We investigated whether baseline sagittal-plane ankle, knee, and hip contribution to the total support moment (TSM) are each associated with baseline-to-2-year tibiofemoral and patellofemoral tissue damage worsening in adults with knee osteoarthritis. Ambulatory lower-limb kinetics were captured and computed. TSM is the sum of ankle, knee, and hip extensor moments at each instant during gait. Ankle, knee, and hip contributions to TSM were computed as joint moments divided by TSM, expressed as percentages. Participants underwent MRI of both knees at baseline and 2 years later. Logistic regression models assessed associations of baseline ankle contribution to TSM with baseline-to-2-year cartilage damage and bone marrow lesion worsening, adjusted for age, sex, BMI, gait speed, disease severity, and pain. We used similar analytic approaches for knee and hip contributions to TSM. Sample included 391 knees from 204 persons (age[SD]:​ 64[10] years;​ 76.5% women). Greater ankle contribution may be associated with increased odds of tibiofemoral cartilage damage worsening (OR = 2.38;​ 95% CI:​ 1.02–5.57) and decreased odds of patellofemoral bone marrow lesion worsening (OR = 0.14;​ 95% CI:​ 0.03–0.73). The ORs for greater knee contribution were in the protective range for tibiofemoral compartment and in the deleterious range for patellofemoral. Greater hip contribution may be associated with increased odds of tibiofemoral worsening (OR = 2.71;​ 95% CI:​ 1.17–6.30). Greater ankle contribution to TSM may be associated with baseline-to-2-year tibiofemoral worsening, but patellofemoral tissue preservation. Conversely, greater knee contribution may be associated with patellofemoral worsening, but tibiofemoral preservation. Preliminary findings illustrate potential challenges in developing biomechanical interventions beneficial to both tibiofemoral and patellofemoral compartments.