Advances in hyaluronic acid therapy for knee osteoarthritis: monotherapy and combination strategies: an evidenced based review

INTRODUCTION

Knee osteoarthritis (KOA) is a progressive and common joint disease, affecting nearly 25% of individuals over 50, and is a leading cause of disability worldwide.^1–5 In addition to articular cartilage degeneration, KOA also affects periarticular soft tissues. Progressive erosion of the capsular-ligamentous compartment may predispose patients to myotendinous lesions, worsening disability and functional decline. These musculoskeletal complications demonstrate the broader systemic impact of KOA beyond the joint itself.⁶ As life expectancy and obesity rates continue to rise, the incidence of KOA is expected to increase further, emphasizing the urgent need for effective, scalable, and personalized non-surgical treatments.^1,5,7

Intra-articular hyaluronic acid (HA) is a well-established non-operative therapy for KOA, particularly in the early to moderate stages. HA exerts mechanical effects by restoring the viscosity of synovial fluid and biological effects through anti-inflammatory and chondroprotective pathways. Clinical studies have demonstrated that HA injections may improve pain and function in selected patients. For instance, a comprehensive network metaanalysis conducted by Han et al⁸ included 43 RCTs and 5,554 patients. The study revealed that HA significantly reduced pain compared to a placebo (SMD 0.94, 95% CI 0.09–1.78) and was associated with a low rate of adverse events. These results highlight the favorable balance of clinical benefits and tolerability in KOA management.⁸ Moreover, Bahrami et al⁹ found that a single injection of cross-linked high-molecular-weight (HMW) HA was as effective as three weekly injections of linear low-molecular-weight (LMW) HA in improving pain and function at 2 and 6 months, with the exception of better stiffness outcomes in the LMW group at 2 months. Nevertheless, real-world effectiveness remains variable, and clinical practice guidelines differ in their recommendations.^1,10

Despite its widespread use, HA monotherapy may only provide short-term benefits, especially in patients with advanced KOA or active synovitis. Comparative studies indicate that symptom relief may decrease after 3 to 6 months, and treatment response is affected by HA molecular weight, cross-linking, and the patient’s specific inflammatory burden.^9,11–18 These limitations have generated interest in improving HA efficacy through combination therapies.

Combination strategies that include HA and other intra-articular agents, such as plateletrich plasma (PRP), corticosteroids (CS), or polydeoxyribonucleotide (PDRN), have demonstrated promising synergistic effects. For instance, Yu et al¹⁹ reported that patients who received a combination of HA and PRP experienced significantly greater improvements in

WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain scores, with a mean reduction of 5.58 points, as well as functional scores compared to those treated with HA or PRP alone. The rationale for combination therapy is based on its ability to modulate both humoral and cellular immune responses, promote angiogenesis, and inhibit inflammatory cytokines, which may prolong symptom relief and delay structural progression of KOA.¹⁹

However, the existing literature lacks a comprehensive synthesis that compares HA monotherapy to combination regimens across various levels of KOA severity. Most available trials and reviews focus on single interventions or fail to provide direct comparisons between strategies, leading to fragmented guidance for clinical decision-making.^1,10 Variations in trial design, HA formulations, and outcome measures complicate interpretation. This narrative review aims to synthesize evidence on the clinical efficacy of intra-articular HA, whether used alone or in combination, for KOA management. We analyze RCTs and meta-analyses published from 2010 to 2025, highlighting mechanisms of action, comparing HA formulations, evaluating combination strategies, and discussing implications for personalized treatment in clinical practice.

METHODS

A comprehensive literature search was conducted across major electronic databases - PubMed, Embase, Web of Science, and the Cochrane Library - covering the period from January 2010 to April 2025. The search strategy combined Medical Subject Headings (MeSH), Emtree terms, and relevant keywords, including “hyaluronic acid,” “hyaluronan,” “knee osteoarthritis,” “platelet-rich plasma,” “intra-articular injection,” “viscosupplementation,” and “corticosteroids.” Boolean operators (AND, OR) were applied to optimize search sensitivity and specificity. Reference lists of included studies were also manually screened for additional eligible articles.

