DOI: https://doi.org/10.21203/rs.3.rs-1355824/v1
Background: The purpose of this analysis was to explore the relationship between estradiol and total bone mineral density (BMD) in American adults aged 40 to 60 years.
Methods: We used a cross-sectional study. Data for the study came from the National Health and Nutrition Examination Survey (NHANES) . The study examined data from a sample of the American population.
Results: Data analysis showed a significant association between estradiol levels and total bone mineral density in US adults aged 40 to 60 years. When estradiol levels were below the threshold of 33.3pg/mL, estradiol was positively associated with total BMD in all ethnic groups. There was no significant correlation between estradiol levels above the threshold of 33.3pg/mL. When estradiol levels in men were below the threshold of 40.3pg/mL, estradiol was positively correlated with total BMD. When estradiol levels in women were below the threshold of 25pg/mL, estradiol was positively correlated with total BMD.
Conclusions: In the 40-60 year old population, when estradiol level is at a lower concentration, estradiol level is positively correlated with total BMD. Increasing estradiol level can promote bone health. When estradiol levels are at higher concentrations, changes in estradiol levels may have no significant effect on bone health.
Osteoporosis is a common clinical degenerative disease in adults aged 40–60 years. According to normal physiological changes, after menopause, estrogen levels decrease significantly, and bone mineral density levels decrease accordingly. While, the relationship between estrogen level and osteoporosis in middle-aged and elderly men is often ignored1.In the traditional view, When estrogen levels are significantly reduced, osteoclast activity increases, bone resorption is greater than femoral formation, resulting in bone loss and osteoporosis.High concentration of estrogen can accelerate the apoptosis of osteoclasts2, 3, reduce the survival time of osteoclasts and inhibit the differentiation of osteoclasts4. But this theory lacks experimentation and research.
Women's bone mineral density seems to be linked to estradiol levels and women's exercise. A study population consisted of 151 female athletes with amenorrhea in Japan showed that BMD was significantly higher in the experimental group than in the untreated group after 12 months of treatment with transdermal estradiol5. Another study involving 482 Chinese men with type 2 diabetes found that estradiol levels are important for maintaining bone health, with estradiol concentrations affecting BMD and fracture risk in males6. It may be clinically necessary to detect BMD in menopausal women with estrogen deficiency7. In addition, a large number of experimental results and clinical evidence have demonstrated a close relationship between estradiol levels and BMD.
Evidence on estradiol and BMD is limited. Osteoporosis in middle-aged people varies by age, sex, race, and country. In addition, estradiol concentration was also affected by age, sex, body composition and other factors affecting BMD. To further investigate, we conducted a cross-sectional study based on an American national population to explore the relationship between estradiol and BMD in US adults aged 40–60 years.
NHANES is a major program of the National Center for Health Statistics (NCHS). This study screened data from the database from 2013 to 2016. This is a stratified, multistage sample. Survey methods and detailed data on the NHANES database can be found at www.cdc.gov/nchs/nhanes/. Study subjects were limited to participants aged 40–60 years (n = 6,005). The NCHS Ethics Review Board approved the actions of NHANES and obtained the written informed consent of all participants.
The main independent variable was estradiol and the main dependent variable was total BMD. Serum estradiol was determined using the same method as the reference method of the National Institute of Standards and Technology (NIST). Estradiol is preformed via isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) method for routine quantitation of estradiol based on the National Institute for Standards and Technology’s (NIST) reference method. Dual-energy x-ray absorptiometry (DXA) is the most widely accepted method of measuring body composition. The NHANES DXA examination provides nationally representative data on body composition. The following covariates were included: age, sex, race/ethnicity, level of education, income-poverty ratio, total protein, serum phosphorus, and serum calcium. Detailed information about the data measurement process is available at www.cdc.gov/nchs/nhanes/.
