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Does platelet-rich plasma have a role in the treatment of osteoarthritis?
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Does platelet-rich plasma have a role in the treatment of osteoarthritis? Paul Ornetti a,b,∗ , Geoffroy Nourissat c,d , Francis Berenbaum d,e , Jérémie Sellam d,e , Pascal Richette f , Xavier Chevalier g , under the aegis of the Osteoarthritis Section of the French Society for Rheumatology (Société Franc¸aise de Rhumatologie, SFR) a
CIC-P Inserm 803, plateforme d’investigation technologique, Dijon University Hospital, 21000 Dijon, France Département de rhumatologie, hôpital universitaire de Dijon, Bocage Central, 14, rue Paul-Gaffarel, 21079 Dijon, France c Département de chirurgie orthopédique, groupe Maussins, 75019 Paris, France d UPMC Paris VI, Inserm UMR-S938, université de la Sorbonne, 75012 Paris, France e Département de rhumatologie, hôpital Saint-Antoine, 75012 Paris, France f Département de rhumatologie, université Paris VII, hôpital Lariboisière, 75010 Paris, France g Département de rhumatologie, université Paris XII, hôpital Henri-Mondor, 94000 Créteil, France b
a r t i c l e Article history: Accepted 2 July 2014 Available online xxx Keywords: Platelet-rich plasma Hip Knee Osteoarthritis Review Treatment
i n f o
a b s t r a c t Platelet-rich plasma (PRP) has been generating considerable attention as an intra-articular treatment to alleviate the symptoms of osteoarthritis. Activated platelets release a host of soluble mediators such as growth factors and cytokines, thereby inducing complex interactions that vary across tissues within the joint. In vivo, PRP may promote chondrocyte proliferation and differentiation. The available data are somewhat conflicting regarding potential effects on synovial cells and angiogenesis modulation. PRP probably exerts an early anti-inflammatory effect, which may be chiefly mediated by inhibition of the NF-B pathway, a hypothesis that requires confirmation by proof-of-concept studies. It is far too early to draw conclusions about the efficacy of PRP as a treatment for hip osteoarthritis. The only randomized trial versus hyaluronic acid showed no significant difference in effects, and no placebo-controlled trials are available. Most of the randomized trials in knee osteoarthritis support a slightly greater effect in alleviating the symptoms compared to visco-supplementation, most notably at the early stages of the disease, although only medium-term data are available. Many uncertainties remain, however, regarding the best administration regimen. Serious adverse effects, including infections and allergies, seem rare, although post-injection pain is more common than with other intra-articular treatments for osteoarthritis. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Osteoarthritis is the most common of all joint diseases and exacts a heavy economic toll due to its high prevalence in the general population and potential for causing progressive disability [1]. To date, the pharmacological armamentarium for osteoarthritis is confined to symptomatic treatments, whose goal is to diminish functional impairments and pain severity. No drugs have been proven capable of inducing clinically relevant chondro-protective effects [2]. Platelet-rich plasma (PRP) was initially used to improve outcomes of dental implant procedures. In recent years, the musculoskeletal effects of PRP have been the focus of considerable interest, most notably in sports medicine and orthopedics [3–5].
∗ Corresponding author. Département de rhumatologie, hôpital universitaire de Dijon, Bocage Central, 14, rue Paul-Gaffarel, 21079 Dijon, France. E-mail address: [email protected] (P. Ornetti).
