Background <p>Pathologies of the subchondral bone include both structural alterations such as osteonecrosis and bone marrow edema. Both entities are amenable to pharmacological therapy.</p> Objective <p>Presentation of current recommendations for drug therapy of osteonecrosis and bone marrow edema of the knee joint based on the clinical data.</p> Methods <p>The currently available literature is evaluated and discussed.</p> Results <p>Antiresorptives such as bisphosphonates and denosumab and the osteoanabolic agent teriparatide therapeutically address the locally diminished bone density potentially resulting in insufficiency fractures. In contrast, vitamin&#xa0;K antagonists, heparin and new/direct oral anticoagulants, as well as iloprost exert their effects at the vascular and hemostatic level. All drug treatment concepts are “off-label” use. They are particularly promising in the early stages of primary, idiopathic osteonecrosis and bone marrow edema.</p> Conclusion <p>In osteonecrosis and bone marrow edema of the knee joint, complementary drug therapy may be beneficial. However, the available data is not yet sufficiently robust for general treatment recommendations.</p>