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Hyaluronic Acid / Viscosupplementation
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Hyaluronic Acid / Viscosupplementation

Hyaluronic acid (HA) is a naturally occurring large molecule that helps to calm down inflammation. It also increases the expression of anti-inflammatory molecules in the knee and in cartilage cells, or ‘chondrocytes’.

HA stimulates the cells that generate the synovial fluid in the knee, called synoviocytes. This, in turn, promotes the release of HA into the synovium and the synovial fluid. Together, these effects support the regulation (homeostasis), of the joints by calming down inflammation and helping to promote anti-inflammatory factors or proteins in the joints.

HA helps to regulate the equilibrium of those factors if they are unbalanced, which can occur in patients with acute articular cartilage damage, and especially in both early and late osteoarthritis.

Intended audience

This article is intended for anyone suffering from damage to their articular cartilage and their families who would like to find out about hyaluronic acid/viscosupplementation, as well as anyone interested in cartilage problems.

What is Hyaluronic Acid / Viscosupplementation?

HA is a treatment concept that was proposed 70 years ago by Hungarian scientist Endre A Balasz, who used it first in horses. HA was known to occur in the synovial fluid and the articular, or joint, cartilage. Within the synovial fluid, HA was considered to be the main constituent that allowed the sliding properties of the joint. Scientifically speaking, HA decreases the coefficient of friction on the joint surface and allows for the smooth motion to occur between the two opposing articular cartilage surfaces. Therefore, the use of HA injections into the joint is a method of supplementing the viscous properties of the joint, or ‘viscosupplementation,’ and it aims to facilitate better gliding properties within the joint during movement.

In the 1960s, scientists learned how to extract HA from animal material, such as a rooster’s comb or other tissues where you can isolate HA in large quantities. The HA was then chemically formulated into very large molecules known as macromolecules and injected into the joint. Then, in the 1980s, scientists learned how to synthesise HA using an artificial form of DNA called recombinant DNA through the genetic manipulation of cells, which made them produce HA. This helped clinicians move away from animal-derived HA, and led to the widespread introduction of the drug that is now commonly used throughout the world.

HA is typically registered as a medicinal product, rather than as a pharmaceutical drug. The reason for this is that it was introduced purely for viscosupplementation to help the joint, similar to the way oil is used in an engine. There has been a lengthy debate about the classification of HA has a drug, because some studies have shown that it has some pharmacological, or drug-like, properties. However, this discussion is ongoing and there are only a few HA products that are registered as a drug, while the large majority of these products are still classified as a medicinal product. It is possible that this debate will be settled once the results of the ongoing research that is focused on how HA modulates the inflammatory cascade located in the joint is published.

What are the advantages and disadvantages of Hyaluronic Acid / Viscosupplementation?

What are the advantages of Hyaluronic Acid / Viscosupplementation?

A review carried out by The Cochrane Collaboration – a not-for-profit global network of researchers – concluded that, based on the available evidence, viscosupplementation is an effective treatment for osteoarthritis. Specifically, the review indicated that it has benefits in terms of pain, function and the overall patient experience, particularly in the first 5–13 weeks after injection. Although some analyses looked at by the reviewers suggested viscosupplementation was as effective as other treatments, they cautioned it was associated with some adverse effects, especially local reactions to the intra-articular injections.

There have been numerous studies showing a benefit of HA in moderate osteoarthritis cases or in patients developing osteoarthritis, classified using the Kellgren & Lawrence scale as grade 2 and 3. These grades mean that there is still some space in the joint, but it is narrower than that the space in the corresponding joint on the other side of the body. In these joints, HA helps to decrease symptoms and pain, and it increases function and mobility, as well as quality of life scores. In other words, HA is more effective in younger arthritic patients – i.e., those in their 60s, not those in their 80s – and in those with medium or moderate osteoarthrosis.

However, these reports of good outcomes after intra-articular HA injections should be tempered by recent reports from systematic reviews and meta-analyses of randomized controlled trails of intra-articular HA injection that have shown that it only has a modest effect on early to moderate knee OA. Furthermore, this effect usually peaks around 2 months after the injection and its effect after 6 months is unclear. The most recent Osteoarthritis Research Society International (OARSI) evidence-based, consensus recommendations guidelines on the treatment of knee arthritis was only able to provide intra-articular HA injections with an “uncertain” recommendation. This occurred because the panel thought that although HA has been shown to be beneficial in terms of pain and function, the available literature was not consistent in terms of reports of it’s overall safety profile especially in relation to the risk of joint “flare ups” that can occur.