PRP is autologous plasma enriched in platelets, which can release a host of mediators and growth factors when activated by exogenous agents [6–8]. Numerous clinical trials are under way to determine whether PRP alleviates osteoarthritis symptoms when administered locally either during surgical procedures (application of PRP gel during orthopedic surgery) or as in situ injections (e.g., at sites of tendinopathy or within muscle or cartilage lesions). The results of these trials are conflicting [3,5]. Despite the wealth of recent publications, many uncertainties persist regarding the use of PRP to treat disorders of bone and cartilage [9]. A key issue is the variability in the composition of PRP [10,11]. The platelet concentration in PRP varies 5-fold across studies (from 300,000/mm3 to over 1,500,000/mm3 ). These variations are ascribable to differences in donors, collected blood volumes, agents used for platelet activation (thrombin or calcium chloride), number of centrifugations, and whether the product obtained is frozen. They obviously constitute a major obstacle
http://dx.doi.org/10.1016/j.jbspin.2015.05.002 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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to comparisons and also limit the validity of study results, since neither the in vitro nor the clinical results can be generalized to all PRP preparations [10,12]. In addition, widely variable intraarticular injection schedules are used, although most of them are patterned after those advocated for other intra-articular treatments for osteoarthritis (e.g., corticosteroid or hyaluronic acid), in the absence of pharmacological evidence to support this practice. Additional uncertainties stem from the presumed biological effects of PRP once introduced into the joint cavity. The release by the activated platelets of large numbers of soluble mediators such as growth factors and cytokines results in complex interactions that vary across tissues (cartilage, fibrocartilage, subchondral bone, and synovial membrane) [13]. Furthermore, PRP may exert different effects on a given tissue (e.g., presence or absence of pro-anabolic or anti-inflammatory effects) depending on the concentrations of specific mediators or on the presence of leukocytes in the preparation [7,8]. Nevertheless, this new therapeutic option may hold theoretical appeal in osteoarthritis. PRP therapy involves the direct introduction within the joint of an autologous product that may be capable of limiting the inflammatory response and promoting healing over a fairly long period [4,6]. These theoretical considerations provide a rationale for investigating PRP as a treatment for cartilage disorders, including focal lesions and the diffuse damage seen in osteoarthritis [9,14]. The objective of this article is to review current data on the use of PRP to treat osteoarthritis with the goal of better defining the potential role for PRP within the fairly limited pharmacological armamentarium. 1. What is platelet-rich plasma? 1.1. Regulatory framework The use of autologous platelet products administered by local injection has been authorized in France since the Bioethics Law was passed on August 7, 2004, an amendment to which was introduced in 2007. The French Healthcare Product Safety Agency (ANSM, previously named AFSSAPS) defines PRP as a labile blood product prepared only from autologous material and administered only by local injection. The use of PRP can be a component of standard care. No special expertise is required to use PRP, in contrast to other platelet concentrates. When PRP therapy was first introduced in sports medicine, it was classified among performance enhancers based on its non-negligible growth factor content. In January 2011, the World Anti-Doping Agency removed PRP from the list of banned performance enhancers, and the use of PRP has been allowed by the International Olympic Committee, two changes that have contributed to the rapid development of PRP therapy in sports medicine [12]. 1.2. Background, composition, and nomenclature From a practical viewpoint, about 30 ready-to-use kits are available to facilitate the preparation of PRP from autologous blood without necessarily having to involve a hospital laboratory. The only legal requirement is the use of an accredited centrifuge that complies with European standards. Depending on the preparation method, PRPs may contain up to 10 times the normal platelet concentration, although in most studies the platelet concentration was increased 3-fold to 6-fold [15]. Once separated from the erythrocyte supernatant, the platelet concentrate is activated (with thrombin or calcium chloride) to induce the release of the largest possible amount of mediators. The panel of released mediators, or secretome, can contain up to 800 protein components [10,16].
