
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-04657
00023
10.1097/MD.0000000000039612
3
4700
Research Article
Observational Study
Correlation between serum hemoglobin levels and bone mineral density in adults: A cross-sectional study
https://orcid.org/0009-0005-6695-9171
Cheng Xiaosong MB a
Zhang Liangliang MD b
Cao Bo MD b
Zhao Chengjin MD b*
a Medical School of Yan’an University, Yan’an, Shaanxi, China
b Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, China.
* Correspondence: Chengjin Zhao, Affiliated Hospital of Yan’an University, Yan’an, Shaanxi, 716000, China (e-mail: qqagui2004@163.com).
13 9 2024
13 9 2024
103 37 e3961202 5 2024
14 6 2024
16 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Serum hemoglobin plays an important role in bone metabolism. However, the association between serum hemoglobin levels and bone mineral density (BMD) remains unclear. Therefore, this study aimed to explore the relationship between serum hemoglobin levels and lumbar spine BMD in adults. We conducted a cross-sectional study by utilizing data from the National Health and Nutrition Examination Survey from 2011 to 2018. The serum hemoglobin level was examined as an independent variable, while the lumbar spine BMD was utilized as the dependent variable. Weighted multivariate linear regression models and stratified analysis by age, sex, and race/ethnicity were applied after controlling for confounding factors to assess the relationship between serum hemoglobin levels and the lumbar spine BMD. Additionally, smooth curve fitting and threshold effect analyses were utilized to depict the nonlinear relationship between the 2 variables. A total of 11,658 participants (6004 men and 5654 women) aged ≥ 18 years were included in this study. When the serum hemoglobin level was represented as a continuous variable and fully adjusted in the regression model, the hemoglobin level was significantly negatively correlated with the lumbar spine BMD (β = ‐0.0035, 95% confidence interval: ‐0.0065 to ‐0.0004, P = .024555); this significant negative correlation persisted when the serum hemoglobin level was transformed into a categorical variable, except in the Q2 group (β = ‐0.0046, 95% confidence interval: ‐0.0142 to ‐0.0050, P = .348413). When different confounding factors were used including sex, age, and race/ethnicity, the stratified subgroups exhibited a negative correlation between the serum hemoglobin level and the lumbar spine BMD. Additionally, smooth curve fitting and threshold effect analyses showed a negative correlation between the serum hemoglobin level and the lumbar spine BMD, with a saturation effect at 15 g/dL. Our findings demonstrated an association between hemoglobin levels and the lumbar spine BMD in adults, characterized by a nonlinear relationship. Thus, monitoring the serum hemoglobin level could aid in the early detection of risks associated with bone metabolic disorders such as osteoporosis.

bone mineral density
NHANES
osteoporosis
serum hemoglobin
National Natural Science Foundation of China 10.13039/501100001809 82160431 Chengjin ZhaoOPEN-ACCESSTRUE
==== Body
pmc1. Introduction

Osteoporosis is a condition marked by decreased bone mineral density (BMD) and increased risk of fractures, and is among the most prevalent skeletal disorders worldwide.[1–3] The lifetime risk of osteoporotic fractures worldwide is approximately 40% to 50% for women and 13% to 22% for men.[4] With the increase in the number of elderly people, the incidence of osteoporosis continues to increase.[5] Anemia, marked by low levels of hemoglobin concentration, is a prevalent public health concern, impacting approximately one-quarter of the world’s population.[6,7] Compared to healthy individuals, the prevalence of BMD in the lumbar spine and femoral neck of 21 patients aged 10 years and above with hemoglobin H disease was significantly lower. Anemia or relatively lower levels of hemoglobin, even within the normal range, are associated with an increased risk of decreased BMD and fractures.[8] Thus, the BMD, utilized as a measure to evaluate mineral content within bones, is frequently employed for diagnosing osteoporosis.[9] A low BMD is closely associated with heightened fracture risks, thereby increasing the prevalence and mortality rates among elderly women.[10] As osteoporosis is usually asymptomatic prior to a person experiencing fractures, early screening and detection play a vital role in managing the condition. Considering the heightened risk of fragility fractures and the global disease burden, the early identification of potential modifiable factors associated with a low BMD is crucial from a public health standpoint. Therefore, this study utilized data from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018 to examine the association between the serum hemoglobin levels and the lumbar spine BMD in adults.

