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Recent improvements in the understanding of the pathophysiology of the disease have led to novel treatments. Strontium ranelate inhibits subchondral bone resorption by regulating the activity of osteoprotegerin, RANK ligand, and matrix metalloproteinases produced by osteoblasts. Strontium may have a direct effect on cartilage; this is supported by the observation that it promotes proteoglycan synthesis, which stimulates cartilage matrix formation in vitro. Nerve growth factor (NGF) is postulated to modulate signals that control expression of peripheral and central pain substances and sensitizes adjacent nociceptive neurons in response to stimulation. Tanezumab is a highly selective immunoglobulin G2 antibody against NGF. Several studies have shown that in patients with moderate to severe knee OA tanezumab results in greater improvement in knee pain, stiffness, and increase function compared with placebo. However, side effects include osteonecrosis leading to the medication being placed on hold by the FDA. Regenerative therapy has been one the latest rapidly growing strategies to treat OA. Platelet-rich plasma, which is harvested from a patient’s blood with the theory that it will provide important growth factors, has been investigated. A systematic review found that platelet-rich plasma resulted in clinical improvement up to 12 months following injection. Mesenchymal stem cells (MSCs) are a cell source that can be easily obtained from a variety of tissues such as bone marrow, adipose tissue, and synovium. The stem cells are capable of rapid proliferation, chondro-differentiation and immunosuppression. One study showed mild improvements in pain for 5 years after injection of MSCs into the knee joint. Another area of investigation is the use of radiofrequency ablation in the treatment of knee OA. These procedures thermally lesion sensory nerves, which include the superior lateral and medial and inferior medial genicular nerves of the anterior joint capsule of the knee, in order to decrease pain. To date, results are promising for improvement in pain and reducing disability.