Intra-articular corticosteroid, over the counter anti-inflammatory (such as Ibuprofen) and prescribed anti-inflammatory pain medications (such as Meloxicam, Celebrex, Naprosyn, etc.) all still play a major role in the treatment of joint pain. Some of these can even be used to have a synergistic viscosupplementation. Therefore, it is important for you to talk to your health care provider about the risk and benefits of this treatment.

What are the disadvantages of Hyaluronic Acid / Viscosupplementation?

There are very few adverse effects with HA. One of the most concerning adverse effects that can occur is a “flare up” of the joint and this is generally thought to be related to the molecular weight of the HA that is used. Generally speaking, the higher molecular weight products can initially cause some reactions in the joint that can lead to difficulty moving the joint, increased pain and sometimes can also result in an effusion (swelling) and redness about the joint. Fortunately, these reactions are not very common and generally resolve over the course of a few days. It is important for you to contact your health care provider to inform them if you experience any of these symptoms, because they can also be a sign of an underlying infection.

Frequently Asked Questions (FAQs)

How does HA compare with other treatments?

In terms of adverse events, HA is a very well tolerated drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) or steroids.

In particular, steroids may stop the inflammation, but they also stop all the regenerative capabilities of the cartilage. Furthermore, the effectiveness of steroids is reduced after two or three injections. Consequently, although steroids are effective at the time, they have the potential to make whatever problems are already present in the cartilage permanent and prevent any regeneration.

Will the HA cure my osteoarthrosis or osteoarthritis?

HA slows down the progression of a disease such as osteoarthritis, but the progression is not completely stopped. The patient cannot expect to be cured from osteoarthritis or osteoarthrosis, but perhaps can expect to have a slower course of degeneration.

One way of explaining it is that, with a treatment like HA, it can be expected that a potential total joint replacement, which might happen at some point, is delayed for some time. Depending on the individual, the delay can be between three and five years with HA, if the patient is considered a ‘responder’.

For patients who do not respond, the course of the osteoarthritis has become too inflamed and the activation of the anti-inflammatory components by HA cannot calm down the knee. HA should not be repeated if it has not worked the first time around. It makes no sense to do it over again, because the balance of the knee or joint cannot be altered by this treatment. If it doesn’t work, it doesn’t work.

How many injections will I need?

There are different methods of administering HA. Some formulations have a treatment schedule of five weeks, with one injection every week. While others require three injections over a three week period, while another only requires just one injection.

The number of injections required relates to the molecular weight of the drug, and how long the drug is estimated to remain in the joint after injection. We know that, the lower the molecular weight, the less time that it stays in the joint. However, the way in which the synovium reacts to the HA can be different with a higher molecular weight drug. These larger drugs stay longer in the synovium and can cause some reactions.

The number of injections should therefore be clarified, depending on whether the patient needs five injections in a row, three injections in a row or maybe just one injection. The clinical studies published so far have not been able to determine which number of injections achieves the best results.

One practice used by some people who use the product that recommends the 5 injections is to give three injections and then evaluate their success, or ‘efficacy’. Patients can then have two further injections three months later, if required, to prolong the efficacy of the HA, as there are five injections in a package.

The efficacy of the treatment should be assessed between six months and 12 months after the initial injection, and the symptoms should decrease during that timeframe. A patient can therefore expect to have one series of injections every year, if needed.

Further reading

There have been several studies on the effectiveness of HA, including a Cochrane review and the recent OARSI guidelines, which analysed all of the available high quality literature:

  • Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006(2):CD005321.
  • Trigkilidas D, Anand A. The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain. Ann R Coll Surg Engl 2013; 95: 545–551.
  • McAlindon TE, Bannuru RR, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis and Cartilage 22 (2014) 363-388.

One of the difficulties with carrying out studies on osteoarthritis is the fact that patient’s symptoms may vary based on a variety of different factors. Furthermore, the collection of outcome data adds an element of bias, such as a recall in which the patient is asked to recall what the level of their discomfort or function from different time point in the past. There is also the possibility that some of the patients reported improvement is a result from a placebo effect, as opposed to the HA injection actually providing relief from their symptoms. Needleless to say, more high quality studies are needed to determine if intra-articular HA injections are in fact a viable option in the non-operative treatment of arthritis.

Hyaluronic acid (HA) is…
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