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. 2024 Dec 11;3(4):363–372. doi: 10.1021/envhealth.4c00143

Associations between Per- and Polyfluoroalkyl Substances Exposures and Bone Mineral: A Systematic Review and Best Evidence Synthesis

Kai Tao †,‡, Bin Zeng †,‡, Linghui Deng §,∥, Wei Zhang †,‡, Xianghong Zhou †,‡, Yuming Jin †,‡, Zilong Zhang †,‡, Weichao Huang †,‡, Xiaoli Zou ⊥, Yu Zhan ∇, Ping Lu 7, Shi Qiu †,‡, Lu Yang †,‡,*, Qiang Wei †,‡,*
PMCID: PMC12012664  PMID: 40270528

Abstract

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Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their bioaccumulative nature. Reduced bone mineral density (BMD) is associated with an increased risk of developing osteoporosis. This pioneering study aims to assess the effects of different PFAS compounds on bone mineral. We conducted searches on online databases. Inclusion criteria included the presence of associations between perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) and BMD, BMD z-score, and bone mineral content (BMC). Meta-analyses were performed. Best evidence synthesis (BES) was performed to summarize the results. The results of BES showed that the evidence of PFOS, PFOA and PFNA with reduced bone mineral were moderate. The variability in methods for assessing bone mineral and sex differences are potential sources of heterogeneity in the results. Meta analysis showed that PFOA was associated with BMD (β −0.01, 95% CI −0.01 to −0.00; I2 = 0%). Subgroup analysis by sex showed that PFOS (β −0.01, 95% CI −0.01 to −0.00; I2 = 50%), PFOA (β −0.01, 95% CI −0.01 to +0.00; I2 = 29%) were negatively correlated with BMD. This systematic review and BES revealed negative correlations between exposure to PFOS, PFOA, PFNA and bone mineral. Sex emerged as a potential factor affecting the negative effects of PFAS on bone mineral. The damage of PFAS to bone mineral still requires further exploration.

Keywords: Perfluoroalkyl substances, Bone mineral, Osteoporosis

Introduction

Per- and polyfluoroalkyl substances (PFAS) refer to a class of fluorinated chemicals applied in various aspects in life including textiles that resist stains and water, cookware with nonstick surfaces, protective coatings for food containers, polishes for flooring, foams for firefighting, and surfactants in industrial processes.1,2 As “forever chemicals”, PFAS can exist in the environment for a long time and appear in the human body through a variety of exposure routes such as ingestion of contaminated food, water and dust.3,4 PFAS including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonate (PFOS) have a half-life of 2 to 9 years in the human body and can be measured in the serum of more than 95% of the U.S. people.4−6 PFAS belong to environmental endocrine-disrupting chemicals (EDCs) defined as “an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action”.7,8 Previous studies have shown that PFAS may be related to metabolism, endocrine system, reproductive system, development and immunity.9

Bone mineral density (BMD) and bone mineral content (BMC) are two important indicators of bone health. BMD is more predictive of fracture risk and osteoporosis compared to BMC.10 BMD can be influenced by several endocrine disorders such as hypogonadism, hyperthyroidism and hyperparathyroidism.11 The BMD z-score, a commonly utilized metric for assessing BMD, quantifies the deviation of an individual’s BMD from the age- and sex-specific mean in terms of standard deviation units.12 Osteoporosis is an aging-related disease characterized by low BMD, which affects more than 9% of Americans older than 50.13 Osteoporosis is closely associated with high-incidence fractures that carry significant mortality and morbidity rates, and it has a narrow range of therapeutic options available.14 Therefore, focusing on bone health and reducing the occurrence of osteoporosis can greatly improve life quality.

As a kind of pollutant that interferes with endocrine, EDCs can also affect BMD, and it has been confirmed by some studies that various EDCs like the bisphenols, organic tin compounds, the phthalate esters, alkylphenols, dioxin, and dioxin-like compounds can affect bone remodeling process and the skeletal formation by altering the systemic hormonal regulation.15−17 As a type of EDCs, the effect of PFAS on bone mineral has also attracted attention. The long-term accumulation of PFAS in the body has a significant impact on BMD, which greatly affects people’s quality of life. Several studies have suggested that some subtypes of PFAS may impair bone health by interfering with sex and thyroid hormones or by affecting bone metabolism.15,18,19 Concurrently, as multiple PFAS may coexist within the body, a limited number of studies have begun to explore the cumulative effects of PFAS mixtures on BMD. Beglarian et al. examined the associations of the PFAS mixture with BMD by quantile g-computation in Hispanic adolescents with high weight and obesity and young adults with a history of adolescent obesity, which revealed that there was no significant negative correlation between PFAS and BMD.20 Additionally, while the use of PFAS is being reduced due to their toxicity, PFAS alternatives also have the potential to adversely affect BMD.21

