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The management of osteoarthritis in the young and active population is one of the most difficult clinical problems faced by orthopedists and sports medicine physicians today. The use of biological adjuncts, such as hyaluronic acid and platelet-rich plasma, have become popular as a noninvasive management strategy for osteoarthritis. However, clinical data supporting their efficacy remain elusive. As physicians and researchers, we must be critical of ourselves by following our patients carefully and performing the necessary research to determine the appropriate indications for using these treatments. In this regard, investigators should report both positive and negative results, and positive results should be independently verified in the absence of industry or marketing bias.
In this Orthopedics Today Round Table, four internationally recognized sports medicine leaders critically discuss the potential use of these biological treatment strategies in the management of osteoarthritis.
Freddie H. Fu, MD, DSc (Hon), DPs (Hon):What is the science behind using platelet-rich plasma (PRP) and hyaluronic acid (HA) for the treatment of osteoarthritis (OA)?
Annunziato Amendola, MD:There is extensive basic science research on the use of HA in animal models of OA. Other than OA models, there seems to be an explosion of basic science research on the use of PRP in early cartilage lesions, muscle injury and regeneration, tendon and ligament healing which may or may not be applicable to joint OA. Many factors affect the response of the animal and human joint to HA and PRP, including age, degree of joint injury, type and frequency of application, and bias in evaluation. Therefore, it is difficult to make definitive conclusions. In addition, the mechanism of action in which these two compounds work is not clear. It appears that with HA in the animal model there is both a mechanical effect protecting the joint surface and biologic effects reducing inflammation, reducing the rate of degeneration and a regenerative effect.
In terms of clinical science, many HA studies, reviews and recommendations have been published. It has been established that it has a good safety profile and gives temporary pain relief to arthritic knees and possibly other joints. However, most of the early published studies were industry-sponsored trials, and recommendations from the American Academy of Orthopaedic Surgeons a few years ago found the evidence for efficacy of HA inconclusive. Fewer clinical studies on PRP in OA are published and a couple of recent (one level 1 and one level 2) trials comparing HA and PRP were favorable for the use of PRP. In one of the studies, PRP was less efficacious on more arthritic knees.
Lisa R. Callahan, MD:The goal of viscosupplementation therapy is to reproduce viscous properties of synovial fluid, which is disrupted in the degenerative joint. Originally used in Europe and Asia, it was approved by the FDA in 1997 for treatment of knee OA. Since that time, scientific studies have differed in conclusions of this treatment’s efficacy. A recent review in the Annals of Internal Medicine by Anne W.S. Rutjes, PhD, and colleagues suggest that viscosupplementation in patients with knee OA appears to have minimal clinical benefit vs. sham procedures, but is associated with an increased risk for serious adverse events.
It has been proposed that autologous platelet-associated growth factors may have therapeutic effects in OA via multiple mechanisms. Many animal and basic science studies suggest that PRP treatment can improve healing in soft tissue and bone, and physicians have been quick to extend this to use in OA. Although our knowledge is limited by a dearth of large scientific studies in this area, at least one trial found autologous PRP injections had more and longer efficacy than HA injections in reducing pain and symptoms in knee OA.
Jón Karlsson, MD, PhD: There is limited science behind the treatment of OA using PRP and HA. There are both differences and similarities though. HA has been used for a long time, especially in veterinary medicine, often with good clinical success. Around 15 years to 20 years ago its use in humans with OA increased markedly. One of the reasons is because it is a normal lubricant of the body itself, and therefore, never harmful. Several randomized controlled studies comparing HA and saline have been carried out with varying success. Taken together, some of these studies showed good, and sometimes lasting, pain relief. However, most of the studies did not show any major differences compared with placebo. No major adverse events were evident on the other hand. However, due to treatment failure and its high cost, HA treatment disappeared and is used little today.
PRP is more recent and quickly gained popularity in a short time. The hypothesis is that the concentrated growth factors will enhance healing is several parts of the body and PRP might be useful in the treatment of several different diseases. It has been used mostly in patients with tendinopathies, such as Achilles tendinopathy, and less in patients with OA. The scientific evidence for use of PRP in patients with OA is still limited.
