Knee osteoarthritis (KOA) is a prevalent chronic musculoskeletal disorder of the knee, defined by the progressive degradation of cartilage, subchondral bone remodeling, inflammation of the synovial lining, pain, stiffness, and functional limitation of the knee.[1] It is an important and increasing cause of disability in the world.[2] In 2019, the WHO estimated that there were 528 million people who were suffering from OA worldwide, with knee OA accounting for an estimated 365 million people.[3] Around 73% of people with osteoarthritis are over age 55, with women making up some 60% of people with the condition.[4] The rising number of older people, sedentary lifestyles, and obesity are likely to exacerbate the burden of KOA further in the future.[5]

Obesity is a key modifiable KOA risk factor.[6] In 2022, there were around 890 million adults with obesity, including 16% of the adult population.[7]  Obesity is not only associated with mechanical overloading of the weight-bearing knee in KOA.[8] While the stresses placed on the articular cartilage by increases in body weight are biomechanical, there is mounting evidence that adipose tissue, and fat in particular, is a site of joint pathology by metabolic and inflammatory mechanisms.[9] Adipose tissue, including the infrapatellar fat pad, is an endocrine organ and secretes adipokines and cytokines which have been shown to impact synovial inflammation, cartilage metabolism, and subchondral bone remodeling.[10] A meta-analysis of prospective studies reported that obesity was associated with approximately 4.55-fold higher risk of knee OA, while every 5 kg/m² increase in BMI was associated with a 35% increase in KOA risk.[11]

The metabolic consequences of obesity may therefore contribute to a distinct phenotype of KOA.[12] Adipokines, including leptin, adiponectin, resistin, and inflammatory mediators, including C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), have been suggested to play a role in the pathogenesis of joint degradation associated with obesity.[13] The effects of leptin in the cartilage and synovial tissues might be pro-inflammatory and catabolic, while those of adiponectin might be more nuanced and context-dependent.[14] There is also some evidence that resistin is linked to inflammation and structural changes in the joints. Importantly, these mechanisms show that obesity can contribute to KOA beyond mechanical loading, via a systemic metabolic-inflammatory milieu.[15]

This idea is somewhat supported by recent clinical evidence. In KOA patients, serum leptin, adiponectin, resistin, and high-sensitivity CRP correlated with different clinical and structural aspects of the disease.[16] Leptin was associated with osteophyte size, cartilage abnormalities, synovitis, and joint effusion after adjusting for age, sex, and BMI, and hs-CRP was associated with meniscal extrusion.[17]  Likewise, inflammatory and metabolic markers have been used to show that a variety of combinations of cytokines, adipokines, and metabolic markers can define different phenotypes in KOA, such as an obesity-associated phenotype, which is characterized by higher levels of systemic and local inflammation.[16] These results help confirm the emerging concept that KOA is a biologically heterogeneous disease and that metabolic health status could influence its inflammatory signature.

However, the role of obesity in the overall metabolic and inflammatory profile of individuals with a diagnosis of KOA has not been fully described, especially among South Asian populations, which are at a high risk of obesity, metabolic abnormalities, and KOA. It may be possible to differentiate the biological changes associated with obesity from those due to KOA alone by comparing obese and non-obese patients with identical underlying joint disease. This information might help to better define heterogeneity in the disease and help identify patients who might benefit from treatments that address not just joint symptoms but weight loss, metabolic dysfunction, and systemic inflammation. Therefore, the present study was designed to compare the metabolic and inflammatory profiles of obese and non-obese patients with knee osteoarthritis. The purpose of this study was to assess whether there were measurable differences in the metabolic and inflammatory/ adipokine parameters between obese patients with KOA and non-obese patients, and to offer insight into the metabolic-inflammatory phenotype of obesity-associated KOA and potential implications for more personalized disease management.