The estimated values are calculated according to the sample weights of NHANES database. The independent relationship between estradiol and total BMD was investigated using weighted multiple regression analysis. Weighted generalized additive models and smooth curve fittings were employed to address the non-linearity of estradiol and total BMD in the subgroup analyses. The researchers calculated differences between groups using a weighted linear regression model (continuous variables) and a weighted Chi-square test (categorical variables). P < 0.05 was considered statistically significant. Empower software was used for data analysis (www.empowerstats.com; X&Y solutions, Inc., Boston MA) and R version 3.4.3 (http://www.R-project.org, The R Foundation).
The description of weighted characteristics is shown in Table 1. There were 4,075 eligible participants in the survey. They were 46.99% male, 53.01% female, 34.58% Non-Hispanic white, 21.84% Non-Hispanic black, 15.75% Mexican American and 27.83% other races. The estradiol data were grouped according to quartile and divided into Q1-Q4 groups. Data was included age, sex, race/ethnicity, income-poverty rate, total protein, total BMD, serum phosphorus and serum calcium. In the fully-adjusted model (Fig. 1-a, Fig. 1-b and Table 2), after controlling for the potential confounders, we observed a significantly positive correlation between estradiol and total BMD in a certain threshold range. The effect of estradiol (PG /mL) on the threshold of total bone mineral density (G /cm2) was analyzed by piecewise linear regression (Table 3). We used smooth curve fittings to find the relationship between estradiol and total BMD, stratified by age, sex, and race/ethnicity (Figs. 2, 3). Estradiol was positively correlated with total BMD in all racial/ethnic populations in men aged 40 to 60 years when estradiol concentration was lower than 40.3pg/mL. In women aged 40–60, estradiol was positively associated with total BMD in all racial/ethnic populations at concentrations below 25pg/mL, but not significantly associated with total BMD at concentrations greater than 25pg/mL.
|
Estradiol (pg/mL) |
Total |
Q1 |
Q2 |
Q3 |
Q4 |
P-value |
|---|---|---|---|---|---|---|
|
Age(years) |
49.8 ± 6.1 |
50.0 ± 5.9 |
50.0 ± 5.9 |
49.9 ± 6.0 |
46.6 ± 5.0 |
< 0.0001 |
|
Sex(%) |
< 0.0001 |
|||||
|
Male |
46.99 |
9.7 |
79.2 |
85.5 |
17.7 |
|
|
Female |
53.01 |
90.3 |
20.8 |
14.5 |
82.3 |
|
|
Race/ethnicity (%) |
< 0.0001 |
|||||
|
Non-Hispanic white |
34.6 |
68.9 |
64.7 |
69 |
60.1 |
|
|
Non-Hispanic black |
21.8 |
10.2 |
9 |
11.4 |
14.9 |
|
|
Mexican American |
15.8 |
7.9 |
10.9 |
7.1 |
9.5 |
|
|
Other race/ethnicity |
27.8 |
13.3 |
15.3 |
12.5 |
15.5 |
|
|
Level of education (%) |
0.0151 |
|||||
|
Less than high school |
22.8 |
14.8 |
16.4 |
13.3 |
13.0 |
|
|
High school |
21.4 |
19.2 |
21.3 |
23 |
17.8 |
|
|
More than high school |
55.8 |
66.1 |
62.2 |
63.7 |
69.2 |
|
|
Income to poverty ratio |
2.7 ± 1.7 |
3.1 ± 1.7 |
3.3 ± 1.6 |
3.4 ± 1.6 |
3.2 ± 1.7 |
0.0132 |
|
Total protein (g/dL) |
7.1 ± 0.5 |
7.0 ± 0.4 |
7.0 ± 0.4 |
7.1 ± 0.4 |
7.1 ± 0.4 |
0.0406 |
|
Serum calcium (mg/dL) |
9.4 ± 0.4 |
9.4 ± 0.3 |
9.4 ± 0.4 |
9.4 ± 0.3 |
9.3 ± 0.3 |
< 0.0001 |
|
Serum phosphorus (mg/dL) |
3.7 ± 0.6 |
3.9 ± 0.5 |
3.7 ± 0.6 |
3.6 ± 0.6 |
3.7 ± 0.5 |
< 0.0001 |
|
Total BMD (g/cm2) |
1.1 ± 0.1 |
1.0 ± 0.1 |
1.1 ± 0.1 |
1.1 ± 0.1 |
1.1 ± 0.1 |
