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A case–control study based on the National Health and Nutrition Examination Survey to evaluate the effects of human papilloma virus on bone health in women

BMC Medicine volume 23, Article number: 75 (2025) Cite this article

Abstract

Background

Human papillomavirus (HPV) infection and osteoporosis (OP) are global health concerns, with higher prevalence observed in women compared to men. However, the impact of HPV infection on bone health remains uncertain.

Methods

This case–control study utilized data from the National Health and Nutrition Examination Survey (NHANES). Comparable datasets were created using nearest neighbor propensity score matching (PSM) at a ratio of 1:1. The association between HPV infection and bone mineral density (BMD) was analyzed using the Welch two-sample t-test. Furthermore, linear mixed models were employed for validation purposes. Restricted cubic spline (RCS) analysis and Kendall’s tau-b tests were performed to explore the effect of different types of HPV infection on BMD.

Results

Individuals with HPV infection (mean age 38.11 ± 11.32 years) had lower BMD in the femur and lumbar spine compared to uninfected individuals (mean age 37.92 ± 11.42 years). RCS analysis revealed that an increasing number of cooccurring HPV types in women was associated with lower BMD. Specifically, four HPV types were negatively associated with femur BMD, while 14 HPV types were negatively associated with lumbar spine BMD. Additionally, HPV types 53, 59, and 89 exhibited effects on both femur and lumbar spine BMD.

Conclusions

HPV infection is associated with a decrease in BMD, and co-infection with multiple types of HPV implies even lower BMD. Appropriately designed trials are needed to determine if interventions targeted at preventing HPV infection can have a protective effect on BMD.

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Background

Osteoporosis (OP) is a prevalent chronic skeletal disease characterized by reduced bone mineral density (BMD) and deterioration of bone structure [1, 2]. OP is of significant clinical importance as it is a major risk factor for fractures and has a substantial impact on human health and quality of life [3, 4]. Worldwide, there are over 200 million individuals affected by OP [5, 6], with an approximate 40% prevalence rate in elderly populations in certain regions [7,8,9]. The economic and social burdens imposed by OP and its associated fractures are substantial. Due to its multifactorial nature, it is crucial to gain a better understanding of emerging risk factors associated with the disease in order to develop effective prevention and treatment strategies for high-risk individuals.

Human papillomavirus (HPV) is one of the most well-known viruses affecting humans, with a relatively high infection rate ranging from 2 to 44% [10,11,12]. The majority of individuals will encounter HPV infection at some point in their lives. HPV has become the most common sexually transmitted infection worldwide and is recognized as a causal factor for cervical cancer [13, 14]. It has also been implicated as a risk factor for other malignancies such as laryngeal carcinoma, anal squamous cell cancer, lung cancer, and colorectal cancer [15,16,17,18,19,20]. The rate of HPV infection is significantly higher in women than in men [21, 22]. Similarly, being female is an independent risk factor for OP. A cross-sectional study has shown that women are more likely to develop osteoporosis than men [23,24,25]. However, the association between HPV and BMD has not been confirmed. HPV infection is associated with chronic inflammation and immunosuppression, both of which are critical factors in the development of OP. For instance, a study supports the link between systemic (such as HIV, immunosuppressive drugs) and local immunosuppression (such as alterations in the vaginal microbiota) and an increased risk of poor prognosis in HPV and cervical diseases [26]. Furthermore, HPV infection may increase the risk of certain types of breast cancer by inducing chronic inflammatory responses, with inflammatory factors such as IL-1, IL-6, and TNF-α being expressed at higher levels in HPV-positive breast cancer patients compared to HPV-negative breast cancer patients and healthy controls [27]. These findings suggest that HPV infection may affect bone health through similar inflammatory pathways, although this association has not been thoroughly investigated in the context of osteoporosis. Therefore, we aim to fill this knowledge gap through our research to explore the impact of HPV infection on women’s bone health.

