Introduction
Knee osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage degradation, joint pain, stiffness, and functional limitation. It is increasingly prevalent with the global aging demographic and is a leading cause of disability worldwide. Treatment strategies for knee OA aim to alleviate symptoms, improve joint function, and delay progression. Intra-articular hyaluronic acid (HA) injections are widely utilized to restore synovial fluid viscosity, improve lubrication, and modulate intra-articular inflammation. However, clinical efficacy remains debated due to heterogeneity in trial outcomes, with discrepancies potentially arising from factors such as HA molecular weight, OA severity, and patient-specific characteristics.
HA formulations vary by molecular weight: low (approximately 500–730 kDa), medium (800–2000 kDa), and high (>2000 kDa). Higher molecular weight HA is hypothesized to have prolonged joint residence time and potentially enhanced symptomatic benefit, yet may increase local adverse reactions. Clinical evidence on differential efficacy between these formulations remains inconclusive. Patient-reported outcome measures (PROMs), such as the visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lequesne index, are critical to capture the subjective experience of treatment impact but vary widely between studies.
Study Design
This systematic review adhered to the 2020 PRISMA guidelines, focusing exclusively on level I evidence from randomized controlled trials (RCTs) evaluating intra-articular HA injections for knee OA. English, German, Italian, French, and Spanish studies were included, with exclusion of those combining HA with other biologics or experimental interventions. Data were synthesized from 71 RCTs encompassing 10,590 patients (67% female), with a mean age of 61.8 ± 5.1 years and mean BMI of 27.8 ± 2.3 kg/m². OA severity was assessed via Kellgren–Lawrence (KL) grading.
Outcomes extracted included VAS at rest and during exercise, WOMAC total and subscales (pain, stiffness, function), and Lequesne index scores at multiple follow-up intervals from 2 weeks to 6 months. The independent effects of patient demographics (age, sex, BMI), OA severity, and HA molecular weight on PROMs were quantitatively evaluated using pairwise correlation analyses and linear regression.
Key Findings
Analysis revealed a biphasic symptomatic response to HA injections. During the initial 4 weeks, patients—especially those with advanced OA—experienced worsening PROMs across pain and function domains. However, patients with early-stage OA demonstrated significant symptomatic improvement beyond this early period.
More detailed findings include:
- Age and Sex: Older age strongly correlated with greater improvement in VAS and WOMAC scores from 5 weeks onward. Female sex was also associated with significantly better long-term outcomes, including lower WOMAC pain, stiffness, and function scores, sustained up to 6 months.
- OA Severity: Early KL grades I and II were positively associated with improved PROMs at later follow-ups, whereas KL grades III and IV patients showed worsening outcomes particularly within the first 4 weeks and during extended follow-up periods.
- HA Molecular Weight: Higher molecular weight HA demonstrated a negative association with WOMAC stiffness and VAS pain scores in early and mid-term follow-ups, suggesting improved symptom control, though evidence remained limited and heterogenous.
- BMI: No consistent significant correlations were observed between BMI and clinical outcomes.
Overall, these data suggest that intra-articular HA injections may confer substantial long-term benefit mainly for patients with less advanced knee OA and particularly older women.
Expert Commentary
The reviewed evidence supports a patient-tailored approach to HA therapy for knee OA, considering disease stage and demographic factors. Hormonal influences may partly explain the enhanced response seen in older female patients, aligning with known sex differences in OA pathophysiology. The initial symptom exacerbation post-injection in advanced OA likely reflects joint structural degeneration and ongoing inflammation, which may limit therapeutic effect.
The specific contribution of HA molecular weight to efficacy remains unclear, with conflicting data on whether high molecular weight compounds provide superior outcomes compared with lower molecular weight formulations. Furthermore, study methodological heterogeneity in injection protocols, dosage, follow-up durations, and outcome measures complicates definitive conclusions. Importantly, longer-term RCTs with standardized protocols and head-to-head comparisons are necessary to clarify these factors.
Integration of HA injections within multimodal management, including physical therapy and weight management, remains critical. Emerging biologic therapies such as platelet-rich plasma and mesenchymal stem cells may offer complementary disease-modifying effects, with future research warranted to delineate optimal treatment algorithms.
Conclusion
Intra-articular HA injections for knee osteoarthritis appear to induce an initial symptom worsening in the first month but subsequently provide meaningful symptomatic relief in patients with early-stage OA, particularly in older women. The impact of molecular weight on clinical outcomes is yet to be definitively established. Clinical application should emphasize patient-specific factors, recognizing the limited benefit in advanced OA stages.
Future research should prioritize standardized, long-term RCTs evaluating HA molecular weight, injection regimens, and direct comparisons with other conservative treatments. This will improve evidence-based personalization of HA therapy and clarify its role in comprehensive knee OA management.
Clinicians must counsel patients on potential early symptom worsening and set realistic expectations, focusing treatment on those with less advanced disease where the benefit-risk balance is most favorable.
