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But it does work (and we know that it does)…
  1. C Niek van Dijk
  1. Correspondence to Professor C Niek van Dijk, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands; C.NiekvanDijk{at}

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We generally agree how to manage knee osteoarthritis (OA), and in this issue, Parker et al 1 summarise in their current concepts article on the non-operative options. What is our approach? Well, we start by suggesting small changes to lifestyle, such as weight loss and strengthening exercises. If these serve no purpose, we prescribe oral anti-inflammatories. However, anti-inflammatory medication has serious side effects, so we replace them—or follow them—with intra-articular injections.

We probably all agree that this is best praxis. Our regulators, however, do not. The current guidelines of the American Society of Orthopaedic Surgeons (AAOS) are ‘inconclusive’ about injections with corticosteroid and PRP, and there is a strong recommendation against hyaluronic acid (HA).2 The previous guideline on HA was ‘inconclusive’, but after changing the criteria of clinical relevance, the guidelines are now ‘strongly against’.2 The UK’s National Institute for Health and Care Excellence,3 in their current guideline, is equally definitive: ‘Do not offer intra-articular HA injections for the management of OA’.

These strong recommendations against intra-articular HA are not without consequence as they dissuade insurance companies from reimbursing HA.

However, if you scratch intra-articular injections, you eliminate an important step between anti-inflammatory drugs and surgery, and we all know these patients which benefit from their annual HA injection. An American journalist recently wrote: ‘The insanity of covering a $50 000 total knee replacement operation, but not a relatively cheap HA injection, is one of the reasons why the US health care system is the most expensive’.4

That journalist was right, and not just about the economics. A recent meta-analysis from the American Medical Society for Sports Medicine (AMSSM) showed a small but clinically significant difference for intra-articular HA versus a placebo.5 Another recent systematic review found a clinically significant improvement, in pain and function, for HA versus an intra-articular placebo.6

But why have previous studies disagreed? There are various reasons. First, the literature has been dominated by company sponsored studies that are very biased—also known as mine is better than yours. As such, the literature showing the effectiveness of HA is weak. Second, it is difficult to demonstrate a significant difference when HA is compared with saline.7 8 Arthrocentesis with or without saline has been recognised as an effective intervention for patients with knee OA.9 So intra-articular saline injections should really be categorised as ‘treatment’ (as an ‘active-control’) rather than a mere ‘placebo’.

But why inject only saline, when HA is also available? HA is a major component of synovial fluid, which facilitates lubrication and shock absorption. HA suppresses inflammatory mediators like cytokines, prostaglandins and nitric oxide.10 11 It is significant that OA is accompanied by changes to the HA: its decreasing molecular weight (MW) and its decreasing concentration in the synovial fluid. Quite simply, ‘topping-up’ the HA restores joint homeostasis, and its anti-inflammatory properties act as a local pain killer.

There are many HA products on the market, however. In Italy alone, there are 57.12 These versions differ by MW, by molecular structure (whether they are cross-linked), by concentration and by means of production (whether or not they are derived from animals). However, when hospitals lack the relevant knowledge, they can only select by price.

Although AAOS is aware that different HA versions give different results, they do not—unfortunately—draw the obvious conclusions.

Let’s consider the figures. As regards safety: bio-HA (non-animal) has a better safety profile than animal-derived HA.13 As regards rheology and density: HA versions with a high molecular weight (HMW) are consistently more efficient than versions with lower molecular weight (LMW).13 For example, HMW intra-articular HA produces results which, by its own criteria, AAOS should classify as ‘significant’. The value of the Altman paper is that the pooled results for HMW analysis were derived from 11 randomised controlled trials, which included 2094 patients. LMW analysis was derived from 15 trials of 2639 patients. The numbers take out product bias. Why has HMW better results then HMW? Among others, HMW means a higher concentration of active HA molecules per injected volume.

A normal knee joint contains on average 2 mL synovial fluid, containing HA with a MW of 800 kDaltons.14 Such HA is produced by chondrocytes and synovial cells and has a half-life of about 8 days. The half-life of unmodified commercial hyaluronan, however, is less than 24 hours.15 Manufacturers have tried to increase the half-life time of their injectables, therefore making it more difficult to leave the joint. They achieved this by cross-linking. Cross-linking increases the HA half-life time to 28–32 days. Cross-linking thus has greatly increased the residence time in the joint.

What does all this mean? It means that a single injection (of cross-linked HMW) HA can produce a lasting result, compared with 5 weekly injections of a shorter half-life version. It is easier for the patients, cheaper and less of a burden for the system.

Do all patients benefit from intra-articular HA? It seems that some respond more robustly than others, and these ‘good responders’ continue to respond to subsequent injections. Good clinical practice, therefore, requires common sense and a careful patient assessment.16 However, intra-articular HA should definitely be included in the treatment algorithm for patients with Kellgren Grade II and III, before surgical interventions are recommended.

We strongly recommend that AAOS revises its position about HA for patients with Kellgren Grade II and Grade III. If not for all HA, then at least for the second generation HMW cross-linked versions.


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  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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