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That Elusive Biological Magic Bullet for Tendinopathy

Hi all,
Welcome to blog 51 (subscribe here).
Here are some dates for remaining Mastering Lower Limb Tendinopathy course dates for 2017 in Perth, Brisbane and Adelaide.
This week we focus on biological therapies in tendinopthy. This basically includes platelet rich plasma (PRP) and stem cells. They are often wrapped up with many promises from enthusiastic clinicians but what does the evidence show and should we be recommending them? I wrote a similar blog focusing on PRP a while ago, this one extends the discussion into stem cells.

That elusive biological magic bullet for tendinopathy

I have wanted to write this blog for a while, mainly for the benefit of patients wondering about these treatments. For 11 years now I have worked in clinics were we only see tendinopathy patients who have tried (and obviously failed as otherwise they would not be there) basically every treatment. This commonly includes PRP. So yes, I am biased, but I admit people also commonly fail exercise and other evidence based treatments. So just because someone fails a treatment does not mean it is bad. We need to consider scientific first principles (biological plausibility) and the evidence. With this in mind, what do we know about biologic therapies in tendinopathy?
What is a biologic therapy?
Biologic therapies are produced by living organisms (This recent narrative review by Andia and Maffulli provides a detailed and balanced position and was the motivation for this blog). The aim of biologic therapies is to harness the potential of growth factors, cells and other biological factors to be used towards tissue healing. One of the issues is this aim, i.e. tissue healing. Although, an admirable aim, in a clinical context we often try and influence pain and function. It is far from clear whether tissue healing is necessary to achieve this. And even whether it is a realistic aim. We’ll explore this below.
Platelet Rich plasma (PRP)
The most commonly used biological therapy in tendinopathy is no doubt PRP injections. Blood is spun (centrifuged) to concentrate the platelets. Growth factors (GF) (eg platelet-derived epidermal GF, platelet-derived GF, transforming GF, insulin-like GF) and cytokines ‘with tissue healing potential’ from your own blood are injected into your own tendon. The growth factors have a role in tissue-repair, cell proliferation, and other processes, and that sound impressive. This is in my opinion one of the biggest issues with PRP. It comes from your body, it must be doing good. The story is so damn easy to sell.
But does it work? It depends on the study you read. As highlighted in the Andia review, ‘a moderate amount of basic science work shows that the approach may work, and a sizeable amount of animal work shows that biological interventions seem to have some effect.’ But does it work on humans? We know from imaging studies that improvement in tendon structure in imaging either does not occur or occurs partially, for most people, after PRP injections (e.g. Abate et al. 2014de Vos et al. 2011). And in any case, Drew et al. 2012 showed that structural change on imaging is not necessary for clinical improvements. Although this may be because structural changes on imaging are not sensitive enough to microstructural tendon adaptations. 
So, if the promise of better healing is not reality, can PRP at least improve pain and function? If you look at high quality trials, there does not even appear to be much benefit over placebo (e.g. de Vos et al. 2010, de Vos et al. 2014). A brief side note here. A recent RCT that I was involved with has challenged this. It was led by colleagues in Denmark including Anders Boesen and Henning Langberg and published in the American Journal of Sports Medicine. There were three groups. They all received eccentric exercise for 12 weeks, and two groups also had either PRP (4 injections) or high volume injection (HVI – 1 active and 3 placebo injections). Even the exercise only group received 4 placebo injections. We were able to blind patients and outcome assessors to the injection received. The findings were surprising – see the graph below for self-reported pain and function (VISA) outcome. The HVI was superior in the short term, but at 6 months PRP and HVI were equivalent and both superior to placebo control (exercise only). When I lecture about this I admit I am not an advocate of PRP but am an author on the only high quality study that shows it is more effective than placebo. It still does not change the overall evidence message. Of four Achilles trials, three show no benefit of PRP or blood products over placebo and only one shows benefit. Our finding may be explained by very poor execution and progression of the exercises.
Screen Shot 2017-07-09 at 8.51.02 pm.png
You might ask then, why is PRP so popular? As a doctor, you may see improvement in some of your patients and base your opinion on these cases (confirmation bias), and as a patient you may have a friend who had a great outcome (anecdotal evidence). This distortion of evidence is no doubt coloured by financial rewards for clinicians and the promise of a quick fix for patients. Andia and Maffulli suggest the biologic therapy/regenerative medicine industry will be worth US$8 billion by 2020.
Stem cells
The new kid on the block, sexy as hell, are the cell biologic therapies including stem cells. The mechanisms of healing related to tendon stem cell therapies are not known but may involve restoring homeostatic conditions and modulating the inflammatory response. Similar situation to PRP in that there is evidence they may be beneficial in lab and animal studies but translation to humans is very limited.
In the Andia review they identified nine studies that have used cell therapies to manage tendinopathy and only one was a randomized controlled trial. The remaining were case series which cannot tell us about the efficacy of these therapies. The one trial by Clarke et al 2011 showed marginal benefit for stem cell injections compared with PRP when added to eccentric exercise for patellar tendinopathy. The difference between groups in VISA change (i.e. 8 points) was well below minimally clinically important difference.
There is no doubt that these technologies will develop and this story may change in the future. For example, with PRP there is ongoing debate about the number of injections required, the optimal type of PRP preparation (e.g. leukocyte rich vs poor PRP), etc, etc. However, I struggle to get passed the underlying rationale of healing, given that it is conceivable that you can have a biological therapy that heals your tendon but does nothing for your tendon pain, and certainly nothing for function. So what are you trying to 'fix' or address?
Here are some take home messages:
1. Biological therapies are damn sexy
2. They promise a quick fix and the potential for healing
3. Cell and animal studies support this potential for healing
4. BUT this has not translated well to human studies
5. AND clinical outcomes from these outcomes may be no different to placebo
6. YET PRP is one of the most popular treatments for tendinopathy
7. What the?? This defies logic
8. Until you consider clinician financial incentives and patients desire for a ‘fix’
Peter Malliaras
Tendinopathy Rehabilitation

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