Table 1 Platelet growth factors present in platelet-rich plasma (PRP), with their main effects. Growth factors
Role in the joint
Transforming growth factor beta (TGF)
Regulates collagen production and proteoglycan synthesis Promotes chondrocyte proliferation and differentiation Stimulates angiogenesis Regulates the release of other growth factors Inhibits the pro-inflammatory NF-B pathway Stimulates angiogenesis Increases angiogenesis and blood vessel permeability Promotes endothelial cell proliferation Increases angiogenesis Promotes fibroblast and osteoblast proliferation and differentiation Regulates collagen production and proteoglycan synthesis Inhibits the pro-inflammatory NF-B pathway Stimulates osteoblast and chondrocyte proliferation and differentiation Stimulates the production of extracellular matrix Promotes chondrocyte and mesenchymatous stem cell differentiation Stimulates chondrocyte proliferation Stimulates hyaluronic acid production by synovial cells Increases angiogenesis Stimulates angiogenesis Promotes chondrocyte differentiation Promotes platelet adhesion
Hepatocyte growth factor (HGF) Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF)
Insulin-like growth factor (IGF)
Fibroblast Growth Factor-2 (FGF)
Connective tissue growth factor (CTGF)
The main components include growth factors (Table 1), soluble mediators involved in resolution of the inflammatory response (interleukin-1 receptor antagonist [IL-1-RA], IL-4, IL-8, IL-10, arachidonic acid metabolites, and others), pro-inflammatory mediators (IL-1, IL-6, TNF, alpha-2-macroglobulin, and others), and mediators that modulate angiogenesis and coagulation [17]. Some PRPs also contain various amounts of cells belonging to the leukocyte lineage (L-PRP) and capable of producing metalloproteinases and free radicals that exert deleterious effects on the joint and may increase the risk of post-injection pain. Nevertheless, L-PRP may exert beneficial anti-microbial effects at the injection site [18]. The variability of the cell composition of PRP has prompted the development of an international classification system, known as PAW [19] and based on three characteristics: the absolute platelet count, rated from low (P1) to high (P4, more than 4-fold the normal count); the manner in which platelet activation is induced; and the presence or absence of white blood cells. When comparing the results of clinical studies, the PAW classification must be taken into account to avoid drawing incorrect conclusions. 1.3. Precautions for use No absolute medical contraindications to the use of PRP therapy have been identified [3]. The use of autologous blood to prepare PRP eliminates all risk of incompatibility and of transmission of blood borne microorganisms [15]. However, few studies have assessed changes over time in PRP contents depending on storage duration and conditions (freezing) [10]. In addition, as PRP contains growth factors, which may have effects on carcinogenesis, an often cited precaution consists in avoiding PRP injection in the vicinity of malignant or dysplastic tissues. Furthermore, non-steroidal anti-inflammatory drugs inhibit platelet function and consequently should not be applied near or at the injection site within 48 hours to 1 week of the injection [20]. The absence of reported serious adverse events may seem reassuring, given the broad spectrum of situations in which PRP is
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now used to treat osteoarticular conditions. A surprising fact, however, is the absence of reported cases of septic arthritis, which is a well-known complication of intra-articular injections, although anti-microbial effects of PRP have been suggested [18,21]. The most often reported adverse effect is pain, which seems more common after intra-articular injection of PRP than of corticosteroids or hyaluronic acid [7,9] and correlates with the platelet concentration [20]. The routine use of ultrasound guidance to ensure proper needle position before injecting PRP has been recommended [22]. 2. Key data in osteoarthritis Fig. 1 indicates the main components of PRP after activation of the platelet pool. The concentrate of soluble mediators released by activated platelets interacts with the various tissues involved in the osteoarthritis process (cartilage, synovial membrane, synovial fluid, and subchondral bone). However, given the large number of mediators and complexity of the interactions, elucidating the exact effects is difficult both in vitro and in vivo. 2.1. Chondrocytes and extracellular matrix In most of the available in vitro studies, PRP promoted the proliferation of animal or human chondrocytes [23–28]. This effect may depend on the platelet concentration [20]. A similar mitogenic effect has been demonstrated on cultured fibrocartilage cells from menisci and on mesenchymatous stem cells [14,26,29]. In addition, PRP may promote the recruitment of mesenchymatous stem cells, their adhesion, and their differentiation toward a chondrocyte phenotype [27,28,30,31]. An anabolic effect of chondrocytes on proteoglycan and collagen type II synthesis was found in some studies, both in vitro and in animal models [24,32], but not in others [26,28]. Few data are available on the duration of these effects on chondrocytes [27]. Studies in some animal models of osteoarthritis suggest a short-term decrease in the rate of cartilage loss [33,34]. Longer-term studies in larger samples are needed to confirm these results. 