2. Materials and methods

2.1. Study population

The NHANES, a cross-sectional, stratified, multi-stage epidemiological study conducted in the United States, aimed to evaluate the health and nutritional status of both adults and children. Written informed consent and assent were obtained from all adult participants and those under 18 years of age, respectively. The NHANES was approved by the Institutional Review Board of the National Center for Health Statistics, and all participants provided consent for their data to be utilized in subsequent research. Our analysis utilized data collected from 4 NHANES dataset cycles spanning from 2011 to 2018.

From the NHANES data collected between 2011 and 2018, a total of 39,156 participants were initially included. After excluding individuals with missing lumbar spine BMD data (20,484 individuals), missing hemoglobin data (1164 individuals), those under the age of 18 years (5555 individuals), and individuals with various types of cancer (395 individuals), a final cohort of 11,658 participants was included in this study (Fig. 1).

Figure 1. Flow chart of participant selection.

2.2. Study variables

The studied outcome variable was the lumbar spine BMD, which was measured with dual-energy X-ray absorptiometry scanning by trained and certified radiologic technologists using the Hologic Densitometer Discovery A. The exposure variable in the study was the serum hemoglobin level. The 6C® Cell Control is a hematology reference control used to monitor the performance of instruments with complete CBC and VCS differential technology. The 6C® Cell Control utilizes human blood so repeated measurements to monitor daily performance of the instrument system are possible. Beckman Coulter’s® DxH diluent, DxH Lyse Reagent, and DxH Diff Pack are used to determine the accuracy of dilution, as well as the WBC counts, RBC counts, platelet counts, hemoglobin levels, and differential counts. The transmittance of light at 525 nm through a lysed WBC solution is determined using the hemoglobin cuvette and is compared to the transmittance of the same light through a reagent blank. The system converts this ratio to the hemoglobin value using a calibration factor. The weight (mass) of hemoglobin was determined from the degree of absorbance found through photo current transmittance and expressed in g/dL. The NHANES website provides a comprehensive explanation of the hemoglobin measurement process in the Laboratory Method Files section.

The analyzed covariates included age; sex; race/ethnicity; body mass index (BMI); education level; smoking history (a smoker was defined as a person who smoked at least 100 cigarettes in life); alcohol consumption (a consumer was defined as a person who drank at least 12 alcoholic drinks in 1 year); family income; and levels of albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen, creatine phosphokinase (CPK), cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin. The physiological, clinical, and laboratory parameters were evaluated by trained medical experts. More information on the variable measurement is available on the NHANES website (https://www.cdc.gov/nchs/nhanes/).

2.3. Data analysis

Data analysis was conducted using NHANES-weighted samples. The study participants were divided into quartiles based on their serum hemoglobin levels. Weighted multivariable linear regression models were used to analyze the relationship between the serum hemoglobin level and the lumbar spine BMD. We utilized the weighted chi-square test for categorical variables and a weighted linear regression model for continuous variables. Subsequently, we described the baseline characteristics of all participants included in the study using means (for continuous variables) or proportions (for categorical variables). Weighted multiple linear regression analysis was then conducted to assess the relationship between the hemoglobin levels and the lumbar spine BMD. These analyses were conducted following the guidelines of Strengthening the Reporting of Observational Studies in Epidemiology (STROBE).[11] Smoothed curve fitting and generalized additive models were employed to examine potential nonlinear relationships. When a nonlinear relationship was observed, a two-segment linear regression model was utilized to determine the threshold effects. Three models were established: Model I, unadjusted; Model II, minimally adjusted for age, sex and race/ethnicity; and Model III, adjusted for age, sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, family income, and levels of albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin. Data were analyzed using R (The R Foundation; http://www.r-project.org; version 3.4.3) and Empower (R) (www.empowerstats.com, X&Y Solutions, inc. Boston, MA). A P-value <.05 (two-tailed) was considered statistically significant.

3. Results

3.1. Characteristics of the study population

This study included 11,658 participants. Table 1 presents the weighted characteristics of the study sample, including the demographic and medical characteristics categorized by the serum hemoglobin levels (Q1: 6.10–13.10 g/dL; Q2: 13.20–14.10 g/dL; Q3: 14.20–15.10 g/dL; and Q4: 15.20–19.90 g/dL).

Table 1 Weighted characteristics of participants based on quartiles of serum haemoglobin.

