Objectives Knee osteoarthritis (KOA) is a leading cause of disability, yet which patients will experience structural decline remains unclear. Body mass index (BMI) and lower limb alignment are established risk factors for KOA, but their independent and interactive effects on compartment-specific cartilage loss and total knee replacement (TKR) have not been characterized at scale.

Methods We analyzed 5,832 limbs from 3,016 participants in the Osteoarthritis Initiative followed over 7 years. Cartilage thickness in the weight-bearing medial and lateral femur and tibia was quantified, and lower limb alignment was measured using hip-knee-ankle (HKA) angle obtained from full-limb radiographs. Linear mixed-effects models estimated the independent and interactive effects of BMI and lower limb alignment on longitudinal cartilage thinning, and mixed-effects logistic regression modeled TKR risk.

Results In the medial compartment, BMI and varus alignment interacted multiplicatively, with their combined effect exceeding the sum of independent contributions (femur: p = 0.011; tibia: p < 0.001). At +10 kg/m² BMI and +10° varus, the rate of medial femur cartilage thinning was 243.5% faster than the reference rate. In the lateral compartment, BMI and valgus alignment were independently associated with faster cartilage thinning, with no significant interaction. TKR risk increased exponentially with HKA deviation (odds ratio [OR] = 1.38 per 1°; ∼five-fold at 5° malalignment) but was not associated with BMI.

Conclusion BMI and lower limb alignment influence structural KOA progression through compartment-specific pathways. The multiplicative interaction in the medial compartment identifies high BMI combined with varus malalignment as a discrete high-risk phenotype, with implications for clinical risk stratification and disease-modifying intervention design.

The authors have declared no competing interest.

NIH R01AR079431, R01AR083018, R01AR077604, R01EB002524, R01AR079431, P41EB027060, P50HD118632

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The datasets used in this study were individual-level data drawn from the Osteoarthritis Initiative (OAI), a publicly available longitudinal cohort. All data were de-identified prior to release by the OAI and accessed through their public data repository. https://nda.nih.gov/oai

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Conflict of interest: A.C. receives research support from GE Healthcare, Siemens, Philips, Microsoft, Amazon, Google, NVIDIA, Stability; A.C. has provided consulting services to Patient Square Capital, Chondrometrics GmbH, and Elucid Bioimaging; A.C. is co-founder of and receives personal fees from Cognita Imaging; has equity interest in Subtle Medical, LVIS Corp, Brain Key and Radiology Partners. A.A.G is a shareholder of NeuralSeg, GeminiOV, and NodeAI.

Funding: NIH R01AR079431, R01AR083018, R01AR077604, R01EB002524, P41EB027060, P50HD118632

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process: During the preparation of this work the author(s) used Claude (Anthropic) in order to improve clarity and readability of the manuscript text. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.