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Asthma, social isolation and loneliness, and risk of incident osteoarthritis

Arthritis Research & Therapy volume 27, Article number: 29 (2025) Cite this article

Abstract

Background

Incidence of osteoarthritis (OA) was increased in patients with asthma, while no prospective cohort study has tested the association of asthma with OA, and the modified effect of social isolation and loneliness remains unclear.

Methods

This prospective cohort study included 448,920 participants without OA at baseline from UK Biobank cohort. The evaluation of asthma was based on diagnosis and self-reported history. The outcome was OA including knee OA, hip OA and hand OA by referring to hospital admission records. Two Cox regression models were constructed to assess the relationship of asthma and risk of OA.

Results

With a median of 12.5 years of follow up, a total of 57,573 incident OA were recorded. Compared with participants without asthma, the hazard ratios (HRs) were 1.32 (95% CI: 1.29–1.35) for all OA, 1.21 (95% CI: 1.16–1.25) for knee OA, 1.12 (95% CI: 1.07–1.18) for hip OA and 1.62 (95% CI:1.42–1.85) for hand OA in participants with asthma. In addition, we found that social isolation and loneliness significantly modified the associations of asthma with OA (P-interaction < 0.001). Asthma was a stronger predictor of OA than lifestyle risk factors including smoking, alcohol and healthy diet.

Conclusions

In this cohort study of UK Biobank participants, asthma was related to increased risk of OA; such association was more pronounced among those with higher social isolation or loneliness score.

Introduction

Osteoarthritis (OA) is characterized by pain, functional impairment, and diminished quality of life [1]. Approximately 250 million people of the world’s population are affected by OA, predominantly among the elderly [2, 3]. Despite its widespread occurrence, considerable economic implications, and incapacitating effects, the current treatments are limited and focus on symptom management [4]. Currently, there are no efficacious pharmaceutical interventions capable of arresting, decelerating, or reversing the advancement of OA [4, 5].

Asthma is characterized by airway inflammation and an immunoglobulin type E (IgE)-mediated response, commonly referred to as atopy, which is one of the primary risk factors for the disease’s development [6, 7]. Recent research highlighted the important role of chronic inflammation in the onset and progression of OA [8, 9]. Meanwhile, IgE-mediated activation by mast cells has been found to play a key role in driving the pathogenesis of OA in mice [10]. Previous study presented that OA showed a high prevalence in asthma patients [11] and a retrospective study observed an increased incidence of OA in patients with atopic disease [12]. Additionally, A mendelian randomization study in european population showed that social isolation was causally associated with osteoarthritis [13]. However, no prospective cohort study has tested the association of asthma with risk of incident OA, and no study has investigated the potential interactions of asthma with social isolation and loneliness in relation to OA.

In the present study, we prospectively analyzed the association of asthma with risk of incident OA in multiple sites including all OA, knee OA, hip OA, and hand OA. We particularly investigated the modified effect of social isolation and loneliness in relation to risk of incident OA. Additionally, we compared the significance of asthma against lifestyle-related risk factors for OA.

Methods

Study population

The UK Biobank commenced its recruitment in 2006, enrolling more than 500,000 individuals aged 40 to 69 years from 22 different locations across the United Kingdom (England, Scotland, or Wales). This initiative has effectively gathered a wealth of biological and medical data through a combination of touch screen surveys, verbal interactions, medical records, physical assessments, biological specimens, and advanced imaging techniques [14]. Participants who had withdrawn from UK Biobank cohort (n = 45) and those diagnosed with OA (n = 21245) or with self-reported history of OA (n = 32132) at baseline were excluded. Additionally, we removed the participants with IgE-mediated conditions incuding allergic rhinitis, atopic dermatitis, food allergies, drug allergies, allergic conjunctivitis and allergic urticaria participants at baseline (n = 69). A total of 448,920 participants who were free of OA and IgE-mediated conditions at baseline were included (Supplement Fig. 1).

Exposure

Asthma was defined based on self-reported history from baseline questionnaires or diagnosis using International Classification of Diseases codes, 9th Revision (ICD 9) (codes: 493, 4930, 4931, 4939) or ICD 10 (code: J45).

Outcomes

Information on the Incident OA was defined by analyzing hospital inpatient records, which included data on admissions and diagnoses from the Hospital Episode Statistics for England, Scottish Morbidity Record data for Scotland, and the Patient Episode Database for Wales. The participants with OA were defined based on ICD 10 codes M15-M19. The detailed disease definition was shown in Supplement Table 1. The timing of incident OA was collected from cumulative medical records of hospital diagnoses, collected until November 27, 2021. The follow-up duration was determined starting from the recruitment date to either the first OA diagnosis, loss to follow-up, death, or the conclusion of the current monitoring period, whichever happened first.