Studies were included if they met the following criteria: (1) original clinical research conducted in humans, including RCTs and meta-analyses; (2) evaluation of intra-articular HA, either as monotherapy or in combination with PRP or CS; and (3) outcomes addressing pain relief, functional improvement (e.g., WOMAC, VAS, IKDC), or treatment safety. Exclusion criteria were (1) animal or in vitro studies without direct clinical relevance, (2) publications not in English, or (3) studies focused on non-knee joints or non-KOA conditions.

Following initial screening and eligibility assessment, a total of 70 studies were included in this review. These comprised 50 RCTs and 20 meta-analyses. PRISMA flow diagram of study selection process is presented in Figure 1. Although this review utilizes a narrative synthesis approach rather than a formal systematic review, the inclusion process is summarized in a diagram for transparency. The methodological framework adheres to the SANRA (Scale for the Assessment of Narrative Review Articles) guideline, emphasizing defined inclusion criteria, a comprehensive search strategy, and structured thematic synthesis.

Figure 1.PRISMA flow diagram of study selection process

A total of 901 records were retrieved from four electronic databases (PubMed, Embase, Web of Science, and Cochrane Library). After removing 463 duplicates and 9 entries marked as ineligible by automation tools, 429 records were screened. Out of these, 314 were excluded based on abstract review. The full texts of 115 articles were assessed, and 45 were excluded for not meeting the inclusion criteria. Ultimately, 70 studies were included in the final synthesis, consisting of 50 randomized controlled trials (RCTs) and 20 meta-analyses.

Mechanism of action of Hyaluronic Acid

HA improves joint biomechanics by restoring the viscoelasticity of synovial fluid. In patients with KOA, the breakdown of endogenous HA leads to reduced lubrication and shock absorption within the joint, exacerbating cartilage wear. Exogenous HA injection compensates for this deficiency by increasing synovial fluid viscosity, reducing mechanical friction, and enhancing shock-buffering capacity during weight-bearing activity.^17,20,21

HA exerts biological effects through anti-inflammatory and cartilage-protective pathways. It binds to CD44 receptors on chondrocytes and synoviocytes, resulting in the downregulation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and suppression of matrix metalloproteinases (MMP-1, 3, 9, and 13), enzymes involved in extracellular matrix degradation. Additionally, HA promotes the synthesis of proteoglycans and type II collagen, supporting the structural maintenance of articular cartilage.^17,21

Immunologically, HA modulates synovial inflammation by altering cellular infiltration and cytokine activity. Histological evidence shows that HA reduces mononuclear cell infiltration and synoviocyte hyperplasia in KOA joints, reflecting its immunomodulatory effects on local inflammation.²⁰ Furthermore, intra-articular HA has been shown to decrease synovial concentrations of MMP-9, an enzyme associated with inflammation-induced cartilage breakdown and angiogenesis.¹⁷

The therapeutic efficacy of HA is influenced by its molecular weight. HMW HA demonstrates superior rheological properties, longer intra-articular residence time, and stronger interaction with CD44 receptors compared to LMW formulations. This translates to more sustained anti-inflammatory and chondroprotective effects.^21,22

Additionally, formulation characteristics such as origin, cross-linking, and injection protocol play a critical role in clinical outcomes. Products vary in their molecular structure, source (avian-derived vs. bacterial fermentation), and dosing regimens. Cross-linked HA has formulation differences that have been linked to variations in therapeutic durability and patient tolerance.^9,20,23,24

Taken together, these mechanisms highlight the multifaceted role of HA in KOA treatment and underscore the importance of selecting appropriate formulations tailored to the disease stage and patient profile.

Clinical Efficacy of HA in KOA

Short-term efficacy within a 3-month period

The short-term efficacy of intra-articular HA in KOA remains limited and inconsistent.^25–28