Nicola Maffulli, MD, MS, PhD, FRCP, FRCS (Orth), FFSEM: The effectiveness of these products has not been proved yet. Even though PRP is widely used in orthopedic and sports medicine practice, the molecular mechanisms are still unknown and the evidence is questionable. Considering the large number of growth factors contained in PRP formulations, and the fact that many still may not have been identified, it is possible some of them could be anti-inflammatory and reduce the local state of inflammation, and therefore, the level of pain. The action of PRP as a cartilage generator, facilitator or effector is far from being clarified.
There is evidence that some growth factors, such as VEGF, may promote angiogenesis, which predisposes to the development of OA. Therefore, it should be interesting to investigate the effects of PRP formulation where such factors have been removed. However, if we dwell in this other field, we may be contravening World Anti-Doping Agency rules, as a manipulation of the product will have been performed.
Concerning the analgesic action of PRP, the debate is open. PRP might act directly on nociceptors, and the issue of cartilage innervation is still controversial. However, it is possible that the simple injection of PRP, or for this matter any other products, may stress the joint capsule and surrounding soft tissues, leading nociceptive fibers or pain mediator cells to be rearranged to a point where they become silent.
Since HA is normally produced by chondrocytes, it is not surprising that it is expected to be reduced in patients with OA. When injected, HA would vicariate the actions of native HA, lubricate joint surfaces and improve their biomechanics. In addition, it is possible the injection of HA can bring back some life to the remaining chondrocytes to produce further HA. This action has not been proved yet.
Fu:Do you use PRP and/or HA in your practice for the treatment of OA? If yes, what are the indications? If no, why not?
Amendola: I use HA for treating OA (mostly knee OA), but I do not use PRP for OA at this point.
The rationale for using HA is that there appears to be significant basic science that is somewhat chondroprotective. It has been used extensively in clinical studies with few adverse events or complications and some evidence exists for success in multiple studies. Multicompartmental early knee OA in the active patient is common in my practice, which is a difficult population to treat. Great surgical options do not exist in this group, and the mainstay of treatment is modification of activity, physical therapy, NSAIDs and injections. Often when the knee is too painful to do any activity or therapy, muscle weakness ensues making joint function worse. The HA injection often affords a period of pain relief to allow some exercises and return toward more normal biomechanics of the knee joint. The effect may then last longer.
I have not used PRP for knee OA or other joints. Even though there may be some early clinical evidence of some benefit and some basic science support, I am not ready to use for the treatment of knee OA. It is also an out-of-pocket expense at this point.
Callahan:I do not personally use either. I hear lots of anecdotal evidence, but have not seen enough scientific evidence to feel confident recommending either type of injection for OA. These are expensive treatment options. I try to educate patients about the “state of the art,” sharing the knowledge we have and separating it from what we do not know yet. We discuss lifestyle factors that may apply and the pros and cons of various treatment options, including HA and PRP. If a patient is interested in HA or PRP injections, then I refer them to a clinical trial or a colleague who has or is gaining expertise in that particular treatment.
Karlsson:Currently, I do not use either PRP or HA in my practice. The reason why I do not use PRP is because of the limited scientific knowledge. Also, cost probably plays a role. Around 10 years to 15 years ago, I frequently used HA and even conducted a randomized controlled trial where HA was compared with placebo (saline). The most important result of that study was there was no significant difference between HA and placebo in terms of pain relief (12-month follow-up). The interesting thing was the pain relief by using HA was good; however, there was no significant difference compared with placebo after 6 months. This made me stop using HA in patients with knee OA.
Maffulli: We do not use any PRP or HA in our clinical practice. As you know, we are actively engaged in both clinical and basic science research in PRP and HA, but the evidence is such that I remain dubious about their clinical applications. In the United Kingdom, the National Institute of Clinical Excellence is at best skeptical, and this implies that many insurance companies do not finance the use of such products. When this happens, patients are hard-pressed to pay from their own pockets. This limits the use of such products in routine clinical practice.
Fu:Do you believe there is a placebo effect associated with PRP and/or HA in the treatment of OA?