Ascertainment of covariates

Covariates were selected based on previous epidemiological evidence and data availability at baseline. The age, sex, ethnic background, townsend deprivation index, education years, BMI, smoking status and healthy diet score were obtained according to questionnaire. A healthy diet score was derived from the self-reported diet information and ranged from 0 to 5 according to previous study [15, 16] (Supplement Table 2). Each one point was added for each favorable diet factor: vegetable intake ≥ four tablespoons/day, fruit intake ≥ three pieces/day; fish intake ≥ twice/week, unprocessed red meat intake ≤ twice/week, and processed meat intake ≤ twice/week.

The social isolation score was calculated by three questions [17, 18]: (1) “Including yourself, how many people are living together in your household?”; (2) “How often do you visit friends or family or have them visit you?”; (3) “Which of the following (sports club or gym, pub or social club, religious group, adult education class, other group activity) do you attend once a week or more often?”. The responses including living alone, having friends and family visit less than once a month, and not participating in social activity at least once per week were defined as high-risk factors, which were coded as score = 1, and those responses with low-risk factors were coded as score = 0. The loneliness score was assessed via two questions: (1) “Do you often feel lonely?”; (2) “How often are you able to confide in someone close to you?”. The responses including feeling lonely and once every few months/never or almost never being able to confide were defined as high-risk factors, which were coded as score = 1, and those responses with low-risk factors were coded as score = 0 (Supplement Table 3). Comprehensive information about all variables incorporated in the study is accessible on the UK Biobank website (www.ukbiobank.ac.uk).

Statistical analysis

The presentation of continuous variables was indicated as mean ± standard deviation (SD), with categorical variables displayed as counts and percentages. The associations between asthma and all OA, knee OA, hip OA and hand OA were analyzed using Cox proportional hazard regression models stratified by sex. The proportionality of hazards was authenticated via Schoenfeld residuals and Kaplan-Meier methods, with all analyses adhering to predefined conditions. The model 1 was adjusted for age (years) and sex (women or men) and the model 2 was adjusted for age (years) and sex (women or men), ethnic background (white or others), Townsend deprivation index (continuous), education years (continuous), BMI (< 25, 25-<30 or ≥ 30 kg/m2), smoking status (never, previous or current smoking), alcohol intake (< 3 or ≥ 3 times/week) and healthy diet score (< 3 or ≥ 3). For categorical predictors, when encountering missing values, we introduced an indicator category labeled as ‘Missing’. For continuous variables, we imputed missing values using the mean of the observed values for that specific variable. Regarding the assessment of the patterns of missing data, we performed a Little’s MCAR test, which did not reject the null hypothesis that the data were missing completely at random (p > 0.05). Supplement Table 4 provides a thorough account of the count and percentage of participants with missing covariates.

Additionally, we performed a series of subgroup analyses stratified by social isolation score (0, 1 or 2), loneliness score (0, 1 or 2), and other potential risk factors including age (< 60 or ≥ 60 years), sex (women or men), ethnic background (white or others), Townsend deprivation index (≥ median vs. < median), education years (< 10 vs. ≥ 10 years), BMI (< 25, 25-<30 or ≥ 30 kg/m2), smoking status (never, previous or current smoking) and healthy diet score (< 3 or ≥ 3). We used the same Cox model by adding interaction terms.

Sensitivity analyses

To confirm the reliability of the results, we conducted three sensitivity analyses. First, we removed those participants who died within the first 2 years of follow-up period. Second, we excluded the participants with respiratory diseases (J09-J98) other than asthma at baseline. Third, we deleted the participants with missing data for covariates. Fourth, we imputed the missing data for all covariates using multiple imputation. Our statistical examinations were accomplished using SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.1.2 (www.r-project.org), treating a two-sided P-value of less than 0.05 as a sign of statistically significant deviations.

Results

Baseline characteristics

The baseline characteristics of participants according to gender and asthma status are shown in Table 1. The mean age was 56.0 and 240,460 (53.6%) were women. In comparison to those without asthma, participants with asthma tended to be younger, white, and economically worse off. They also showed a current smoking status and a lower frequency of alcohol consumption.

Table 1 Baseline characteristics
Full size table

Association of Asthma with OA

The median follow-up time was 12.5 years. A total of 57,573 incident OA including 21,837 knee OA, 14,439 hip OA and 1,553 hand OA were documented. Figure 1 shows the cumulative hazard curves for the probability of OA among participants with and without asthma. The results from model 1 adjusted for age and sex showed that asthma was significantly associated with an increased risk of all OA, knee OA, hip OA and hand OA. Results from model 2 indicated that the hazard ratios (HRs) were 1.32 (95% CI: 1.29–1.35) for all OA, 1.21 (95% CI: 1.16–1.25) for knee OA, 1.12 (95% CI: 1.07–1.18) for hip OA and 1.62 (95% CI:1.42–1.85) for hand OA (Table. 2).