Several high-quality meta-analyses have shown minimal or no clinical benefit during the first 1-3 months post-injection. Jevsevar et al¹⁰ analyzing 79 RCTs and including 56 in their network meta-analysis, reported no significant improvement in pain or function versus placebo at 6 weeks, with an effect size (-0.05) below the minimal clinically important difference (MCID). Colen et al²⁹ found that HA offered only marginal benefit over placebo (VAS difference -10.2 mm), while Wang et al³⁰ found comparable efficacy between HA and CS at 1 month, but demonstrated superior pain relief with HA at 3 and 6 months. Supporting these findings, RCTs by Askari et al³¹ and Tammachote et al³² showed that CS provided faster pain relief than HA within 3 months. Similarly, according to Khan et al,³³ CS provided rapid pain relief within the first 2 weeks but its effectiveness diminished after 6 weeks. In contrast, HA acted more slowly but offered sustained improvement from week 6 to the third month in the treatment of KOA.³³ While Kesiktas et al¹⁶ observed significant short term pain reduction with HA within the first month, its effects particularly for resting pain were not sustained at 3 months. However, in a randomized controlled trial by Küçükakkaş et al,³⁴ after one month of treatment, both patient groups receiving PRP and HA injections showed significant improvement in clinical symptoms. Specifically, VAS scores at rest and during movement decreased markedly compared to baseline, and WOMAC scores were also significantly reduced in both groups. Structurally, only the HA group demonstrated a statistically significant increase in lateral femoral cartilage thickness. In contrast, the PRP group did not exhibit any significant changes in cartilage thickness at this time point. These findings suggest that while both treatments are effective in improving early clinical symptoms, HA may have a superior impact on cartilage structure during the initial post-injection phase.³⁴ Overview of RCTs using intra-articular HA monotherapy for KOA is shown in Table 1.

These outcomes may be explained by HA’s delayed biological activity, requiring time to modulate inflammation and restore viscoelasticity. In contrast, CS act rapidly. Therefore, HA may not be ideal for immediate symptom relief and should be considered for longer-term therapeutic goals.

Mid-term efficacy of HA within a 3- to 6-month period

HA demonstrates greater clinically meaningful benefits during this mid-term period, particularly between 3 and 6 months after injection.^{25,29,35,36,41,45,47,49,50}

Several meta-analyses and RCTs report pain and functional improvements exceeding MCID thresholds, suggesting that this timeframe is optimal for HA to exert therapeutic effects. A systematic review by Altman et al⁵⁰ found that HMW HA provided significant pain and function improvements at 3–6 months, often surpassing the MCID. Similarly, Migliorini et al²² showed that HMW and ultra-high-molecular-weight (uhMW) formulations achieved the greatest pain reduction on the VAS scale at 4–6 months, outperforming lower-weight products. Colen et al²⁹ reported that the benefits of HA became apparent only after several weeks, suggesting a delayed-onset response rather than immediate relief.

Several RCTs support these findings. Arliani et al¹³ found that both HA and PRP led to temporary pain relief and improved function for up to 6 months, with no significant difference between the two groups. Ahmad et al¹¹ observed that intra-articular HA resulted in significant pain and function improvements after 6 months, indicating sustained effectiveness in the midterm. Leighton et al³⁵ showed that cross-linked HMW HA injection provided lasting clinical benefits for KOA from week 12 to 26. Although both HA and CS showed similar pain relief at week 12, HA maintained or enhanced its effects over time, while CS efficacy declined. By week 26, HA demonstrated significantly better outcomes in pain reduction, joint function, and stiffness, with a favorable safety profile and no serious adverse events.³⁵

These outcomes align with HA’s delayed-onset biological actions, including CD44 receptor interaction, modulation of inflammatory cytokines, and restoration of synovial fluid rheology. Together, they suggest that HA achieves optimal therapeutic efficacy in the mid-term phase, especially in patients with mild-to-moderate KOA. This evidence supports the clinical preference for HA in patients seeking symptomatic relief beyond the acute phase, warranting further evaluation of its long-term utility.

Long-term efficacy of HA beyond a 6-month period

Long-term data suggest that HA can provide sustained symptom relief beyond 6 months, although the magnitude of benefit remains modest. This sustained effect appears to be more prominent with high-quality formulations or repeated injection protocols. While early improvements may be limited, some studies report gradual, cumulative benefits over time.^{24,37–40,43,44,46}

Supporting this, several RCTs provide corroborating evidence. In a 52-week RCT, Buendía-López et al⁴⁶ found that a single injection of HMW HA resulted in limited short- to medium-term improvements in WOMAC and VAS scores, but no sustained benefit at 12 months.

