BMI and Varus Malalignment Compound to Define a High-Risk Phenotype for Compartment-Specific Knee Osteoarthritis Progression

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.