**Background:** Osteoarthritis (OA) is the most common chronic joint disease, affecting over 300 million people worldwide, yet no disease-modifying drug exists. Emerging evidence suggests vascular pathology may play a role in OA pathogenesis. Popliteal artery wall thickness is a validated surrogate marker of atherosclerosis. Previous studies in asymptomatic populations found associations between greater popliteal artery wall thickness and cartilage loss, but it was unknown whether this relationship persists in established symptomatic knee OA.
**Methods:** This prospective cohort study analyzed 176 participants from the Osteoarthritis of the Knee Statin (OAKS) study, a multicenter randomized, double-blind, placebo-controlled trial examining atorvastatin's effect on structural progression in knee OA over 2 years. Participants were aged 40–70 years with symptomatic knee OA for ≥6 months, pain ≥20 mm on a 100 mm VAS, and meeting ACR clinical criteria. Exclusion criteria included severe radiographic OA, inflammatory arthritis, accepted indications for statin therapy, and cardiovascular risk >15% over 5 years. Participants underwent MRI at baseline and ~2-year follow-up (mean 2.1 years, SD 0.2). Popliteal artery wall thickness was measured on axial fat-suppressed proton density MRI at the femoral intercondylar notch level using OsiriX software, expressed as (arterial area – luminal area)/arterial area (%). Tibial cartilage volumes (medial and lateral) were measured on sagittal T1-weighted images. The intra-observer ICC for popliteal artery wall thickness was 0.95; inter-observer ICC for cartilage volume was 0.91. Rapid progression was defined as the top quartile of annual cartilage volume loss. Multivariable linear and logistic regression adjusted for age, sex, BMI, smoking, vigorous physical activity, compartment-specific tibial bone area, and intervention group allocation. A meta-analysis combined results with two prior pre-OA studies.
**Key Results:** At baseline, every 10% increase in popliteal artery wall thickness was associated with 120.8 mm³ lower medial tibial cartilage volume (95% CI 5.4, 236.2; P=0.04) and 151.9 mm³ lower lateral tibial cartilage volume (95% CI 12.1, 291.7; P=0.03) after multivariable adjustment. Longitudinally, each 10% increase in popliteal artery wall thickness was associated with a 1.14% greater annual rate of medial tibial cartilage loss (95% CI 0.09%, 2.20%; P=0.03) and a 2.28-fold increased risk of rapid medial progression (95% CI 1.07, 4.83; P=0.03). No significant association was found for lateral cartilage change. Sex-specific quartile analysis showed a dose-response trend (P for trend=0.04), with the top quartile having OR 2.92 (95% CI 0.91, 9.32) for rapid progression vs the bottom quartile. The association between popliteal artery wall thickness and medial cartilage loss was significant in the atorvastatin group (regression coefficient –2.90%, 95% CI –4.67% to –1.12%) but not the placebo group (0.02%, 95% CI –1.26% to 1.31%). Meta-analysis of pre-OA populations showed a smaller magnitude of association (regression coefficient –0.06% per 1% increase in popliteal artery wall thickness, 95% CI –0.11% to –0.01%) compared with the OA population (–0.11%, 95% CI –0.22% to –0.01%), though the difference was not statistically significant (P=0.40).
**Clinical Implications:** These findings support a role for vascular pathology in knee OA progression across the disease spectrum from pre-clinical to established symptomatic disease. The observed effect is clinically meaningful: a 10% increase in popliteal artery wall thickness corresponds to a 1.14% greater annual cartilage loss, and prior research indicates that each 1% increase in annual cartilage loss raises knee replacement risk by 20% over 3 years. The proposed mechanism involves reduced blood flow to the subchondral bone via the popliteal artery, leading to subchondral ischemia, impaired nutrient supply to avascular articular cartilage, osteocyte apoptosis, and altered bone mechanical properties. Limitations include measurement on a single MRI slice and moderate sample size. Strengths include validated measurements with excellent reproducibility, 2-year follow-up with 86.4% retention, and inclusion of a meta-analysis. Targeting atherosclerosis through risk factor modification may offer a novel therapeutic avenue for slowing knee OA progression and reducing the need for total knee replacement.