Hemoglobin (g/dL)	Total	Q1 (6.10–13.10)	Q2 (13.20–14.10)	Q3 (14.20–15.10)	Q4 (15.20–19.90)	P-value	
Age (years, mean ± SD)	38.23 ± 12.19	38.39 ± 11.77	38.69 ± 12.37	38.64 ± 12.38	37.37 ± 12.14	<.0001	
Sex (%)	<.0001	
 Male	52.33	6.95	24.55	67.11	94.51		
 Female	47.67	93.05	75.45	32.89	5.49		
Race/ethnicity (%)	<.0001	
 Mexican American	10.73	10.84	8.65	10.10	12.98		
 Other Hispanic	7.34	8.75	7.65	6.81	6.55		
 Non-Hispanic white	60.12	46.49	60.99	64.26	65.40		
 Non-Hispanic black	12.08	23.10	12.51	9.96	5.76		
 Other race	9.72	10.82	10.20	8.88	9.31		
BMI (kg/m2, mean ± SD)	28.89 ± 6.90	29.14 ± 7.81	28.79 ± 7.36	28.63 ± 6.52	29.03 ± 6.07	.0247	
Education level (%)	<.0001	
 Less than high school	14.17	13.95	12.41	13.97	15.97		
 High school	22.75	19.06	20.80	24.23	25.65		
 More than high school	63.09	66.99	66.79	61.79	58.38		
Smoking history (%)	<.0001	
 Yes	39.47	27.85	33.99	44.14	48.16		
 No	60.53	72.15	66.01	55.86	51.84		
Alcohol consumption (%)	<.0001	
 Yes	79.49	69.08	77.53	83.60	84.84		
 No	20.51	30.92	22.47	16.40	15.16		
Ratio of family income to poverty (%, mean ± SD)	2.91 ± 1.67	2.72 ± 1.68	3.04 ± 1.69	2.99 ± 1.69	2.88 ± 1.63	<.0001	
Albumin (g/L, mean ± SD)	43.24 ± 3.38	41.23 ± 3.30	42.72 ± 3.06	43.72 ± 3.09	44.67 ± 3.13	<.0001	
ALT (U/L, mean ± SD)	26.02 ± 19.70	19.71 ± 14.60	22.22 ± 15.67	26.27 ± 17.58	33.48 ± 24.65	<.0001	
AST (U/L, mean ± SD)	25.16 ± 17.00	22.49 ± 16.61	23.43 ± 13.88	25.23 ± 17.75	28.44 ± 18.34	<.0001	
ALP (IU/L, mean ± SD)	67.41 ± 22.89	65.32 ± 22.98	65.87 ± 22.20	67.17 ± 22.85	70.42 ± 23.13	<.0001	
Blood urea nitrogen (mmol/L, mean ± SD)	4.56 ± 1.52	4.24 ± 1.75	4.41 ± 1.40	4.76 ± 1.49	4.72 ± 1.40	<.0001	
CPK (IU/L, mean ± SD)	164.10 ± 247.09	127.89 ± 150.09	142.25 ± 206.82	182.92 ± 291.57	191.03 ± 282.10	<.0001	
Cholesterol (mmol/L, mean ± SD)	4.93 ± 1.03	4.78 ± 0.96	4.94 ± 1.02	4.94 ± 1.03	5.03 ± 1.07	<.0001	
Creatinine (µmol/L, mean ± SD)	75.73 ± 23.85	68.30 ± 40.25	69.95 ± 16.46	78.21 ± 16.15	83.59 ± 14.49	<.0001	
γ-Glutamyl transferase (U/L, mean ± SD)	27.86 ± 42.98	21.59 ± 33.52	25.39 ± 52.46	27.40 ± 38.27	34.82 ± 43.40	<.0001	
Lactate dehydrogenase (U/L, mean ± SD)	129.99 ± 28.78	126.97 ± 28.31	128.99 ± 28.26	130.56 ± 28.17	132.49 ± 29.84	<.0001	
Total bilirubin (µmol/L, mean ± SD)	10.48 ± 5.43	8.40 ± 4.19	9.80 ± 4.80	10.64 ± 5.29	12.39 ± 6.14	<.0001	
Total protein (g/L, mean ± SD)	71.50 ± 4.33	70.77 ± 4.52	71.16 ± 4.22	71.59 ± 4.23	72.21 ± 4.26	<.0001	
Uric acid (µmol/L, mean ± SD)	319.04 ± 81.11	274.25 ± 71.27	291.95 ± 71.10	332.75 ± 78.62	361.08 ± 72.76	<.0001	
Globulin (g/L, mean ± SD)	28.26 ± 4.21	29.54 ± 4.67	28.44 ± 4.08	27.87 ± 4.06	27.54 ± 3.88	<.0001	
Glycohemoglobin (%, mean ± SD)	5.51 ± 0.90	5.55 ± 0.86	5.49 ± 0.85	5.51 ± 0.85	5.50 ± 1.01	.0870	
Lumbar spine BMD (g/cm2, mean ± SD)	1.04 ± 0.15	1.06 ± 0.15	1.05 ± 0.15	1.03 ± 0.15	1.03 ± 0.15	<.0001	
Mean ± SD for continuous variables: the P-value was calculated by the weighted linear regression model.