By contrast, the AMELIA trial, a 40-month randomized, placebo-controlled study, demonstrated that repeated intra-articular HA injections significantly improved KOA symptoms compared to placebo (80.5% vs. 65.8% responders, p = 0.004). Clinical benefits increased over successive cycles and persisted up to one year after the final injection, indicating a sustained carry-over effect. HA was well tolerated, with a safety profile comparable to placebo, supporting its role in long-term symptomatic management of KOA.²⁴

Similarly, in a five-year double-blind RCT, Di Martino et al⁴⁴ evaluated the long-term clinical outcomes of intra-articular HA injections in patients with KOA. HA treatment led to significant improvements in knee function and symptoms up to 24 months post-injection, with the International Knee Documentation Committee (IKDC) score rising from 50.3 ± 13.2 at baseline to 62.1 ± 20.8. However, at final follow-up (mean 64.3 months), the clinical benefit had diminished, with IKDC scores returning close to baseline (55.7 ± 18.8, not significant). The median duration of patient-reported symptom relief was approximately 9 months.⁴⁴

Overall, these findings indicate that the long-term efficacy of HA may depend on the injection regimen and patient selection. The delayed but progressive biological mechanisms— such as synovial restoration, anti-inflammatory signaling, and cartilage protection—likely contribute to sustained effects. Accordingly, repeated administration or synergistic combinations may optimize long-term outcomes. Significantly, HA continues to demonstrate durable clinical utility beyond the short and mid-term, especially when tailored to formulation and patient phenotype.

Comparative Efficacy of High- versus Low-Molecular-Weight HA

The clinical efficacy of intra-articular HA has been shown to vary across different formulations, with molecular weight emerging as a crucial factor that influences treatment outcomes. This section aims to summarize the current evidence comparing HMW and uhMW HA with LMW formulations, focusing on symptom relief, longevity, and direct comparisons from clinical trials.

HMW and uhMW HA have been found to offer better pain relief and functional improvement compared to LMW formulations. Several systematic reviews and meta-analyses have shown that not all HA products yield equivalent clinical benefit, with molecular weight being a key distinguishing factor. In a comprehensive network meta-analysis of 137 RCTs, Bannuru et al⁵¹ identified HMW HA as one of the most effective non-surgical treatments for KOA, ranking it higher than LMW HA and various oral interventions. Similarly, in a systematic review of 68 studies, Altman et al⁵⁰ reported that HMW HA led to greater improvements in pain, often exceeding the MCID. These results collectively confirm that molecular size is a clinical factor in determining the efficacy of HA treatment.

HMW and uhMW HA are also associated with longer-lasting symptom relief and a reduced need for repeat injections. The durability of treatment effect is particularly important in chronic conditions such as KOA, where frequent interventions may pose practical and economic challenges. In a network meta-analysis of 64 RCTs, Phillips et al⁵² showed that HMW HA was the only intra-articular treatment to consistently exceed the MCID for both pain and function at 3 months, whereas LMW HA did not. These findings suggest that HMW HA may provide more durable symptomatic relief, which could potentially translate into reduced reinjection requirements. These sustained benefits are believed to be due to superior viscoelastic properties, longer intra-articular residence time, and enhanced interaction with CD44 receptors on chondrocytes and synoviocytes. These biological mechanisms result in improved joint biomechanics and delayed symptom recurrence, supporting the preferential use of HMW formulations in long-term management. Supporting this, a 40-month RCT by Navarro-Sarabia et al²⁴ demonstrated that repeated cycles of HA (900 kDa) led to cumulative improvements in pain and function, with responder rates exceeding 80% by the fourth cycle, reinforcing the importance of durability in HA therapy.

Direct head-to-head RCTs provide additional support for the clinical superiority of uhHMW over LMW HA. In a study by Huang et al,⁵³ a head-to-head RCT compared PRP combined with either LMW or uhMW HA. The results showed that the uhMW HA group had better outcomes in terms of pain and WOMAC scores especially in patients with more severe symptoms, underscoring the enhanced efficacy of higher molecular weight formulations.

Overall, these recent findings from head-to-head RCTs further validate the clinical rationale for prioritizing HMW or uhMW HA in the management of mild-to-moderate KOA.

