## 4 Discussion  
The mean KOOS of the A-alone group decreased between 3 and 6 months, and the success rate in the A-alone group was higher at 3 months than at 6 months for both 50% and 20% improvement in the A-alone group. These results suggest that the effect of APS therapy alone on severe knee OA, such as KL4, lasted for at most 3 months. This result is consistent with those reported by [PERSON] et al. (2019). However, the average KOOS in the A + E group increased between 3 and 6 months, and the success rates in the A + E group were higher after 6 months than after 3 months for both 50% and 20% improvement. These results suggest that ESWT after the APS injection improved the duration of the effects and the performance rate. In addition, the IV at 3-6M was significantly higher in the A + E group than in the A-alone group, suggesting that ESWT contributed significantly to improved performance from 3 to 6 months. Furthermore, the IV at 3-6M in the A + E group was 5.1 \(\pm\) 12.1 compared with 7.5 \(\pm\) 12.6 at Pre-3M; however, it was still a positive change. Further improvement could be expected if irradiation continued after 6 months by adding ESWT. Therefore, additional irradiation (booster irradiation) is considered effective in improving performance. In more severe cases of KL4, the duration and success rate of ESWT after APS injection were higher than those of APS alone, suggesting that the combination of APS and ESWT was more synergistic than ESWT or APS alone. However, the mechanism underlying the synergistic effect remains unknown, although several hypotheses were proposed. The mechanism can be inferred from highly severe knee OA characteristics, such as KL4. According to [PERSON] et al., increased pathological free nerve endings in knee joints with advanced OA are important when considering the mechanism underlying chronic pain generation ([PERSON] et al., 2019). In the present study, all patients were irradiated with ESWT once before APS injection; however, in highly severe OA, such as KL4, BMLs are often enlarged or advanced, and it is believed that there are more pathological free nerve endings. Consequently, a single irradiation was not sufficient, and it is thought that multiple additional ESWT irradiations are required to destroy the free nerve endings present in BMLs. Additionally, as symptoms and living standards improve, activity levels naturally increase. OA may worsen over time compared with before the APS injection. Therefore, multiple and additional ESWT irradiations contribute to symptom or pathological improvement. In addition, KL4 knee OA has less synovitis than KL2 and KL3, and fewer inflammatory cytokines are expressed ([PERSON] et al., 2019). APS targeting inflammatory cytokines may inevitably be less effective for severe knee OA, such as KL4. However, if ESWT stimulation increases inflammatory cytokines, such as TNF\(\alpha\), even temporarily, it may make it easier for APS to work effectively in response to TNF\(\alpha\)([PERSON] et al., 2019). Consequently, ESWT causes pseudo-inflammation, which facilitates the action of APS-containing anti-inflammatory cytokines. In addition, cell adhesion factors that have an affinity for APS and PRP may be stimulated by ESWT, facilitating the effects of APS. In addition, combined treatment may be expected to produce anti-inflammatory and cell proliferation effects, as seen on radiographs of the KL4 front-of-knee OA of a 64-year-old woman before APS therapy and 48 months after APS therapy. This patient continued ESWT approximately once or twice a month after the APS injection but showed a slight opening of the joint dehiscence compared with that before the APS injection (Figure 4). MRI of the same patient 48 months later showed the reduction in BML in T1 (upper photo), and the disappearance of bone cysts in T2 (lower photo) was confirmed (Figure 5).