Several epidemiological studies have investigated the relationship between BMD and PFAS, but the results are controversial among different populations and types of pollutants. In order to determine the effect of PFAS on bone health, we carried out a comprehensive systematic review and best evidence synthesis (BES) of existing literature and evaluated the potential bias.

Methods

Search Strategy and Selection Criteria

This systematic review and BES were conducted following PRISMA guidelines (Supporting Information) and registered at PROSPPERO (No. CRD42024503741). We systematically searched PubMed, EMBASE, and Web of Science from their inception up to September 5, 2024, without any language limitations. Our database queries involved Boolean search strings to pinpoint studies examining PFAS exposures and BMD. The concise search strategy included the following terms: Theme words “bone density” and theme words “fluorocarbons” as free text. The complete search strategies for the three databases are shown in the Supporting Information. We will also search gray literature to supplement valid articles missing from the database.

Selection Criteria and Data Extraction

The literature was screened by two independent reviewers with a process for conflict resolution. Initial screening was based on the title and abstract, and further screening was performed by reading the full text. From careful literature searches and subsequent screening, we restricted the results relevant to bone health to this systematic review.

Both exclusion and inclusion criteria were prespecified. The inclusion criteria were formulated according to the PECOS (population, exposure, comparator, outcome, study design) framework, which includes (1) subjects were humans. (2) the studies selected at least one subtype of PFAS as exposure, (3) outcomes were reported as BMD, BMD z-score, or BMC z-score, and (4) the research utilized either a cohort or a cross-sectional study design. Exclusion criteria encompassed (1) duplicate articles, (2) nonoriginal research, and (3) incomplete data or data that cannot be calculated. The screening process was conducted independently by two researchers to identify whether studies were eligible to be included. Disputes over study inclusion between the two investigators were resolved through consultation with the senior author if necessary.

Participant data from cohort studies and cross-sectional studies were extracted and analyzed. Two researchers extracted the data on study characteristics including the first author, study period, region of study, study design, study size, object of study, participants age, sex, body mass index (BMI), race, physical activity, adjusted factors, regression coefficient, and 95% CI.

Quality Assessment and Risk of Bias Assessment

Newcastle–Ottawa scale (NOS) was conducted to assess the quality of the observational study. NOS evaluates the quality of articles from three aspects: selection, comparability, and outcome/exposure. Scores of 7–9 were considered high quality studies, scores of 4–6 were moderate quality studies, and scores of less than 4 were considered low quality studies.22

Meta Analysis

All statistical analyses were carried out using Review Manager 5.4.1 and Stata 17.0 software. Detailed statistical methods were used as follows: (1) We used the regression coefficients, which are β-values, to represent the association between PFAS exposure and bone mineral. All statistical tests were two-sided and used a significance level of P < 0.05. Forest plots were employed to visualize estimates and corresponding 95% CIs for each study and the merger. (2) Heterogeneity test (Q-test): We conducted the I2 statistic to assess the heterogeneity of the results. A fixed-effects model was used when there was no significant heterogeneity (I2 < 50% and P > 0.1), otherwise a random-effects model was used.23 (3) Subgroup analyses: Subgroup analyses were conducted to explore potential sources of heterogeneity. (4) Test for publication bias: To evaluate potential publication bias, funnel plots and Eggers’ tests were applied if at least six studies were included.

Best Evidence Synthesis

Due to the heterogeneity in the results of the included literature and the inability to directly pool and calculate some results for methodological differences, we employed the BES methodology to summarize the findings.24,25 Potential sources of heterogeneity include sex differences in the included populations, methods of BMD measurement, and sources of samples for PFAS detection. The BES framework evaluates the quality of evidence according to these standards: (1) Strong: findings are consistently reported across various (≥2) high-quality studies. (2) Moderate: findings are generally aligned in one high-quality study and at least one low-quality study or are uniformly reported in multiple (≥2) low-quality studies. (3) Insufficient: evidence is limited to a single study or findings vary among various (≥2) studies. (4) No evidence: results consistently suggest no relationship in at least one high-quality study and at least one low-quality study or uniformly indicate no association in multiple (≥2) low-quality studies.