Combination Therapy

HA and PRP

The combination of HA and PRP offers superior pain relief and functional improvement compared to monotherapies. Several RCTs have demonstrated that HA and PRP yield greater clinical benefits than either agent alone. The HA and PRP combination therapy for KOA is presented in Table 2.

In a double-blind RCT, Lanna et al⁵⁴ reported that patients receiving HA and PRP showed significantly greater reductions in VAS at all time points up to 12 months compared to those receiving HA alone (with p-values ranging from 0.011 to <0.0001). Additionally, HA and PRP outperformed PRP alone in WOMAC physical activity scores at early time points (1-3 months). Ciapini et al⁵⁶ also found that HA and PRP achieved superior improvements in both VAS and WOMAC scores at 6 months compared to HA or PRP monotherapy, with statistically significant pain reduction (p < 0.005). In a large-scale trial involving 360 patients, Yu et al¹⁹ observed that the HA and PRP group had the greatest reduction in total WOMAC score over 52 weeks (mean reduction: 23.7 points), significantly outperforming HA alone (10.9) and PRP alone (15.8) (p < 0.0001). These findings are further supported by a meta-analysis conducted by Du et al,⁶² which confirmed the clinical superiority of the PRP and HA combination over PRP monotherapy across multiple outcome measures, including pain and function scores.

HA and PRP show potential benefits for structural improvements and diseasemodifying effects. In addition to providing relief from symptoms, recent evidence suggests that HA and PRP may have a positive impact on structural outcomes in KOA. A study by Zhang et al⁵⁸ utilized MRI-based WORMS scoring and found that at 12 months, HA and PRP significantly reduced bone marrow edema, a benefit not observed in the HA only group. While overall symptom scores were similar between the two groups, the structural changes seen may indicate a disease-modifying effect. Wu et al²¹ also emphasized the synergistic biological mechanisms of HA and PRP: HA improves the rheological environment, while PRP promotes chondrogenesis. Together, they work to reduce inflammation through CD44 and TGF-βII signaling pathways, ultimately contributing to the protection and regeneration of cartilage.

HA and PRP may prolong therapeutic effects and decrease the frequency of reinjections. Some studies suggest that this combination therapy provides longer-lasting benefits.^54,55,58 In a 12-month study, Lanna et al⁵⁴ reported sustained improvements in VAS and WOMAC scores for the HA and PRP group compared to the HA-only group, demonstrating better durability throughout the study period. Zhang et al⁵⁸ further noted that while HA provided better shortterm relief, the HA and PRP group exhibited progressive structural and symptomatic improvements over time, indicating additive benefits with repeated cycles. According to a meta-analysis by Zhang et al⁶³ which included 9 RCTs the combination of PRP and HA in the treatment of KOA resulted in slight improvements in pain and joint function compared to PRP alone. However, these improvements did not reach the threshold for clinical significance. Notably, the combination therapy significantly reduced the incidence of adverse events, and may be a preferred option for patients prioritizing minimizing side effects, despite its modest symptomatic benefits. Although long-term data are still limited, the combination appears promising for reducing the need for frequent intra-articular injections. However, findings are not entirely consistent. In a double-blind RCT, Fossati et al⁵⁷ found no significant differences in WOMAC, VAS, KOOS, or IKDC scores at 6 or 12 months among patients treated with HA and PRP, HA alone, or PRP alone. Subgroup analyses based on age, BMI, or KOA grade did not show superior outcomes for the combination therapy. These results suggest that the potential benefits of HA and PRP may depend on patient selection, protocol standardization, and the specific formulation used.

HA and CS

The combination of HA and CS provides synergistic effects, offering both rapid symptom relief and longer-term functional improvement. CS exhibit fast-acting anti-inflammatory effects, typically within days, while HA takes longer time to demonstrate its viscoelastic and chondroprotective benefits.⁶⁴ The complementary pharmacodynamics of these agents make their combination clinically appealing for KOA. The combination therapy of HA and CS for KOA is presented in Table 2.

In a double-blind RCT, Wang et al⁶¹ found that HA and CS resulted in greater pain reduction at 1 and 3 months compared to HA monotherapy. By 6 months, the effect of CS diminished, while HA maintained its efficacy, making the combination comparable to HA alone. Similarly, Campos et al⁶⁰ reported that the combination of CS and HA led to greater improvements in

Lysholm and Knee Society Score (KSS) scores at one month in patients with Kellgren– Lawrence grade IV KOA, reflecting the rapid-onset effect of CS. However, these benefits diminished over time, and by 6 months, no significant differences were found between treatment groups.