< 0.0001 |
| Mean ± SD for continuous variables: the P value was calculated by the weighted linear regression model. (%) for categorical variables: the P value was calculated by the weighted chi-square test. Abbreviation: BMD, bone mineral density. | ||||||
|
Model1 |
Model2 |
Model3 |
|
|---|---|---|---|
|
β(95% CI) P-value |
β(95% CI) P-value |
β(95% CI) P-value |
|
|
Estradiol (pg/mL) |
0.0001 (0.0001, 0.0002) 0.0001 |
0.0003 (0.0002, 0.0003) < 0.000001 |
0.0003 (0.0002, 0.0003) < 0.000001 |
|
Estradiol categories |
|||
|
Q1 |
0 |
0 |
0 |
|
Q2 |
0.0768 (0.0658, 0.0878) < 0.000001 |
0.0299 (0.0170, 0.0427) 0.000005 |
0.0237 (0.0103, 0.0371) 0.000542 |
|
Q3 |
0.1102 (0.0993, 0.1210) < 0.000001 |
0.0572 (0.0441, 0.0703) < 0.000001 |
0.0534 (0.0396, 0.0671) < 0.000001 |
|
Q4 |
0.0821 (0.0711, 0.0931) < 0.000001 |
0.0679 (0.0565, 0.0793) < 0.000001 |
0.0676 (0.0556, 0.0795) < 0.000001 |
|
Subgroup analysis stratified by sex |
|||
|
Men |
0.0019 (0.0012, 0.0025) < 0.000001 |
0.0016 (0.0010, 0.0022) < 0.000001 |
0.0017 (0.0011, 0.0024) < 0.000001 |
|
Women |
0.0003 (0.0002, 0.0004) < 0.000001 |
0.0002 (0.0001, 0.0003) < 0.000001 |
0.0002 (0.0001, 0.0003) < 0.000001 |
|
Subgroup analysis stratified by race/ethnicity |
|||
|
Non-Hispanic white |
0.0001 (0.0000, 0.0002) 0.021392 |
0.0003 (0.0002, 0.0004) < 0.000001 |
0.0003 (0.0002, 0.0004) 0.000002 |
|
Non-Hispanic black |
0.0001 (-0.0000, 0.0003) 0.152722 |
0.0002 (0.0000, 0.0003) 0.039708 |
0.0002 (-0.0000, 0.0003) 0.085202 |
|
Mexican American |
0.0001 (-0.0000, 0.0003) 0.122470 |
0.0002 (0.0001, 0.0004) 0.004273 |
0.0002 (0.0000, 0.0004) 0.011490 |
|
Other race/ethnicity |
0.0002 (0.0000, 0.0003) 0.009624 |
0.0003 (0.0002, 0.0004) 0.000044 |
0.0003 (0.0002, 0.0005) 0.000043 |
| Model 1: no covariates were adjusted. Model 2: age, sex, and race/ethnicity were adjusted. Model 3: age, sex, race/ethnicity, education, income poverty ratio, total protein, serum phosphorus and serum calcium were adjusted. In the subgroup analysis stratified by sex and race/ethnicity, the model is not adjusted for sex and race/ethnicity. | |||
|
Adjusted β (95% CI)P-value |
||
|---|---|---|
|
Males |
||
|
Estradiol < 40.3 (pg/mL) |
0.0027 (0.0019, 0.0035), < 0.0001 |
|
|
Estradiol > 40.3 (pg/mL) |
-0.0015 (− 0.0033, 0.003), 0.0941 |
|
|
Females |
||
|
Estradiol < 25 (pg/mL) |
0.0029 (0.0021, 0.0036), < 0.0001 |
|
|
Estradiol > 25 (pg/mL) |
0.0001 (− 0.0000, 0.001), 0.1813 |
|
|
Total |
||
|
Estradiol < 33.3 (pg/mL) |
0.0025 (0.0020, 0.0029), < 0.0001 |
|
|
Estradiol > 33.3 (pg/mL) |
0.0000 (− 0.0001, 0.0001), 0.6950 |
|
| Age, sex, race/ethnicity education, income poverty ratio, total protein, serum phosphorus and serum calcium were adjusted in the model. | ||
Reduced BMD can lead to an increased risk of osteoporotic fractures. The relationship between estradiol and bone mineral density has been widely studied and concerned. In a cross-sectional study of 270 women between 40 and 48 years of age, Gerardo Huitrón-Bravo et al. found that when serum estradiol levels were low in premenopausal women, the risk of bone density loss was significantly increased8. A study population consisted of 151 female athletes with amenorrhea in Japan showed that BMD was significantly higher in the experimental group than in the untreated group after 12 months of treatment with transdermal estradiol5. Another study involving 482 