An analytical cross-sectional study was conducted at Independent Medical College over a period of six months, from 1st November 2025 to 30th April 2026,

The sample size was calculated using OpenEpi based on a previously published study by Richter et al., which compared serum adipokine concentrations among obese and normal-weight patients with primary knee osteoarthritis. The mean concentration of leptin in obese patients was 47.99 ± 40.18 ng/mL, and 16.49±14.90 ng/mL in normal-weight patients, which were statistically significantly different between the groups.[18] A two-sided 95% confidence level, 80% power, and equal allocation between groups resulted in a calculated minimum sample size of 32 participants. To allow for the possibility of incomplete clinical data or insufficient blood samples, the final number of patients was expanded to 36, including 18 obese and 18 non-obese participants.

A non-probability consecutive sampling technique was used. Patients included were those with primary knee OA confirmed clinically and radiologically, aged 40-75 years. Included patients were both men and women with knee osteoarthritis who gave informed consent. Patients with a BMI of ≥30 kg/m² were classified as obese, whereas those with a BMI below 30 kg/m² were classified as non-obese. Patients with secondary osteoarthritis that had previously suffered from trauma to the knee, inflammatory arthritis (e.g., rheumatoid arthritis, gout), autoimmune or connective-tissue disorders, active infection, malignancy, chronic kidney disease, or chronic liver disease were excluded from the study. Patients who had received intra-articular corticosteroid or hyaluronic acid injection in the last three months, or had undergone knee surgery, were also excluded. Those who were pregnant and women on systemic corticosteroids or other drugs that significantly affect inflammatory biomarker levels were excluded. There were also patients with incomplete clinical data and/or poor-quality blood samples that were not included in the final analysis.

Demographic and clinical data were gathered using a structured data collection proforma, and ethical approval was obtained from the relevant institutional review committee, and informed written consent was obtained from each participant. Data on age, sex, place of residence, occupation, smoking habits, physical activity level, duration of knee symptoms, presence of relevant comorbidities, medication use, and family history of metabolic or musculoskeletal disease were obtained. The severity of knee osteoarthritis was determined clinically using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and existing knee radiographs were graded using the Kellgren-Lawrence (KL) grading system.[19]

Anthropometric evaluation was done according to standard methods. Body weight was measured by using a calibrated weighing scale in light clothes, and height was measured using a stadiometer. Body mass index (BMI) was determined by dividing the weight by the height squared in meters. Waist circumference was measured at the midpoint between the lowest rib and the iliac crest. The participants were then classified as obese and non-obese based on BMI.

Venous blood was obtained after overnight fasting from each participant for biochemical assessment (approx. 5 mL). The samples were left to coagulate and centrifuged as per standard lab protocol. Serum was separated and analyzed for metabolic parameters such as fasting blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Serum insulin was also measured (where available), and insulin resistance was calculated based on the homeostatic model assessment of insulin resistance (HOMA-IR). The inflammatory and obesity related biomarkers measured were: high-sensitivity C-reactive protein (hs-CRP), tumour necrosis factor (TNF-α), interleukin-6 (IL-6), adiponectin, leptin and resistin. Commercial ELISA kits were used for the measurement of serum biomarkers as per the manufacturer's instructions. All samples were processed under the same laboratory conditions, and wherever possible, laboratory staff were blinded to the obesity-group classification.

All the collected data were entered, cleaned, and then coded and analyzed in IBM SPSS Statistics, version 26.0. Continuous variables were assessed for normality using the Shapiro-Wilk test and were presented as mean ± standard deviation for normally distributed data or median with interquartile range for non-normally distributed data. Categorical variables were displayed in the form of frequencies and percentages. Demographic, anthropometric, clinical, metabolic, and inflammatory parameters were compared between obese and non-obese patients. An independent-samples t-test was performed to compare normally distributed continuous variables, while the Mann-Whitney U test was performed to compare non-normally distributed continuous variables. The chi-square test and Fisher's exact test were used for categorical variables.

