Association Between Low Testosterone Levels and the Risk of Osteoarthritis: A Cross-Sectional Analysis of NHANES Data (2011-2016)

Association Between Low Testosterone Levels and the Risk of Osteoarthritis: A Cross-Sectional Analysis of NHANES Data (2011-2016) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association Between Low Testosterone Levels and the Risk of Osteoarthritis: A Cross-Sectional Analysis of NHANES Data (2011-2016) Ning Ma, Fang Gao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5234089/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2025 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted 10 You are reading this latest preprint version Abstract Background Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts quality of life, particularly in older adults. Testosterone, a crucial hormone for musculoskeletal health, has been suggested to play a role in OA development. This study aims to investigate the relationship between low testosterone levels and the risk of OA in a nationally representative sample from NHANES (2011–2016). Methods This cross-sectional study utilized data from 4,548 participants in NHANES, excluding individuals with missing testosterone or OA data. Testosterone levels were categorized as low or normal, with low testosterone defined as less than 300 ng/dL for men. The presence of OA was based on self-reported physician diagnosis. Multivariable logistic regression models were used to analyze the association between testosterone levels and OA, adjusting for age, sex, race/ethnicity, education, marital status, income, smoking, alcohol consumption, hypertension, diabetes, hyperlipidemia, and BMI. Restricted cubic spline analysis was performed to explore non-linear associations. Subgroup analyses and interaction terms were included to assess effect modification. Results Among the 4,548 participants, 812 (17.9%) had OA. Participants with OA were older, predominantly female, and had higher rates of obesity, hyperlipidemia, and smoking compared to those without OA. Low testosterone levels were associated with a significantly increased risk of OA in unadjusted (OR, 2.22; 95% CI, 1.90–2.59; P < 0.001) and fully adjusted models (OR, 1.22; 95% CI, 1.02–1.46; P = 0.028). A non-linear relationship between testosterone levels and OA risk was observed, with increased OA risk at lower testosterone levels. Subgroup analyses indicated that the association between low testosterone and OA was consistent across demographic and clinical groups, with no significant interactions. Conclusion Low testosterone levels are independently associated with an increased risk of OA. This finding underscores the importance of hormonal health in OA pathogenesis and suggests that testosterone replacement therapy may be considered as a potential intervention to reduce OA risk in individuals with testosterone deficiency. Further longitudinal studies are warranted to explore the causal relationship between testosterone and OA. Osteoarthritis Testosterone NHANES Hormonal health Joint disease Cross-sectional analysis Testosterone replacement therapy Figures Figure 1 Figure 2 Figure 3 1. Introduction Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases worldwide, affecting millions of individuals and leading to significant morbidity and impaired quality of life, especially among older adults [ 1 , 2 ]. It is characterized by the progressive breakdown of joint cartilage, bone remodeling, and synovial inflammation, resulting in pain, stiffness, and reduced joint function [ 3 , 4 ]. As the global population ages, the incidence of OA is projected to increase, making it a significant public health challenge [ 5 ]. The etiology of OA is complex and multifactorial, with various risk factors including age, genetics, obesity, joint injury, and mechanical stress [ 6 , 7 ]. Recently, there has been increasing interest in the role of systemic hormonal factors, particularly sex hormones, in the pathogenesis of OA [ 8 , 9 ]. Testosterone, a key sex hormone in both males and females, plays a critical role in musculoskeletal health, influencing bone density, muscle mass, and cartilage integrity [ 10 , 11 ]. Testosterone deficiency, particularly in men, has been associated with increased risk of several age-related conditions, including osteoporosis, sarcopenia, and cardiovascular diseases [ 12 , 13 ]. Emerging evidence suggests that testosterone may also play a protective role in joint health. Testosterone receptors have been identified in articular cartilage, and animal studies have shown that testosterone exerts anabolic effects on cartilage, promoting matrix synthesis and inhibiting degradation [ 14 , 15 ]. Furthermore, testosterone has anti-inflammatory properties that may mitigate the chronic low-grade inflammation observed in OA [ 16 , 17 ]. Conversely, low testosterone levels have been linked to increased levels of pro-inflammatory cytokines and oxidative stress, which are key contributors to the pathophysiology of OA [ 18 , 19 ]. Several observational studies have reported an association between low serum testosterone levels and an increased risk of OA, particularly in men [ 20 , 21 ]. For example, a cross-sectional analysis of older men from the Osteoporotic Fractures in Men (MrOS) study found that lower testosterone levels were significantly associated with a higher prevalence of radiographic knee OA [ 22 ]. Similarly, data from the European Male Ageing Study (EMAS) demonstrated that men with testosterone deficiency were more likely to report symptoms of OA and had higher levels of cartilage degradation markers [ 23 ]. The National Health and Nutrition Examination Survey (NHANES) provides a valuable dataset for investigating the relationships between hormone levels and chronic diseases. NHANES collects comprehensive health data from a representative sample of the U.S. population, including serum testosterone levels and self-reported diagnosis of OA [ 24 ]. Recent studies using NHANES data have explored the associations between sex hormones and various musculoskeletal disorders, such as osteoporosis and sarcopenia, but the specific relationship between testosterone levels and OA has not been extensively examined [ 25 – 27 ]. Given the potential links between hormonal health and joint integrity, further analysis of testosterone levels in relation to OA using large, population-based data like NHANES could provide new insights into the role of hormonal factors in OA development and progression. Understanding these associations may have important implications for identifying individuals at higher risk of OA and could help guide future preventive and therapeutic strategies. 2. Methods 2.1 Study Population This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. NHANES is a stratified multistage probability survey designed to collect nationally representative data on the non-institutionalized civilian population of the United States. The National Center for Health Statistics (NCHS) Research Ethics Review Committee reviewed and approved the survey, confirming that informed consent was obtained from all participants. The initial sample included 24,133 participants. After excluding individuals with missing testosterone measurements (n = 2,541), the remaining sample consisted of 21,592 participants. We further excluded participants without osteoarthritis data, reducing the sample to 8,693. Lastly, after excluding participants with missing covariates, the final analytic sample included 4,548 participants, of whom 3,736 did not have osteoarthritis, and 812 had osteoarthritis (Fig. 1 ). 2.2 Variables The primary outcome variable was the presence of osteoarthritis, determined through self-reported physician diagnosis. The primary exposure of interest was testosterone level, categorized as low or normal based on reference ranges specific to male and female participants. Covariates included in the analysis were based on demographic, lifestyle, and clinical factors that are known to influence osteoarthritis and testosterone levels. These covariates included age (< 50 or ≥ 50 years), sex (male, female), race/ethnicity (non-Hispanic White, non-Hispanic Black, Mexican American, other Hispanic, other race), education level (less than high school, high school or equivalent, more than high school), marital status (married/cohabitating, widowed/divorced/separated, never married), poverty-income ratio (PIR: ≤1, > 1 to ≤ 3, >3), smoking status (ever smoked at least 100 cigarettes in their lifetime), alcohol consumption (≥ 12 drinks in the past year or not), hypertension, diabetes, hyperlipidemia, and body mass index (BMI: <25, 25-29.9, ≥ 30 kg/m²). 2.2.1 Testosterone Assessment Testosterone levels were measured using mass spectrometry assays from morning blood samples collected during NHANES laboratory examinations. The testosterone levels were categorized into two groups: low testosterone, defined as levels below the 2.5th percentile of the population distribution, and normal testosterone levels. For men, low testosterone was defined as less than 300 ng/dL, while in women, a low testosterone threshold was used based on population norms [ 28 ]. 