Patients with knee osteoarthritis are commonly seen in orthopedic clinics. The role of the sports medicine physician is to improve their pain and prolong their knee function to avoid a total knee arthroplasty. Hyaluronic acid (HA) is naturally found in synovial fluid and acts as a shock absorber, aids in joint lubrication, and decreases energy forces transmitted to the knee (Kirk Campbell, 2015; Anne Rutjes, 2012). When analyzing the synovial fluid in patients who have osteoarthritis their fluid is found to have depolymerized HA, decreased molecular weight HA, increased joint clearing of hyaluronic acid, and overall decreased viscosity of synovial fluid (Anne Rutjes, 2012; VM Goldberg, 2005). The changes seen in HA led to the field of viscosupplementation to help supplement the naturally occurring HA (Anne Rutjes, 2012). HA injections can improve the knee’s ability to absorb shock and aids in lubricating the knee (Raveendhara Bannuru, 2009). Recent studies have also found evidence of chondroprotection with HA (Raveendhara Bannuru, 2009).
HA injections can be a single injection or as part of a series of 2-5 injections. The average amount paid per series of injections was found to range from $180 to $350 (Vinod Dasa, 2016). Currently, there are avian derived and bacterial derived HA injections available (Gloria Maria Pontes-Quero, 2019). The purpose of our review here today is to look at multiple reviews on viscosupplementation to see if there is general agreement.
There have been multiple different reviews published on the role of viscosupplementation for knee osteoarthritis. They have been published in the Annals of Internal Medicine, the Journal of American Academy of Orthopedic Surgery, the British Journal of Sports Medicine, and countless more. Despite most of these reviews analyzing the same papers, they all look at different outcome measures. This has led to confusion over the role of viscosupplementation, since the reviews offer differing conclusions. What we hoped to do in this article was to review the outcomes in some of these major reviews to see where the differences exist.
A meta-analysis published in Arthroscopy in 2015 reviewed 14 studies to determine if there was an advantage to intra-articular hyalgan injection compared to oral NSAIDs, corticosteroids, and intra-articular PRP (Kirk Campbell, 2015). They found that 10 studies compared intra-articular hyalgan to placebo and of those, only four found clinically significant improvements in knee function (Kirk Campbell, 2015). However, they did find that the positive results seen with intra-articular hyalgan injections lasted longer than those seen in a corticosteroid injection (Kirk Campbell, 2015). They also did not find a significant difference between intra-articular hyalgan and oral NSAIDs (Kirk Campbell, 2015). However, due to the favorable side effect profile of hyalgan, they concluded that HA injections would be recommended.
There have been several proponents to intra-articular hyalgan injections. The AAOS published their review on treatment options for osteoarthritis in 2013. They reviewed 14 studies that were looking at the role of intra-articular hyaluronic acid injections and osteoarthritis (Directors, 2013). They found that the injections done with the high molecular weight viscosupplementation had better outcomes than the low molecular weight viscosupplementation (Directors, 2013). However, they concluded that the use of intra-articular hyaluronic acid did not meet minimum clinical important improvement (MCII) (Directors, 2013). The AMSSM evaluated the clinical significant of the AAOS’s outcome measure, known as the minimum clinical important improvement (MCII), in an article published in the British Medical Journal. What they found was that the MCII is not a validated measure that should dictate clinical decision making (Thomas Trojan, 2016). As a result, the AMSSM did their own review on intra-articular hyaluronic acid, but looked at individual patient benefits and not the average benefit across a group (Thomas Trojan, 2016). What they found was that in patients who underwent viscosupplementation, they had a 15% greater chance of responding the treatment compared to intra-articular joint injection (Thomas Trojan, 2016).
In a review published in the Annals of Internal Medicine, patients with OA who received intra-articular HA were evaluated for response using the Western Ontario and McMaster Universities Arthritis Index pain subscores (WOMAC) and using VAS (visual analogue scale) scores (Anne Rutjes, 2012). They defined a clinically important difference in patients who reported an improvement of 9mm on a 10cm VAS (Anne Rutjes, 2012). Their reports on knee pain following intra-articular HA found that the injections met conventional criteria for statistically significant pain relief, but did not provide pain relief set to their criteria on what they defined as minimally important pain relief (Anne Rutjes, 2012). Based on those results, they concluded that viscosupplementation provided minimal or nonexistent benefit on pain and function in patients with symptomatic osteoarthritis (Anne Rutjes, 2012). This study did not discriminate injections based on the weight of the hyaluronic acid.
A Cochrane Review was also performed, where they broke down each section by brand of HA to see if there was a difference in safety or efficacy between injections. What they found was that there was a wide variability in clinical response to HA (N Bellamy, 2005). They found that one identifiable factor that led to a change in clinical response was the weight of the HA product (N Bellamy, 2005). Overall, they report a significant clinical improvement in patients receiving HA. (N Bellamy, 2005).
A meta-analysis done in 2009 in Arthritis and Rheumatism compared HA to corticosteroids. They found that at 4 weeks, corticosteroids held an advantage in pain relief, but past 8 weeks the advantage went to HA (Raveendhara Bannuru, 2009).
Due to the heterogeneity between studies and outcomes in trials looking at the benefits of HA, a study was done that looked at the intrinsic differences between the different HA products (Mathew Nicholls, 2018). What they found was that the highest molecular weight identified among commercially available options is Synvisc and Synvisc-One at 6000 KDA. This is compared to only 620-1170 KDA for Supartz and Euflexxa 2400-2600 KDA (Mathew Nicholls, 2018). However, they also analyzed the HA based on their dilution characteristics. They found that naturally occurring HA was semi-dilute and they found that Orthovisc and Euflexxa both acted like semidilute solutions (Mathew Nicholls, 2018).
Despite apparent advantages in heavier molecular weight HA, weight alone cannot be used to determine which HA is superior. Studies also suggest that there is more cartilage protection with the lower weight HA derivatives (Vinod Dasa, 2016).
Scientists are now looking at new ways to improve and deliver HA injections. In order to enhance the effects of the HA, newer formulations of HA are being encapsulated to delay drug release and increase retention in the joint (Gloria Maria Pontes-Quero, 2019). Newer data also points to a benefit with HA and PRP combination injection (Gloria Maria Pontes-Quero, 2019). The thought process behind this process is to provide the PRP in order to deliver high growth factor concentrate to help repair knee cartilage and the HA to stabilize the synovial fluid (Gloria Maria Pontes-Quero, 2019).
After analyzing the multiple reviews done on intra-articular HA, we have been overwhelmed with the widespread differing of opinions on these injections. However, one main take away has been that outcomes are potentially better with a heavier weight of HA. We have yet to see any of the reviews focus on the pain outcomes from HA with only the heavier weighted HA injections. Future studies should continue to focus on improving ways to delivering HA injections.