Co-formulated intra-articular injections that combine HA and CS may enhance early symptom relief and improve treatment adherence through single-dose administration. Fixeddose formulations that deliver both agents simultaneously provide logistical advantages and may optimize short-term efficacy, particularly for patients seeking rapid pain control. In a RCT, Petrella et al⁵⁹ assessed a novel injectable formulation containing cross-linked HA and triamcinolone acetonide. This injectable combination led to significantly greater VAS pain reduction at 2 weeks (-35.6 mm vs. -23.3 mm, p = 0.04), with benefits sustained through 26 weeks, compared to HA alone and a standard HMW HA comparator. These findings support the therapeutic rationale for combining anti-inflammatory and viscoelastic components into a single preparation to achieve early efficacy without compromising durability.

Multifunctional HA combinations: beyond viscosupplementation

Combining HA with biologically active agents enhances symptomatic relief and functional outcomes in KOA more effectively than HA alone. While HA provides viscoelastic support and modest anti-inflammatory effects, pairing it with agents like fibrinogen, peptides, PDRN, and neuromodulators may amplify therapeutic efficacy through complementary mechanisms. These strategies aim not only to improve lubrication but also to modulate the joint microenvironment, reduce oxidative stress, and stimulate tissue regeneration.

For instance, in a randomized trial, Kandel et al⁶⁵ showed that HA conjugated with fibrinogen significantly improved pain (measured by VAS), function (WOMAC), and IKDC scores at 6 months compared to baseline, likely due to better retention and enhanced extracellular matrix stability. Similarly, Kesiktas et al¹⁶ found that a peptide-enriched HA formulation containing oligopeptides resulted in greater reductions in WOMAC pain scores than both PRP and HA monotherapy at 3 months (p < 0.05), indicating that peptide-mediated modulation of inflammatory cytokines may boost HA efficacy. Furthermore, Yoon et al⁶⁶ reported that HA combined with PDRN outperformed HA alone in all categories of the KSS at 6 months, demonstrating potential regenerative synergy without compromising safety.

These findings collectively support the development of next-generation HA formulations that integrate mechanical support with molecular or cellular-level interventions, especially for patients with moderate KOA who are seeking both pain relief and functional recovery. The details are presented in Table 3, which covers emerging intra-articular combinations in KOA treatment, and Table 4, which provides an overview of meta-analyses on HA monotherapy and combination strategies in managing KOA.

Review and Insights

Intra-articular HA remains a crucial option for managing symptoms of KOA, especially for patients with mild to moderate disease who do not respond to oral medications or are unwilling to undergo surgery. This review of current literature provides valuable insights into the effectiveness of HA, both as a standalone treatment and when used in combination with other intra-articular agents.

Meta-analyses and high-quality RCTs consistently demonstrate that HA monotherapy results in statistically significant, albeit modest, improvements in pain and function compared to placebo or CS.^{15,17,29,31,33,42,48,71} These benefits are particularly notable when using high or ultrahigh molecular weight formulations, which may offer improved viscoelasticity, longer synovial residence time, and a higher likelihood of achieving MCID thresholds.^22,50–52 However, the variability in patient response underscores the importance of careful patient selection. Evidence suggests that HA is most effective in early-stage KOA (Kellgren–Lawrence I-II), with reduced efficacy in more advanced stages. Molecular weight is also an important factor in patient selection. HMW HA has demonstrated more consistent and clinically meaningful improvements in pain and function, making it suitable for patients with moderate-to-severe symptoms or those who require longer-lasting relief before considering surgery. In contrast, LMW HA may be more appropriate for individuals with earlier-stage disease or for those who place greater emphasis on cost, although the clinical benefits are generally less pronounced and repeat treatment may be required sooner.⁵²

Additionally, differences in HA formulations appear to impact treatment outcomes. While early studies did not consistently demonstrate the superiority of one formulation over another,²⁹ more recent meta-analyses suggest that factors such as molecular weight, crosslinking, and injection protocols (single vs. multi-dose) can significantly influence clinical results.^22,24,50,74 These findings support a more tailored approach to HA product selection in clinical practice.