Results

Study Characteristics

We identified a total of 1,219 articles through careful literature searches from PubMed, Embase and Web of Science. We excluded 360 duplicate articles. Of the remaining 859 articles, we excluded reviews, conference abstracts, and studies in animals. Next, we read the abstracts and excluded articles that did not meet the inclusion and exclusion criteria and finally included 11 articles. K.T. and B.Z. independently completed the review process, with a senior author, S.Q., reassessing articles with uncertain eligibility. The process is illustrated in Figure 1.

Figure 1.

Figure 1

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Study selection.

Among the 11 articles, nine studies were implemented in the United States, one in the United Kingdom, and one in Denmark. Three studies were prospective cohort studies, and eight studies were cross-sectional studies. Participants from seven articles were under 18 years old. All studies applied whole body dual-energy X-ray absorptiometry to measure BMD or BMC. Three studies reported BMD z-score, six studies reported BMD value, and two studies reported BMC z-score. All studies expressed total body less head BMD or BMC by measuring several sites in the femur, femoral neck, and lumbar spine. Cluett et al.,29 Carwile et al.28 and Højsager et al.30 measured concentrations of PFOS, PFOA, PFHxS, perfluorodecanoic acid (PFDA) and PFNA. Seven studies examined the concentrations of PFOS, PFOA, PFHxS, and PFNA, while one study only examined the concentrations of PFOS and PFOA.26Table 1 summarizes the characteristics of each study included in the systematic review and BES.

Table 1. Study Characteristics for the Included Studies.

Reference number Study period Region Study design Object of study Number Age Male (%) Adjustment factors
(27) 2003–2006 USA prospective cohort mother–child pairs 206 12.3 (0.7) 45 maternal delivery age, midpregnancy BMI, race/ethnicity, household income, prenatal vitamin use, average blood lead concentration, and child age, parity, child sex and child sex by child age
(28) 2011–2016 USA cross-sectional 12–19-year-old participants 848 15 ± 2.1 53 age, race/ethnicity, moderate/vigorous physical activity, indoor smoking by a household member, recent sugar-sweetened beverage consumption, recent total dairy consumption, weights, and cycle
(29) 1999–2002 USA cross-sectional mother–child pairs 576 7.9 ± 0.8 51 maternal age, education, census tract median household income, individual household income, and child age, sex, year of blood draw, race/ethnicity, dairy intake, and physical activity
(30) 2010–2012 Denmark prospective cohort mother–child pairs 668 7 52 height z-score, total duration of breastfeeding and maternal education
(31) 2005–2010 USA cross-sectional adolescents aged 12–19 years 1228 15.44 ± 2.23 55 age, race, income poverty ratio, serum cotinine, vigorous physical activity, moderate physical activity, BMI, serum lead, albuminuria, and anemia
(32) 2009–2010 USA cross-sectional U.S. population 1914 42.6 ± 0.64 50 age, ethnicity, BMI, serum cotinine, physical activity, milk consumption, and blood lead concentration.
(26) 2005–2008 USA cross-sectional U.S. population older than 20 2338 NA 51 age, race/ethnicity, BMI, smoking, drinking, treatment for osteoporosis, use of of prednisone or cortisone daily
(33) 2005–2014 USA cross-sectional U.S. population 6416 45.0(0.38) 50.00 age, race, BMI, smoking, alcohol intake, milk intake, and physical activity.
(34) 1991–1992 England cross-sectional mothers and 17 year-old daughters 257 17 0 age at clinic visit, maternal education, gestational age at sample collection, height, and lean mass
(20) 2001–2012/2014–2018 USA prospective cohort adolescents/young adults 304/137 11.3 ± 1.7/19.9 ± 1.3 42.4/55.5 sex, race/ethnicity, parental education, study wave and Tanner stage
(35) 2003–2006 USA cross-sectional adolescents 197 12.4 ± 0.7 46 maternal parity, infant breastfeeding, sex, and 12-year household income, age, secondhand smoke exposure, fish intake, dairy intake, calcium intake, vitamin D intake, Health Eating Index score, and Physical Activity Questionnaire for Older Children
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Best Evidence Synthesis Results