Percent (%) for categorical variables: the P-value was calculated by the weighted chi-square test.

ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CPK = creatine phosphokinase.

The weighted average age was 38.23 ± 12.19 years. Significant differences (P < .05) were observed in age; sex; race/ethnicity; BMI; education level; smoking history; alcohol consumption; family income; levels of albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, and globulin; and lumbar spine BMD considering different levels of serum hemoglobin.

3.2. Relationship between the serum levels of hemoglobin and the lumbar spine BMD

Table 2 shows the negative correlation between the serum hemoglobin level and the lumbar spine BMD in Model 1 [‐0.0079 (‐0.0097, ‐0.0061) < 0.000001]. This negative correlation persisted in the adjusted models (Model 2: ‐0.0059 [‐0.0082, ‐0.0035] < 0.000001; Model 3: ‐0.0035 [‐0.0065, ‐0.0004] 0.024555). In Model 1, the serum hemoglobin level in the Q2, Q3, and Q4 groups were all negatively correlated with the lumbar spine BMD. In the adjusted models, the serum hemoglobin level was negatively correlated with the lumbar spine BMD for all the groups except for the Q2 group in Model 2 [‐0.0053 (‐0.0132, 0.0025) 0.180321]. In Model 3, the lumbar spine BMD decreased by 0.0153 g/cm2 in the Q4 group compared to the Q1 group.

Table 2 The correlation between serum hemoglobin (g/dL) and lumbar spine BMD (g/cm2).

	Model 1
β (95% CI) P-value	Model 2
β (95% CI) P-value	Model 3
β (95% CI) P-value	
Hemoglobin (g/dL)	‐0.0079 (‐0.0097, ‐0.0061) < 0.000001	‐0.0059 (‐0.0082, ‐0.0035) < 0.000001	‐0.0035 (‐0.0065, ‐0.0004) 0.024555	
Quintiles of hemoglobin (g/dL)	
 Q1 (6.10–13.10)	Reference	Reference	Reference	
 Q2 (13.20–14.10)	‐0.0127 (‐0.0205, ‐0.0048) 0.001663	‐0.0053 (‐0.0132, 0.0025) 0.180321	‐0.0046 (‐0.0142, 0.0050) 0.348413	
 Q3 (14.20–15.10)	‐0.0192 (‐0.0270, ‐0.0113) 0.000002	‐0.0148 (‐0.0238, ‐0.0058) 0.001279	‐0.0158 (‐0.0270, ‐0.0046) 0.005852	
 Q4 (15.20–19.90)	‐0.0297 (‐0.0375, ‐0.0220) < 0.000001	‐0.0220 (‐0.0321, ‐0.0119) 0.000021	‐0.0153 (‐0.0281, ‐0.0025) 0.019221	
P for trend	<.001	<.001	.010	
Model 1: No covariates were adjusted. Model 2: Age, sex and race/ethnicity were adjusted. Model 3: Age, sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted.

ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CI = confidence interval, CPK = creatine phosphokinase.

Table 3 shows the subgroup analyses for sex, age, and race/ethnicity. For men and women, the serum hemoglobin levels were significantly negatively correlated with the lumbar spine BMD, although the male sex was not a significant factor in Model 3 [‐0.0006 (‐0.0052, 0.0040) 0.7888]. We stratified the age into 3 groups for analysis (<30 years old, 30–49 years old, and ≥50 years old). In Model 1, only the ≥50 years old group was not significant [0.0009 (‐0.0036, 0.0054) 0.6982], but in Model 2, the ≥50 years old group was negative and significant [‐0.0063 (‐0.0115, ‐0.0011) 0.0175]. In Model 3, the <30 years old group was negative and significant. Table 3 shows the negative correlation between the serum hemoglobin level and the lumbar spine BMD across sex, age, and race/ethnicity-stratified subgroups.