Thus, we conducted a comprehensive case–control study utilizing data from the National Health and Nutrition Examination Survey (NHANES) to examine the relationship between HPV infection and BMD. By elucidating the strength and nature of this association, we aim to provide evidence to guide targeted public health interventions.

Methods

General information about the NHANES

The National Center for Health Statistics of the Centers for Disease Control and Prevention in the USA conducted a multistage, large-scale, nationally representative study named the NHANES [28]. This cross-sectional survey gathered comprehensive demographic, dietary, examination, and questionnaire data. Detailed information regarding the NHANES protocol can be found elsewhere [29]. The data utilized in this study were obtained from the 2009–2014 NHANES database.

Definition of variables

HPV infection

All eligible female participants underwent vaginal swab collection. According to the protocol in NHANES, examined female participants aged 18–59 years were eligible. The collected samples were analyzed using the Roche linear array HPV genotyping test to identify the presence and specific type of HPV infection. This method allowed for the detection of 37 HPV types, including 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, 89, and IS39.

Subjects who tested negative for HPV were grouped into group A, while those who tested positive for any HPV type were placed in group B. Subjects with missing data were excluded from the analysis.

Measurement of BMD

Dual-energy X-ray absorptiometry (DXA) was utilized to measure BMD in eligible female subjects. According to the protocol in NHANES, DXA scans were administered to eligible survey participants aged 18–59. Reasons for exclusion from the DXA examination were as follows: Pregnancy (positive urine pregnancy test and/or self-report at the time of the DXA examination). Self-reported history of radiographic contrast material (barium) use in past 7 days. Self-reported weight over 450 pounds or height over 6′5″ (DXA table limitation).

The scanning procedure encompassed the entire body, but our study concentrated specifically on the BMD of the lower limbs and lumbar spines.

The BMD of the lower limbs was determined by averaging the BMD values of the bilateral total femur, while the BMD of the lumbar spine was calculated by averaging the BMD values of L1-4. If the BMD measurement for one lower limb was missing, the BMD of another limb was used in place of the missing value. Subjects whose BMD measurements for the lower limbs or lumbar spine could not be computed were excluded from the analysis. Raw BMD values in gm/cm2 units were employed for subsequent analyses.

Covariates

We included various covariates of interest in our study. These covariates include age, race, education level, marital status, poverty-to-income ratio, smoking status, alcohol consumption status, presence of diabetes, depression score, sleeping difficulty, intake of calcium and vitamin D, sun exposure, and human immunodeficiency virus (HIV) infection.

To ensure consistency and accuracy in our measurements, we defined smoking as having smoked ≥ 100 cigarettes in a lifetime [30]. We defined alcohol consumption as having 4/5 or more drinks every day (past 12 months) [31, 32].

Subjects were considered to have diabetes if they met any of the following criteria: being told by doctors or other health professionals they had diabetes, using insulin, or using diabetes medication to lower their blood sugar [33].

We deemed subjects to have clinically relevant depression if they had a Patient Health Questionnaire (PHQ)−9 total score of ≥ 10 [8, 34].

Additionally, subjects who answered “yes” to the question “Have you ever been told by a doctor that you have a sleep disorder?” were considered to have sleeping difficulty.

To investigate the intake of calcium and vitamin D, we conducted dietary interviews and examined total nutrient intakes on the first and second day. We used the average value of the intake for downstream analysis.

For sun exposure, we obtained data from the dermatology questionnaire section. Subjects who answered “always,” “most of the time,” or “don't go out in the sun” to the question “When you go outside on a very sunny day, for more than one hour, how often do you stay in the shade?” or “Wear a long-sleeved shirt?” or “Use sunscreen?” were considered to have insufficient sun exposure [35].