Combination therapies are increasingly recognized for their potential to improve outcomes by targeting different pathological pathways. Among these, the combination of HA and PRP is the most well-supported, with numerous RCTs and meta-analyses indicating superior pain relief and functional outcomes compared to monotherapy.^{53,55,58,62,63,75,77,78} HA combined with CS also shows short-term benefits, particularly for managing symptomatic flares, although these effects tend to diminish after 12 weeks.^{30,59–61,72} Additionally, newer combinations such as HA with fibrinogen, HA with botulinum toxin type A, and HA analogues such as polynucleotides (PN) and PDRN have demonstrated promising preliminary results. However, many of these strategies remain investigational, with limited long-term data and significant variability in study design, agent composition, and injection protocols.

It is essential to recognize the limitations within the current evidence base. Many trials are hindered by small sample sizes, short follow-up periods, and a lack of direct comparisons. Furthermore, there has been limited investigation into long-term structural changes, imaging outcomes, and cost-effectiveness - all critical factors in chronic disease management. Future studies should focus on standardized outcome reporting, longer follow-up durations, and stratification by disease severity to enhance personalized treatment algorithms.

Overall, HA is a clinically relevant and well-tolerated option for patients with KOA, especially within a framework of individualized, multimodal management. Ongoing research into formulation optimization and synergistic combinations is likely to enhance its therapeutic utility. Until more robust data are available, clinical decisions should consider patient phenotype, disease stage, and therapeutic goals when selecting HA-based interventions.

The findings of this review have significant implications for clinical decision-making and individualized treatment planning in KOA. As the disease burden increases among aging populations, particularly in areas with limited access to surgical options, intra-articular therapies like HA are becoming essential in bridging the gap between conservative and surgical care.⁸

First, the clinical effectiveness of HA as a standalone treatment is well established, particularly in patients with early to moderate-stage KOA who prefer non-systemic interventions with a favorable safety profile.^73,78 It is crucial for clinicians to understand that not all HA products are the same; factors such as molecular weight, crosslinking, and injection frequency can affect both efficacy and duration of benefit.⁵⁰ Customizing product selection based on patient characteristics, such as age, activity level, comorbidities, and radiographic severity, can improve therapeutic outcomes and enhance patient satisfaction.

Secondly, there is increasing evidence supporting the effectiveness of combination therapies, especially when HA is combined with PRP or CS. For instance, combining HA with PRP may be advantageous for younger, active patients with early cartilage degeneration who are seeking regenerative stimulation.^19,58,78 On the other hand, pairing HA with CS could offer rapid symptom relief for patients experiencing acute inflammatory flares or those who cannot use biologics.⁷⁶ These approaches enable clinicians to tailor intra-articular treatment plans based on individual clinical presentations and therapeutic objectives.

Emerging combinations of HA including those with fibrinogen, botulinum toxin type A, human plasma protein solutions, PDRN, and peripheral blood stem cells are still under investigation and have not yet been established for routine clinical practice. Preliminary evidence, such as observational data from non-randomized cohorts like the study by Conrozier et al,⁷⁹ which assessed cross-linked HA with mannitol, suggests these combinations may be promising for selected patients with persistent symptoms or those seeking biologically based interventions with limited systemic exposure. In RCTs, several combinations have demonstrated encouraging results. For instance, Kandel et al⁶⁵ reported that HA combined with fibrinogen improved VAS pain scores compared to placebo at 3 months, potentially due to enhanced intra-articular retention and matrix stabilization. Similarly, Seihee Yoon et al⁶⁶ showed that HA plus PDRN yielded superior improvements in WOMAC and KSS scores over

HA alone, supporting the anti-inflammatory and chondroprotective properties of PDRN. Hegde et al⁷⁰ compared HA combined with either PRP or botulinum toxin A and found that both combinations improved outcomes, though PRP appeared more effective overall; this supports the hypothesis that these agents may reduce nociceptive signaling and promote cartilage repair. Turajane et al⁶⁸ observed significantly better WOMAC outcomes and higher avoidance of total knee arthroplasty in patients receiving HA with PBSCs (with or without growth factors), suggesting regenerative potential. Meanwhile, Bettonville et al⁶⁹ explored a formulation of HA with plasma protein and clonidine, which did not outperform HA alone in the primary endpoint but showed clinical benefit in pooled analyses. Other pharmacological agents such as periarticular corticosteroid-lidocaine and peptide-enriched HA have also been investigated, with transient but meaningful pain relief observed.^16,67 As higher-quality randomized trials and long-term safety data become available, these innovative approaches could broaden the therapeutic options for KOA.

