Intra-articular hyaluronic acid (viscosupplementation) for osteoarthritis – is it effective?

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

Osteoarthritis is a massive problem in Australia with over 2 million Australians suffering from it right now. That number just continues to rise and comes not only with a substantial morbidity burden for individual patients, but enormous economic and societal costs for our country. In amongst that, it's understandable that many people explore all sorts of potential solutions, and it's unsurprising that joint injections have often been considered.

One of the more controversial ones for hip and knee osteoarthritis is hyaluronic acid, which has been around for some time and for many is just a short internet search away, but does it work? And how do we discuss this with patients? I'm David Liew, your host today, and I'm joined by Huai Leng Jessica Pisaniello, a rheumatologist in Melbourne and a research fellow at Monash University. She and her colleagues have written an excellent article for Australian Prescriber on intra-articular hyaluronic acid, a viscosupplementation of osteoarthritis. Jessica, welcome to the Australian Prescriber Podcast.

Thank you, David, for having me.

So first of all, tell me about what hyaluronic acid is. I think a lot of us have heard about it, but what is it in the context of knee osteoarthritis? And is there a possibility that it could work?

Many people would relate hyaluronic acid to other uses as in skincare. However, when we talk about hyaluronic acid as a treatment option for osteoarthritis, which is a common chronic arthritis in adults worldwide and also in Australia, it's known as a viscosupplementation.

Hyaluronic acid, intra-articular injection, the main objective is to treat joint pain and reduce inflammation in the joints. We know that hyaluronic acid, it's a natural component that exists in the tissues and especially we could find them naturally in the synovium or the joint lining, and it's responsible for the joint lubrication and also the biomechanical properties of the joint.

There has been a lot of clinical use first found in the early 1970s. It's thought that the hyaluronic acid, if provided in the joint, could restore the biomechanical properties of the joint and therefore promoting joint healing and increasing mobility, and that's why it's been a popular treatment option for knee osteoarthritis.

When you say it like that, it makes a lot of sense, it's being considered for knee osteoarthritis and why it's the kind of thing that's been explored and still gets talked about. Is this the kind of thing though that we are using routinely in practise right now? Where do we sit in Australia in terms of how accessible it is and how it's given?

In the private practise in rheumatology, there has been a lot of patients handing out brochures to myself and talking about what are the treatment options and whether I, as the treating rheumatologist, would think that this is the best options. And in fact in Australia, it's quite a popular treatment option. Some imaging services has offered image guidance, either ultrasound or CT or computed tomography guidance injections for knee osteoarthritis.

Let me explain what's been happening in Australia. So hyaluronic acid derivatives are actually classified as medical devices under the Therapeutic Goods Regulations in 2002. However, a subsidy under the Medicare Benefits Schedule or MBS or the Pharmaceutical Benefits Scheme, PBS, both had not been approved and specifically the MBS precludes a benefit for consultation associated with hyaluronic acid injection.

However, because the injection is done under imaging guidance, the cost of the image guidance, if it's not borne by the patient, it will be charged to Medicare. And we know that image guidance is not really necessary for any knee joint injection – we could do it under anatomical guidance; however, it's needed for [injection into] the hip. And we know also that CT guided injections are more costly and exposing patients to unnecessary radiation and have much larger carbon footprint when we think about climate change and costs may rise with multiple injections and therefore it's a very costly treatment option for knee osteoarthritis.

That's a substantial cost. Is it the kind of thing that gets recommended though in Australia right now?

So currently in Australia, despite the increasing popularity of the intraarticular hyaluronic acid injections in Australia, we have an Osteoarthritis of the Knee Clinical Care Standard published in 2024 by the Australian Commission on Safety and Quality and Healthcare, which recommends against offering this hyaluronic acid intraarticular injections. This clinical care standard has been endorsed by our Australian Rheumatology Associations, other relevant Australian organisations such as the Australian Orthopaedic Association, Australian Society of Medical Imaging and Radiation Therapy, and also the Australian College of Sport and Exercise Physicians.

Our paper also looked at many different guidelines nationally as well as internationally. And in Australia, the 2018 Royal Australian College of General Practitioners Guideline for the management of knee and hip osteoarthritis had made a conditional recommendation against intraarticular hyaluronic acid injection for knee osteoarthritis and strongly recommending against the use of hyaluronic acid for hip osteoarthritis.

