Based on results of this study clinical improvement with a single cross-linked HMW-HA injection could be relatively equal to that of triple injection of a linear LMW-HA, within the periods of two and six months follow-up. Moreover, a comparison between the two groups indicates that there exists no statistically significant superiority. An exception was the improvement of WOMAC stiffness subscale which was significantly higher in LMW-HA group in 2 months.
Altman[29] review which included 68 randomized trials proved that HMW-HA efficacy was superior to LMW-HAs. Conversely in our study, there was no difference in efficacy between these two types of HAs. In the study conducted by Zhang et al,[36] the therapeutic effectiveness of single injection of a cross-linked HMW-HA (Durolane) was compared to five injections of a LMW-HA (Artz), showing that during a period of 26 weeks, Durolane was non-inferior to Artz in terms of pain, physical activity and knee-stiffness. Our study revealed a similar result within a period of same length.
Similarly, Diracoglu et al[33] evaluated the efficacy of two HA types with different molecular weights and number of injections. The first group received a single cross-linked moderate-molecular-weight HA (Monovisc), while the other one underwent three consecutive weekly injections of a linear LMW-HA (Adant). In both groups, WOMAC scores and VAS-pain showed statistically significant improvements compared to the baseline level, without any remarkable superiority between the two groups. However, in both groups, WOMAC stiffness showed no significant improvement. Meanwhile, VAS improvement for the group receiving Adant was remarkably higher than the Monovisc group. The latter study found that a single cross-linked HA can be as effective as a triple linear LMW-HA, exactly similar to our study. It should be pointed out that the HA used in our trial was much heavier than the one used by Diracoglu. Unlike the mentioned results, WOMAC stiffness in our investigation was associated with a statistically significant improvement. This change was even more evident in the group receiving LMW-HA compared to HMW-HA group.
Another study by Estades-Rubio et al,[35] evaluated a single dose of Durolane versus a five-time GO ON® injection. Mobility and WOMAC were assessed during six months. A statistically significant change was observed for both groups compared to their baseline level. In addition, a remarkable superiority was observed in WOMAC scores of the group receiving Durolane compared to the GO ON® group, although no difference was detected in mobility values. From the economic point of view, the total price of using a single injection of Durolane was lower than that of multiple injections of GO ON®. In comparison, the results of our RCT showed some dissimilarities since the improvement in the Durolane as a cross-linked HMW-HA is statistically more significant than GO ON®. However, this finding proves that a single cross-linked HMW-HA can be as effective as or even better than multiple linear LMW-HA injections.
In the meta-analysis conducted by Concoff et al,[34] the efficacy of multiple HA injections versus a single dose of HA was studied. The pooled data showed that a single HA injection was not significantly more effective than IA-Saline in a period of six months. Another systematic review and meta-analysis by Zhao et al,[42] was carried out to compare the results of Hylan G-F 20 and LMW-HA in knee OA patients. The final results indicate a similarity between the Hylan G-F 20 and LMW-HA groups in terms of their pain-relief effect. However, Hylan G-F 20 was more effective in pain improvement from 2-3 months. It should be pointed out that in the present meta-analysis, Hylan G-F 20 injections were administered more than once; however, this number was less than the number of LMW-HA injections in most trials. These findings, similar to our study, showed the effectiveness of HMW-HA with lower number of injections compared to LMW-HA with multiple injections.
In our study, the rate of minor complications and injection-induced pain was not statistically different between two HA products. In Bannuru`s meta-analysis,[43] none of the HA products were significantly different from each other with regard to incidence of adverse events and were relatively equal to IA placebo. Altman et al,[29] concluded that there is no significant difference in the occurrence of effusion across molecular weight subgroups. Different brand names of HA exist in the market, claiming to be effective by a single injection. So far, few studies have been conducted to compare a single HA injection with multiple HA injection. Although most single-injection HAs are of HMW and cross-linked type, some differences can be observed in their structure. To examine the exact effects of such viscosupplements, further well-designed investigations should be performed. Evidently, single injections possess the advantage of lower cost, patients’ comfort and lower risk of complications owing to the lower number of injections.
An advantage of this research is employing various outcome measures for evaluating patients’ symptoms including WOMAC subscales, Lequesne and VAS indices. The washout period was considered in this study. The fact that the physician was not blind in this study, is an important limitation. Due to ethical issues, it was not possible to do second and third sham injections in HMW-HA group. Rather, all assessors in this study were completely blinded. It would be better to enroll a higher number of patients in the future studies. Although our follow-up was for 6 months, yet longer follow-up time can be suggested. As the last limitation to be mentioned, no economic analysis was conducted in our trial.