Moreover, the excellent tolerability and low systemic risk associated with HA-based interventions make them particularly attractive in populations where the use of NSAIDs or opioids is limited due to polypharmacy, cardiovascular risk, or gastrointestinal intolerance.⁵⁰ These qualities also enhance the role of HA in shared decision-making, as patients increasingly prefer non-pharmacologic, locally administered, and disease-modifying options.

In summary, HA-based therapies, whether used alone or in combination, provide a flexible, personalized, and evidence-supported approach to improving pain, function, and quality of life for individuals with KOA. Their significance is especially notable in multidisciplinary care models that emphasize symptom control, mobility preservation, and patient engagement in long-term management.

CONCLUSIONS

HA continues to play a crucial role in the non-surgical treatment of KOA. It offers a safe and locally acting option that can be used at various stages of the disease. Clinical studies have demonstrated that HA monotherapy is particularly effective in the early to moderate stages of KOA. Higher efficacy has been observed with HMW formulations and multi-injection protocols. There is a growing trend of combining HA with other intra-articular agents. Among these combinations, intra-articular HA and PRP have shown the most consistent synergistic effects on pain and function. Additionally, combining HA with CS provides short-term symptom relief, especially during acute flares. New combinations with fibrinogen, polynucleotides, and botulinum toxin A show promise, but differences in trial design, patient selection, and product characteristics hinder direct comparisons. Future randomized trials with standardized methods and long-term outcomes are necessary. Personalizing HA-based 501 strategies based on disease stage, comorbidities, and patient expectations will be crucial for 502 optimizing care.

LIST OF ABBREVIATIONS

CS: Corticosteroid

HA: Hyaluronic acid

HMW: High-molecular-weight

IL-1β: Interleukin-1 beta

IKDC: International Knee Documentation Committee

KOA: Knee osteoarthritis

KSS: Knee Society Score

LMW: Low-molecular-weight

MCID: Minimal clinically important difference

MMP: Matrix metalloproteinase

PBSC: Peripheral blood stem cell

PDRN: Polydeoxyribonucleotide

PRP: Platelet-rich plasma

RCT: Randomized controlled trial

SANRA: Scale for the Assessment of Narrative Review Articles

uhMW: Ultra-high-molecular-weight

VAS: Visual analog scale

WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable.

Data availability

All data generated during this study are included in this published article and its supplementary information files.

Competing interests

The authors declare no competing interests.

Funding

The authors received no specific funding for this work.

Authors’ contributions

KXC conducted the literature review, drafted the manuscript, and coordinated data organization.

HNAT provided supervision and contributed to the interpretation of findings.

MHT critically revised the manuscript, provided major intellectual input and gave final approval.

All authors read and approved the final manuscript

Acknowledgements

None

Artificial intelligence use

We hereby disclose that we used AI for proofreading and grammar checking to assist with text revisions. We clarify that we did not use AI for generating content.

Authors’ Information

KXC is a researcher and lecturer at the Department of Pharmacy, Faculty of Health Sciences, Industrial University of Ho Chi Minh City, Vietnam. Her research interests include musculoskeletal pharmacotherapy and regenerative medicine applications.

HNAT is an orthopedic surgeon at Xuong Khop Viet Clinic, Ho Chi Minh City, Vietnam. He currently serves as President of the ASEAN Society for Sports Medicine and Arthroscopy (ASSA) and the Asian Arthroscopy Association (AAA). His clinical and research focus is on knee osteoarthritis, cartilage repair, and arthroscopic surgery.

MHT is an Associate Professor and Head of the Department of Pharmacology, School of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam. His main area of expertise includes experimental pharmacology and pharmacological therapy.