2.2. Synoviocytes and synovial fluid Published data about potential PRP effects on the synovial membrane are considerably less numerous and more conflicting. Osteoarthritis is characterized by active cross-talk between the cartilage and synovial membrane [35]. A significant increase in the production of hyaluronic acid by type B synoviocytes has been reported after the addition of PRP during knee arthroplasty for osteoarthritis [36]. PRP may also promote the production by synoviocytes of hepatocyte growth factor (HGF), which is known to limit the inflammatory response within the synovial membrane [36–38]. In these studies, the production by synoviocytes of procatabolic enzymes such as MMP1 and MMP3 was not increased. In contrast, other studies documented significant increases in the production of several metalloproteinases (MMP1 and MMP9) and pro-inflammatory cytokines (TNF, IL-6, and IL-1) by the synovial membrane [39]. 2.3. Angiogenesis and joint inflammation PRP contains proangiogenic growth factors (VEGF, PDGF, TGF, and FGF) that may play a role in the healing process after damage to several tissue types (e.g., tendons and muscle fibers) [17,30]. Uncontrolled angiogenesis, however, can exert deleterious effects in osteoarthritis by contributing to perpetuate the inflammatory process, most notably via the effects of VEGF and TGF. In several in vitro studies, neither VEGF nor TGF levels increased in response to PRP [36,38]. This limited angiogenic effect despite the presence
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of proangiogenic factors may be partly ascribable to the presence among the many mediators released by platelets of angiogenesis inhibitors such as platelet factor 4 and thrombospondin 1 [7,8]. The effects of PRP on synovial inflammation are complex and vary over time, as well as with the platelet concentration and presence or absence of leukocytes (L-PRP). Thus, some PRP components have pro-inflammatory effects, such as the cytokines IL-1 and TNF␣ and the proteins contained in alpha-granules (␣2macroglobulin and vitamin D binding protein) [8]. Nevertheless, most of the in vitro results support fairly prolonged blunting of the inflammatory response due, in particular, to a decrease in the deleterious pro-inflammatory effects of IL-1 [17,31,37]. This antiinflammatory effect may be chiefly ascribable to inhibition of the NF-B pathway, which is one of the key pathways involved in the pathogenesis of osteoarthritis [40,41]. This effect may be promoted by increased production by synoviocytes of insulin-like growth factor (IGF) and HGF, which are potent NF-B pathway inhibitors [36,42]. Many unresolved issues remain regarding the in vitro antiinflammatory effect of PRP. Further investigations are needed via both in vitro approaches and therapeutic trials in animals and humans [4,6,8]. 3. Clinical data in osteoarthritis The flurry of clinical trials performed over the last 5 years reflects the high level of interest in this new symptomatic treatment option. Most of these trials used an open-label design and focused on knee osteoarthritis. Few studies have been conducted in hip osteoarthritis (only two open-label trials and a single recent randomized trial, which compared PRP to hyaluronic acid [43–45]). 3.1. PRP therapy in hip osteoarthritis Two open-label studies in small samples (n = 20 and n = 40, respectively) are available [43,44]. In the first trial, patients with symptomatic hip osteoarthritis received three ultrasoundguided intra-articular injections of 5 mL of PRP 15 days apart. The PRP platelet count is not specified in the study report. Scores for pain and function (WOMAC and Harris) showed significant improvements after 3 months (P < 0.05) and smaller but still significant improvements after 12 months. Half the patients reported injection-related pain, which resolved within 48 h with analgesic therapy. The same investigators recently reported a randomized trial versus high-molecular-weight hyaluronic acid in a total of 100 patients. Each patient received three injections at 15-day intervals. The symptoms were similarly alleviated in both groups, with no significant superiority of PRP, despite the limited efficacy of hyaluronic acid in available studies of hip osteoarthritis. The second trial used a similar regimen of three injections separated by 1-week intervals but with a higher volume of 8 mL per injection. After 7 weeks and 6 months, the visual analog scale (VAS) pain score, WOMAC, and Harris score were determined. At the month-time point, 57% of patients exhibited a response defined as a greater than 30% decrease in the VAS pain score. Of the 11 non-responders, 10 belonged to the subgroup characterized by advanced radiological changes (Tonnis 3). Although the VAS pain score decreases were statistically significant after 7 weeks and 6 months, they were not clinically relevant (mean improvement < 15/100). A transient sensation of heaviness in the hip after the injections was a frequent complaint. One patient experienced a generalized cutaneous allergic reaction that resolved spontaneously [44]. In the only randomized controlled trial of PRP in hip osteoarthritis, which was published recently [45], 100 patients were allocated at random to PRP or high-molecular-weight hyaluronic acid. In both
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Fig. 1. Main components of platelet-rich plasma (PRP), with their potential effects on the osteoarthritis process.