Chinese men with type 2 diabetes found that estradiol levels are important for maintaining bone health, with estradiol concentrations affecting BMD and fracture risk in males6. Barbieri et al. proposed a new hypothesis called estrogen threshold hypothesis through research. The research team proved that estradiol levels in the range of 30–45 pg/ml can effectively prevent bone loss, although estradiol sensitivity varies from individual to individual9. Kathryn E Ackerman et al. studied the effect of estrogen on BMD in normal-weight young adults in a large number of experiments. The team discussed differences in BMD under different conditions, including no estrogen, physiological dose estrogen, transdermal estrogen administration, and estrogen in combination with oral contraceptives10, 11. The institute found that BMD would improve over 12 months with transdermal estradiol administration compared with combined oral contraceptives or no oestrogen.
We analyzed a larger sample size in our study, allowing us to better generalize the U.S. population. But there are also shortcomings. First, the eligible sample size in the database is still too small. Secondly, other confounding factors not included in this study may have influenced the results. Women, for example, have biologically higher levels of estradiol than men. Therefore, sex hormone differences during pubertal development in adults aged 40–60 years may be a potential confounding factor that needs to be considered.
In summary, estradiol level and total BMD differed by sex and race, and there are thresholds. When male estradiol level is below the threshold of 40.3pg/mL, estradiol level is positively correlated with total BMD, and increasing estradiol level can promote bone health. When estradiol levels in women fall below the threshold of 25pg/mL, increased estradiol levels contribute to bone health. When female estradiol concentrations are above the threshold of 25pg/mL, increased estradiol levels have little effect on bone health.
Ethics approval and consent to participate
The ethics review board of the National Center for Health Statistics approved all NHANES protocols and written informed consent was obtained from all participants.
Consent for publication
Not applicable.
Availability of data and materials
The data are publicly available on the internet for researchers throughout the world. https://www.cdc.gov/nchs/nhanes/
Competing interests
The authors declare that they have no competing interests
Funding
This study received no funding.
Authors' contributions
Nan Wang contributed to the study design and writting the manuscript. Ying Zhang and Chengcheng Huang contributed to data collection and analysis. All authors read and approved the final manuscript.
Acknowledgements
The study authors thank the participants for their time and effort in the data acquisition phase of the NHANES database project.
Abbreviations
BMD: bone mineral density
NHANES: National Health and Nutrition Examination Survey
Author details
1Department of Orthopaedics, Zhejiang Chinese Medical University Affiliated Jiangnan Hospital , Hangzhou, Zhejiang 311200, China
2Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
3Department of Osteoporosis Care and Control, The First People’s Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China
Guidelines
All procedures were performed in accordance with relevant guidelines.