A total of 11 articles were included in the BES (Table 2). The BES evaluated the effects of PFAS on bone health as well as potential sex differences and variations in methods used to assess bone health. Given that all observational studies were classified as low quality, the BES process did not yield any strong synthesized evidence. The moderate synthesis of evidence was summarized below. Seven studies examined the relationship between PFAS exposure and bone health in the general population. A moderate level of evidence indicated that PFOS, PFOA, and PFNA were associated with reduced bone mineral. Of these, six studies utilized BMD values to assess bone health, while three employed BMD z-scores, and two utilized BMC z-scores. After accounting for methodological differences in assessing bone mineral, the evidence for a negative correlation between PFOS and BMD values was graded as moderate. Seven studies reported outcomes for both males and females. The relationship between PFOS and bone mineral was negatively correlated in both sexes. In males, PFOA was associated with reduced bone mineral, whereas in females, PFNA was associated with reduced bone mineral.

Table 2. Best Evidence Synthesis Resultsa.

Outcomes Level of evidence Synthesis of evidence Origin of evidence
Total effect      
PFOS Moderate PFOS exposure was associated with reduced bone mineral. (20,27,29−31,33,35)
PFOA Moderate PFOA was negatively correlated with bone mineral. (20,27,29−31,33,35)
PFHxS Insufficient The association between PFHxS and bone mineral was unclear. (20,27,29−31,33,35)
PFNA Moderate PFNA was negatively correlated with bone mineral. (20,27,29−31,33,35)
PFDA No evidence Evidence for the association between PFDA and bone mineral was lacking. (20,29,30,33)
Measurement differences      
PFOS      
BMD value Moderate PFOS was negatively correlated with BMD. (20,31,33)
BMD z-score Insufficient Insufficient evidence was available to establish a negative correlation between PFOS and BMD z-score. (29,30)
BMC z-score Insufficient There was no sufficient evidence. (27,35)
PFOA      
BMD value Insufficient There was no sufficient evidence. (20,31,33)
BMD z-score Insufficient   (29,30)
BMC z-score Insufficient   (27,35)
PFHxS      
BMD value Insufficient There was no sufficient evidence. (20,31,33)
BMD z-score Insufficient   (29,30)
BMC z-score No evidence Evidence was lacking. (27,35)
PFNA      
BMD value Insufficient There was no sufficient evidence (20,31,33)
BMD z-score Insufficient   (29,30)
BMC z-score Insufficient   (27,35)
PFDA      
BMD value No evidence Evidence was lacking. (20,33)
BMD z-score No evidence   (29,30)
Sex differences      
PFOS      
Male Moderate Exposure to PFOS was associated with reduced bone mineral in males. (26−28,30−33)
Female Moderate Exposure to PFOS was associated with reduced bone mineral in females. (26−28,30−34)
PFOA      
Male Moderate Exposure to PFOA was associated with reduced bone mineral in males. (26−28,30−33)
Female Insufficient There was no sufficient evidence. (26−28,30−34)
PFHxS      
Male No evidence Evidence was lacking. (27,28,30−33)
Female Insufficient The association between PFHxS and bone mineral in female was unclear. (27,28,30−34)
PFNA      
Male No evidence Evidence was lacking. (27,28,30−33)
Female Moderate Exposure to PFNA was associated with reduced bone mineral in females. (27,28,30−34)
PFDA      
Male No evidence Evidence was lacking. (28,30,33)
Female No evidence   (28,30,33,34)
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a

PFOS: perfluorooctane sulfonate. PFOA: perfluorooctanoic acid. PFHxS: perfluorohexane sulfonic acid. PFNA: perfluorononanoic acid. PFDA: perfluorodecanoic acid. BMD: bone mineral density. BMC: bone mineral content.

Meta Analysis of PFAS and BMD

The meta-analysis included results from four cohorts, which showed a significantly negative correlation between PFOA and BMD (β −0.01, 95% CI −0.01 to −0.00; I2 = 0%) (Figure 2).

Figure 2.