2.3 Assessment of Covariates All covariates were assessed through standardized NHANES questionnaires and laboratory measurements. Age, sex, race/ethnicity, education, marital status, and poverty-income ratio (PIR) were self-reported. Smoking status and alcohol use were determined via interview questions regarding lifetime cigarette use and alcohol consumption. The presence of hypertension, diabetes, and hyperlipidemia was ascertained through a combination of self-reported physician diagnoses and objective laboratory measurements. BMI was calculated based on measured height and weight during physical examinations. 2.4 Statistical Analysis All analyses accounted for NHANES's complex, multistage probability sampling design. Descriptive statistics were used to summarize participant characteristics, with continuous variables presented as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. Differences between participants with and without osteoarthritis were compared using independent t-tests for continuous variables and chi-square tests for categorical variables. We used multivariable logistic regression models to examine the association between testosterone levels and osteoarthritis. Three models were developed: Model 1 was unadjusted; Model 2 was adjusted for age and sex; Model 3 was additionally adjusted for race/ethnicity, education level, marital status, PIR, smoking status, alcohol use, hypertension, diabetes, hyperlipidemia, and BMI. To assess potential non-linear relationships between testosterone levels and osteoarthritis, we used restricted cubic splines with testosterone levels as the continuous variable. Subgroup analyses were conducted to evaluate whether the association between testosterone and osteoarthritis varied across key covariates, including age, sex, race/ethnicity, and BMI. Interaction terms were included in the models to test for significant interactions between testosterone and these covariates. A two-sided p-value of < 0.05 was considered statistically significant for all analyses. All analyses were performed using SPSS 27.0 and R 4.4.1 software, considering the complex survey design of NHANES. 3. Results 3.1 Baseline Characteristics of the Study Population The baseline characteristics of the 4,548 participants included in the study are presented in Table 1 . Of the total participants, 812 (17.9%) were diagnosed with osteoarthritis (OA). Significant differences were observed between participants with and without OA across several demographic and clinical variables. Participants with OA were older compared to those without OA (60.26 ± 15.06 years vs. 44.92 ± 16.88 years, P < 0.001) and were more likely to be female (71.4% vs. 49.2%, P < 0.001). Regarding racial/ethnic distribution, non-Hispanic Blacks constituted a larger proportion of OA cases (10.8%) compared to the control group (32.3% non-Hispanic Black). Educational attainment was also significantly associated with OA, with a higher percentage of participants with less than a high school education having OA (P = 0.001). In terms of lifestyle factors, a larger proportion of individuals with OA were smokers (P < 0.001), and fewer consumed alcohol compared to those without OA (P = 0.020). Clinical characteristics showed significant differences, with higher proportions of individuals with OA having hyperlipidemia (54.0% vs. 28.9%, P < 0.001) and obesity (BMI ≥ 30: 43.6% vs. 28.7%, P < 0.001). Table 1 Characteristics of the study population based on the Rheumatoid arthritis people. Characteristics Overall Osteoarthritis P -value No Yes n 4548 3736 812 Gender, n (%) < 0.001 Male 2129(46.8%) 1897(41.7%) 232(5.1%) Female 2419(53.2%) 1839(40.4%) 580(12.8%) Age, years 47.66 ± 17.58 44.92 ± 16.88 60.26 ± 15.06 < 0.001 Race, n (%) < 0.001 Mexican American 518(11.4%) 443(9.7%) 75(1.6%) Other Hispanic 408(9.0%) 356(7.8%) 52(1.1%) Non-Hispanic Black 1961(43.1%) 1469(32.3%) 492(10.8%) Non-Hispanic White 911(20.0%) 775(17.0%) 136(3.0%) Other races 750(16.5%) 693(15.2%) 57(1.3%) Education, n (%) 0.001 Less than 9th grade 277(6.1%) 220(4.8%) 57(1.3%) 9-11th grade 564(12.4%) 470(10.3%) 94(2.1%) High school graduate 994(21.9%) 832(18.3%) 162(3.6%) Some college or AA degree 1460(32.1%) 1174(25.8%) 286(6.3%) College graduate or above 1253(27.5%) 1040(22.9%) 213(4.7%) Marital Status, n (%) 0.756 Married 2404(52.9%) 1958(43.1%) 446(9.8%) Widowed 302(6.6%) 184(4.0%) 118(2.6%) Divorced 491(10.8%) 372(8.2%) 119(2.6%) Separated 119(2.6%) 99(2.2%) 20(0.4%) Never married 919(20.2%) 836(18.4%) 83(1.8%) Living with partner 313(6.9%) 287(6.3%) 26(0.6%) PIR, n (%) 0.767 3 1823(40.1%) 1489(32.7%) 334(7.3%) Smoke, n (%) < 0.001 Yes 1748(38.4%) 1392(30.6%) 356(7.8%) No 2800(61.6%) 2344(51.5%) 456(10.0%) Alcohol Use, n (%) 0.020 Yes 3132(68.9%) 2578(56.7%) 554(12.2%) No 1416(31.1%) 1158(25.5%) 258(5.7%) Hypertension, n (%) 0.179 Yes 1510(33.2%) 1074(23.6%) 436(9.6%) No 3038(66.8%) 2662(58.5%) 376(8.3%) Hyperlipidemia, n (%) < 0.001 Yes 1517(33.4%) 1079(23.7%) 438(9.6%) No 3031(66.6%) 2657(58.4%) 374(8.2%) Diabetes, n (%) 0.946 Yes 521(11.5%) 362(8.0%) 159(3.5%) Borderline 97(2.1%) 69(1.5%) 28(0.6%) No 3930(86.4%) 3305(72.7%) 625(13.7%) BMI < 0.001 =30 1427(31.4%) 1073(23.6%) 354(7.8%) 3.2 Association Between Testosterone and Osteoarthritis The results of the logistic regression analysis assessing the association between testosterone levels and osteoarthritis are presented in Table 2 . In the unadjusted model (Model 1), low testosterone levels were significantly associated with an increased risk of OA (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.90–2.59; P < 0.001). After adjusting for age and gender in Model 2, the association remained significant, though attenuated (OR, 1.25; 95% CI, 1.05–1.48; P = 0.012). In the fully adjusted model (Model 3), which accounted for additional covariates such as race/ethnicity, marital status, education, poverty-income ratio, smoking status, alcohol use, hypertension, diabetes, hyperlipidemia, and BMI, low testosterone levels were still associated with a higher risk of OA (OR, 1.22; 95% CI, 1.02–1.46; P = 0.028). Table 2 Weighted logistic regression analyses of association between testosterone and osteoarthritis. Model 1 Model 2 Model 3 OR 95%CI P value OR 95%CI P value OR 95%CI P value Normal Reference Reference Reference Low testosterone 2.22(1.90,2.59) < 0.001 1.25(1.05,1.48) 0.012 1.22(1.02,1.46) 0.028 Model 1: Unadjusted Model 2: Adjusted for gender and age. Model 3: Additionally, adjusted for race, marital status, education, poverty-income ratio smoke, alcohol Use, hypertension, hyperlipidemia, diabetes, BMI, and sleep time. 3.3 Non-linear Relationship Between Testosterone Levels and Osteoarthritis The restricted cubic spline analysis indicated a non-linear association between testosterone levels and the risk of OA (Fig. 2 ). As testosterone levels decreased, the risk of OA increased, suggesting a potential threshold effect at lower testosterone levels. This relationship plateaued at moderate testosterone levels, but the risk sharply increased as testosterone levels fell below the identified threshold. 3.4 Subgroup and Interaction Analyses Subgroup analyses were conducted to examine whether the association between testosterone levels and OA was consistent across different demographic and clinical subgroups, including age, sex, race/ethnicity, and BMI (Fig. 3 ). No significant interactions were observed between testosterone levels and these covariates (P for interaction > 0.05 for all), indicating that the association between low testosterone levels and increased risk of OA was robust across subgroups. 4. Discussion In this study, we explored the relationship between testosterone levels and the risk of osteoarthritis (OA) using data from NHANES (2011–2016). Our findings suggest that low testosterone levels are significantly associated with an increased risk of OA, even after adjusting for multiple covariates, including age, sex, race/ethnicity, and several metabolic risk factors. These results add to the growing body of evidence that highlights the role of hormonal factors, particularly testosterone, in musculoskeletal health and the development of osteoarthritis. 4.1 Comparison with Previous Studies Our results are consistent with previous research that has demonstrated a link between low testosterone and musculoskeletal disorders. For instance, Freystaetter et al. (2020) found that low levels of testosterone were associated with an increased risk of developing osteoarthritis, particularly in older men [ 29 ]. Similarly, Schwanbeck (2020) observed that lower testosterone levels were associated with reduced muscle mass and strength, which are important factors in the development of OA [ 30 ]. Moreover, several studies have highlighted the role of testosterone in maintaining muscle mass and joint health, with reduced levels contributing to sarcopenia and joint deterioration [ 31 , 32 ]. Our study extends these findings by showing that the relationship between testosterone and OA is not only linear but also remains robust across different subgroups, including age and BMI categories [ 33 ]. Interestingly, our restricted cubic spline analysis revealed a non-linear relationship between testosterone levels and OA risk. This suggests that the risk of OA does not increase uniformly as testosterone levels decrease but rather exhibits a threshold effect at lower levels of testosterone. Such non-linear patterns have also been reported by Cupka, who found a threshold effect for fracture risk in older men with low testosterone levels [ 34 ]. These findings suggest that testosterone's protective effects on joint and bone health may be most pronounced at lower ranges, and once a certain threshold is crossed, the risk of OA increases sharply [ 35 ]. 