Finally, to determine the HIV infection status, we collected serum samples from the subjects and conducted tests to detect the presence of HIV antibodies. To be specific, all specimens were tested using the Synthetic Peptide Enzyme Immunoassay (Genetic Systems HIV-1/HIV-2 Peptide EIA) for the detection of antibody to human immunodeficiency virus type 1 or type 2 (HIV-1 or HIV-2) or both (Bio-Rad Laboratories, Redmond, WA).

Ethical statement

The National Center for Health Statistics Research Ethics Review Board had approved the NHAHES. Therefore, NHANES data could be accessed without ethical or administrative permission.

Statistical analyses

Normal Q-Q plots were utilized to assess the distribution of the data. Continuous variables were analyzed using either Welch two-sample t tests or nonparametric Mann–Whitney U tests. Categorical variables were compared using either chi-square tests or Fisher’s exact tests.

Previous studies have demonstrated the effectiveness of propensity score matching (PSM) in reducing selection bias in retrospective studies [7, 36, 37]. In our study, we employed PSM with the 1:1 nearest neighbor matching algorithm to match subjects. Subsequently, linear mixed models were utilized to further investigate the association between HPV infection and BMD. BMD was treated as a continuous variable in this analysis. HPV infection was treated as categorical and set as a fixed effect. The remaining parameters used their default settings.

For nonlinear a priori associations, we employed restricted cubic spline (RCS) models to describe the dose‒response relationships between the continuous exposure and outcomes [38, 39]. In this study, RCS models with five knots were utilized to further explore the association between HPV infection and BMD.

Lastly, Kendall’s tau-b test was employed to analyze the association between HPV type and BMD. Only the individual effects of each HPV type were calculated in this test, without considering interactions between different types. A significance level of P < 0.05 was applied, and all tests were one-sided. Data extraction, merging, statistical analyses, and figures were conducted using R (version 4.1.1) and SPSS (version 22). The study design is presented in Additional file 1.

Results

Participant characteristics before matching

A total of 4673 female subjects were included in this study after screening. Group A (n = 2614) had a mean age of 39.00 ± 11.97 years, while group B (n = 2059) had a mean age of 36.67 ± 12.29 years. Additional file 2 presents the comparisons of baseline characteristics between the two groups. The results revealed statistically significant differences in the vast majority of characteristics, including age and education level (P < 0.001). This indicated the presence of significant selection bias between the two groups of subjects. Consequently, PSM was conducted to mitigate this phenomenon.

Construction of matched datasets

Following 1:1 matching, datasets containing BMDs in the legs and lumbar spine were obtained. A total of 753 subjects were included in both group A and group B. Analysis of baseline characteristics revealed the absence of selection bias (P > 0.05). Further details can be found in Additional file 3. Figure 1A depicts the BMD values of the lower limbs and lumbar spine across different age groups. Figure 1B–D demonstrate that BMD follows a significant normal distribution according to the Normal Q-Q plots.

Fig. 1
figure 1

A comparison of bone mineral density (BMD) in the femurs and lumbar spine across different age groups after matching. Gray bars represent. Group A, and blue bars represent Group B. Error bars indicate the standard error (A). The normal Q-Q plots of BMD to assess the normality of the data in group A (B, C) and group B (D, E). Points close to the diagonal line in the Q-Q plots suggest that the data are approximately normally distributed

Full size image

Lower BMD in subjects with HPV infection

Subjects infected with HPV exhibited lower BMD in both the lower limbs and lumbar spine, as indicated by Welch two-sample t tests (P < 0.001). There was a greater decrease in BMD in the lumbar spine compared to the lower limbs (Table 1). Linear mixed models revealed that subjects infected with HPV had a mean decrease of 0.015 (P = 0.015) in lower limb BMD compared to HPV-negative subjects. Additionally, a mean decrease of 0.017 (P = 0.006) was observed in lumbar spine BMD. These findings corroborated the results obtained from PSM and Welch two-sample t tests. Detailed data can be found in Table 2.