groups, the patients received three ultrasound-guided injections 15 days apart. Significant improvements in pain (VAS score) and function (Harris score) were documented in both groups after 1 month then after 3 and 6 months. The improvements were less marked after 12 months but remained statistically significant compared to baseline. No differences were found between the two groups in any of the disease severity subgroups (Kellgren II to IV). This result should be interpreted in the light of randomized trials showing that hyaluronic acid is not superior over a placebo in hip osteoarthritis. Post-injection pain was twice as common with PRP as with hyaluronic acid (P < 0.05).
3.2. PRP in knee osteoarthritis A literature review [9] identified over 20 open-label studies, often with several studies performed by the same groups. The results suggest efficacy in improving both pain and function. The many limitations of these studies include heterogeneity in the patient populations, differences in the PRP administration regimens (amount and concentration of the PRP preparation and number and spacing of the injections), and a follow-up duration usually no longer than 1 year. The only study that assessed potential structural effects of PRP on early knee osteoarthritis (Kellgren I or II) used a prospective open-label design and showed absence of cartilage damage progression detectable by magnetic resonance imaging in 73% of patients [46]. Nevertheless, the level of evidence from this study is low, given the small sample size of only 20 patients and the study design. A more accurate assessment of the risk/benefit ratio of PRP therapy in knee osteoarthritis requires an analysis confined to randomized controlled trials, of which seven have been published to date, including a Korean trial that is not assessable. Oddly enough, none of these trials compared PRP to
intra-articular corticosteroid therapy, which is among the standard symptomatic treatments for knee osteoarthritis. A single randomized controlled trial compared PRP to a placebo (intra-articular saline) [47]. This trial included 78 patients with bilateral osteoarthritis who were allocated at random to treatment of both knees with a single PRP injection, two PRP injections, or a single saline injection. Thus, full blinding was not feasible. The two PRP groups showed statistically significant and similar changes after 12 and 24 weeks in the primary outcome measure (VAS pain score) and secondary outcome measures (WOMAC domains). Pain exacerbation occurred only in the PRP groups and was more common when two injections were given (44% versus 22% with a single injection, P < 0.05). The unusual study design, single-center patient recruitment, limited statistical power, and absence of change in the placebo group call into question the authors’ conclusion that PRP is superior over a placebo. The occurrence of pain exacerbation in the placebo group of intraarticular therapy for knee osteoarthritis challenges the validity of the study design, particularly regarding blinding of the patients and evaluators. The five other randomized controlled trials compared PRP to hyaluronic acid. Each included about 100 patients. The study designs were similar regarding the measures of pain and function used to assess efficacy, as well as the PRP regimen (1-week interval between injections, as with hyaluronic acid). Differences occurred, however, in PRP preparation and composition, a fact that hinders comparisons and invalidates the results of a recent meta-analysis [48]. In the first study of PRP versus hyaluronic acid [49], 60 patients were allocated to each group (mean age, 66 years; Kellgren I to III) and received four injections of either PRP containing leukocytes (L-PRP) or hyaluronic acid. The WOMAC was administered after 4, 12, and 24 weeks. The symptoms improved significantly in both groups versus baseline and these improvements were significantly
