Hypothetical model of osteoarthritis (OA) pathogenesis. Normal subchondral bone suffering from a non-physiological strain (induced by risk factors) starts a pathological cascade reaction, leading to osteoarthritic changes in different tissues. In early-stage OA, subchondral plate becomes thinner and more porous, together with initial cartilage degeneration. Subchondral trabecular bone also deteriorates, with increased separation and thinner trabeculae. At the same time, microdamage begins to appear in both calcified cartilage and subchondral bone, which will persist throughout the whole pathological process. In late-stage OA, calcified cartilage and subchondral plate become thicker, with reduplicated tidemarks and progressive non-calcified cartilage damage. Subchondral trabecular bone becomes sclerotic. The sclerosis of periarticular mineralized tissues may be a biomechanical compensational adaptation to the widespread cysts and microdamage in subchondral bone, which render subchondral bone structure more fragile.