Table 1 Comparison of BMD between the two groups after matching
Full size table
Table 2 Linear mixed model of BMD, with HPV infection as a categorical variable
Full size table

RCS analysis was performed to gain a clearer understanding of the association between HPV infection and BMD. Figure 2 demonstrates a nonlinear association (P < 0.001) between the number of cooccurring HPV types and BMD. As the number of cooccurring HPV types increased, BMD decreased.

Fig. 2
figure 2

Restricted cubic spline models for the relationship between the number of infected human papilloma virus (HPV) types and bone mineral density (BMD) after matching

Full size image

Subsequently, we performed an analysis on individual HPV types to identify those that had the most significant impact on BMD. The data revealed that four HPV types (06, 53, 59, and 89) exhibited a negative correlation with lower limb BMD (P < 0.05). Notably, type 89 exhibited the strongest correlation (r = − 0.060). Fourteen HPV types demonstrated a negative correlation with lumbar spine BMD, with type 53 showing the strongest correlation (r = − 0.085). Specifically, three HPV types (53, 59, and 89) had a significant effect on both lower limb and lumbar spine BMDs. In our analysis, the effects of specific HPV types could not be evaluated individually because there is no participant data in the NHANES database for those who are solely infected with HPV types 26, 64, and 82. Therefore, these types of HPV were not included in this study. Additional detailed data can be found in Tables 3 and 4.

Table 3 The correlation between HPV types and BMD of lower limbs
Full size table
Table 4 The correlation between HPV types and BMD of lumbar spine
Full size table

Discussion

The current literature regarding the association between viral infection and OP is limited. Viruses such as HIV, hepatitis B virus, hepatitis C virus, and severe acute respiratory syndrome coronavirus 2 have been found to be associated with OP [40,41,42,43,44]. By integrating the findings from the PSM, linear mixed models, and RCS analyses, we established a negative correlation between HPV infection and BMD. Specifically, individuals infected with HPV (average age 38.11 ± 11.32 years) exhibited lower bone density in the femur and lumbar vertebrae compared to uninfected individuals (average age 37.92 ± 11.42 years). Furthermore, a higher number of co-occurring HPV types was associated with decreased BMD.

As mentioned earlier, we confirmed the association between HPV and BMD. However, it is more important to determine the causal relationship between them. The decline in BMD and its progression to OP often occur over an extended period of time. In contrast, HPV infection can be regarded as an immediate occurrence. We posit that the decline in BMD is more likely caused by HPV infection rather than the other way around. Furthermore, the results after statistical adjustment provide support for our hypothesis. PSM eliminated selection bias, safeguarded our findings from confounding factors, and enhanced the strength of evidence. Nevertheless, prospective studies are essential to establish the causal relationship between HPV infection and BMD.

However, the biological mechanisms responsible for the decline in BMD due to HPV infection are still unclear. Persistent HPV infection is known to elicit various responses, such as immunosuppression and abnormal cell destruction [45]. In a prospective study, Scott et al. discovered elevated IL-12 concentrations in cervicovaginal lavage fluid specimens from women with persistent HPV infection [46]. This might indicate the activation of macrophages induced by IL-12 and the ensuing chronic inflammation [47]. The tissue damage resulting from inflammation is self-evident. Furthermore, cervical HPV infection leads to the infiltration of macrophages and dendritic cells. Activation of these cells also results in the release of TNF, IL-8, and IL-12 [ [48, 49]. Additionally, HPV infection-induced oxidative stress and lipid peroxidation contribute to cellular damage that may result in cell death [50]. While these effects are primarily observed in locally infected tissues, prolonged effects can lead to systemic damage, including bone damage.

