Our study, involving a novel high-density viscoelastic gel of HA, has demonstrated its efficacy in terms of pain relief for patients with symptomatic knee OA. This significant clinical benefit was indeed achieved early (2 weeks after the injection) and maintained for, at least, 24 weeks. In general, clinical improvement has been established with a minimum difference of 20% in efficacy outcomes [23], like scores in the WOMAC questionnaire. Our results are in agreement with the literature implicating diverse HA products [8–10, 12, 24, 25]. For instance, Berenbaum et al., [24] in a randomized, double-blind, controlled trial compared the efficacy of 3-weekly injections between an intermediate- versus a low-MWHA in 426 patients with symptomatic knee OA. The decrease in WOMAC pain score at the 24-week (after the end of treatment) was significantly greater with the intermediate-MWHA preparation (mean: 22.9 mm, SD: 1.4) than the low one (mean: 18.4, SD: 1.5 mm). Moreover, the proportion of responders (OMERACT-OARSI criteria) with the intermediate-MWHA was also significantly higher (73% versus 58%). The percentage of patients reporting AEs was similar in both groups (35.2% versus 33.2%). Raman et al., [25] in a prospective, randomized, clinical trial compared the effectiveness of a high- versus low-MWHA in 392 patients with knee OA. Compared with baseline, scores in the WOMAC pain subscale at the 24-week post-injection visit were significantly lower with the high-MWHA (mean: 9.2 versus 5.1) than with the low one (mean: 8.8 versus 8.3). Nevertheless, the number of patients suffering from treatment-related AEs was higher with the high-MWHA (n=39) than the low one (n=30). In fact, one patient receiving the high- MWHA experienced a serious AE (pseudo-sepsis in the knee) and required hospitalization [25]. Our study also revealed the efficacy of the high-density viscoelastic gel of HA regarding pain on movement, joint stiffness, functional capacity, and quality of life, in agreement with previous studies [8–10, 12, 22]. Raynauld et al. [22], in a prospective, randomized, multicenter study compared the effectiveness of a high-MWHA product versus conventional care in 255 patients with knee OA. Changes at 12-month post-injections were significantly greater for the high-MWHA in WOMAC pain score (-38.4% versus -13.3% with conventional care), stiffness (-34.7% versus -10.4%), and physical function (-31.4% versus -14.5%). Nonetheless, the percentage of patients experiencing AEs was numerically greater with high-MWHA (96%) than conventional care (90%).
Overall, the efficacy of high-MWHA has been demonstrated to be superior to intermediate- and low-MWHA. Altman et al., [12] in a meta-analysis determined the efficacy of HA products according to their MW in 11 randomized clinical trials and 2,094 patients. Pooled efficacy results revealed a greater pain relief for high-MWHA (effect size: -0.52, 95%CI: -0.56 to -0.48) than intermediate- (effect size: -0.31, 95%CI: -0.42 to -0.20) and low-MWHA (effect size: -0.18, 95%CI: -0.19 to -0.17). By contrast, the percentage of AEs is also higher in products with high-MWHA [24, 25]. Reichenbach et al., [26] in a systematic review and meta-analysis, revealed a double risk for local AEs and post-injection flares with high-MW, cross-linked HA formulations than with intermediate- or low-MWHA preparations. In addition, pseudosceptic reactions (granulomatous inflammation of the synovium) have been reported in few cases, especially with cross-linked formulations of the highest-MWHA [9, 27]. In our study, only mild AEs were reported and were predominantly resolved within few days.
On the other hand, most HA preparations implicate between 3 and 5 injections, nevertheless, there are cross-linked formulations that require a single-shot, delivering the same HA dose as multi-injection preparations. Petterson et al., [28] in a multicenter, double-blind, randomized, placebo-controlled trial demonstrated the superior success rate (≥ 50% improvement and ≥ 20 mm absolute improvement, concerning baseline, in WOMAC pain subscale at the 26-week) with a 4-mL single HA injection than with saline. The clinically meaningful reduction of pain was evidenced within the 2-week post-injection. Although studies specifically designed are required, single-shots formulations of HA may also contribute to minimizing the risk for the development of AEs.
In our opinion, the notable results obtained in our study, especially the 48% reduction in WOMAC pain subscale, 66.0% of patients achieving more than 50% improvement in pain subscale, the early initiation of the clinical benefit (within 2 weeks), and its maintenance for a long-term period of time (24 weeks, at least), are greater than expected by an intermediate-MWHA preparation. These superior effects might be associated with the high concentration and amount of HA, and thus to the high-density of the viscoelastic gel. In HA-based aqueous solutions, higher concentrations of HA are correlated (linear relationship) with higher densities of the viscoelastic solution [29, 30]. Therefore, it could be hypothesized that high-density viscoelastic gels of HA provide higher efficacy (similar to high-MWHA) while avoiding the higher incidence of AEs. To our knowledge, to date, none of the studies have specifically evaluated the efficacy of HA products considering the density of the viscoelastic gel.
The main limitation of our study was the absence of a control or comparator group. Although the treatment of OA has an important placebo effect [31], and acknowledging that a control group would have strengthened the conclusions, results are in concordance with controlled studies, revealing a superior effect of HA injections. Another limitation was related to the limited sample size of the study (n=166), not fulfilling the estimated one in the protocol (n=300). Despite extending considerably the recruitment period, the availability of patients was insufficient. Yet, results found in our study are in concordance with other HA products [8–10, 12, 24, 25].