Arthritis has reached epidemic proportions in the United States. It is the leading cause of disability, affecting about one-third of adults. Osteoarthritis (OA) is the most common form of arthritis with a prevalence conservatively estimated at 21 million Americans, or 12.1% of the adult population. We recently showed that a 5% weight loss in obese adults with knee OA had a modest effect on clinical outcomes; however, these participants remained obese at the conclusion of the intervention, so their risk of disease progression was not altered. Indeed, the nature of the relationships between weight loss and the mechanisms associated with disease progression are undetermined. We hypothesize that a more intensive weight loss (2 to 3 times greater than previously achieved in this population) would provide the stimulus necessary to reduce inflammation and joint loads and alter disease progression. The study population will consist of 450 overweight and obese, older (age > 60 yrs) adults with tibiofemoral osteoarthritis of one or both knees. Participants will be randomized to 1 of 3, 24-month interventions: intensive dietary restriction-plus-exercise; exercise-only; or intensive dietary restriction-only. The primary aim is to compare the effects of these interventions on inflammatory biomarkers and knee joint loads in overweight and obese adults with knee OA. Secondary aims are: to compare the effects of these interventions on self-reported function and pain, and mobility; to determine the dose response to weight loss on disease progression and the mechanisms associated with the OA disease pathway; to determine if inflammatory biomarkers and knee joint loads are mediators of the interventions, with significant effects on function, pain, and disease progression; and to determine the association between quadriceps strength and disease progression as a function of knee alignment. Weight loss is the most modifiable risk factor for knee OA; however, no study has determined the extent of weight loss that is beneficial for this population. This study could make intensive weight loss the standard-of- care for overweight and obese adults with knee OA, as it enhances our understanding of the OA disease process and weight-loss recommendations for older people generally. [unreadable] [unreadable] [unreadable] [unreadable]