The relationships between BMI, metabolic parameters, inflammatory biomarkers, adipokines, and WOMAC scores were evaluated by correlation analysis using Pearson's correlation coefficient for variables with normal distribution and Spearman's rank correlation coefficient for variables with non-normal distribution. Multivariable linear regression analysis was done to assess whether obesity was independently associated with metabolic and inflammatory biomarkers after adjusting for potential other confounding factors such as age, sex, disease duration, physical activity, and relevant comorbidities. A two-sided p-value ≤ 0.05 was regarded as statistically significant.

A total of 36 patients with knee osteoarthritis were included, comprising 18 obese and 18 non-obese participants. The two groups were similar with respect to age, sex, place of residence, occupation, smoking status, and family history. Low physical activity and cardiometabolic comorbidities were more frequently observed among obese participants, although most of these differences were not statistically significant. The two groups were also similar in terms of length of disease. (Table 1)

The anthropometric burden and the clinical and radiographic disease were significantly higher in obese patients. Other differences included obese participants having significantly higher WOMAC scores (pain, stiffness, and functional limitation). Obesity was also linked to structural damage severity, as evidenced by the higher occurrence of advanced Kellgren-Lawrence grades in obese patients. (Table 2)

Obese patients had a uniform metabolic profile of metabolic dysfunction. The glycemic and lipid profile was less favorable, and insulin resistance was higher for the obese group than the non-obese group. Obese patients with KOA had a significantly higher metabolic burden due to impaired glucose regulation, lipid abnormalities, and elevated HOMA-IR. (Table 3)

There was also a significant difference in inflammatory and adipokine profiles. Systemic inflammatory markers and pro-inflammatory adipokines such as leptin and resistin were higher in obese participants, while the levels of adiponectin were lower. This indicates increased low-grade systemic inflammation and adipose-tissue dysfunction in obese KOA patients. (Table 4)

The results of the correlation analysis showed that higher BMI was correlated with worsening metabolic and inflammatory abnormalities. BMI was also a significant factor with respect to both symptomatic severity and radiographic disease grade. HDL-C and adiponectin, however, showed an inverse relationship with BMI, where the higher the BMI, the lower the HDL-C and adiponectin levels. (Table 5)

Obesity was also independently associated with some of the poor outcomes even after adjusting for age, sex, disease duration, physical activity, and appropriate comorbidities. The continued association with hs-CRP, HOMA-IR, leptin, adiponectin, and the WOMAC score indicated that the association between obesity and the metabolic-inflammatory phenotype and clinical KOA severity was not fully accounted for by the assessed demographic and clinical confounders. (Table 6)

Table 1. Sociodemographic and clinical characteristics of patients with knee osteoarthritis

Table 2. Anthropometric and clinical characteristics according to obesity status

Table 3. Metabolic profile of obese and non-obese patients

Table 4. Inflammatory and adipokine profiles according to obesity status

Table 5. Correlation of BMI with metabolic, inflammatory, adipokine, and clinical parameters

Table 6. Multivariable linear regression analysis of factors associated with selected biomarkers

and WOMAC score

In the present study, it was shown that there are metabolic, inflammatory, and adipokine differences between obese and non-obese patients with knee osteoarthritis (KOA). Body weight, BMI, WOMAC scores, and radiographic disease were significantly higher in the obese patients. They also showed increased fasting blood glucose, HbA1c, total cholesterol, triglycerides, LDL-C, serum insulin, HOMA-IR, hs-CRP, IL-6, TNF-α, leptin, and resistin, and decreased HDL-C and adiponectin. In addition, BMI was strongly positively correlated with several metabolic and inflammatory parameters and WOMAC scores, whereas obesity was independently associated with hs-CRP, HOMA-IR, leptin, adiponectin, and WOMAC score after adjusting for potential confounding factors. These results confirm a link between obesity in KOA and the mechanical loading of the knee as well as a metabolically and immunologically active phenotype.

