Background
Osteoarthritis (OA) is a leading causes of global disability, and the number of people affected is anticipated to substantially increase over the coming decades [
1]. Osteoarthritis at the knee joint, the most commonly involved lower limb site, can cause pain and physical dysfunction and impaired quality of life. There is no cure for knee OA, and to date, most research has focused on treatments to alleviate pain and prevent functional decline.
Recommended drug therapies (such as analgesics and anti-inflammatory agents) and non-drug therapies (such as exercise) have short-term clinical benefits, but effect sizes are small to moderate at best [
2,
3]. Furthermore, drug therapies can have adverse events, while uptake and maintenance of exercise are often poor leading to lack of long-term benefit. Intra-articular therapies in clinical use for knee OA include glucocorticoids and hyaluronic acid (a viscosupplement). Intra-articular glucocorticoids are generally recommended [
4‐
6], although not universally [
7], and for short-term pain relief only given that benefits are limited to a few weeks [
6,
8]. Furthermore, a recent clinical trial highlighted a potential small deleterious effect of repeated corticosteroid injections on knee joint cartilage [
9]. Hyaluronic acid is controversial with most clinical guidelines advising against its use [
4,
10], or providing an uncertain recommendation [
6]. As knee OA is a chronic disease, with both symptoms and structural deterioration drivers for surgical joint replacement, identifying efficacious, safe treatments that address both is an important objective.
One therapy with the potential to address underlying biological processes responsible for OA pathogenesis is platelet-rich plasma (PRP), an autologous blood product that contains an elevated concentration of platelets. Activation of PRP releases an initial burst then a sustained release of growth factors and other molecules, including platelet-derived growth factor, transforming growth factor-β, type I insulin-like growth factor and vascular endothelial growth factor [
11]. Animal studies have shown that these proteins are responsible for a range of critical tissue healing roles such as chondrocyte apoptosis inhibition, bone and vessel remodelling, inflammatory modulation, and importantly, collagen synthesis. Additionally, other bioactive molecules released by platelets, such as fibrin, act as a scaffold and chemo-attractant for further migration of stem and other cells to the damaged tissue [
11]. Given the limited repair capacity of articular cartilage, these roles offer a mechanism by which PRP may enhance tissue healing and cartilage regeneration in knee OA.
There is some randomised controlled trial (RCT) evidence about the symptomatic effects of PRP for knee OA. A recent systematic review that included 14 RCTs concluded that PRP was likely to be more effective for pain relief and physical function when compared with control injections that included normal saline, HA or glucocorticoids [
12]. However, all RCTs were found to be at a moderate to high risk of bias, and most lacked longer-term follow-up and were inadequately powered with small sample sizes. Only three trials compared PRP to placebo, with results showing significantly greater improvements in symptoms over normal saline at six [
13] and 12 months [
14,
15]. However, all three studies suffered from major methodological flaws including a lack of adequate blinding suggesting the benefits may have been overestimated. No study has investigated the structural effects of PRP.
Heterogeneity in the preparation and injection methods used by published studies has also limited the ability to determine optimal PRP protocols. However, protocol characteristics of those RCTs that have reported positive effects on pain and function have generally utilised a single centrifugation at a slower speed (approximately 1500 g) for approximately 5 min to yield leucocyte poor PRP, and injected fresh PRP (i.e. not frozen and then thawed for subsequent injections) over 3 injections at weekly intervals [
16]. There is some preliminary evidence to suggest younger patients, and those with less severe radiographic disease may experience greater symptomatic benefits [
14,
17‐
19].
The primary aim of this two-arm randomised, placebo-controlled trial is to determine if a series of injections of PRP into the knee joint leads to significantly greater reductions in average knee pain severity and less loss of medial tibial cartilage volume when compared to placebo saline injections over 12 months in people with symptomatic knee OA. The secondary aim is to determine if PRP has significantly greater benefits for other clinical (other knee pain measures, physical function, quality of life, participant global rating of change) and magnetic resonance imaging (MRI) structural outcomes (effusion, synovitis, cartilage morphology, bone marrow lesions, cartilage defects, meniscal morphology) compared to placebo injections at 2 (clinical) and 12 (clinical and MRI) months. We will also conduct an embedded economic evaluation of PRP if benefits are found.
Discussion
Identifying treatments that reduce symptoms and slow disease progression in knee OA is an important OA research objective. Outcomes from this study will provide the first high-quality RCT evidence of the symptomatic and structural benefits of PRP to either support or discourage use of PRP for knee OA. This is important given that several systematic reviews [
22,
45,
46] have highlighted the limited number of RCTs that included a placebo control, all previous trials have a moderate to high risk of bias, and none have included structural outcomes. Likewise, current clinical guidelines vary in their recommendation for PRP, with some not including recommendations either for or against PRP given the lack of evidence [
47,
48], and others recommending against their use [
4]. Findings from the RESTORE trial will, therefore, provide essential information to fill a major evidence gap in the literature and will inform international clinical practice guidelines.