Table 3 Stratified analysis of the correlation between serum hemoglobin (g/dL) and lumbar spine BMD (g/cm2).

	Model 1
β (95% CI) P value	Model 2
β (95% CI) P value	Model 3
β (95% CI) P value	
Stratified by sex	
 Male	‐0.0141 (‐0.0177, ‐0.0106) < 0.0001	‐0.0038 (‐0.0074, ‐0.0002) 0.0411	‐0.0006 (‐0.0052, 0.0040) 0.7888	
 Female	‐0.0126 (‐0.0156, ‐0.0095) < 0.0001	‐0.0070 (‐0.0101, ‐0.0040) < 0.0001	‐0.0061 (‐0.0101, ‐0.0021) 0.0026	
Stratified by age	
 <30 years old	‐0.0075 (‐0.0106, ‐0.0044) < 0.0001	‐0.0029 (‐0.0073, 0.0014) 0.1910	‐0.0064 (‐0.0121, ‐0.0006) 0.0304	
 30–49 years old	‐0.0116 (‐0.0141, ‐0.0091) < 0.0001	‐0.0027 (‐0.0060, 0.0006) 0.1079	0.0009 (‐0.0033, 0.0052) 0.6712	
 ≥50 years old	0.0009 (‐0.0036, 0.0054) 0.6982	‐0.0063 (‐0.0115, ‐0.0011) 0.0175	‐0.0044 (‐0.0109, 0.0021) 0.1822	
Stratified by race/ethnicity	
 Mexican American	‐0.0021 (‐0.0059, 0.0016) 0.2695	‐0.0035 (‐0.0088, 0.0018) 0.1917	‐0.0083 (‐0.0155, ‐0.0012) 0.0227	
 Other Hispanic	‐0.0069 (‐0.0124, ‐0.0014) 0.0139	‐0.0123 (‐0.0196, ‐0.0051) 0.0009	‐0.0072 (‐0.0163, 0.0018) 0.1170	
 Non-Hispanic white	‐0.0056 (‐0.0088, ‐0.0023) 0.0008	‐0.0033 (‐0.0075, 0.0010) 0.1310	0.0021 (‐0.0030, 0.0072) 0.4239	
 Non-Hispanic black	‐0.0005 (‐0.0045, 0.0036) 0.8261	‐0.0115 (‐0.0167, ‐0.0063) < 0.0001	‐0.0107 (‐0.0176, ‐0.0037) 0.0026	
 Other race	‐0.0010 (‐0.0050, 0.0031) 0.6403	‐0.0020 (‐0.0074, 0.0033) 0.4506	0.0007 (‐0.0069, 0.0083) 0.8616	
Model 1: No covariates were adjusted. Model 2: Age, sex and race/ethnicity were adjusted. Model 3: Age, sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted.

ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CI = confidence interval, CPK = creatine phosphokinase.

3.3. Nonlinear relationship between the serum hemoglobin levels and the lumbar spine BMD

We further examined the nonlinear relationship between the 2 variables using a smoothing curve fitting method, as shown in Figure 2. Figures 3–5 illustrate the fitted smoothing curves depicting the linear or nonlinear associations between the serum hemoglobin levels and the lumbar spine BMD. A two-segment linear regression model revealed a saturation effect value of 15 g/dL between the serum hemoglobin levels and the lumbar spine BMD. Specifically, the effect value was ‐0.0043 [‐0.0043 (‐0.0081, ‐0.0004) 0.0321] for serum hemoglobin levels below 15 g/dL and 0.0076 [0.0076 (0.0008, 0.0143) 0.0281] for serum hemoglobin levels higher than 15 g/dL, as demonstrated in Table 4.

Table 4 Threshold effect analysis of serum hemoglobin and lumbar spine BMD using the two-piecewise linear regression model.