The marked difference in BMI and waist circumference between the 2 groups is in line with current research that obesity is associated with KOA via mechanical and systemic metabolic pathways. Batushansky et al. highlighted that obesity and metabolic factors interact with mechanical loading, adipose tissue, and metabolic dysfunction and chronic low-grade inflammation to drive osteoarthritis.[20] Similarly, a recent population-based cohort study by Cheng et al. involving 389,807 UK Biobank participants demonstrated that both metabolically healthy and metabolically unhealthy obesity were associated with accelerated development of KOA, highlighting the importance of obesity itself in the pathogenesis of weight-bearing joint osteoarthritis.[21]

Significantly higher WOMAC scores and a higher percentage of advanced Kellgren-Lawrence grades were also found in obese subjects in the present study. This result is similar to that of Lambova et al., who compared the levels of leptin and resistin in the serum of KOA patients and found increased levels of both adipokines in obese patients; thus, a metabolic phenotype of KOA exists.[22] Their results indicated that adipokine abnormalities related to obesity might be linked to higher disease activity and severity in these patients. Thus, our observation of greater symptomatic and radiographic severity among obese patients is in agreement with previous evidence.

One of the most striking results in our study was the high level of leptin in obese patients. Leptin also showed a high positive correlation with BMI and was found to be an independent predictor of obesity following adjustment for the potential confounding factors. This finding closely agrees with Lambova et al., who reported significantly higher serum leptin levels among obese patients with KOA and suggested that leptin may contribute to the metabolic phenotype of the disease.[22] Additional support was provided by Chong et al., who examined 137 patients with early KOA and concluded that serum leptin was independently correlated with MRI findings of osteophyte size, cartilage abnormalities, infrapatellar synovial effusion, and infrapatellar synovitis, after adjusting for age, sex, and BMI.[23] These results indicate that leptin could play a role other than just adiposity and could be involved in pathways related to structural joint damage.

Our finding of significantly lower adiponectin levels among obese patients is also consistent with the recognized relationship between obesity and altered adipokine secretion. In osteoarthritis, Ilia et al. summarised the role of adiponectin and its complicated relationship with obesity and joint metabolism.[24] Moreover, Chong et al. reported that adiponectin had an association with WOMAC pain and functional outcomes in KOA.[23]  In our study, BMI was inversely correlated with adiponectin, and obesity remained independently associated with lower adiponectin levels. This discovery indicates that low levels of adiponectin may be a component of the metabolic-inflammatory milieu linked to obesity in KOA.

A higher concentration of resistin in obese compared with lean participants is also consistent with previous studies. Recently, Vasileva et al. examined serum and synovial adipokines in KOA and found correlations between resistin and inflammatory markers, suggesting that resistin might be involved in inflammatory activity in KOA.[25] Thus, increased resistin concentrations could be a marker for increased inflammatory signaling in adipose tissue in the obese group.

The inflammatory findings of this current study are significant. Obese participants had significantly higher hs-CRP, IL-6, and TNF-α concentrations than non-obese participants. The results indicate that obesity is associated with low-grade systemic inflammation, which could potentially affect the biological landscape of the osteoarthritic joint. Zhu et al. studied the inflammatory markers and adipokines in KOA patients and showed relationships between serum inflammatory markers, clinical symptoms, and structural changes.[26] This observation is consistent with our results that metabolic and inflammatory disorders can coexist in patients with KOA.

Our results also confirmed the association between metabolic abnormalities and KOA, as elevated fasting glucose, HbA1c, triglycerides, LDL-C, insulin, and HOMA-IR, and reduced HDL-C levels were seen in obese patients. These results suggest that there is a more general metabolic dysfunction associated with obesity. In their large 2026 UK Biobank cohort study, Cheng et al. showed that the risk of KOA was associated with obesity, in addition to a substantial risk of metabolic abnormalities when the metabolic health status was unhealthy.[27] Our results support this population-based data by showing that, within the patient population with KOA, obesity is linked to a poorer metabolic profile.

