Knee osteoarthritis (OA) is a prevalent and progressive musculoskeletal disorder that affects millions of individuals worldwide, particularly older adults. It is characterized by the gradual degeneration of articular cartilage, subchondral bone remodeling, osteophyte formation, and varying degrees of synovial inflammation. These pathophysiological changes culminate in joint pain, swelling, stiffness, reduced range of motion, and a decline in physical function and quality of life.

According to the Global Burden of Disease Study, OA is among the leading causes of disability globally and poses a significant socioeconomic burden due to increased healthcare utilization and productivity loss. The management of knee OA is multifaceted, encompassing lifestyle modification, pharmacologic interventions, physical therapy, and in advanced cases, surgical intervention. Among non-surgical options, intra-articular (IA) injections have gained popularity as a minimally invasive strategy to manage symptoms and improve joint function.

Two commonly administered IA agents are corticosteroids (CS) and Hyaluronic Acid (HA). CS injections are recognized for their potent anti-inflammatory properties, providing rapid symptom relief, especially during acute flare-ups of pain and swelling. However, repeated administration has raised concerns regarding potential cartilage degeneration and diminishing therapeutic effects over time. In contrast, HA serves as a viscoelastic supplement that mimics the natural hyaluronan found in   synovial   fluid.   It   is   believed   to   restore   joint lubrication, reduce friction, and potentially delay structural progression, although its clinical efficacy remains a subject of ongoing debate.

In recent years, researchers and clinicians have explored the potential of combining CS and HA in a single IA injection regimen. The rationale is to capitalize on the immediate anti-inflammatory action of CS and the prolonged biomechanical support provided by HA. This synergistic approach may enhance both short-term and long-term symptom control compared to either therapy alone. Therefore, a systematic assessment of existing evidence is essential to guide clinical decision-making.

This systematic review aims to evaluate and compare the efficacy and safety of intra-articular corticosteroids, hyaluronic acid, and their combination in the treatment of patients with knee osteoarthritis.        

A comprehensive literature search was conducted using databases such as PubMed, Embase, and the Cochrane Library up to April 2025. The search terms included 'knee osteoarthritis,' 'intra-articular injection,' 'corticosteroids,' 'hyaluronic acid,' and 'combination therapy.' Randomized controlled trials (RCTs), meta-analyses, and systematic reviews comparing IA CS, HA, and their combination in knee OA patients were included. Studies focusing on other joints, non-human subjects, or lacking comparative data were excluded.

Data extraction focused on study design, sample size, intervention details, outcome measures (e.g., pain relief, functional improvement), follow-up duration, and adverse events. The primary outcomes assessed were pain reduction and functional improvement, measured using standardized tools such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Visual Analog Scale (VAS).

Intra-Articular Corticosteroids

IA CS injections have demonstrated significant short-term pain relief in knee OA patients. A meta-analysis by Bannuru et al. reported that CS injections provided superior pain relief compared to placebo at 1–2 weeks post-injection; however, the effect diminished over time, with no significant difference observed beyond 4 weeks [1]. Concerns have been raised regarding the potential deleterious effects of repeated CS injections on cartilage health. McAlindon et al. conducted a 2-year RCT and found that patients receiving triamcinolone injections every 12 weeks experienced greater cartilage volume loss compared to those receiving saline injections [2].

Intra-Articular Hyaluronic Acid

HA injections aim to restore the viscoelastic properties of synovial fluid, potentially providing longer-term symptom relief. A systematic review by Xing et al. [3] concluded that HA injections are effective in treating knee OA without increasing the risk of adverse events. However, the efficacy of HA has been debated. Migliorini et al. [4] and others have indicated that the clinical improvement may fall below the minimal clinically important difference.

Combination Therapy: Corticosteroids and Hyaluronic Acid

Combining CS and HA for IA injections has been explored to leverage the rapid anti-inflammatory effects of CS and the prolonged viscoelastic benefits of HA. A meta-analysis by Tammachote et al. included eight RCTs and found that combined IA injections of CS and HA led to reductions in pain at 2–4, 24–26, and 52 weeks compared to HA injections alone [5]. Similarly, a study by Lee et al. demonstrated that repeated co-injections of CS and HA more effectively decreased pain and improved physical function than injections of HA alone from 1 week through 6 months post-treatment [6,7]. Network meta-analyses have further supported that combination therapy offers superior outcomes over monotherapy [4,8].

The management of knee OA remains a challenge, with IA injections serving as a valuable tool in the therapeutic arsenal. CS injections offer rapid pain relief, making them suitable for acute exacerbations. However, their benefits are short-lived, and repeated use may pose risks to cartilage integrity [2].