We also noted a larger decline in BMD in the lumbar spine than in the lower limbs in HPV-infected individuals. Fourteen HPV types showed an inverse association with lumbar spine BMD, a significantly higher number compared to the lower limbs (four types). This finding indicates that lumbar spine BMD is more responsive than lower limb BMD. This finding aligns partially with the results of previous studies. For instance, Snyder et al. discovered that testosterone was associated with increased BMD in older men, with a greater increase observed in the spine compared to the hip [51]. The reviewer pointed out that this phenomenon may be explained by the more active metabolism of trabecular bone (which predominates in the lumbar spine) compared to cortical bone. We agree with this view and further discuss this biological mechanism. Trabecular bone, particularly in the lumbar region, may be more sensitive to the effects of HPV infection due to its higher metabolic activity [52]. In comparison to cortical bone, trabecular bone has a higher rate of metabolic turnover, which suggests that it may be affected more rapidly under pathological conditions, such as HPV infection [53, 54]. This difference in metabolic activity may be one of the reasons why we observed that lumbar BMD is more sensitive to HPV infection than lower limb BMD.

Currently, more than 20 types of HPV are known to infect the genital tract [55]. These types have been classified as either “high-risk” or “low-risk” based on their probability of causing cancer [56, 57]. A study identified fifteen high-risk HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 [58]. Among them, HPV-16 is considered to have the highest risk for carcinogenicity, followed by HPV-18 [59]. On the other hand, types 6 and 11 are commonly found in benign lesions and are therefore classified as low risk. However, based on epidemiological evidence and molecular research, types 26, 53, and 66 might also be considered high risk [60]. In our study, we analyzed data on all 37 types of HPV included in NHANES, which included the aforementioned types. Our findings revealed a negative association between three types of HPV (53, 59, and 89) and BMDs in both the lumbar spine and lower limbs. Therefore, public HPV preventive measures and the detection of HPV infection should prioritize these three types. Further research focusing on these types could help elucidate the biological mechanisms underlying the association between HPV and BMD.

Although our statistical analysis minimized selection bias, there are still some limitations in the present study. Firstly, to truly establish a causal association between HPV infection and BMD decline, prospective evidence is necessary. Secondly, additional molecular experiments are required to better understand the biological mechanisms linking HPV and BMD. Lastly, our study only included 37 types of HPV, and it remains unknown whether other types not detected in NHANES have an impact on bone health in women.

Conclusions

In conclusion, our analysis of data from a nationally representative database of US adults revealed a negative association between HPV infection and BMD in female subjects. Additionally, we observed that a higher number of cooccurring HPV types was associated with lower BMD levels.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

BMD:

Bone mineral density

DXA:

Dual-energy X-ray absorptiometry

HIV:

Human immunodeficiency virus

HPV:

Human papillomavirus

NHANES:

National Health and Nutrition Examination Survey

OP:

Osteoporosis

PHQ:

Patient Health Questionnaire

PSM:

Propensity score matching

RCS:

Restricted cubic spline

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Acknowledgements

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Funding

This research was supported by the Natural Science Foundation of Shandong Province (ZR2021MH293).

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Author notes

  1. Guangjun Jiao and Yunzhen Chen contributed equally as corresponding authors.

Authors and Affiliations

  1. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China

    Xiang Li, Guangjun Jiao & Yunzhen Chen

  2. Department of Orthopedics, Qilu Hospital of Shandong University, No.107, Wenhuaxi Road, Jinan, Shandong, 250000, China

    Xiang Li, Guangjun Jiao & Yunzhen Chen

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  1. Xiang Li
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Contributions

Xiang Li contributed to the conception and design of the study, performed the data analysis, and drafted the manuscript. Guangjun Jiao was involved in the acquisition of data, interpretation of results, and provided critical revisions to the manuscript for important intellectual content. Yunzhen Chen contributed to the study design, supervised the data collection. All authors read and approved the final manuscript.

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Correspondence to Guangjun Jiao or Yunzhen Chen.

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Li, X., Jiao, G. & Chen, Y. A case–control study based on the National Health and Nutrition Examination Survey to evaluate the effects of human papilloma virus on bone health in women. BMC Med 23, 75 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-03909-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-03909-2

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BMC Medicine

ISSN: 1741-7015

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