Background Previous studies have shown that obesity accelerates the development of osteoarthritis (OA). However, obesity is metabolically heterogeneous. The association between metabolic heterogeneity of obesity and incident OA remains unclear.

Methods A total of 381,036 participants from the UK Biobank (UKBB) were included baseline. Metabolic heterogeneity of obesity was evaluated based on four obesity and metabolic phenotypes: metabolically healthy non-obesity (MHNO), metabolically unhealthy non-obesity (MUNO), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). Incident OA cases were identified through self-reported diagnoses and hospital records. Multivariable-adjusted Cox proportional hazards models were used to evaluate the associations of these obesity phenotypes with OA incidence.

Results In the UKBB (mean age 56.07 ± 8.13 years; 59.1% female; median follow-up 12.35 years [Interquartile range (IQR) 1.8 years]), the cohort included 246,565 MHNO, 30,960 MHO, 46,834 MUNO, and 56,677 MUO participants. Longitudinal analyses revealed distinct risk patterns between metabolic heterogeneity of obesity and OA development. For total OA, risk was elevated across all groups compared with MHNO: MUNO (HR 1.20, 95% CI 1.17–1.23), MHO (HR 1.72, 95% CI 1.68–1.77), and MUO (HR 1.87, 95% CI 1.83–1.91), with the highest risk observed in the MUO group, indicating a synergistic effect of obesity and metabolic dysfunction. This gradient pattern was particularly evident for knee OA, where MUO (HR 2.56, 95% CI 2.47, 2.66) had the greatest risk, followed by MHO (HR 2.42, 95% CI 2.31, 2.53) and MUNO (HR 1.23 [1.18, 1.29]). For hip OA, MUO (HR 1.49 [1.42, 1.56]) and MHO (HR 1.51 [1.42, 1.61]) showed similar elevations, while MUNO (HR 1.04 [0.99, 1.10]) were not significantly associated. For hand OA, MUO (HR 1.13 [1.02, 1.26]) had a moderate risk, slightly lower than MUNO (HR 1.18 [1.06, 1.31]), while MHO (HR 1.08 [0.94, 1.24]) showed no significant association. Importantly, metabolic dysfunction independently contributed to OA risk across all weight categories. Mediation analysis further indicated that metabolic factors explained approximately 15% of the BMI effect on total OA and 11% on knee OA, whereas BMI had no significant total effect on hand OA.

Conclusions The study highlights the importance of maintaining and promoting metabolic health, particularly in overweight/obese individuals, to reduce OA risk. Metabolic factors were identified as key mediators of the association between BMI and OA in weight-bearing joints, emphasizing the need for targeted strategies addressing both metabolic dysfunction and obesity.

The authors have declared no competing interest.

This study received financial support from the National Natural Science Foundation of China (NO. 82372428).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The North West Multi-Centre Research Ethics Committee of the National Health Service (NHS) National Research Ethics Service gave ethical approval for this work (REC reference: 11/NW/0382). The UK Biobank approved the use of data for this study under Application ID 67654.

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This research has been conducted using the UK Biobank resource under Application ID 67654. Data are available upon application to the UK Biobank (https://www.ukbiobank.ac.uk/), subject to their terms and approval process.

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