## 4 Discussion
Since APS is a PRP product, it originally contains a large amount of TGF\(\beta\); however, the increased TGF\(\beta\) level due to ESWT stimulation may have contributed to the anti-inflammatory effect and the regulation of cell proliferation and differentiation ([PERSON] et al., 2019; [PERSON] et al., 2019). If ESWT stimulates endogenous stem cells, the interaction between the stimulated endogenous stem cells and the injected APS solution may promote cell proliferation [26; 27]. However, further studies are required to confirm this hypothesis. In addition, in severe knee OA, surgery, such as joint replacement, may be recommended, but it can be presented as a transition or alternative therapy for patients who cannot undergo surgery due to age restrictions or various social backgrounds. Regenerative medicine for knee osteoarthritis has recently attracted attention, and orthologics, such as PRP or MSC therapy, have attracted attention in recent years, but most of them are administered intra-articularly. When intra-articular administration is performed, most of the material is absorbed into the synovial membrane, except in severe cases of the rupture of some subchondral bone plates. The synovial membrane nourishes the cartilage, but even if there is an improvement in pain, it cannot directly improve the BML-derived pain from the bone marrow. However, not all BML-induced bone pain is resolved with ESWT. In particular, there seems to be a limit to pain with bone cysts and BML that contains a large amount of osteonecrotic tissue. In addition, in BMLs where the subchondral bone plate is ruptured, joint fluid easily enters the bone marrow and conservative treatment may be limited. In this study, we recognize that further treatments other than ESWT that can repair BMLs, bone cysts, necrotic tissues, or subchondral plates will be needed in the future. This study had some limitations. First, the only endpoint was the KOOS, and thus, the results are limited. The New Knee Society Score was to be used to evaluate patient-reported outcome measures and objective knee joint function. However, studies in one clinic were limited in assessing the effect of treatment using the KOOS, which is most often used, from the patient's point of view. Second, image evaluation should not only be through KL classification but it should also include the relationship with BMLs. In this study, ESWT was applied on patients with knee OA with BMLs observed on MRI, but the type of BML irradiated and how it is done should be determined. Third, it is unclear whether ESWT irradiation irradiates the BML precisely or whether other areas are also irradiated. In addition, in this series, the number of shock waves was set at 2500 per session, but the shock wave strength and number were not constant and depended on the patient. While these  
Figure 4: Radiography findings in the Rosenberg view showing KL4 medial knee OA in a 64-year-old female patient. (**A**) Joint space before APS. (**B**) Joint space is expanded 48 months after APS + ESWT. APS, autologous protein solution; ESWT, extracorporeal shock wave therapy; KL, Kellgren–Lawrence classification; OA, osteoarthritis. were supposed to be constant, the shock wave level chosen was the maximum strength the patient could tolerate; therefore, we had to observe the patient's reaction during and after the shock wave irradiation and determine the strength and irradiation time of the shock wave. In addition, the number of irradiations was the same regardless of whether there was one large BML or multiple, and thus, the energy irradiated per unit area varied depending on the size and number of BMLs. This was also different from clinical trials, and it was a limitation of the actual treatment. Fourth, there were differences in how patients spent their time after APS or ESWT. It cannot be ruled out that some patients may worsen due to differences in life, work, or sports activities after APS or ESWT. Unlike clinical trials, we believe that this is a limitation of research using actual patients.