4.2 Mechanisms of Testosterone and Osteoarthritis The exact mechanisms underlying the relationship between low testosterone and OA are complex and multifactorial. Testosterone is known to have anabolic effects on muscle and bone tissue and plays a critical role in maintaining cartilage health by modulating chondrocyte activity and reducing inflammation [ 36 , 37 ]. Testosterone deficiency has been linked to cartilage degradation and joint dysfunction, increasing the susceptibility to OA [ 38 ]. Additionally, low testosterone levels are associated with increased systemic inflammation, a well-established risk factor for OA and other musculoskeletal conditions [ 39 ]. Emerging research suggests that testosterone also plays a role in cartilage repair. For instance, testosterone influences the expression of growth factors such as insulin-like growth factor 1 (IGF-1) and transforming growth factor-beta (TGF-β), which are critical for cartilage regeneration [ 40 , 41 ]. Reduced levels of these factors in individuals with low testosterone may hinder cartilage repair, leading to accelerated OA progression [ 42 ]. Additionally, testosterone deficiency has been associated with increased oxidative stress and a reduction in the production of anti-inflammatory cytokines, further contributing to joint damage [ 43 ]. 4.3 Subgroup Analysis and Lack of Interaction Effects Our study demonstrated that the association between low testosterone and OA was consistent across various demographic and clinical subgroups, with no significant interaction effects observed. This suggests that the impact of testosterone on OA risk is relatively uniform across different populations. Prior studies have similarly found that testosterone deficiency is a risk factor for OA in both men and women, although the association tends to be stronger in men due to their higher baseline testosterone levels [ 44 ]. The lack of significant interaction effects in our study contrasts with some earlier research that suggested metabolic syndrome or obesity may amplify the negative effects of low testosterone on joint health [ 45 , 46 ]. However, our findings align with recent research by Han et al. (2021), which found that while both low testosterone and high BMI independently increase the risk of OA, their combined effect is not synergistic [ 47 ]. These findings suggest that while both factors contribute to OA risk, their mechanisms may operate in parallel rather than interacting directly [ 48 ]. 4.3 Implications for Clinical Practice Our findings have important clinical implications for the prevention and management of OA, particularly in populations at risk for testosterone deficiency. Given that testosterone levels naturally decline with age, screening for low testosterone in middle-aged and older adults could be a valuable strategy for early identification of individuals at high risk for OA [ 49 ]. Testosterone replacement therapy (TRT) has shown promise in improving musculoskeletal health in hypogonadal men, and our study suggests that TRT may also help reduce OA risk in individuals with low testosterone [ 50 , 51 ]. Furthermore, our results underscore the importance of addressing modifiable risk factors such as obesity and metabolic syndrome, which are common comorbidities in individuals with low testosterone and OA [ 52 ]. Interventions targeting both hormonal imbalances and metabolic health, including weight management and lifestyle modifications, may be particularly effective in reducing OA risk [ 53 ]. 4.4 Strengths and Limitations One of the key strengths of our study is the use of a large, nationally representative sample from NHANES, which enhances the generalizability of our findings. Additionally, we controlled for a wide range of potential confounders, and the use of restricted cubic splines allowed us to explore the non-linear relationship between testosterone levels and OA risk. However, several limitations should be acknowledged. First, the cross-sectional design of NHANES limits our ability to establish causality between low testosterone and OA. Longitudinal studies are needed to confirm whether low testosterone directly contributes to OA progression over time [ 54 ]. Second, testosterone levels were measured at a single time point, which may not reflect long-term hormone status. Future studies should incorporate repeated measures of testosterone to better capture hormone fluctuations [ 55 ]. Lastly, while we adjusted for a wide range of covariates, residual confounding due to unmeasured factors (e.g., physical activity, dietary habits) cannot be entirely ruled out [ 56 ]. 4.5 Future Directions Future research should focus on longitudinal studies that track testosterone levels and OA progression over time to better understand the causal pathways involved. Additionally, mechanistic studies that explore the biological effects of testosterone on cartilage and bone health will provide valuable insights into potential therapeutic targets for OA [ 57 , 58 ]. Given the complex interplay between hormonal and metabolic factors in OA, future interventions should consider both testosterone supplementation and lifestyle modifications aimed at improving metabolic health and reducing OA risk [ 59 , 60 ]. 5. Conclusion In conclusion, our study provides strong evidence that low testosterone levels are associated with an increased risk of OA, independent of other risk factors. These findings highlight the importance of hormonal health in the development and progression of OA and suggest that testosterone replacement therapy may be a potential strategy for reducing OA risk in individuals with testosterone deficiency. Further research is needed to elucidate the mechanisms underlying this association and to identify effective interventions for preventing OA in at-risk populations. Declarations Acknowledgments None. Author contributions NM was a major contributor to the writing of the manuscript and was involved in the design of the study. GF contributed to the data analysis and interpretation, and critically revised the manuscript for important intellectual content. Funding None. Data availability This study analyzed publicly available datasets and can be found at https://www.cdc.gov/nchs/nhanes/. Ethics approval and informed consent statement All protocols were approved by the NCHS Ethics Review Board and conducted in accordance with the Declaration of Helsinki, with all NHANES participants providing written informed consent. The Institutional Review Board at our institution classified this analysis as exempt, as the dataset employed was entirely de-identified. Clinical trial number Not applicable. Consent for publication Not applicable. Competing interests All the authors declare no competing interests. Author details 1 Department of Orthopedic Trauma, Norinco General Hospital, Xi'an, Shaanxi Province, China; References Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ. Osteoarthritis. 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Nutr J. 2022 May 17;21(1):33. doi: 10.1186/s12937-022-00783-z Freystaetter G, Fischer K, Orav EJ, Egli A, Theiler R, Münzer T, Felson DT, Bischoff-Ferrari HA. Total Serum Testosterone and Western Ontario and McMaster Universities Osteoarthritis Index Pain and Function Among Older Men and Women With Severe Knee Osteoarthritis. Arthritis Care Res (Hoboken). 2020 Nov;72(11):1511-1518. doi: 10.1002/acr.24074. Schwanbeck SR, Cornish SM, Barss T, Chilibeck PD. Effects of Training With Free Weights Versus Machines on Muscle Mass, Strength, Free Testosterone, and Free Cortisol Levels. J Strength Cond Res. 2020 Jul;34(7):1851-1859. doi: 10.1519/JSC.0000000000003349. Paoli A, Cenci L, Pompei P, Sahin N, Bianco A, Neri M, Caprio M, Moro T. Effects of Two Months of Very Low Carbohydrate Ketogenic Diet on Body Composition, Muscle Strength, Muscle Area, and Blood Parameters in Competitive Natural Body Builders. Nutrients. 2021 Jan 26;13(2):374. doi: 10.3390/nu13020374. Hilton EN, Lundberg TR. Transgender Women in the Female Category of Sport: Perspectives on Testosterone Suppression and Performance Advantage. Sports Med. 2021 Feb;51(2):199-214. doi: 10.1007/s40279-020-01389-3. Erratum in: Sports Med. 2021 Oct;51(10):2235. doi: 10.1007/s40279-021-01480-3. Haider SH, Irfan A, Sheikh SM, Abid MT, Naz T, Abbas M, Raza A. Evaluating the impact of testosterone replacement therapy on carotid atherosclerosis: a systematic review and meta-analysis. Future Sci OA. 2024 Dec 31;10(1):2365125. doi: 10.1080/20565623.2024.2365125. Cupka M, Sedliak M. Hungry runners - low energy availability in male endurance athletes and its impact on performance and testosterone: mini-review. Eur J Transl Myol. 2023 Apr 11;33(2):11104. doi: 10.4081/ejtm.2023.11104. Hudson J, Cruickshank M, Quinton R, Aucott L, Wu F, Grossmann M, Bhasin S, Snyder PJ, Ellenberg SS, Travison TG, Brock GB, Gianatti EJ, van der Schouw YT, Emmelot-Vonk MH, Giltay EJ, Hackett G, Ramachandran S, Svartberg J, Hildreth KL, Antonic KG, Tenover JL, Tan HM, Ho Chee Kong C, Tan WS, Marks LS, Ross RJ, Schwartz RS, Manson P, Roberts SA, Skovsager Andersen M, Velling Magnussen L, Aceves-Martins M, Gillies K, Hernández R, Oliver N, Dhillo WS, Bhattacharya S, Brazzelli M, Jayasena CN. Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis. Lancet Healthy Longev. 