Purpose: Subchondral bone contributes to pain in knee osteoarthritis (OA). OA structural change particularly affects weight-bearing components of the joint, most notably the medial femorotibial compartment in people with varus angulation. Subchondral bone marrow lesions (BMLs) detected on MRI in knee OA are strongly associated with pain. BMLs typically occur in regions of the joint with the most severe structural change, for example, full-thickness cartilage lesions. However, the association between subchondral BMLs in weight-bearing components and weight-bearing pain has not been clarified. The purpose of this study was to assess association between BMLs location and weight bearing knee pain using data from the Osteoarthritis Initiative (OAI). We hypothesized that BMLs at the medial femorotibial joint compartment were associated with weight bearing pain, independent of non-weight bearing pain, and that changes in size of the BMLs over time were associated with change in weight bearing pain. Methods: The OAI is a publicly available multi-center, longitudinal, prospective observational study of knee OA. We examined the knees of OAI participants with MRI readings using the MRI Osteoarthritis Knee Score (MOAKS). BMLs, articular cartilage, osteophytes, Hoffa’s synovitis, effusion, meniscal morphology and anterior cruciate ligament tears were scored using the MOAKS, and femorotibial angle (FTA) and Body Mass Index (BMI) were examined. BML scores using MOAKS were available for 4 articular sub-regions (median and lateral femorotibial, and medial and lateral patellofemoral joint) and the subspinous region. Knee pain was assessed at baseline (cross-sectional) and baseline and 2 years (longitudinal) using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We defined weight bearing pain as the sum of three WOMAC questions (pain on climbing stairs, on walking, and on standing) and non-weight bearing pain as the sum of two WOMAC questions (pain in bed and with sitting/lying down). Negative binomial regression was performed, using SPSS version 23 software. Results: 1412 participants were included in the cross-sectional analysis (from OAI project 22, 30 and 65), mean age 62 (±9) years, mean BMI 30 (±5), 61% female, median weight and non-weight bearing WOMAC score 2 (IQR 0, 4) and 0 (IQR 0, 1), and median total BML score 3 (IQR 1, 6). Weight bearing pain was associated with total BML score was r = 0.35 (p < 0.0001), and with BML scores at medial (r=0.29, p < 0.0001) and lateral (r=0.09, p = 0.0009) femorotibial joint compartments. Weight bearing pain was also associated with BML score at medial and lateral patellofemoral joint compartments (r = 0.03, p = 0.3 and 0.13, p < 0.0001, respectively). The association between weight bearing pain and BML scores at medial femorotibial and lateral patellofemoral joint compartments remained significant after adjusting for non-weight bearing pain, age, sex, BMI, FTA, BML scores at the other 4 joint compartments and the other OA related MRI features (osteophyte score, cartilage defect score, medial meniscus extrusion, anterior cruciate ligament tears, synovitis and effusion) (Table 1). 600 participants were included in the longitudinal study (OAI project 22), mean age 62 (± 9) years, mean BMI 31 (± 5), 57% female, median weight and non-weight bearing WOMAC score 1 (IQR 0, 3) and 0 (IQR 0, 1), and median total BML score 3 (IQR 2, 5). From baseline to 2 years, the changes in the mean weight and non-weight bearing 0.5 (±2.2) and 0.1 (±1.4), and mean total BML score were 0.7 (±1.9). The correlation between changes in weight bearing pain and changes in total BML score was r = 0.13 (p = 0.002); between changes in weight-bearing pain and BML score at medial and lateral femorotibial joint compartment were r = 0.16 (p < 0.0001) and -0.03 (p = 0.45), between changes in weight-bearing pain and changes in BML score at medial and lateral patellofemoral joint compartment were r = 0.04 (p = 0.3) and -0.03 (p = 0.5). The association between the changes in BML score at medial femorotibial joint compartment and changes in weight-bearing pain remained significant after adjusting for changes in non-weight bearing pain, age, sex, BMI, BML change at the other four joint compartments and osteophyte score change (Table 2). Conclusions: In this cross sectional and longitudinal study, BMLs at medial femorotibial joint compartment in varus knee OA participants were highly associated with the severity and the change in severity of weight bearing pain. The associations persisted when mutually adjusting for other feature of OA related MRI features, and adjusting for non-weight bearing pain, age, sex and BMI. Our findings suggest that BMLs in weight-bearing areas might contribute to weight bearing pain. Reducing BMLs or weight bearing in joint compartments with BMLs are candidate treatment targets in knee OA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)