Amendola:I believe there is a placebo effect from injecting a joint with fluid. This has been shown in numerous injections studies comparing steroid injection to saline and HA injections to saline. Nonetheless, the injection of a fluid volume, i.e., HA, will cause some improvement of symptoms at least temporarily, be it weeks to months, in which it will allow the muscular and biomechanical function for the muscles around the joint to function more effectively, and thus reduce some of the pain associated with the OA.
Callahan: It is certainly possible. Studies have shown there is often a placebo effect with any intervention, whether it is conscious belief that a treatment will work, or subconscious associations stemming from the experience of being treated, which can stimulate a variety of physiologic responses, including immune responses and the release of hormones. We would be short-sighted to think these injection therapies are exempt from the mind-body process.
Karlsson: Regarding the placebo effect, it is well known that the placebo effect of any injection is approximately 30%. This was also reflected in the randomized placebo-controlled study I mentioned previously. In other words, there might be major placebo effect. Probably a part of the effect of these drugs is placebo, but hardy all of it.
Maffulli:I have no doubts. The placebo effect of these products or indeed any invasive procedures, including a “simple” injection, has been well proven. According to some researchers, it can account for up to 30% of the efficacy of an injection. One should take this into account when planning studies and interpreting data.
Fu:Is there a potential for negative adverse events or complications associated with the use of PRP and/or HA?
Amendola:In my experience, the complications from PRP or HA are minimal, if any. I have used HA for many years and have not had any negative side effects or complications. The most commonly reported complication of HA from the literature is a local flare, which I believe is due to extra-articular injection.
Making sure the HA is injected intra-articularly is most important. First, obtaining backflow by using some local anesthetic in a separate syringe and then exchanging for the HA syringe avoids any extra-articular injection of HA preventing any undue effects or pain. PRP also has been shown to be safe for injection, but a recent study on systemic effects of soft tissue injection of PRP has shown endogenous growth factors are elevated. Injection of PRP for enthesopathies, plantar fascia or muscular injection can be painful at the time of injection, so it is important to educate the patient.
Callahan:Absolutely. I am sure we have all seen a case of “pseudosepsis” or increased pain after injection. The study by Rutjes and colleagues documents an increased risk for adverse events with HA therapy. We need better trials to help us understand which patients might benefit from which therapeutic options. Beyond the potential for negative consequence to the individual patient, of course, is the potential negative consequence to the entire health care system. Misuse or overuse of HA and PRP adds to the financial strain of an already overburdened system.
Karlsson: The potential for negative adverse events or complications is low. According to scientific reports, the negative adverse events and complications are few and far between. In other words, this risk is low and it is not a case against these drugs.
Maffulli:Negative effects are those reported after an injection: infection, neurovascular injuries, iatrogenic damage to cartilage and menisci, local reaction to the product and inflammation, persistence of pain and symptoms. Some of these adverse events have been well recognized, and, when we undertake studies, we clarify them in advance to the patients. In addition, although not an adverse event, patients should be reminded that not all of them produce PRP despite the appropriate protocols being followed.
Kon E. Arthroscopy. 2011;doi:10.1016/j.arthro.2011.05.011.
For more information:
Annunziato Amendola, MD, can be reached at University of Iowa Sports Medicine, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242; email: email@example.com. Lisa R. Callahan, MD, can be reached at Hospital for Special Surgery, 535 East 70th St., New York, NY 10021; email: firstname.lastname@example.org. Freddie H. Fu, MD, DSc (Hon), DPs (Hon), can be reached at University of Pittsburgh School of Medicine, Department of Orthopaedic Surgery, Kaufmann Medical Building, Suite 1011, 3471 Fifth Ave., Pittsburgh, PA 15213; email: email@example.com. Jón Karlsson, MD, PhD, can be reached at Department of Orthopaedics, Sahlgrenska Academy, University of Gothenburg Sahlgrenska University Hospital, SE-431 80 Mölndal, Sweden; email: firstname.lastname@example.org. Nicola Maffulli, MD, MS, PhD, FRCP, FRCS (Orth), FFSEM, can be reached at London Indpendent Hospital, 1 Beaumont Square, London, Greater London E1 4NL, United Kingdom; email: email@example.com. Disclosures: Amendola, Callahan, Fu and Maffulli have no relevant financial disclosures. Karlsson is Editor-In-Chief of Knee Surgery Sports Traumatology Arthroscopy.
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