2023 Oct;4(10):e561-e572. doi: 10.1016/S2666-7568(23)00169-1. Hanna FS, Bell RJ, Cicuttini FM, Davison SL, Wluka AE, Davis SR. The relationship between endogenous testosterone, preandrogens, and sex hormone binding globulin and knee joint structure in women at midlife. Semin Arthritis Rheum. 2007 Aug;37(1):56-62. doi: 10.1016/j.semarthrit.2006.12.008. Audi L, Carrascosa A, Ballabriga A. Androgen metabolism by human fetal epiphyseal cartilage and its chondrocytes in primary culture. J Clin Endocrinol Metab. 1984 May;58(5):819-25. doi: 10.1210/jcem-58-5-819. Pinus H, Ornoy A, Patlas N, Yaffe P, Schwartz Z. Specific beta estradiol binding in cartilage and serum from young mice and rats is age dependent. Connect Tissue Res. 1993;30(2):85-98. doi: 10.3109/03008209309041325. Du S, Zhao J, Chou X, Peng J, Cao Q, Zeng Y, Ao L, Wang X. Testosterone does not mediate the correlation between dietary inflammation and serum klotho levels among males: insights from NHANES database. Front Endocrinol (Lausanne). 2024 Apr 2;15:1370457. doi: 10.3389/fendo.2024.1370457. Kraemer WJ, Ratamess NA, Nindl BC. Recovery responses of testosterone, growth hormone, and IGF-1 after resistance exercise. J Appl Physiol (1985). 2017 Mar 1;122(3):549-558. doi: 10.1152/japplphysiol.00599.2016. Olsen NJ, Zhou P, Ong H, Kovacs WJ. Testosterone induces expression of transforming growth factor-beta 1 in the murine thymus. J Steroid Biochem Mol Biol. 1993 May;45(5):327-32. doi: 10.1016/0960-0760(93)90001-d. Shidaifat F, Al-Trad B, Al-Omari R. Testosterone effect on immature prostate gland development associated with suppression of transforming growth factor-beta. Life Sci. 2007 Feb 6;80(9):829-34. doi: 10.1016/j.lfs.2006.11.021. Mendes LO, Scarano WR, Rochel-Maia SS, Fioruci-Fontaneli BA, Chuffa LG, Martinez FE. Testosterone therapy differently regulates the anti- and pro-inflammatory cytokines in the plasma and prostate of rats submitted to chronic ethanol consumption (UChB). Am J Reprod Immunol. 2014 Sep;72(3):317-25. doi: 10.1111/aji.12268. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59. doi: 10.1210/jc.2009-2354. Khodamoradi K, Khosravizadeh Z, Seetharam D, Mallepalli S, Farber N, Arora H. The role of leptin and low testosterone in obesity. Int J Impot Res. 2022 Nov;34(7):704-713. doi: 10.1038/s41443-022-00534-y. Wei D, Hou J, Liu X, Zhang L, Wang L, Liu P, Fan K, Zhang L, Nie L, Xu Q, Wang J, Song Y, Wang M, Liu X, Huo W, Yu S, Li L, Jing T, Wang C, Mao Z. Interaction between testosterone and obesity on hypertension: A population-based cross-sectional study. Atherosclerosis. 2021 Aug;330:14-21. doi: 10.1016/j.atherosclerosis.2021.06.906. Ho J, Mak CCH, Sharma V, To K, Khan W. Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis. Int J Mol Sci. 2022 Oct 7;23(19):11906. doi: 10.3390/ijms231911906. Zhu S, Ji L, He Z, Zhang W, Tong Y, Luo J, Hong Z, Zhang Y, Yu D, Zhang Q, Bi Q. Association of smoking and osteoarthritis in US (NHANES 1999-2018). Sci Rep. 2023 Mar 8;13(1):3911. doi: 10.1038/s41598-023-30644-6. Hawker GA, King LK. The Burden of Osteoarthritis in Older Adults. Clin Geriatr Med. 2022 May;38(2):181-192. doi: 10.1016/j.cger.2021.11.005. Skinner JW, Otzel DM, Bowser A, Nargi D, Agarwal S, Peterson MD, Zou B, Borst SE, Yarrow JF. Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2018 Jun;9(3):465-481. doi: 10.1002/jcsm.12291. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebæk A. Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocr Rev. 2018 Aug 1;39(4):389-423. doi: 10.1210/er.2017-00212. Sampath SJP, Venkatesan V, Ghosh S, Kotikalapudi N. Obesity, Metabolic Syndrome, and Osteoarthritis-An Updated Review. Curr Obes Rep. 2023 Sep;12(3):308-331. doi: 10.1007/s13679-023-00520-5. Hossain FM, Hong Y, Jin Y, Choi J, Hong Y. Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent? J Clin Med. 2019 Sep 8;8(9):1415. doi: 10.3390/jcm8091415. Tang X, Wang S, Zhan S, Niu J, Tao K, Zhang Y, Lin J. The Prevalence of Symptomatic Knee Osteoarthritis in China: Results From the China Health and Retirement Longitudinal Study. Arthritis Rheumatol. 2016 Mar;68(3):648-53. doi: 10.1002/art.39465. Wang Y, Aimuzi R, Nian M, Zhang Y, Luo K, Zhang J. Perfluoroalkyl substances and sex hormones in postmenopausal women: NHANES 2013-2016. Environ Int. 2021 Apr;149:106408. doi: 10.1016/j.envint.2021.106408. Huang X, Hu L, Tao S, Xue T, Li J, Wang X. Association between cardiometabolic index and testosterone levels in adult men: NHANES 2011-2016. PLoS One. 2024 Aug 28;19(8):e0306401. doi: 10.1371/journal.pone.0306401. Tanamas SK, Wijethilake P, Wluka AE, Davies-Tuck ML, Urquhart DM, Wang Y, Cicuttini FM. Sex hormones and structural changes in osteoarthritis: a systematic review. Maturitas. 2011 Jun;69(2):141-56. doi: 10.1016/j.maturitas.2011.03.019. Park S, Moon BR, Kim JE, Kim HJ, Zhang T. Aqueous Extracts of Morus alba Root Bark and Cornus officinalis Fruit Protect against Osteoarthritis Symptoms in Testosterone-Deficient and Osteoarthritis-Induced Rats. Pharmaceutics. 2020 Dec 21;12(12):1245. doi: 10.3390/pharmaceutics12121245. Sattler L, Kan A, Hing W, Vertullo C. The addition of structured lifestyle modifications to a traditional exercise program for the management of patients with knee osteoarthritis: A systematic review and meta-analysis of randomised trials. Musculoskelet Sci Pract. 2023 Nov;68:102858. doi: 10.1016/j.msksp.2023.102858. Roddy E, Doherty M. Changing life-styles and osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol. 2006 Feb;20(1):81-97. doi: 10.1016/j.berh.2005.09.006. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2025 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted Editorial decision: Revision requested 13 Nov, 2024 Reviews received at journal 12 Nov, 2024 Reviews received at journal 12 Nov, 2024 Reviewers agreed at journal 05 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers invited by journal 04 Nov, 2024 Editor invited by journal 15 Oct, 2024 Editor assigned by journal 13 Oct, 2024 Submission checks completed at journal 13 Oct, 2024 First submitted to journal 09 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5234089","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":377929967,"identity":"173b20bc-2bf2-4101-9ea8-887a0e0c4d3e","order_by":0,"name":"Ning Ma","email":"","orcid":"","institution":"Norinco General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ning","middleName":"","lastName":"Ma","suffix":""},{"id":377929968,"identity":"d8afd642-8af1-42f3-b867-6d5a6ec6f5af","order_by":1,"name":"Fang Gao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYFACHgbmHxUScmzszQdI0MJwxsKYj+dYAglaGNsqEudJ5CgQp4G//+zh1wVsEultDDkMDD8qthHWInEjL816Bo9EbhvD2QOMPWduE9ZiIMFjZsAjAdTC2JcAdCExWvjPALUYSKSzMfMYEKmFIcf4MU+CRAIbG7FaQH5hnHFAwrCNhy3hIFF+AYXYh4//6uTl5z8++OBHBRFagIBNAsY6QJR6IGD+QKzKUTAKRsEoGKEAANXJN4ITkfY7AAAAAElFTkSuQmCC","orcid":"","institution":"Norinco General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Fang","middleName":"","lastName":"Gao","suffix":""}],"badges":[],"createdAt":"2024-10-09 16:23:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5234089/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5234089/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12891-024-08272-6","type":"published","date":"2025-01-07T15:57:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69887795,"identity":"ade4da69-1c58-4913-9b66-cfa554a7482f","added_by":"auto","created_at":"2024-11-26 09:57:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":368188,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of participant selection\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5234089/v1/c270db1b6b2ecd570fd468f3.png"},{"id":69887796,"identity":"d74419af-29c6-464d-ba3b-74a4e2f2c8c0","added_by":"auto","created_at":"2024-11-26 09:57:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":782164,"visible":true,"origin":"","legend":"\u003cp\u003eDetermination of the association between testosterone and osteoarthritis by restricted cubic spline (RCS) regression analysis.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5234089/v1/a5b4aab04a8ef84f70ee1412.png"},{"id":69887798,"identity":"e3a35141-8c54-4a72-bd5e-50171fc1a02d","added_by":"auto","created_at":"2024-11-26 09:57:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":262973,"visible":true,"origin":"","legend":"\u003cp\u003eVerification of the association between testosterone and osteoarthritis by subgroup analyses and interaction analyses.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5234089/v1/6c4970677941dbefe81f34df.png"},{"id":73694111,"identity":"83ded197-a5b7-46bb-a836-51e7c3169e6e","added_by":"auto","created_at":"2025-01-13 16:11:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2413158,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5234089/v1/1a3b6c1a-4bba-4370-b3fb-a36729454007.