Lumbar spine BMD	Adjusted β (95% CI) P value	
Fitting by the standard linear model	‐0.0009 (‐0.0041, 0.0022) 0.5535	
Fitting by the two-piecewise linear model	
 Inflection point	15	
 Serum hemoglobin < 15 g/dL	‐0.0043 (‐0.0081, ‐0.0004) 0.0321	
 Serum hemoglobin > 15 g/dL	0.0076 (0.0008, 0.0143) 0.0281	
Log likelihood ratio	0.005	
Age, sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted.

ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CI = confidence interval, CPK = creatine phosphokinase.

Figure 2. The correlation between serum hemoglobin and lumbar spine BMD. (A) Each black point represents 1 participant serum ALP sample. (B) The solid red line illustrates the smooth fitting curve between variables, and 2 blue band illustrate the 95% confidence interval of the fitting. Age, sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted. ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CPK = creatine phosphokinase.

Figure 3. The correlation between serum hemoglobin and lumbar spine BMD by sex. Age, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted. ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CPK = creatine phosphokinase.

Figure 4. The correlation between serum hemoglobin and lumbar spine BMD by age. Sex, race/ethnicity, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein, triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted. ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CPK = creatine phosphokinase.

Figure 5. The correlation between serum hemoglobin and lumbar spine BMD by race/ethnicity. Age, sex, BMI, education level, smoking history, alcohol consumption, ratio of family income to poverty, albumin, ALT, AST, ALP, blood urea nitrogen, CPK, cholesterol, creatinine, γ-glutamyl transferase, lactate dehydrogenase, total bilirubin, total protein,triglycerides, uric acid, serum uric acid, globulin, and glycohemoglobin were adjusted. ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMD = bone mineral density, BMI = body mass index, CPK = creatine phosphokinase.

4. Discussion

This study utilized data from the NHANES database from 2011 to 2018 to investigate the association between the serum hemoglobin levels and the lumbar spine BMD. The results of this study demonstrated a negative correlation between the serum hemoglobin levels and the lumbar spine BMD. This negative correlation persisted in multiple regression analysis and subgroup analyses (sex, age, and race/ethnicity). Smooth curve fitting also revealed a nonlinear relationship between the serum hemoglobin level and the lumbar spine BMD, exhibiting a “U”-shaped curve. Threshold effect analyses showed that when serum hemoglobin levels were below 15 g/dL, the lumbar spine BMD decreased as the serum hemoglobin level increased, whereas when the serum hemoglobin levels were above 15 g/dL, the lumbar spine BMD increased with increasing hemoglobin levels. This negative correlation between the serum hemoglobin level and the BMD is consistent with previous research findings.[12]

Iron deficiency not only causes anemia, but also plays a significant role in collagen synthesis and vitamin D metabolism. Reduced intracellular iron levels can disrupt the activity and function of osteoblasts and osteoclasts, leading to an imbalance in bone homeostasis and ultimately resulting in bone loss.[13] Prolonged anemia can result in relative hypoxia, which may enhance the differentiation and activity of osteoclasts through hypoxia-inducible factors and osteoclast-specific factors, thus promoting increased bone resorption. Chronic hypoxia might also impact bone formation and remodeling processes.[14] Furthermore, pro-inflammatory cytokines can impact hematopoiesis, with a negative correlation observed between hemoglobin concentration and serum IL-6 levels.[15] This effect may be attributed to the suppression of erythropoietin production or its interaction with erythropoietin receptors, leading to adverse effects on hematopoiesis.[16]

Liver lipid metabolism also affects BMD or osteoporosis.[17] Hemoglobin, which plays a vital role in oxygen transport and is involved in lipid metabolism, may see its abnormal levels affect the oxygenation status of bone marrow and lipid metabolism, thereby impacting the metabolism of osteocytes and bone density. In the study by Xie et al[18] nonalcoholic fatty liver disease in adolescents was found to be positively correlated with bone density, with subgroup analysis indicating that this positive correlation was mainly observed in boys, whites and blacks. They also found a positive correlation between bone density and advanced fibrosis and cirrhosis.[19] Other studies have concluded that high-density lipoprotein cholesterol is positively associated with lumbar BMD in adults,[20] while low-density lipoprotein cholesterol is negatively associated.[21] However, Maghbooli et al[22] reported a negative correlation between high-density lipoprotein and BMD. Nevertheless, some believe there is no significant correlation between lipid metabolism and bone density or osteoporosis. For example, Pliatsiaka et al[23] in their study of 591 postmenopausal women, compared the indicators of total cholesterol, triglycerides, and low-density lipoprotein with bone density and found no significant strong correlation between these lipid metabolism indicators and bone density.