In general, the present study is in favor of a hypodimensional model of obesity-associated KOA involving insulin resistance, dyslipidemia, changes in adipokine secretion, and low-grade systemic inflammation. In obese patients, leptin, resistin, hs-CRP, IL-6, and TNF-α are all increased while adiponectin levels are decreased, indicating that the biological environment in which KOA develops and progresses may be influenced by obesity. The positive associations of BMI with inflammatory markers, WOMAC scores, and radiographic severity also suggest a clinical relevance of the metabolic phenotype. The results suggest that weight management and metabolic optimization may contribute to the treatment of KOA. These associations should, however, be interpreted with caution because they are based on a small number of respondents and have a cross-sectional design, which does not allow for temporal relationships to be established. Larger longitudinal studies are needed to establish if these biomarkers are risk factors for radiographic progression and if modifications in obesity and metabolic abnormalities can alter KOA progression.

LIMITATIONS

There were several limitations of this study. The number of participants in the study (36) was relatively small, which reduced the power and precision of the subgroup comparisons. The cross-sectional design limited the ability to determine temporal or causal associations between obesity, metabolic abnormalities, inflammatory biomarkers, and knee osteoarthritis severity. The non-probability consecutive sampling technique from a single medical college may have led to selection bias, which may restrict the generalizability of the study results to other populations. There were several factors that may have confounded the results, such as diet, socioeconomic status, specific medication use, and the length of time obese, that could not be fully controlled. Short-term metabolic and inflammatory changes can also affect the concentration of biomarkers. Further, serum biomarkers were only evaluated at a single time point, which makes it difficult to assess longitudinal changes. Lastly, instead of an MRI-based assessment, conventional Kellgren-Lawrence (KL) radiographic grading was used, which could have meant that early structural abnormalities were not detected.

Patients with obesity who had knee OA had significantly higher levels of metabolic dysfunction, systemic inflammation, adipokine imbalance, and clinical and radiographic disease severity compared with non-obese patients. There was a positive relationship between BMI and insulin resistance, inflammatory markers, leptin, resistin, radiographic severity, and WOMAC scores, and a negative relationship with adiponectin and HDL-C. After controlling for potential confounders, obesity was independently related to several metabolic and inflammatory abnormalities. These results are consistent with the hypothesis of an obesity-related metabolic-inflammatory phenotype of knee OA, and suggest that weight management and metabolic control may be important to the holistic treatment of KOA. Further studies are required to establish causation and whether or not modifying these factors can influence disease progression.

