The last decade has shown a growing interest in the use of HA formulations as viscosupplementation for OA. HA occurs naturally in the synovial fluid of joints, ensuring their adequate lubrication. However, the different types of HA used in studies make it difficult to compare findings and indicate which formulation provides the most clinical benefit [7, 17, 18]. Hybrid HA has been demonstrated to be safe and effective in the treatment of knee OA owing to its increased viscoelasticity, anti-inflammatory properties, and longer half-life [19]. Low molecular weight HA has anti-inflammatory properties, while high molecular weight HA has viscosupplementary effects. The short and long chains are linked by hydrogen bonds, and the hybrid HA has been shown to be more resistant to enzymes, despite their lack of cross-linking agents [20, 21].

The results of this study are in alignment with other studies in the field [21]. A large randomized clinical trial of 692 patients demonstrated that a single injection of hybrid HA resulted in a marked decrease in the VAS pain score, which continued throughout a follow-up period of 24 weeks [22]. A review of viscosupplementation in knee OA found that the most robust response to hybrid HA injections takes place within 5–13 weeks after treatment, yet patients report a health-related QoL for up to 6 months [7].

The efficacy of HA injections in treating knee OA has been documented, primarily focusing on pain relief and functional improvement. As detailed by Lu et al. [23], HA injections not only enhance the lubricating properties of the synovial fluid but also promote the restoration of the damaged HA layer on articular cartilage surfaces, potentially alleviating arthritic symptoms. Gupta et al. highlighted significant improvements in pain and joint function among patients who received HA injections, particularly in cases where conservative treatments, such as acetaminophen, were ineffective [24]. Furthermore, a meta-analysis indicates that intra-articular HA injections lead to considerable reductions in pain scores and improvements in functional outcomes for patients with knee OA [25].

Hybrid HA formulations, which may include cross-linking agents or combined viscosupplementation techniques, have also exhibited promising results. Scaturro et al. demonstrated that a single injection of hybrid HA in overweight patients yielded significant improvements in knee pain and function, which were maintained for up to 25 weeks post-injection [26]. These findings align with those reported by Zhang et al., who noted the long-term benefits of HA injections despite variations in individual responses [27]. These results collectively support the notion that HA injections can serve as a pivotal intervention for managing knee OA when conventional therapies fail.

Safety remains a major consideration in the application of intra-articular injections. An important factor in the use of hybrid HA is its tolerability and favorable safety profile. Within the reviewed literature, HA injections have generally been reported to have a favorable safety profile. A consensus statement reiterated that the incidence of adverse effects is low, as HA is biocompatible [28]. As was the case in this study, there were no adverse events reported, with side effects limited to temporary pain and swelling at the injection site [7, 29]. HA may also be safer for patients with comorbidities, such as obesity and diabetes, as it does not have the same side effects as other medications used in viscosupplementation, such as corticosteroids [16]. However, some studies have reported rare complications, such as joint infections resulting from improper injection techniques [30]. Most adverse reactions were transient and minor, consisting of localized pain or swelling, underscoring the importance of utilizing ultrasound-guided injections for improved accuracy and reduced complications [31]. Studies suggest that using ultrasound guidance may enhance the therapeutic benefits while minimizing procedural risks [32].

The ultrasound-guided administration of hybrid HA may be viewed as a best practice technique, particularly in overweight patients [16, 24].

In our study only the lateral access to the knee joint was utilized with good outcome. The recent study by Farì et al. [33] compared medial and lateral HA injection approaches and no statistically significant difference was found between medial and lateral injections in terms of efficacy in pain relief and functional improvement. As safety profiles were similar for both techniques they conclude that the choice between medial or lateral injection may depend on clinician preference or patient anatomy, as neither demonstrated superiority.

Furthermore, the evaluation of different hybrid HA formulations is crucial. Hylan G-F 20, a cross-linked HA, has been shown to effectively manage OA symptoms in patients who had not responded adequately to other therapies [34]. Such preparations can enhance the duration of relief compared to standard HA. While hybrid formulations have exhibited prolonged effects, there remains some debate on their efficacy relative to other treatments [25].

Moreover, hybrid HA injections have been compared against alternative treatments. Studies show that, while HA is beneficial, emerging therapies like platelet-rich plasma (PRP) also demonstrate substantial efficacy in knee OA management, prompting a comparison of joint-specific injections [35]. Notably, Raeissadat et al. conducted a study that emphasized the cost-utility of various intra-articular options, confirming that HA remains a valuable option amidst evolving treatment paradigms [36].

Although this was a small study, our findings indicate that some patient subpopulations experienced increased clinical benefit compared to others: patients with medial and lateral types of OA had greater improvement than those with patellofemoral OA, assessed using WOMAC scores. Patients with osteophytes (bone spurs) also showed less improvement compared to patients without osteophytes. In a recent review, Chevalier and Sheehan concluded that viscosupplementation with intra-articular HA injections may benefit certain subpopulations more than others, e.g., younger patients with less severe disease and normal BMI [37]. This real-world study demonstrated the overall improvement of OA symptoms for all types of patients, yet incorporating various subpopulations in the design of future studies may provide additional information on the efficacy of hybrid HA viscosupplementation.

Recapitulating these findings, we observed a narrative supporting the efficacy and relative safety of hybrid HA injections in knee OA treatment. Multiple clinical trials consistently underscore the ability of HA to improve joint function and reduce pain, thereby enhancing life quality for individuals suffering from this degenerative condition. HA shows promising senomorphic potential in preclinical studies, but further clinical research is needed to confirm its mechanisms in humans [38].

If proven, HA could become a dual-purpose therapy—not just for symptom relief but also for modifying OA disease progression. As the medical community continues to explore and refine treatment approaches, hybrid HA will likely remain a cornerstone treatment modality for knee OA, particularly as our understanding of its bioactivity and structural properties evolves.

This study was observational, open-label, and uncontrolled, and therefore had inherent limitations in terms of susceptibility to bias, confounding and restricting the ability to define causality. However, this study was designed to evaluate the daily clinical practice regarding heterogeneous patient populations and the medical interventions they received. Data generated in a real-life setting is essential to assess and improve clinical practice worldwide and to complement controlled trials.