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association Between Low Testosterone Levels and the Risk of Osteoarthritis: A Cross-Sectional Analysis of NHANES Data (2011-2016)","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOsteoarthritis (OA) is one of the most prevalent degenerative joint diseases worldwide, affecting millions of individuals and leading to significant morbidity and impaired quality of life, especially among older adults [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. It is characterized by the progressive breakdown of joint cartilage, bone remodeling, and synovial inflammation, resulting in pain, stiffness, and reduced joint function [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As the global population ages, the incidence of OA is projected to increase, making it a significant public health challenge [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe etiology of OA is complex and multifactorial, with various risk factors including age, genetics, obesity, joint injury, and mechanical stress [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recently, there has been increasing interest in the role of systemic hormonal factors, particularly sex hormones, in the pathogenesis of OA [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Testosterone, a key sex hormone in both males and females, plays a critical role in musculoskeletal health, influencing bone density, muscle mass, and cartilage integrity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Testosterone deficiency, particularly in men, has been associated with increased risk of several age-related conditions, including osteoporosis, sarcopenia, and cardiovascular diseases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that testosterone may also play a protective role in joint health. Testosterone receptors have been identified in articular cartilage, and animal studies have shown that testosterone exerts anabolic effects on cartilage, promoting matrix synthesis and inhibiting degradation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Furthermore, testosterone has anti-inflammatory properties that may mitigate the chronic low-grade inflammation observed in OA [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Conversely, low testosterone levels have been linked to increased levels of pro-inflammatory cytokines and oxidative stress, which are key contributors to the pathophysiology of OA [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral observational studies have reported an association between low serum testosterone levels and an increased risk of OA, particularly in men [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. For example, a cross-sectional analysis of older men from the Osteoporotic Fractures in Men (MrOS) study found that lower testosterone levels were significantly associated with a higher prevalence of radiographic knee OA [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similarly, data from the European Male Ageing Study (EMAS) demonstrated that men with testosterone deficiency were more likely to report symptoms of OA and had higher levels of cartilage degradation markers [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe National Health and Nutrition Examination Survey (NHANES) provides a valuable dataset for investigating the relationships between hormone levels and chronic diseases. NHANES collects comprehensive health data from a representative sample of the U.S. population, including serum testosterone levels and self-reported diagnosis of OA [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recent studies using NHANES data have explored the associations between sex hormones and various musculoskeletal disorders, such as osteoporosis and sarcopenia, but the specific relationship between testosterone levels and OA has not been extensively examined [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Given the potential links between hormonal health and joint integrity, further analysis of testosterone levels in relation to OA using large, population-based data like NHANES could provide new insights into the role of hormonal factors in OA development and progression. Understanding these associations may have important implications for identifying individuals at higher risk of OA and could help guide future preventive and therapeutic strategies.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Population\u003c/h2\u003e \u003cp\u003eThis study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. NHANES is a stratified multistage probability survey designed to collect nationally representative data on the non-institutionalized civilian population of the United States. The National Center for Health Statistics (NCHS) Research Ethics Review Committee reviewed and approved the survey, confirming that informed consent was obtained from all participants.\u003c/p\u003e \u003cp\u003eThe initial sample included 24,133 participants. After excluding individuals with missing testosterone measurements (n\u0026thinsp;=\u0026thinsp;2,541), the remaining sample consisted of 21,592 participants. We further excluded participants without osteoarthritis data, reducing the sample to 8,693. Lastly, after excluding participants with missing covariates, the final analytic sample included 4,548 participants, of whom 3,736 did not have osteoarthritis, and 812 had osteoarthritis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Variables\u003c/h2\u003e \u003cp\u003eThe primary outcome variable was the presence of osteoarthritis, determined through self-reported physician diagnosis. The primary exposure of interest was testosterone level, categorized as low or normal based on reference ranges specific to male and female participants.\u003c/p\u003e \u003cp\u003eCovariates included in the analysis were based on demographic, lifestyle, and clinical factors that are known to influence osteoarthritis and testosterone levels. These covariates included age (\u0026lt;\u0026thinsp;50 or \u0026ge;\u0026thinsp;50 years), sex (male, female), race/ethnicity (non-Hispanic White, non-Hispanic Black, Mexican American, other Hispanic, other race), education level (less than high school, high school or equivalent, more than high school), marital status (married/cohabitating, widowed/divorced/separated, never married), poverty-income ratio (PIR: \u0026le;1, \u0026gt;\u0026thinsp;1 to \u0026le;\u0026thinsp;3, \u0026gt;3), smoking status (ever smoked at least 100 cigarettes in their lifetime), alcohol consumption (\u0026ge;\u0026thinsp;12 drinks in the past year or not), hypertension, diabetes, hyperlipidemia, and body mass index (BMI: \u0026lt;25, 25-29.9, \u0026ge;\u0026thinsp;30 kg/m\u0026sup2;).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1 Testosterone Assessment\u003c/h2\u003e \u003cp\u003eTestosterone levels were measured using mass spectrometry assays from morning blood samples collected during NHANES laboratory examinations. The testosterone levels were categorized into two groups: low testosterone, defined as levels below the 2.5th percentile of the population distribution, and normal testosterone levels. For men, low testosterone was defined as less than 300 ng/dL, while in women, a low testosterone threshold was used based on population norms [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Assessment of Covariates\u003c/h2\u003e \u003cp\u003eAll covariates were assessed through standardized NHANES questionnaires and laboratory measurements. Age, sex, race/ethnicity, education, marital status, and poverty-income ratio (PIR) were self-reported. Smoking status and alcohol use were determined via interview questions regarding lifetime cigarette use and alcohol consumption. The presence of hypertension, diabetes, and hyperlipidemia was ascertained through a combination of self-reported physician diagnoses and objective laboratory measurements. BMI was calculated based on measured height and weight during physical examinations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e \u003cp\u003eAll analyses accounted for NHANES's complex, multistage probability sampling design. Descriptive statistics were used to summarize participant characteristics, with continuous variables presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and categorical variables as frequencies and percentages. Differences between participants with and without osteoarthritis were compared using independent t-tests for continuous variables and chi-square tests for categorical variables.\u003c/p\u003e \u003cp\u003eWe used multivariable logistic regression models to examine the association between testosterone levels and osteoarthritis. Three models were developed: Model 1 was unadjusted; Model 2 was adjusted for age and sex; Model 3 was additionally adjusted for race/ethnicity, education level, marital status, PIR, smoking status, alcohol use, hypertension, diabetes, hyperlipidemia, and BMI.\u003c/p\u003e \u003cp\u003eTo assess potential non-linear relationships between testosterone levels and osteoarthritis, we used restricted cubic splines with testosterone levels as the continuous variable. Subgroup analyses were conducted to evaluate whether the association between testosterone and osteoarthritis varied across key covariates, including age, sex, race/ethnicity, and BMI. Interaction terms were included in the models to test for significant interactions between testosterone and these covariates. A two-sided p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant for all analyses. All analyses were performed using SPSS 27.0 and R 4.4.1 software, considering the complex survey design of NHANES.