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greater in the PRP group after 12 and 24 weeks. The between-group differences were greatest in the patients with severe structural damage (Kellgren III). In the second study [50], 55 patients in each group received three injections of PRP or hyaluronic acid 1 week apart. The KOOS, IKDC score, and motion range were determined after 2, 6, and 12 months. No significant difference was demonstrated between the two groups. An early symptomatic effect was noted in both groups and was sustained after 1 year. This improvement seemed greatest in the patients with early disease (Kellgren I or II) who were treated with PRP. Tolerance was slightly less satisfactory in the PRP group, in which a higher proportion of patients experienced post-injection pain. The third study [51] did not use random allocation. Instead, three centers recruited patients, and each center used one of the following treatments: PRP, low-molecular-weight hyaluronic acid, and high-molecular-weight hyaluronic acid. After 2 months, the VAS pain score and IKDC score were significantly improved in the PRP and low-molecular-weight hyaluronic acid groups compared to the high-molecular-weight hyaluronic acid group. After 6 months, the patients given PRP exhibited significantly greater symptom relief than did those in the two hyaluronic acid groups. Factors associated with a good response to PRP therapy were age < 50 years and limited structural damage. The fourth trial [52] included 176 patients allocated at random to hyaluronic acid or PRP (platelet concentration more than 5-fold the normal value). Both treatments were administered as three injections 1 week apart. The primary outcome measure was the proportion of patients with an at least 50% decrease in the WOMAC pain score after 24 weeks. The secondary outcome measures were the OARSI response rate, other WOMAC scores, and Lequesne index. The primary outcome measure showed a difference in favor of PRP of borderline significance (34% ± 38% vs. 21% ± 24% of responders, P = 0.05). No differences were found for any of the secondary outcome measures, including analgesic consumption. Finally, a randomized trial [53] compared 60 patients given PRP (4-fold the normal platelet concentration) to 60 patients given hyaluronic acid, with three injections 1 week apart in both groups. The VAS pain score and total WOMAC showed significantly greater improvements in the PRP group after 3 months, and this difference was sustained after 6 months. Post-injection pain was reported by 6 patients in the PRP group and resolved within 48 hours. The data on PRP therapy for osteoarthritis at other sites are more limited. The recent body of evidence consists chiefly of open-label studies in small numbers of patients. The only exception is a randomized controlled trial of PRP versus hyaluronic acid in 32 patients with osteochondral lesions of the tibiotalar joint [54]. The results suggest a greater effect of PRP in improving pain and function.
4. PRP to treat osteoarthritis: take-home messages Although the therapeutic armamentarium for osteoarthritis is still limited, a number of uncertainties persist regarding the potential benefits from extending it to PRP. These uncertainties have not yet been resolved by the growing body of clinical evidence about PRP therapy in osteoarthritis, as well as in focal cartilage lesions [4,9,20]. The available evidence does not support the use of PRP as a first- or second-line treatment for lower-limb osteoarthritis. On the regulatory front, commendable efforts have been made to develop an unequivocal international classification system [19], which is of considerable assistance for navigating what has been termed the “PRP jungle” [15]. This system serves to determine when differences in PRP preparations preclude comparisons between studies. The readiness shown by regulatory agencies to approve the use of this innovative product obtained from labile
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blood products without requiring the usual preclinical and clinical validation studies is somewhat surprising. A pharmacological rationale for using PRP to treat degenerative joint diseases is difficult to establish, given the large number of compounds released by activated platelets and the complexity of their effects, which vary not only with the target tissue, but also with the concentration [8]. Thus, the often-cited anti-inflammatory and visco-inducing effects of PRP have not been firmly established by in vitro studies. Proof-of-concept studies are needed to answer the many open questions about the rationale for using PRP to treat osteoarthritis. The available data are not sufficient to allow conclusions about the efficacy of PRP in hip osteoarthritis. The only randomized trial reported to date compared PRP to hyaluronic acid, and no studies have used a placebo as the comparator [43,44]. Most of the randomized trials