The relationship between hemoglobin levels and BMD remains unclear. Li et al[24] revealed a negative correlation between BMD and white blood cells, red blood cells, platelets, and hemoglobin levels in postmenopausal women. In another cross-sectional study, analysis revealed a positive correlation between hemoglobin levels and hip and femoral neck bone density in both men and women.[25] In contrast, in a study of 662 male patients in which the relationship between serum hemoglobin levels, BMD, and fracture risk was evaluated using Fracture Risk Assessment Tool scores, the hemoglobin was positively associated with the BMD but negatively associated with the risk of hip fracture and major osteoporotic fracture.[26] A cross-sectional study found a positive correlation between hemoglobin levels and the hip and femoral neck BMD in elderly men. Each 1 g/L increase in hemoglobin levels corresponded to a 3% decrease in osteoporosis risk. However, this association was not observed in elderly women.[27] In a case–control study conducted in Korea, among adult patients aged 40 years and above, each 1 g/L increase in hemoglobin levels corresponded to a 2% decrease in the risk of osteoporosis.[28] Chuang et al[29] suggested that the relationship between hemoglobin levels and the BMD is age-dependent: in adult women under 50 years, the hemoglobin level and the BMD are negatively correlated, while in those over 50 years, they are positively correlated. In the current study, we found a negative correlation between the hemoglobin level and the lumbar spine BMD overall. However, in subgroup analysis, this correlation was less evident in men and more pronounced in women. Moreover, the negative correlation observed in individuals aged 50 years or older was not statistically significant. This study has some limitations. Owing to the cross-sectional nature of NHANES data, we could not determine the causal relationship between the hemoglobin level and the BMD. Hence, prospective cohort studies are needed in the future to better evaluate this relationship.

5. Conclusion

The findings of the current study revealed the nonlinear association between the hemoglobin levels and the lumbar spine BMD in adults. Therefore, monitoring the serum hemoglobin levels could aid in the early detection of the risks associated with bone metabolic disorders such as osteoporosis. However, further research is needed to explore this relationship.

Acknowledgments

We express our gratitude to all NHANES staff for their dedication and efforts. We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Author contributions

Data curation: Xiaosong Cheng.

Investigation: Liangliang Zhang, Bo Cao.

Writing – original draft: Xiaosong Cheng.

Writing – review & editing: Chengjin Zhao.

Abbreviations:

ALP alkaline phosphatase

ALT alanine aminotransferase

AST aspartate aminotransferase

BMD bone mineral density

BMI body mass index

CPK creatine phosphokinase

NHANES National Health and Nutrition Examination Survey

This work was supported by the National Natural Science Foundation of China (No. 82160431).

NHANES has been approved by the Institutional Review Board of the National Center for Health Statistics, and all participants provided informed consent for their data to be utilized in subsequent research.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are publicly available.

How to cite this article: Cheng X, Zhang L, Cao B, Zhao C. Correlation between serum hemoglobin levels and bone mineral density in adults: A cross-sectional study. Medicine 2024;103:37(e39612).
==== Refs
References

