## 4 Discussion  
Based on radiographic measurement, using sensitive image analyses like KIDA, KJD seems to induce increased osteophyte formation in the first two years following treatment. This argues against the general assumption that osteeophylotsis is solely a hallmark of OA worsening or joint degeneration, since this osteeophylotsis during KJD is combined with a significant increase in clinical benefit and joint space widening (supported in previous studies by MRI cartilage volume measurements [21; 22; 33]). Increased osteophyte presence  
Figure 4: Box plots for the changes in synovial fluid concentrations over the course of 6 weeks of knee joint distraction, of (**A**) transforming growth factor-\(\beta\)1 (TGF-\(\beta\)1) and (**B**) interleukin-6 (IL-6), categorized into groups of patients with a decrease (\(n=5\)), no change (\(n=3\)) or increase (\(n=6\) for TGF\(\beta\)-1; \(n=7\) for IL-6) in total Altman osteophyte score. The bar represents the median, whiskers represent the minimum and maximum value, the + represents the mean. has often been associated with increased pain in knee OA patients [40; 41; 42], but with improvement in clinical outcome for KJD patients, including a significant decrease in pain, parallel with an increase in osteophyte size. No correlation could be found between (changes in) osteophyte size and WOMAC scores or JSW (except between baseline JSW and osteophyte size, see Supplementary Tables S6 and S7), expectedly due to limited numbers. Treatment-related osteophyte formation is not limited to KJD, but is demonstrated after HTO as well. HTO patients were compared with KJD\({}_{\text{HTO}}\) patients, since those groups were randomized as such in the original RCT, and showed similar osteophyte formation. While KJD\({}_{\text{HTO}}\) patients showed similar results as the entire KJD group, their baseline osteophyte size was smaller and more comparable with the HTO group. This is likely because while KJD\({}_{\text{HTO}}\) patients who were in regular care indicated for a HTO, all other KJD patients were in regular care indicated for TKA and thus likely had further progressed OA. Nevertheless, both treatments showed changes predominantly in the lateral compartment. While in HTO patients this might be explained by an increased load on the lateral side as a result of the medial unloading, such a shift is not necessarily expected in KJD. Since HTO showed an osteophyte increase on the medial side as well, loading may not be directly involved in osteophyte formation after these treatments. Like in KJD, osteophyte formation in HTO accompanied clinical improvement and JSW increase, further questioning the role of osteophytes in OA. Other studies have shown similar findings, showing that lateral osteophyte presence is not associated with lateral cartilage degeneration or with medial knee OA severity [43; 44; 45]. Our findings suggest that the presence, size and localization of osteophytes may not be such a clear indication of joint degeneration and accompanying symptoms as is generally assumed. With the analysis of untreated patients from the CHECK cohort it was shown that the increase in osteophytes after KJD was greater than the natural progression that can be expected in knee OA patients. It should be noted however that, despite making a selection of patients that received TKA during follow-up, the CHECK patients differed in baseline characteristics and seemed to have less severe OA at the moment of treatment (TKA) than the KJD patients, as shown by Kellgren-Lawrence grade and osteophyte size. This might be related to the specific characteristics of this CHECK cohort where pain was an essential inclusion criterion, and might be irrelevant for comparison with KJD or HTO, as in none of the groups did the baseline osteophyte size or Kellgren-Lawrence grade have a significant influence on the change in osteophyte size (CHECK: \(p=0.391\) and \(p=0.457\), respectively).