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline Characteristics of the Study Population\u003c/h2\u003e \u003cp\u003eThe baseline characteristics of the 4,548 participants included in the study are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the total participants, 812 (17.9%) were diagnosed with osteoarthritis (OA). Significant differences were observed between participants with and without OA across several demographic and clinical variables. Participants with OA were older compared to those without OA (60.26\u0026thinsp;\u0026plusmn;\u0026thinsp;15.06 years vs. 44.92\u0026thinsp;\u0026plusmn;\u0026thinsp;16.88 years, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and were more likely to be female (71.4% vs. 49.2%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Regarding racial/ethnic distribution, non-Hispanic Blacks constituted a larger proportion of OA cases (10.8%) compared to the control group (32.3% non-Hispanic Black). Educational attainment was also significantly associated with OA, with a higher percentage of participants with less than a high school education having OA (P\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eIn terms of lifestyle factors, a larger proportion of individuals with OA were smokers (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and fewer consumed alcohol compared to those without OA (P\u0026thinsp;=\u0026thinsp;0.020). Clinical characteristics showed significant differences, with higher proportions of individuals with OA having hyperlipidemia (54.0% vs. 28.9%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30: 43.6% vs. 28.7%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the study population based on the Rheumatoid arthritis people.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eOsteoarthritis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4548\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3736\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e812\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2129(46.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1897(41.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e232(5.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2419(53.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1839(40.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e580(12.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.66\u0026thinsp;\u0026plusmn;\u0026thinsp;17.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.92\u0026thinsp;\u0026plusmn;\u0026thinsp;16.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.26\u0026thinsp;\u0026plusmn;\u0026thinsp;15.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMexican American\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e518(11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e443(9.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75(1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Hispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e408(9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e356(7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52(1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic Black\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1961(43.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1469(32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e492(10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-Hispanic White\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e911(20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e775(17.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136(3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther races\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e750(16.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e693(15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57(1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEducation, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLess than 9th grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e277(6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e220(4.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57(1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9-11th grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e564(12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e470(10.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94(2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh school graduate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e994(21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e832(18.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e162(3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSome college or AA degree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1460(32.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1174(25.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e286(6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCollege graduate or above\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1253(27.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1040(22.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e213(4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMarital Status, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.756\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2404(52.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1958(43.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e446(9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWidowed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e302(6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e184(4.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e118(2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e491(10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e372(8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119(2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeparated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119(2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20(0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever married\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e919(20.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e836(18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83(1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiving with partner\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e313(6.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e287(6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26(0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePIR, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.767\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;=1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e946(20.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e803(17.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e143(3.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1779(39.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1444(31.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e335(7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1823(40.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1489(32.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e334(7.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoke, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1748(38.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1392(30.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e356(7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2800(61.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2344(51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e456(10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcohol Use, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3132(68.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2578(56.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e554(12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1416(31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1158(25.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e258(5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.179\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1510(33.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1074(23.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e436(9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3038(66.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2662(58.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e376(8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyperlipidemia, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1517(33.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1079(23.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e438(9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3031(66.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2657(58.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e374(8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.946\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e521(11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e362(8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e159(3.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBorderline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97(2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69(1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28(0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3930(86.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3305(72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e625(13.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1580(34.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1366(30.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e214(4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1541(33.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1297(28.