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The prognosis of osteoarthritis (OA) is worsened by persistent subchondral defects known as bone marrow lesions (BMLs), which herald severe joint degeneration and the need for joint replacement. Joint-preserving treatments that reverse the progression of pain and immobility are limited. Subchondroplasty is a procedure developed to treat BMLs by injecting a calcium phosphate bone substitute into compromised subchondral bone, under fluoroscopic guidance. Here we evaluate the effectiveness of this approach for relieving pain and improving function in patients with documented BMLs and advanced knee OA, in a retrospective study. Data were collected from a consecutive patient series (n = 66) who underwent subchondroplasty combined with arthroscopy, performed at a single center by one surgeon. We observed significant improvements in both pain and function following subchondroplasty with arthroscopic debridement, as measured by the visual analog scale (VAS) and the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, through 2 years postoperative follow-up. Given that arthroscopic debridement alone has been previously shown to yield insignificant pain relief beyond 6 months postoperatively, our results suggest that subchondroplasty may be a promising approach for the treatment of OA with BMLs.