However, when we look at the international guidelines, they were rather heterogeneous with some conditionally recommending for intraarticular hyaluronic acid for knee osteoarthritis and some against the use, whereas mostly all the recommendations for hyaluronic acid use in other joints such as the hip or the small joints have either been strongly or conditionally against the use of hyaluronic acid.

As you detail out in the article, a lot of the big recommendations, NICE in the UK from the American Academy of Orthopaedic Surgeons from the American College of Rheumatology all have been against use of hyaluronic acid, in line with that Australian guidance that you've mentioned. Why is that so firmly there? Maybe you can talk me through the evidence and how things sit in terms of what might sit in the column for us to consider this and what might be against it.

Yes. The evidence for hyaluronic acid intraarticular injections, it's quite enormous of variable quality in terms of when we look at the studies themselves evaluating the benefits and harms of this treatment. We have more than 160 randomised controlled trials and numerous systematic reviews and most of them were performed in participants with osteoarthritis of the knees and a smaller number of studies in people with osteoarthritis of the hip, the carpometacarpal joints of the thumb and the first metatarsophalangeal joint of the foot.

And I would pull up this most important up-to-date systematic review published by Pereira and his colleagues in the British Medical Journal in 2022. This included intraarticular hyaluronic acid studies for knee osteoarthritis, randomised controlled trials of at least 169 trials involving more than 21,000 participants. So what they have found in terms of benefits, there are major concerns, but also the significance of the findings in terms of pain reduction and function improvement.

So 2 important concerns were, first, they found that there were small-study effects from most of these randomised controlled trials, meaning that small studies resulted in a large effect [i.e. larger effect size than observed in bigger studies] making the study look amazing in terms of the results and the data. However, it's likely to lead to bias when we look at the [overall] results.

And secondly, there were a lot of adequately powered and completely industry funded large trials done for this treatment option and yet they have not published their results and again leading to publication bias. So these are major concerns when we look at hyaluronic acid evidence.

And in terms of pain reduction, again, there was a clinically irrelevant reduction in pain intensity. So when we used the visual analogue or numerical zero to a 100 mm scale at 3 months, there were only 2.0 mm reduction in pain intensity on a 100 mm VAS score. And when we look at function improvement, again, there was small clinically irrelevant improvement in the function of 1.2 points on this zero to 68 function scale of WOMAC, which is the Western Ontario and McMaster University's osteoarthritis index, commonly used to assess function in osteoarthritis, at 3 months. And these effect sizes were not influenced by the hyaluronic acid structures or the molecular weight, which means the frequency of the injections do not matter in terms of the benefits of this results.

In terms of harms, there has been data derived from 15 large placebo controlled trials from this Pereira systematic review noting that there is an increased risk of serious adverse events compared with placebo. And again, a lot of the studies, 11 out of 15 trials reported that none of these serious adverse events were treatment related, but causation is unclear in terms of finding out whether it's direct or indirect association.

However, when we look at other reported studies, there have been adverse events related to hyaluronic acid injections including septic arthritis or severe inflammatory reactions, mimicking septic arthritis and also cutaneous reactions like cellulitis or erythema multiforme and other injection site discomfort or arthralgia as a common non-serious local effects, which usually is self-limited. However, even though I did mention at the very beginning about hyaluronic acid being classified as medical device under the TGA, it's important to report these adverse events. If we come across patients having these injections and having complications, it's important data for the TGA.

Well, I mean, when you lay it out like that, it really is the kind of thing that raises some serious concerns about the use of hyaluronic acid. From what you said, the efficacy data has some real question marks about it despite the large volume of data that exists and then there are some real harms that patients can experience in amongst this. Often it gets thrown around. Well, we need more evidence, we need more data. Do we need more data here? Do we need more evidence? Or is this enough to be able to help inform our decision?

That's a great question, David. There is a clever way of looking at these enormous research data where Pereira, in the same systematic review, used trial sequential analysis, which is a clever method of identifying whether a conclusive evidence could be achieved depending on the publication order of the trials published. So they managed to find conclusive evidence of lack of benefit from hyaluronic acid injections and knee osteoarthritis has already existed in 2009. And therefore, subsequent multiple randomised controlled trials published beyond 2009 did not change this conclusion and highlighting another important concern is research waste.

So no more research required in this. We've got what we need in this situation, but it still makes for a slightly tricky discussion, I can imagine, in clinic when this kind of thing is getting discussed. How do you approach this when patients come to you asking about hyaluronic acid? How does that conversation go and how would you advise the rest of us to try and approach it?