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e244(5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;=30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1427(31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1073(23.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e354(7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Association Between Testosterone and Osteoarthritis\u003c/h2\u003e \u003cp\u003eThe results of the logistic regression analysis assessing the association between testosterone levels and osteoarthritis are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the unadjusted model (Model 1), low testosterone levels were significantly associated with an increased risk of OA (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.90\u0026ndash;2.59; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). After adjusting for age and gender in Model 2, the association remained significant, though attenuated (OR, 1.25; 95% CI, 1.05\u0026ndash;1.48; P\u0026thinsp;=\u0026thinsp;0.012). In the fully adjusted model (Model 3), which accounted for additional covariates such as race/ethnicity, marital status, education, poverty-income ratio, smoking status, alcohol use, hypertension, diabetes, hyperlipidemia, and BMI, low testosterone levels were still associated with a higher risk of OA (OR, 1.22; 95% CI, 1.02\u0026ndash;1.46; P\u0026thinsp;=\u0026thinsp;0.028).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eWeighted logistic regression analyses of association between testosterone and osteoarthritis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModel 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eModel 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR 95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR 95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR 95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow testosterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.22(1.90,2.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.25(1.05,1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.22(1.02,1.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eModel 1: Unadjusted\u003c/p\u003e \u003cp\u003eModel 2: Adjusted for gender and age.\u003c/p\u003e \u003cp\u003eModel 3: Additionally, adjusted for race, marital status, education, poverty-income ratio smoke, alcohol Use, hypertension, hyperlipidemia, diabetes, BMI, and sleep time.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Non-linear Relationship Between Testosterone Levels and Osteoarthritis\u003c/h2\u003e \u003cp\u003eThe restricted cubic spline analysis indicated a non-linear association between testosterone levels and the risk of OA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As testosterone levels decreased, the risk of OA increased, suggesting a potential threshold effect at lower testosterone levels. This relationship plateaued at moderate testosterone levels, but the risk sharply increased as testosterone levels fell below the identified threshold.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Subgroup and Interaction Analyses\u003c/h2\u003e \u003cp\u003eSubgroup analyses were conducted to examine whether the association between testosterone levels and OA was consistent across different demographic and clinical subgroups, including age, sex, race/ethnicity, and BMI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No significant interactions were observed between testosterone levels and these covariates (P for interaction\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all), indicating that the association between low testosterone levels and increased risk of OA was robust across subgroups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we explored the relationship between testosterone levels and the risk of osteoarthritis (OA) using data from NHANES (2011\u0026ndash;2016). Our findings suggest that low testosterone levels are significantly associated with an increased risk of OA, even after adjusting for multiple covariates, including age, sex, race/ethnicity, and several metabolic risk factors. These results add to the growing body of evidence that highlights the role of hormonal factors, particularly testosterone, in musculoskeletal health and the development of osteoarthritis.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Comparison with Previous Studies\u003c/h2\u003e \u003cp\u003eOur results are consistent with previous research that has demonstrated a link between low testosterone and musculoskeletal disorders. For instance, Freystaetter et al. (2020) found that low levels of testosterone were associated with an increased risk of developing osteoarthritis, particularly in older men [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Similarly, Schwanbeck (2020) observed that lower testosterone levels were associated with reduced muscle mass and strength, which are important factors in the development of OA [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Moreover, several studies have highlighted the role of testosterone in maintaining muscle mass and joint health, with reduced levels contributing to sarcopenia and joint deterioration [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Our study extends these findings by showing that the relationship between testosterone and OA is not only linear but also remains robust across different subgroups, including age and BMI categories [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterestingly, our restricted cubic spline analysis revealed a non-linear relationship between testosterone levels and OA risk. This suggests that the risk of OA does not increase uniformly as testosterone levels decrease but rather exhibits a threshold effect at lower levels of testosterone. Such non-linear patterns have also been reported by Cupka, who found a threshold effect for fracture risk in older men with low testosterone levels [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These findings suggest that testosterone's protective effects on joint and bone health may be most pronounced at lower ranges, and once a certain threshold is crossed, the risk of OA increases sharply [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Mechanisms of Testosterone and Osteoarthritis\u003c/h2\u003e \u003cp\u003eThe exact mechanisms underlying the relationship between low testosterone and OA are complex and multifactorial. Testosterone is known to have anabolic effects on muscle and bone tissue and plays a critical role in maintaining cartilage health by modulating chondrocyte activity and reducing inflammation [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Testosterone deficiency has been linked to cartilage degradation and joint dysfunction, increasing the susceptibility to OA [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Additionally, low testosterone levels are associated with increased systemic inflammation, a well-established risk factor for OA and other musculoskeletal conditions [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmerging research suggests that testosterone also plays a role in cartilage repair. For instance, testosterone influences the expression of growth factors such as insulin-like growth factor 1 (IGF-1) and transforming growth factor-beta (TGF-β), which are critical for cartilage regeneration [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Reduced levels of these factors in individuals with low testosterone may hinder cartilage repair, leading to accelerated OA progression [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Additionally, testosterone deficiency has been associated with increased oxidative stress and a reduction in the production of anti-inflammatory cytokines, further contributing to joint damage [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Subgroup Analysis and Lack of Interaction Effects\u003c/h2\u003e \u003cp\u003eOur study demonstrated that the association between low testosterone and OA was consistent across various demographic and clinical subgroups, with no significant interaction effects observed. This suggests that the impact of testosterone on OA risk is relatively uniform across different populations. Prior studies have similarly found that testosterone deficiency is a risk factor for OA in both men and women, although the association tends to be stronger in men due to their higher baseline testosterone levels [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe lack of significant interaction effects in our study contrasts with some earlier research that suggested metabolic syndrome or obesity may amplify the negative effects of low testosterone on joint health [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. However, our findings align with recent research by Han et al. (2021), which found that while both low testosterone and high BMI independently increase the risk of OA, their combined effect is not synergistic [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. These findings suggest that while both factors contribute to OA risk, their mechanisms may operate in parallel rather than interacting directly [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Implications for Clinical Practice\u003c/h2\u003e \u003cp\u003eOur findings have important clinical implications for the prevention and management of OA, particularly in populations at risk for testosterone deficiency. Given that testosterone levels naturally decline with age, screening for low testosterone in middle-aged and older adults could be a valuable strategy for early identification of individuals at high risk for OA [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Testosterone replacement therapy (TRT) has shown promise in improving musculoskeletal health in hypogonadal men, and our study suggests that TRT may also help reduce OA risk in individuals with low testosterone [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, our results underscore the importance of addressing modifiable risk factors such as obesity and metabolic syndrome, which are common comorbidities in individuals with low testosterone and OA [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Interventions targeting both hormonal imbalances and metabolic health, including weight management and lifestyle modifications, may be particularly effective in reducing OA risk [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Strengths and Limitations\u003c/h2\u003e \u003cp\u003eOne of the key strengths of our study is the use of a large, nationally representative sample from NHANES, which enhances the generalizability of our findings. Additionally, we controlled for a wide range of potential confounders, and the use of restricted cubic splines allowed us to explore the non-linear relationship between testosterone levels and OA risk.