Figure 2

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Forest plots of associations between log transformed PFAS with BMD. PFOS: perfluorooctane sulfonate. PFOA: perfluorooctanoic acid. PFHxS: perfluorohexane sulfonic acid. PFNA: perfluorononanoic acid. BMD: bone mineral density. SOLAR: Study of Latino Adolescents at Risk of Type 2 Diabetes. CHS: the Southern California Children’s Health Study.

According to the BES results, the sex is an important source of heterogeneity. Four of the total studies, Khalil et al.,32 Xiong et al.,31 Zhao et al.,33 and Lin et al.,26 all explored the associations between log transformed PFAS and BMD in both males and females. Results of Lin et al. for female in menopause and not in menopause were not combined, and we selected women who were not in menopause for inclusion in the analysis to exclude the effect of menopause on BMD. The forest plot for subgroup analysis by sex showed that PFOS (β −0.01, 95% CI −0.01 to −0.00; I2 = 50%), PFOA (β −0.01, 95% CI – to +0.00; I2 = 29%) were negatively correlated with BMD. The negative relationship between PFOS and BMD was more pronounced in women (Figure 3).

Figure 3.

Figure 3

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Forest plots for subgroup analysis by sex of associations between log transformed PFAS with BMD. PFOS: perfluorooctane sulfonate, PFOA: perfluorooctanoic acid, PFHxS: perfluorohexane sulfonic acid, PFNA: perfluorononanoic acid, PFDA: perfluorodecanoic acid, BMD: bone mineral density, BMC: bone mineral content.

Discussion

This study provided comprehensive evidence on the effects of PFAS exposure on bone health, with a summary of the evidence by BES and analysis of results based on 11 observational studies. There was evidence suggesting that higher exposures to PFOS, PFOA, and PFNA are associated with reduced bone mineral density. In the total population, PFOA exhibits a negative correlation with BMD. After the influence of sex is accounted for, both PFOS and PFOA are negatively correlated with BMD.

Recently, several studies have explored the adverse effects of PFAS on bone health, though the mechanism is still not well understood, there are several potential ways for PFAS to influence bone mineral.17 First, PFAS may impact bone health by disrupting endocrine functions. As environmental endocrine disruptors, chronic PFAS exposure may lead to liver damage, neurological harm, adverse effects on reproduction and development, hormonal disruptions, immune system toxicity, and cancer.36 Several experimental studies show that PFAS can interfere with the biological effects of sex hormones.18,37 Epidemiological studies also discovered that PFAS can interplay with sex hormones, which are linked with the delayed onset of puberty, earlier age of menopause, and lower serum estradiol concentration.38,39 Sex hormones play main roles in bone mineral metabolism for gaining peak bone mass during puberty and keeping bone mass during adulthood via balancing bone remodeling between resorption and formation.40 Otherwise, PFAS also influences thyroid hormones with positive associations among changes in TSH, thyroxine (T4) and triiodothyronine (T3) and exposure to PFAS being found,41 which plays a crucial role in bone health and remodeling according to several epidemiological studies and meta-analysis.15,41,42

The second mechanism involves the direct action of PFAS on bone mineral, which was demonstrated by studies on humans and animals. Based on in vitro and in vivo studies, PFOA can directly target bone and bone marrow cells.43,44 Low PFOA concentrations may result in abnormal resorption activity of osteoclasts and increase osteocalcin expression, while high PFOA concentrations cause the opposite effect. PFOA can destroy trabecular bone microstructure and promote osteoblast senescence in adolescent mice by activating the ferroptosis pathway.19 In conclusion, PFOA interferes with the normal bone metabolism. A study evaluated the impact of PFOS on the differentiation of human mesenchymal stem cells derived from bone marrow into osteogenic and adipogenic lineages and discovered that PFOS inhibited the process of osteogenesis.45

Empirical investigations have demonstrated that certain classes of PFAS do not exhibit a statistically significant deleterious correlation with bone mineral. We propose several plausible explanations for these observations. First, the covariates incorporated in the multivariate linear regression analyses vary among studies, which may precipitate divergent findings. Second, PFAS are predominantly encountered in complex mixtures. When assessing the relationship between a specific PFAS and BMD, the original study may not have accounted for the potential interference from other pollutants. Only three studies explored the relationship between PFAS mixture and BMD, and all three studies suggested that PFAS mixture was negatively associated with BMD regardless of whether the results were significant or not.27−29 Further original studies are warranted to directly explore the association between PFAS mixtures and BMD. Third, the original studies may not have conducted detailed stratified analyses within the included population to account for the potential effects of factors such as age, sex, or source of PFAS on the outcomes.

