine, femoral neck, trochanter, Ward’s triangle | 6 |
| Odabasi et al44 2008 | Turkey | 60.5 | Female | 138 | Case-control | 76.9 | Osteoporosis | DXA | Lumbar vertebrae | 5 |
| Wei et al30 2021 | USA | 39.4 | Male and female | 2,545 | Cross-sectional | 128.9 | BMD | DXA | Lumbar vertebrae and total BMDs | 7 |
| Wu et al29 2020 | USA | - | Male and female | 2,983 | Cross-sectional | 131.1 | BMD and fracture | DXA | Spine and femur | 8 |
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BMD, bone mineral density; DXA, dual-energy X-ray absorptiometry.
Dietary selenium intake and bone health
Four studies covering 36,270 subjects assessed the correlation between dietary selenium intake and BMD using multiple linear regression models.27-29,37 The result of the meta-analysis revealed a positive association between dietary selenium intake and BMD (β = 0.04, 95% confidence interval (CI) 0.00 to 0.07, p = 0.029, I2 = 95.91) (Figure 2a).
Fig. 2
Forest plots of association between dietary selenium and bone health. a) Association between dietary selenium intake and bone mineral density (BMD). b) Association between dietary selenium intake and prevalence of osteoporosis. c) Association between dietary selenium intake and fracture. CI, confidence interval.
Two cross-sectional studies addressed the relationship between dietary selenium intake and OP involving 6,391 participants.38,41 The result of the meta-analysis suggested a negative association between dietary selenium intake and OP (OR = 0.47, 95% CI 0.31 to 0.72; p = 0.001, I2 = 0) (Figure 2b). This was consistent with our finding that dietary selenium intake was positively associated with BMD.
Four studies covering 24,325 subjects reported the use of logistic regression models for evaluating the effect of dietary selenium intake on total fracture risk.29,35,39,43 The result of the meta-analysis did not reveal a statistically significant association between dietary selenium intake and total fracture risk (OR = 0.64, 95% CI 0.29 to 1.39; p = 0.261) (Supplementary Figure b). Egger’s test demonstrated no evidence of publication bias (p = 0.528). For hip fracture, meta-analysis of three studies covering 21,585 participants suggested that high dietary selenium intake was associated with lower risk of hip fracture (OR = 0.44, 95% CI 0.37 to 0.52; p < 0.001) (Figure 2c).29,35,39 An I2 = 65.2 suggested significant heterogeneity.
Serum selenium and bone health
Four studies covering 3,370 subjects reported the use of multiple linear regression models for evaluating the association between serum selenium and BMD.29-31,47 The result of the meta-analysis suggested a significantly positive association between serum selenium and BMD (β = 0.13, 95% CI 0.00 to 0.26; p = 0.046, I2 = 86.60) (Figure 3a).
Fig. 3
Forest plots of association between serum selenium and bone health. a) Association between serum selenium and bone mineral density (BMD). b) Difference of serum selenium level between osteoporosis patients and non-osteoporosis controls. c) Association between serum selenium and osteoporotic fracture risk. CI, confidence interval.
Five case-control studies covering 508 subjects reported the difference of serum selenium between OP and healthy subjects.34,40,44-46 The result from the random-effect model did not support a statistically significant difference of serum selenium between OP patients and healthy controls (WMD = -7.48, 95% CI -15.81 to 0.84; p = 0.078). To assess the stability of the result and the influence of each study, we performed a sensitivity analysis. Sequentially omitting each single study from the meta-analysis did not significantly alter the estimate reported by overall analysis except for Al-E-Ahmad et al34 (MD = -23.51, 95% CI -30.98 to -16.04; p < 0.001). After excluding it, the meta-analysis revealed a statistically significant association between serum selenium and OP, indicating that OP patients had lower serum selenium level than healthy controls (WMD = -2.01, 95% CI -3.91 to -0.12; p = 0.037, I2 = 0) (Figure 3b). The result of Egger’s test did not demonstrate evidence of publication bias (p = 0.406).
Three studies reported the association between serum selenium and fracture risk. Two of them had a prospective design,31,36 while the remaining one had a cross-sectional design.29 The pooled result of two prospective studies did not reveal a statistically significant association between serum selenium and hip fracture risk (HR = 1.43, 95% CI 0.68 to 3.03; p = 0.350, I2 = 75.74) (Figure 3c). The cross-sectional study reported an inverse association between serum selenium and history of any fracture (OR = 0.18, 95% CI 0.01 to 0.57; p = 0.006).
Effect of selenium supplementation on bone health
The effect of selenium supplementation on bone health was evaluated by one RCT. By recruiting 120 postmenopausal women with osteopenia or OP and randomly assigning them 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once a day, this RCT demonstrated no evidence of BMD improvement after six-month follow-up.42
Discussion
To our best knowledge, this is the first meta-analysis to comprehensively explore the effect of selenium on bone health. The present meta-analysis shows that dietary selenium intake and serum selenium were both positively correlated with BMD; high selenium intake was negatively associated with risk of OP and hip fracture, and OP patients had lower serum selenium than healthy controls. Nevertheless, no significant association was found between serum selenium with fracture rate.