\u003c/p\u003e \u003cp\u003eHowever, several limitations should be acknowledged. First, the cross-sectional design of NHANES limits our ability to establish causality between low testosterone and OA. Longitudinal studies are needed to confirm whether low testosterone directly contributes to OA progression over time [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Second, testosterone levels were measured at a single time point, which may not reflect long-term hormone status. Future studies should incorporate repeated measures of testosterone to better capture hormone fluctuations [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Lastly, while we adjusted for a wide range of covariates, residual confounding due to unmeasured factors (e.g., physical activity, dietary habits) cannot be entirely ruled out [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Future Directions\u003c/h2\u003e \u003cp\u003eFuture research should focus on longitudinal studies that track testosterone levels and OA progression over time to better understand the causal pathways involved. Additionally, mechanistic studies that explore the biological effects of testosterone on cartilage and bone health will provide valuable insights into potential therapeutic targets for OA [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Given the complex interplay between hormonal and metabolic factors in OA, future interventions should consider both testosterone supplementation and lifestyle modifications aimed at improving metabolic health and reducing OA risk [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn conclusion, our study provides strong evidence that low testosterone levels are associated with an increased risk of OA, independent of other risk factors. These findings highlight the importance of hormonal health in the development and progression of OA and suggest that testosterone replacement therapy may be a potential strategy for reducing OA risk in individuals with testosterone deficiency. Further research is needed to elucidate the mechanisms underlying this association and to identify effective interventions for preventing OA in at-risk populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNM was a major contributor to the writing of the manuscript and was involved in the design of the study. GF contributed to the data analysis and interpretation, and critically revised the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study analyzed publicly available datasets and can be found at https://www.cdc.gov/nchs/nhanes/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and informed consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll protocols were approved by the NCHS Ethics Review Board and conducted in accordance with the Declaration of Helsinki, with all NHANES participants providing written informed consent. The Institutional Review Board at our institution classified this analysis as exempt, as the dataset employed was entirely de-identified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Orthopedic Trauma, Norinco General Hospital, Xi\u0026apos;an, Shaanxi Province, China;\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGlyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ. 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Best Pract Res Clin Rheumatol. 2006 Feb;20(1):81-97. doi: 10.1016/j.berh.2005.09.006.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Osteoarthritis, Testosterone, NHANES, Hormonal health, Joint disease, Cross-sectional analysis, Testosterone replacement therapy","lastPublishedDoi":"10.21203/rs.3.rs-5234089/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5234089/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOsteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts quality of life, particularly in older adults. Testosterone, a crucial hormone for musculoskeletal health, has been suggested to play a role in OA development. This study aims to investigate the relationship between low testosterone levels and the risk of OA in a nationally representative sample from NHANES (2011\u0026ndash;2016).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis cross-sectional study utilized data from 4,548 participants in NHANES, excluding individuals with missing testosterone or OA data. Testosterone levels were categorized as low or normal, with low testosterone defined as less than 300 ng/dL for men. The presence of OA was based on self-reported physician diagnosis. Multivariable logistic regression models were used to analyze the association between testosterone levels and OA, adjusting for age, sex, race/ethnicity, education, marital status, income, smoking, alcohol consumption, hypertension, diabetes, hyperlipidemia, and BMI. Restricted cubic spline analysis was performed to explore non-linear associations. Subgroup analyses and interaction terms were included to assess effect modification.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 4,548 participants, 812 (17.9%) had OA. Participants with OA were older, predominantly female, and had higher rates of obesity, hyperlipidemia, and smoking compared to those without OA. Low testosterone levels were associated with a significantly increased risk of OA in unadjusted (OR, 2.22; 95% CI, 1.90\u0026ndash;2.59; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and fully adjusted models (OR, 1.22; 95% CI, 1.02\u0026ndash;1.46; P\u0026thinsp;=\u0026thinsp;0.028). A non-linear relationship between testosterone levels and OA risk was observed, with increased OA risk at lower testosterone levels. Subgroup analyses indicated that the association between low testosterone and OA was consistent across demographic and clinical groups, with no significant interactions.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eLow testosterone levels are independently associated with an increased risk of OA. This finding underscores the importance of hormonal health in OA pathogenesis and suggests that testosterone replacement therapy may be considered as a potential intervention to reduce OA risk in individuals with testosterone deficiency. Further longitudinal studies are warranted to explore the causal relationship between testosterone and OA.\u003c/p\u003e","manuscriptTitle":"Association Between Low Testosterone Levels and the Risk of Osteoarthritis: A Cross-Sectional Analysis of NHANES Data (2011-2016)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-26 09:57:11","doi":"10.21203/rs.3.rs-5234089/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-14T04:21:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-12T14:29:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-12T13:27:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204809839182019922077615768700927606089","date":"2024-11-05T10:02:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294459918858180338811166165933622447964","date":"2024-11-05T04:13:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-05T02:44:20+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-15T06:24:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-14T02:49:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-14T02:49:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2024-10-09T16:17:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3b715c8a-196c-4c9c-995e-ffba393006c7","owner":[],"postedDate":"November 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-13T16:04:45+00:00","versionOfRecord":{"articleIdentity":"rs-5234089","link":"https://doi.org/10.1186/s12891-024-08272-6","journal":{"identity":"bmc-musculoskeletal-disorders","isVorOnly":false,"title":"BMC Musculoskeletal Disorders"},"publishedOn":"2025-01-07 15:57:58","publishedOnDateReadable":"January 7th, 2025"},"versionCreatedAt":"2024-11-26 09:57:11","video":"","vorDoi":"10.1186/s12891-024-08272-6","vorDoiUrl":"https://doi.org/10.1186/s12891-024-08272-6","workflowStages":[]},"version":"v1","identity":"rs-5234089","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5234089","identity":"rs-5234089","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}