In our study, the relationship between PFAS and bone mineral differed between males and females. Due to the essential role of hormones played in bone metabolism,46 PFAS can affect BMD by interfering with sex hormones. This also partially explains the sex specific differences of association between PFAS and bone mineral. We found that there are differences in the methods used to assess bone mineral. The articles we included used the BMD, BMD z-score, and BMC z-score to evaluate bone health, respectively. Unlike the direct measurement of BMD and BMC, the z-score represents the difference between bone mineral and the average bone mineral of healthy individuals of the same age, race, and sex. Although, in this study, only the evidence level of the relationship between PFOS and BMD is moderate, more research should be conducted to compare the advantages and disadvantages of tools used to assess bone health.

This is the first comprehensive systematic review and BES of PFAS and BMD to consider sex and other sources of heterogeneity. Despite previous meta-analyses on similar topics, we took different research methods, included different literature sources, and had different results. We took into account the influence of sex differences on the effect of PFAS on BMD and summarized the results using more reliable methods, such as BES.

It is undeniable that this study still has certain limitations. First, the number of articles is relatively small after thorough screening, which may lead to bias in the accuracy of the results. Not all studies were included in the qualitative analysis. These findings should be interpreted with caution. Second, our study integrated only the effects of PFAS on BMD. However, adverse bone health effects are usually on account of the coexposure to multiple compounds in real situation. More studies are needed on the effects of PFAS mixtures on BMD. Concurrently, given the increasing use of PFAS alternatives, there is a necessity for further research to investigate the health effects of these substitute compounds. Third, we cannot assess the impact of differences in the PFAS sample sources on the results. Three studies utilized PFAS from maternal serum, while others measured PFAS in their own serum. It is believed that bone density is established early in childhood, and therefore PFAS exposure from the mother and children’s exposure can both impair BMD. Additionally, some evidence supports the transference of PFAS through the placenta from mother to fetus.47 Prenatal and postnatal PFAS are correlated. Therefore, subsequent studies should compare the impacts of prenatal exposure to PFAS and postnatal exposure to PFAS on bone health.

Conclusion

This systematic review and best evidence synthesis reveals that high exposure to PFOS, PFOA, and PFNA may be associated with lower bone mineral content. The inverse correlation exhibits sex differences. The study also suggests directions for future research. Studies are needed to explore the effects of maternal PFAS and acquired PFAS exposure after birth on early bone health, to provide more targeted prevention recommendations. Investigating the health effects of mixed PFAS contaminants is of practical significance. However, the mechanisms and effects variations among different classes of PFAS, particularly in males and females, also warrant attention.

Acknowledgments

None.

Data Availability Statement

All relevant data that support the findings of this study are available within the manuscript and its Supporting Information files.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/envhealth.4c00143.

  • Literature search terms, PRISMA guidelines, quality assessment of included studies (PDF)

Author Contributions

# K.T., B.Z., and L.D. contributed equally to this work. L.Y., Q.W., K.T., B.Z.: conception and design of study; L.D., W.Z., Y.J., Y.Z.: Data curation and data analysis; Z.Z., W.H., X. Zhou: interpretation of data; K.T., B.Z.: writing the original draft; S.Q., L.Y., P.L., Q.W.: revising the paper; L.Y., Q.W.: supervised this study. All authors read and approved the final manuscript.

This work was supported by the National key research and development program of China (2022YFC3602902, 2022YFC3602901, 2020YFC2008601), National Natural Science Foundation of China (Grant No. 82160379), Programs from Science and Technology Department of Sichuan Province (2023NSFSC1906, 2021YJ0462), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2023LC007, Z2024LC003), Postdoctoral Fellowship Program of CPSF (GZC20241158).

Ethics approval and consent to participate: This article does not contain any studies involving human participants or animals performed by the authors.

The authors declare no competing financial interest.

Supplementary Material

eh4c00143_si_001.pdf (113.4KB, pdf)

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Supplementary Materials

eh4c00143_si_001.pdf (113.4KB, pdf)

Data Availability Statement

All relevant data that support the findings of this study are available within the manuscript and its Supporting Information files.

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