Comparison with previous studies
A narrative review by Yang et al20 highlighted the importance of selenium in bone health, but they did not perform a meta-analysis and could not provide precise estimates of the effect. Results from Mendelian randomization, a technique believed less likely to suffer from confounding factors, revealed a positive association only between serum selenium and heel BMD.48 In our analysis, we included all the eligible studies and found that selenium may be protective for BMD, OP, and hip fracture.
Possible explanations
Selenium is an essential trace element for protecting cells against oxidative damage; selenium deficiency increases the risk of disorders including cardiovascular disease,49 cancer,50 hepatopathy,51 and arthropathy.12 Given its antioxidant effect, selenium has been reported as a potential protective factor for osteoarthritis (OA) and rheumatoid arthritis (RA),52-54 and a preclinical study has shown a promising therapeutic effect of selenium nanoparticles in RA-induced animals.55 Given that oxidative stress has been suggested as destructive to bone,56-58 it is reasonable to speculate that selenium has a protective effect on BMD as well as on OP. Since selenium status was positively associated with BMD, an inverse association between selenium and fracture susceptibility was expected. Indeed, the present meta-analysis found a significant association between dietary selenium intake and hip fracture; however, no association between serum selenium and fracture risk was found. One possible explanation may be that low BMD is just one among a cluster of important risk factors for fracture.59-61 Moreover, in one prospective study, only a small number of fractures were recorded during the follow-up.31 Therefore, prospective studies with longer follow-up and a larger number of participants are required to substantiate the link between selenium and fracture. The only RCT included in this work concluded that sodium selenite supplementation for six months did not benefit bone health in postmenopausal women with osteopenia or OP.42 However, it only involved postmenopausal women who had normal serum selenium levels (not less than 70 μg/l)62 at baseline. Thus, it is unknown whether the effect of selenium on BMD would vary in different age groups, males, or those with selenium deficiency. Notably, this research did not find different risks of adverse events between the two groups receiving different doses of selenium, providing evidence for the safety of selenium supplementation in the population with normal serum selenium.
Strength and limitations
The present study has several strengths. First, a systematic literature search strategy was designed and implemented to capture all eligible studies. Second, two indicators of selenium status and three indicators of bone health were considered (including BMD, OP, and fracture), taking into account both OP and its consequences, to comprehensively assess the effect of selenium on bone health. Third, stringent inclusion and exclusion criteria were followed to eliminate irrelevant and low-quality studies, making the results more reliable.
Nevertheless, the limitations of our study should also be acknowledged. First, the meta-analysis was based on observational studies that are susceptible to bias. Second, the number of included studies was relatively small for certain analyses, so we failed to run subgroup analyses as mentioned in the protocol and assess publication bias for all outcomes.33,63 Third, heterogeneity was detected across the studies in certain analyses, which can be partly explained by study design, regional difference, population variability, various methods for selenium and BMD measurement, and varying bioavailability of dietary selenium intake.
Clinical and research implications
Sufficient nutritional intake is important for preventing and treating OP.2,3,64 As an essential trace element for human health,65 the effect of selenium on bone health was inconclusive. Our meta-analysis demonstrated a significant association of selenium with BMD, OP, and hip fracture, without any significant association between serum selenium and fracture, indicating that there may be a more intricate mechanism underlying their relationship. This meta-analysis could help to resolve controversy and uncertainty among previous studies and provide evidence supporting the protective role of selenium on OP, which would serve as a foundation for future research to assess causality and investigate the potential of selenium as an adjuvant therapy for OP. Moreover, our work identified some information gaps in the association between selenium and bone health. Since it was reported that selenium had a dose-response effect on mortality and type 2 diabetes mellitus,14,66 a potential dose-response effect of selenium on bone health could not be ruled out, and more researches are needed to elucidate it. Furthermore, most studies involved participants without evidence of selenium deficiency; future studies should focus on the population with selenium deficiency or relatively low selenium levels.
In summary, this meta-analysis found that selenium was positively associated with BMD, and serum selenium was inversely associated with OP in the population with relative normal selenium. Dietary selenium intake was negatively associated with risk of hip fracture. Future studies are warranted to confirm this effect on populations with different selenium levels.
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Author contributions
H. Xie: Data curation, Formal analysis, Writing – original draft, Visualization.
N. Wang: Data curation, Formal analysis, Writing – original draft, Visualization.
H. He: Methodology, Investigation.
Y. Zidan: Methodology, Investigation.
J. Wu: Methodology, Investigation.
T. Yang: Conceptualization, Validation, Supervision, Writing – review & editing.
Y. Wang: Conceptualization, Validation, Supervision, Writing – review & editing.
Funding statement
The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: this work was supported by the Youth Science Foundation of Xiangya Hospital (2021Q14) and the Natural Science Foundation of Hunan Province (2022JJ40821).
Data sharing
All data generated or analyzed during this study are included in the published article and/or in the supplementary material.
Acknowledgements
Everyone who contributed significantly to the work has been listed as an author.
Open access funding
The authors confirm that the open access fee for this study was self-funded.
Supplementary material
Tables showing complete search strategy and the results of quality assessment for included studies. Figures showing a risk of bias graph for randomized controlled trial and a forest plot of the association between dietary selenium and any fractures.
© 2023 Author(s) et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/