Fig. 1
figure 1

Cumulative hazard curves for the probability of osteoarthritis in participants with asthma and without asthma

Full size image
Table 2 Hazard ratios and 95% confidence intervals for association of asthma with outcome of osteoarthritis
Full size table

Effect modification by social isolation and loneliness

We further estimated the interaction between asthma and social isolation and loneliness in relation to risk of OA. The results indicated that the association of asthma with OA was significantly modified by social isolation and loneliness (P-interaction < 0.001). The association of asthma and OA was stronger in participants with higher social isolation and loneliness score. Similar results were observed for knee OA (P-interaction < 0.05) (Fig. 2).

Fig. 2
figure 2

Association of asthma with risk of osteoarthritis stratified by social isolation and loneliness score via model 2: adjusted for age, sex, ethnic background, townsend deprivation index, education years, body mass index, smoking status, alcohol intake and healthy diet score

Full size image

Stratified analysis

Furthermore, we calculated the interaction of asthma and OA-ralated potential risk factors on the risk of OA (Table 3). It was found that the association of asthma and OA was significantly modified by sex (P-interaction < 0.001) and economic status (P-interaction < 0.001). The association of asthma and OA was stronger in women and participants with higher Townsend deprivation index.

Table 3 Association of asthma with risk of osteoarthritis stratified by potential risk factors via model 2#
Full size table

In the sensitivity analyses, the associations between asthma and the risk of incident of different sites of OA were rarely changed after we removing the participants with OA within 2 years. (Supplementary Table 5). After removing the participants with respiratory diseases other than asthma at baseline, the estimated effects of asthma and the risk of incident of different sites of OA were remained virtually unchanged (Supplementary Table 6). No difference was found in the HRs for OA after we deleted all missing covariate data, or imputed all missing covariate data using multiple imputation (Supplementary Tables 7 and Supplementary Table 8).

Discussion

In this prospective study with 448,920 participants included, we found that asthma was associated with higher risk of all OA, knee OA, hip OA and hand OA. The associations of asthma and OA were stronger in women and in participants with a higher Townsend deprivation index, or a higher social isolation and loneliness score.

To our knowledge, this is the first prospective cohort study to assess the association of asthma with risk of OA. We observed that asthma was significantly associated with increased risk of OA. Our findings were supported by two observational studies. A retrospective study revealed an increased incidence of OA in patients with atopic disease [12]. Another nationwide health and nutrition examination study from Korea reported that the prevalence of OA patients with asthma was as high as 31.9% [11]. Additionally, our findings are inconsistent with a meta-analysis, which suggested that patients with asthma may have higher incidence of OA [19]. Moreover, our study was supported by a mendelian randomization study indicating a causal relationship between asthma and knee OA [20].

Several studies may implicate a possible mechanism for the association between asthma and OA. Inflammation-related cytokines and the oxidative stress activated by asthma may contribute to the development of OA [21, 22]. Inflammation is a fundamental pathological feature common to both diseases. Mast cells are the key cell types in development of asthma. Mast cells are activated in airway inflammation and release chemical mediators such as histamine, prostaglandin (PG), IL-1, and IL-4 [23,24,25]. Additionally, activated mast cells are increased in the symovium of pateints with OA, and cytokines and chemical mediators are detected in the articular synovium in OA patients which may be the mechanism leading to synovial inflammation and joint destruction [26]. Both endogenous and exogenous reactive oxygen species and nitric oxide that cause asthma can also contribute to the development of OA [27,28,29].

Our analysis found that the association between asthma and OA was stronger in individuals with higher levels of social isolation and loneliness. This finding aligns with previous studies suggesting a role of psychosocial factors in chronic inflammatory diseases [13]. Although the exact biological mechanisms for positive association of asthma with social isolation and loneliness in relation to incident OA remain elusive. Nonetheless, there are several plausible mechanisms. Under social isolation and loneliness, the inflammation status of individuals may be actived. A study indicated that inflammatory cytokines such as TNF-α and IL-6 elevated under isolation and loneliness [30, 31]. It has been reported that psychosocial factors lead to the activation of the hypothalamic pituitary adrenal axis, which decreased the microbial diversity thus leading to an increased association of asthma with OA [32]. However, the mechanism behind this interaction warrants further investigation. We hypothesize that increased stress and altered immune responses in socially isolated individuals may amplify the systemic inflammation seen in both asthma and OA. Notably, our study found the strongest HR for hand OA, which contrasts with the results from Mendelian randomization studies that identified a causal relationship between asthma and knee OA, but not hand OA [13]. This discrepancy could stem from differences in study populations, methodologies, or the way joint-specific inflammation is triggered. It’s possible that knee OA, being a weight-bearing joint, is more directly influenced by mechanical stress and inflammation pathways related to asthma, whereas hand OA may involve different, less understood inflammatory pathways. Additionally, we observed an interaction between social isolation/loneliness and knee OA, but not with hip or hand OA. This interaction could reflect the unique biopsychosocial dynamics in knee OA, which often leads to significant functional impairment and thus greater psychological distress, potentially exacerbating inflammation. In contrast, hip and hand OA may not show the same level of psychosocial impact, possibly due to differing disease burden or mechanisms of inflammation. Further studies are needed to explore how these psychosocial factors specifically affect different types of OA.