1. Primorac, D., et al., Knee osteoarthritis: a review of pathogenesis and state-of-the-art non-operative therapeutic considerations. Genes, 2020. 11(8): p. 854.
2. Scheuing, W.J., et al., The burden of osteoarthritis: Is it a rising problem? Best Practice & Research Clinical Rheumatology, 2023. 37(2): p. 101836.
3. Xue, F., et al., Temporal trends and future projections of hip/knee osteoarthritis burden attributable to metabolic risk in women of reproductive age (1990-2021): A multidimensional analysis across 204 countries and territories. 2025.
4. Hawker, G.A. and L.K. King, The burden of osteoarthritis in older adults. Clinics in geriatric medicine, 2022. 38(2): p. 181-192.
5. Xu, J., M. Lei, and D. Xu, Global, regional, and national burden of knee osteoarthritis attributable to high BMI: a systematic analysis from 1990 to 2021 and projections to 2050. Frontiers in Public Health, 2025. 13: p. 1668257.
6. Long, H., et al., Associations between obesity, diabetes mellitus, and cardiovascular disease with progression states of knee osteoarthritis (KOA). Aging Clinical and Experimental Research, 2023. 35(2): p. 333-340.
7. Huang, X., et al., Global, regional, and national burden of type 2 diabetes mellitus caused by high BMI from 1990 to 2021, and forecasts to 2045: analysis from the global burden of disease study 2021. Frontiers in public health, 2025. 13: p. 1515797.
8. Shumnalieva, R., G. Kotov, and S. Monov, Obesity-related knee osteoarthritis—current concepts. Life, 2023. 13(8): p. 1650.
9. Morgan, K., et al., Physical activity and joint health: Implications for knee osteoarthritis disease pathophysiology and mechanics. Experimental Physiology, 2026. 111(6): p. 2828-2839.
10. Wang, M.G., P. Seale, and D. Furman, The infrapatellar fat pad in inflammaging, knee joint health, and osteoarthritis. npj Aging, 2024. 10(1): p. 34.
11. Azhar, N., et al., FREQUENCY OF OSTEOARTHRITIS OF KNEE IN OVERWEIGHT PEOPLE. system. 2: p. 3.
12. Calvet, J., et al., Metabolic and inflammatory profiles define phenotypes with clinical relevance in female knee osteoarthritis patients with joint effusion. Rheumatology, 2023. 62(12): p. 3875-3885.
13. Al-Mansoori, L., et al., Role of inflammatory cytokines, growth factors and adipokines in adipogenesis and insulin resistance. Inflammation, 2022. 45(1): p. 31-44.
14. Belančić, A., et al., Obesity, Low-Grade Chronic Inflammation, and Clinical Outcomes in Spondyloarthritis: A Translational Synthesis. Metabolites, 2026. 16(5): p. 347.
15. Sobieh, B.H., H.O. El-Mesallamy, and D.H. Kassem, Beyond mechanical loading: the metabolic contribution of obesity in osteoarthritis unveils novel therapeutic targets. Heliyon, 2023. 9(5).
16. Tarabeih, N., et al., Pro-inflammatory biomarkers combined with body composition display a strong association with knee osteoarthritis in a community-based study. Biomolecules, 2023. 13(9): p. 1315.
17. Chong, T.K.Y., et al., Association of adipokines with severity of knee osteoarthritis assessed clinically and on magnetic resonance imaging. Osteoarthritis and Cartilage Open, 2023. 5(4): p. 100405.
18. Richter, M., et al., Correlations between serum adipocytokine concentrations, disease stage, radiological status and total body fat content in the patients with primary knee osteoarthritis. International Orthopaedics, 2017. 41(5): p. 983-989.
19. Kwoh, C., et al., Structural damage and effects on knee pain during different activities as assessed by the western ontario and mcmaster universities osteoarthritis index (womac). Osteoarthritis and Cartilage, 2023. 31(5): p. 706-707.
20. Batushansky, A., et al., Fundamentals of OA. An initiative of Osteoarthritis and Cartilage. Obesity and metabolic factors in OA. Osteoarthritis and Cartilage, 2022. 30(4): p. 501-515.
21. Cheng, X., et al., Does metabolically healthy obesity increase the risk of knee and hand osteoarthritis? A population-based cohort study. BMC Musculoskelet Disord, 2026. 27(1): p. 118.
22. Lambova, S.N., et al., Serum Leptin and Resistin Levels in Knee Osteoarthritis-Clinical and Radiologic Links: Towards Precise Definition of Metabolic Type Knee Osteoarthritis. Biomedicines, 2021. 9(8).
23. Chong, T.K.Y., et al., Association of adipokines with severity of knee osteoarthritis assessed clinically and on magnetic resonance imaging. Osteoarthr Cartil Open, 2023. 5(4): p. 100405.
24. Ilia, I., D. Nitusca, and C. Marian, Adiponectin in Osteoarthritis: Pathophysiology, Relationship with Obesity and Presumptive Diagnostic Biomarker Potential. Diagnostics (Basel), 2022. 12(2).
25. Vasileva, E., et al., Association of serum and synovial adipokines (chemerin and resistin) with inflammatory markers and ultrasonographic evaluation scores in patients with knee joint osteoarthritis- a pilot study. Rheumatol Int, 2024. 44(10): p. 1997-2005.
26. Zhu, J., et al., Association of serum levels of inflammatory markers and adipokines with joint symptoms and structures in participants with knee osteoarthritis. Rheumatology (Oxford), 2022. 61(3): p. 1044-1052.
27. Cheng, X., et al., Does metabolically healthy obesity increase the risk of knee and hand osteoarthritis? A population-based cohort study. BMC Musculoskeletal Disorders, 2026. 27(1): p. 118.