[1] French ZP Caird MS Whitney DG . Osteoporosis epidemiology among adults with cerebral palsy: findings from private and public administrative claims data. JBMR Plus. 2019;3 :e10231.31768490
[2] Wilson-Barnes SL Lanham-New SA Lambert H . Modifiable risk factors for bone health & fragility fractures. Best Pract Res Clin Rheumatol. 2022;36 :101758.35750569
[3] Rachner TD Khosla S Hofbauer LC . Osteoporosis: now and the future. Lancet. 2011;377 :1276–87.21450337
[4] Dennison E Mohamed MA Cooper C . Epidemiology of osteoporosis. Rheum Dis Clin North Am. 2006;32 :617–29.17288968
[5] Alejandro P Constantinescu F . A review of osteoporosis in the older adult: an update. Rheum Dis Clin North Am. 2018;44 :437–51.30001785
[6] Balarajan Y Ramakrishnan U Ozaltin E Shankar AH Subramanian SV . Anaemia in low-income and middle-income countries. Lancet. 2011;378 :2123–35.21813172
[7] Crea F Bairey Merz CN Beltrame JF . Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization. Eur Heart J. 2019;40 :2455–62.30608528
[8] Zarei T Haghpanah S Parand S . Evaluation of bone mineral density in patients with hemoglobin H disease. Ann Hematol. 2016;95 :1329–32.27256348
[9] Duh MS Mody SH Lefebvre P Woodman RC Buteau S Piech CT . Anaemia and the risk of injurious falls in a community-dwelling elderly population. Drugs Aging. 2008;25 :325–34.18361542
[10] Cummings SR Black DM Nevitt MC . Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 1993;341 :72–5.8093403
[11] von Elm E Altman DG Egger M . The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370 :1453–7.18064739
[12] Kim HS Park HM Lee HS Lee YJ . Hemoglobin levels and low bone mineral density in non-anemic older adults: secondary analysis of the Korean National Health and Nutrition Examination Survey. Exp Gerontol. 2019;126 :110706.31442611
[13] Safiri S Kolahi AA Noori M . Burden of anemia and its underlying causes in 204 countries and territories, 1990–2019: results from the Global Burden of Disease Study 2019. J Hematol Oncol. 2021;14 :185.34736513
[14] Yu X Jiang H Cheng G Shang W Zhang S . High levels of HIF-1ɑ in hypoxic dental pulps associated with teeth with severe periodontitis. J Mol Histol. 2020;51 :265–75.32394128
[15] Góes MA Iizuka IJ Quinto BM . Serum Soluble-Fas, inflammation, and anemia in acute kidney injury. Artif Organs. 2018;42 :E283–9.23566289
[16] Eisenstaedt R Penninx BW Woodman RC . Anemia in the elderly: current understanding and emerging concepts. Blood Rev. 2006;20 :213–26.16472893
[17] Fan J Jahed V Klavins K . Metabolomics in bone research. Metabolites. 2021;11 :434.34357328
[18] Xie R Zhang Y Yan T . Relationship between nonalcoholic fatty liver disease and bone mineral density in adolescents. Medicine (Baltimore). 2022;101 :e31164.36253982
[19] Xie R Liu M . Relationship between non-alcoholic fatty liver disease and degree of hepatic steatosis and bone mineral density. Front Endocrinol (Lausanne). 2022;13 :857110.35360054
[20] Xie R Huang X Liu Q Liu M . Positive association between high-density lipoprotein cholesterol and bone mineral density in U.S. adults: the NHANES 2011-2018. J Orthop Surg Res. 2022;17 :92.35168655
[21] Xie R Huang X Zhang Y Liu Q Liu M . High low-density lipoprotein cholesterol levels are associated with osteoporosis among adults 20–59 years of age. Int J Gen Med. 2022;15 :2261–70.35250302
[22] Maghbooli Z Khorrami-Nezhad L Adabi E . Negative correlation of high-density lipoprotein-cholesterol and bone mineral density in postmenopausal Iranian women with vitamin D deficiency. Menopause. 2018;25 :458–64.29557847
[23] Pliatsika P Antoniou A Alexandrou A . Serum lipid levels and bone mineral density in Greek postmenopausal women. Gynecol Endocrinol. 2012;28 :655–60.22324476
[24] Li L Ge JR Chen J Ye YJ Xu PC Li JY . Association of bone mineral density with peripheral blood cell counts and hemoglobin in Chinese postmenopausal women: a retrospective study. Medicine (Baltimore). 2020;99 :e20906.32664083
[25] Cui R Zhao Z Fei Z Li Y Gao W . Anemia is related to osteoporosis in Chinese type 2 diabetic patients. Arch Osteoporos. 2021;16 :161.34716464
[26] Chuang MH Chuang TL Koo M Wang YF . Low hemoglobin is associated with low bone mineral density and high risk of bone fracture in male adults: a retrospective medical record review study. Am J Mens Health. 2019;13 :1557988319850378.31081448
[27] Xiu S Mu Z Sun L Zhao L Fu J . Hemoglobin level and osteoporosis in Chinese elders with type 2 diabetes mellitus. Nutr Diabetes. 2022;12 :19.35414128
[28] Kim SY Yoo DM Min C Choi HG . Association between osteoporosis and low hemoglobin levels: a nested case-control study using a national health screening cohort. Int J Environ Res Public Health. 2021;18 :8598.34444347
[29] Chuang TL Koo M Chuang MH Wang YF . Bone mineral density and hemoglobin levels: opposite associations in younger and older women. Int J Environ Res Public Health. 2021;18 :5495.34065536