Additionally, we found that the association between asthma and OA was more marked in women. Similarly, a study from The Netherlands thought that women with asthma were more likely to have chronic complications than men asthma participants, including OA (11.5%) [33]. In a cohort study, the adjusted OA incidence was increased by 44%, and this risk was even higher in women with asthma [34]. In our study, we found that the risk of OA in women with asthma is higher than in the total participants and men with asthma. The possible pathophysiological mechanism of this difference may be due to hormonal/reproductive factors, based on the fact that the mean age of women was around the perimenopausal period [35,36,37]. Changes in hormone levels in women exacerbated this association between asthma and risk of OA [38]. During menopause, there is a large fluctuation in sex hormones and an increased number of comorbidities inculding ashma and OA. A cohort study suggest women during perimenopausal period had increased asthma symptoms and OA incidences compared with pre-menopausal patients [39,40,41]. However, further research on mechanism remains to be explored.

Strengths and limitations

The novelty of the current study highlights the association between asthma and the risk of incident OA for the first time, based on the well-designed prospective cohort including a substantial sample size, extensive details on covariates and relatively robust results with high statistical efficiency due to the information of the UK Biobank. However, there are several potential limitations to be considered. First, our study is limited by the reliance on administrative codes and hospital records, which may not accurately capture early-stage OA, potentially leading to the inclusion of prevalent rather than incident cases. Second, UK Biobank is a non-probability sample which means it was not completely random. Moreover, participants are mostly white British which means our findings could be generalized to other race/ethnic groups would need to be further tested. Third, it is difficult to distinguish between the effects of asthma and potential drugs used to treat them, so we cannot clearly conclude that the association we observe is caused by the asthma itself. Fourth, residual confounders might still exist as some potential covariates, either unmeasured or unknown, may confound the relationship between asthma and OA, although we have carefully controlled for numerous potential confounders.

Conclusions

Our study observed a significant association between asthma and risk of all OA, knee OA, hip OA and hand OA; such association was more pronounced among participants with higher social isolation and loneliness score.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

This research has been conducted using the UK Biobank Resource (https://www.ukbiobank.ac.uk) under Application Number 80610.

Funding

This work was supported by the National Natural Science Foundation of China Young Scientists Fund (82102549), Hunan Provincial Natural Science Foundation (2022JJ30061), The Second Xiangya Hospital of Central South University Postdoctoral Research Start-up Fund, National Natural Science Foundation of China (82072441, 81871783, and 81672176), Hunan Provincial Natural Science Outstanding Youth Fund (2022JJ10095) and Hunan Provincial Innovation Foundation For Postgraduate(CX20230116)and the Fundamental Research Funds for the Central Universities of Central South University (2023ZZTS0026). The study funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Orthopedics, The Second Xiangya Hospital of Central South University, Renmin Middle Road, No. 139, Changsha, China

    Ziyi Wu, Pengcheng Dou, Tang Liu & Jian Zhou

  2. Clinical Medicine Eight-year Program, 2302 Class, 2023 Grade, Central South University, Changsha, Hunan, 410013, China

    Xukun Luo

  3. Postdoctoral Mobile Station of Clinical Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China

    Jian Zhou

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Contributions

JZ and TL designed the study and performed the analysis. JZ and ZW drafted the manuscript. ZW, XL, PD, TL and JZ contributed to the revision of the manuscript. All of the authors have read and approved the final manuscript.

Corresponding author

Correspondence to Jian Zhou.

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Ethics and consent to participate

This research was conducted under the UK Biobank application 80610. The UK Biobank study was approved by the National Health and Social Care Information Management Board and the North West Multicentre Research Ethics Committee (11/NW/0382).

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All studies included in this study got informed consent from each study participant and each study was approved by the ethics committee or institutional review board.

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The authors declare no competing interests.

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Wu, Z., Luo, X., Dou, P. et al. Asthma, social isolation and loneliness, and risk of incident osteoarthritis. Arthritis Res Ther 27, 29 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13075-025-03496-w

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13075-025-03496-w

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Arthritis Research & Therapy

ISSN: 1478-6362

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