It's a very important issue to discuss with patients when they are in a lot of pain. They're likely to have function impairment and disabled day-to-day activities because of their osteoarthritis, especially if they affect the knee or the hip joints. And often, patients would come in a huge dilemma whether they should spend a huge amount of money to fund this treatment. Not many would fund this out of pocket cost or bulk billing.

So I think this evidence should be conveyed in a shared decision-making approach. First of all, prescribers or clinicians should acknowledge the patient's symptoms along with what their values are and their preferences and provide an explanation. And I think this paper has provided a summary as well as a table about the current national and international guidelines of the recommended care of why hyaluronic acid is not a great treatment option. And if we have that shared decision-making process happening between the clinicians and patients, perhaps we can open up the other options as well to discuss looking at other non-pharmacological management of osteoarthritis, including exercise, simple analgesia use if symptomatic and also weight management if necessary.

You've captured it all so beautifully there and really highlighted the considerations that really have supported the recommendations that are made by various different organisations. Since we're talking about intraarticular therapies for osteoarthritis, especially knee and hip, maybe you can talk us through a few of the other things that get bandied around, things like PRP [platelet-rich plasma] and stem cells and corticosteroid injections. Where do they all sit, in brief, for osteoarthritis, are they effective or not?

Yes. In our article, we also mention about other intraarticular interventions for osteoarthritis and we would commonly perform intraarticular corticosteroid injections, if not in the clinic, sometimes under the imaging guidance if it's involving difficult joints for access. Let me go through the intraarticular corticosteroid injections first of all. There is evidence of proven efficacy for short-term pain relief and improvement in functions of 2 to 6 weeks in average.

Cochrane review published in 2015 had found some low certainty evidence of small to moderate benefits for people with knee osteoarthritis and more recently, there has been some confirmation of this evidence that there is some benefit for patients with knee osteoarthritis when they have the corticosteroid injections. However, we have to be mindful about the side effects related to steroid-related injections, either systemic or locally, including hyperglycaemia, flushing, impaired sleep as part of the systemic adverse effects or local adverse effects, including skin changes if inadvertently injected into the subcutaneous tissues.

Septic arthritis is rare, but potentially could be a serious adverse event related to intraarticular steroid injection. There are 2 other quite popular intraarticular interventions that have been increasingly known to patients, including, as you've mentioned, intraarticular PRP or platelet-rich plasma therapy, despite the evidence against its use. So currently, it's not subsidised by Medicare or the PBS, and there has been a recent Australian study of a randomised trial including 288 participants with knee osteoarthritis and found no clinically important benefits in symptoms or joint structures at 12 months. And we will have a Cochrane review underway to evaluate the benefits and harms of PRP therapy in osteoarthritis.

Secondly, we also have been hearing about intraarticular stem cell therapy, which is very expensive and yet promoted to people with osteoarthritis. Recently published Cochrane review last year included 25 randomised controlled trials with more than 1,300 participants. Again, we have low certainty evidence that stem cell therapies may provide slight improvement in pain and function, but the effects on the joint structures and safety remain uncertain.

I have to say with my hat as a clinician on, I think it's always just so heartbreaking when someone's gone and invested so much hope in hyaluronic acid or PRP or stem cells and they really get nothing from it. It really highlights the importance of being able to have these proactive conversations. Have you got any pieces of proactive advice as to what we can be talking to our patients with hip or knee osteoarthritis about?

Yes, I agree with you, David. I think it's an important topic to talk about with patients having symptomatic knee or hip osteoarthritis that even though intraarticular hyaluronic acids might be an appealing treatment options for these patients, we have to be clear about the evidence of benefits and harms in terms of whether they're effective. They remain very costly and unnecessarily low value care for these patients. There are many other resources that patients can access, including publications from the Royal Australian College of General Practitioners, as well as many other resources from Arthritis Australia and from the Australian Rheumatology and Orthopaedic Associations as well.

Yeah, I know a lot of those are at myoa.org.au, which is My Joint Pain, brings together a lot of those things. Good to be able to help direct patients there proactively to try and navigate the situation that you talked about, Jessica.

Yeah, that's right. Yep.

Thank you so much for joining us today on the podcast and for talking us through hyaluronic acid in osteoarthritis.

Thank you, David. My pleasure.

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The views of the guests and the host on this podcast are their own and may not represent Therapeutic Guidelines or Australian Prescriber. Huai Leng Jessica Pisaniello has no conflicts of interest, and I am Medical Director of Arthritis Australia and on the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee. I'm David Liew, and thank you once again for joining us on the Australian Prescriber Podcast.

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