HA injections provide a modest benefit in pain relief and functional improvement, particularly in early-to-moderate OA. Their effects are more sustained compared to CS, but the onset of relief is slower. The cost-effectiveness of HA injections has also been questioned, given the modest benefits observed in some studies [9-11].

Combination therapy with CS and HA appears to offer synergistic benefits, combining the rapid relief from CS with the sustained effects of HA. The evidence suggests that this approach provides superior pain relief and functional improvement compared to monotherapy with either agent [5,6,8]. Importantly, the safety profile of combination therapy is comparable to that of individual treatments [12].

However, heterogeneity among studies regarding injection protocols, dosages, and patient populations makes it challenging to draw definitive conclusions. Further high-quality RCTs with standardized methodologies are needed to establish optimal treatment protocols [13].

IA injections of CS and HA play a significant role in managing knee OA. CS injections are effective for short-term relief, while HA injections offer modest, longer-term benefits. Combination therapy harnesses the advantages of both agents, providing enhanced and sustained symptom relief. Clinicians should consider patient-specific factors, including disease severity, comorbidities, and treatment goals, when selecting IA injection strategies.

1. Bannuru, R.R., et al. "Therapeutic Trajectory of Hyaluronic Acid Versus Corticosteroids in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis." Arthritis & Rheumatology, vol. 61, no. 12, 2009, pp. 1704–1711.

2. McAlindon, T.E., et al. "Effect of Intra-Articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients with Knee Osteoarthritis: A Randomized Clinical Trial." JAMA, vol. 317, no. 19, 2017, pp. 1967–1975.

3. Xing, D., et al. "Intra-Articular Hyaluronic Acid in Treating Knee Osteoarthritis: A PRISMA-Compliant Systematic Review of Overlapping Meta-Analyses." Scientific Reports, vol. 6, 2016, Article ID 32790.

4. Migliorini, F., et al. "Comparison Between Intra-Articular Infiltrations of Placebo, Steroids, Hyaluronic Acid, and PRP for Knee Osteoarthritis: A Bayesian Network Meta-Analysis." Archives of Orthopaedic and Trauma Surgery, vol. 141, no. 9, 2021, pp. 1473–1490.

5. Tammachote, N., et al. "Combined Intra-Articular Injection of Corticosteroid and Hyaluronic Acid Compared with Hyaluronic Acid Alone in Knee Osteoarthritis: A Systematic Review and Meta-Analysis." Knee Surgery, Sports Traumatology, Arthroscopy, vol. 26, no. 10, 2018, pp. 2896–2906.

6. Lee, W.C., et al. "Effects of Repeated Co-Injections of Corticosteroids and Hyaluronic Acid for Knee Osteoarthritis: A Randomized, Double-Blind, Controlled Trial." American Journal of Medicine, vol. 134, no. 4, 2021, pp. e239–e246.

7. Zhao, J., et al. "Effects and Safety of the Combination of Platelet-Rich Plasma (PRP) and Hyaluronic Acid (HA) in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis." BMC Musculoskeletal Disorders, vol. 21, 2020, Article ID 224.

8. Qiao, X., et al. "Efficacy and Safety of Corticosteroids, Hyaluronic Acid, and PRP and Combination Therapy for Knee Osteoarthritis: A Systematic Review and Network Meta-Analysis." BMC Musculoskeletal Disorders, vol. 24, 2023, Article ID 926.

9. Tschopp, M., et al. "A Randomized Trial of Intra-Articular Injection Therapy for Knee Osteoarthritis." Investigative Radiology, vol. 58, no. 5, 2023, pp. 355–362.

10. Pereira, D., et al. "Effectiveness and Safety of Intra-Articular Interventions for Knee and Hip Osteoarthritis Based on Large Randomized Trials: A Systematic Review and Network Meta-Analysis." Osteoarthritis and Cartilage, vol. 33, no. 2, 2024, pp. 123–135.

11. Maheu, E., et al. "Why We Should Definitely Include Intra-Articular Hyaluronic Acid as a Therapeutic Option in the Management of Knee Osteoarthritis: Results of an Extensive Critical Literature Review." Seminars in Arthritis and Rheumatism, vol. 48, no. 4, 2019, pp. 563–572.

12. Najm, A., et al. "Efficacy of Intra-Articular Corticosteroid Injections in Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials." Joint Bone Spine, vol. 88, 2021, Article ID 105198.

13. Jevsevar, D.S., et al. "Mixed Treatment Comparisons for Nonsurgical Treatment of Knee Osteoarthritis: A Network Meta-Analysis." Journal of the American Academy of Orthopaedic Surgeons, vol. 26, no. 9, 2018, pp. 325–336.