## 4 Discussion  
The aim of this study was to compare the efficacy of HA, ACS and BMAC in the treatment of symptomatic knee OA. The most important findings were that all three treatment methods resulted in an improvement in the VAS and WOMAC scores at the 3-month follow-up. However, at 12 months, the WOMAC scores remained improved only in patients treated with BMAC. In addition, BMAC was most effective in the patients with more severe (KL grade III) degenerative changes. The lack of sustained effect of HA treatment is consistent with previous reports in the literature. A meta-analysis of 76 trials comparing various types of HA injections to other treatment options for OA concluded that HA had a positive effect on pain associated with weightbearing function, and the positive effect was most pronounced 5 to 13 weeks post injection [37]. The current AAOS guidelines cannot recommend HA for symptomatic knee OA; although some meta-analyses have shown improvement in the WOMAC score, the number of points with which patients assessed their improvement did not meet the minimal clinically important improvement thresholds [8]. In this study, the treatment with ACS showed an improvement in the VAS but not in the WOMAC score at 1 year after treatment, which is somewhat different from previous studies. [PERSON] et al., looking at the efficacy of ACS in the treatment of symptomatic knee OA in a double-blind placebo-controlled trial, found an improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and in the symptom and sport subscores [38]. Although there appeared to be a trend towards improvement in other three subscores as compared to placebo, this did not reach statistical significance. Similar to the present study, they did not find a significant difference in the WOMAC score at 12-month post treatment [38]. [PERSON] et al. compared ACS to HA and normal saline [20] and found that all three treatment groups showed symptom reduction. In line with the present study, the symptom reduction was better with ACS and HA, but they found no difference in improvement between HA and normal saline. Figure 4: Forest plot showing VAS and WOMAC score changes in patients with different OA grades for the patient groups treated with separate treatment methods. Mean values of score change \(\pm\) SEM are presented. OA = osteoarthritis; VAS = Visual Analogue Scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index. HA = hyaluronic acid; ACS = autologous conditioned serum; BMAC = bone marrow aspirate concentrate. They noted, however, that HA injection had a significantly higher complication rate than ACS and normal saline [20]. BMAC has been found superior to HA and ASC in the present study, showing an effect of treatment even at a 12-month follow-up; it was most effective in patients with higher grade knee OA. A potential explanation may be that the pluripotent stem cells present in BMAC are able to promote chondrogenesis and cartilage regeneration [23; 26; 32; 34; 39]. In addition, these cells can secrete certain growth factors resulting in an anti-inflammatory and immunomododulating effect on the knee, which may slow down or even prevent OA progression [40]. Consistent with this, a meta-analysis by [PERSON] et al. showed a statistically significant improvement after MSC (derived either from bone marrow or adipose tissue) transplantation in all functional outcome measures such as VAS for pain, WOMAC, Lysholm, Knee Injury and Osteoarthritis Outcome Score (KOOS) and radiological outcome parameters such as Whole-Organ Magnetic Resonance Imaging Score (WORMS) at different time intervals with their corresponding controls. The study showed an improvement in OA symptoms with a bone marrow derived cultured stem cell injection; the VAS score was found improved even at 2 years post treatment. However, the authors pointed out that there were no studies comparing the effect of BMAC and culture expanded bone marrow derived mesenchymal stem cells (BM-MSCs) [31].