in patients with knee osteoarthritis support a slightly better symptomatic effect compared to hyaluronic acid, at least in patients with early disease and within the limited study follow-ups (usually 6 months). However, the designs of these trials were not always well suited to the demonstration of non-inferiority, and caution is in order given the well-demonstrated strong placebo effect of intra-articular injections in osteoarthritis [55]. The safety data suggest low frequencies of serious adverse events, including infections and allergic reactions. Post-injection pain may be more common and more severe with PRP than with hyaluronic acid. Despite these gaps in knowledge, it would be inappropriate to discard a novel therapeutic option that complements established treatments for lower-limb osteoarthritis, particularly as new developments can be expected in the near future [56]. Rheumatologists should therefore direct sufficient interest to PRP therapy and participate in multicenter randomized clinical trials in large numbers of patients, which are needed to assess the potential usefulness of PRP therapy in osteoarthritis. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Guillemin F, Rat A-C, Roux CH, et al. The KHOALA cohort of knee and hip osteoarthritis in France. Joint Bone Spine 2012;79:597–603. [2] Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis. Osteoarthritis Cartilage 2010;18:476–99. [3] Smets F, Croisier J-L, Forthomme B. Applications cliniques du plasma riche en plaquettes (PRP) dans les lésions tendineuses : revue de la littérature. Sci Sports 2012;27:141–53. [4] Xie X, Zhang C, Tuan RS. Biology of platelet-rich plasma and its clinical application in cartilage repair. Arthritis Res Ther 2014;16:204. [5] Sheth U, Simunovic N, Klein G, et al. Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. J Bone Joint Surg 2012;94:298–307. [6] Andia I, Sánchez M, Maffulli N. Joint pathology and platelet-rich plasma therapies. Expert Opin Biol Ther 2012;12:7–22. [7] Anitua E, Sanchez M, Nurden AT, et al. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227–34. [8] Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 2013;9:721–30. [9] Zhu Y, Yuan M, Meng HY, et al. Basic science and clinical application of plateletrich plasma for cartilage defects and osteoarthritis: a review. Osteoarthritis Cartilage 2013;21:1627–37. [10] Malgoyre A, Bigard X, Alonso A, et al. Variabilité des compositions cellulaire et moléculaire des extraits de concentrés plaquettaires (platelet-rich plasma, PRP). J Traumatol Sport 2012;29:236–40. [11] Sundman EA, Cole BJ, Fortier LA. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med 2011;39:2135–40. [12] Fortier LA, Hackett CH, Cole BJ. The effects of platelet-rich plasma on cartilage: basic science and clinical application. Oper Tech Sports Med 2011;19:154–9. [13] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 2010;6:625–35.
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Does platelet-rich plasma have a role in the treatment of osteoarthritis? Paul Ornetti a,b,∗ , Geoffroy Nourissat c,d , Francis Berenbaum d,e , Jérémie Sellam d,e , Pascal Richette f , Xavier Chevalier g , under the aegis of the Osteoarthritis Section of the French Society for Rheumatology (Société Franc¸aise de Rhumatologie, SFR) a
CIC-P Inserm 803, plateforme d’investigation technologique, Dijon University Hospital, 21000 Dijon, France Département de rhumatologie, hôpital universitaire de Dijon, Bocage Central, 14, rue Paul-Gaffarel, 21079 Dijon, France c Département de chirurgie orthopédique, groupe Maussins, 75019 Paris, France d UPMC Paris VI, Inserm UMR-S938, université de la Sorbonne, 75012 Paris, France e Département de rhumatologie, hôpital Saint-Antoine, 75012 Paris, France f Département de rhumatologie, université Paris VII, hôpital Lariboisière, 75010 Paris, France g Département de rhumatologie, université Paris XII, hôpital Henri-Mondor, 94000 Créteil, France b
a r t i c l e Article history: Accepted 2 July 2014 Available online xxx Keywords: Platelet-rich plasma Hip Knee Osteoarthritis Review Treatment
i n f o
a b s t r a c t Platelet-rich plasma (PRP) has been generating considerable attention as an intra-articular treatment to alleviate the symptoms of osteoarthritis. Activated platelets release a host of soluble mediators such as growth factors and cytokines, thereby inducing complex interactions that vary across tissues within the joint. In vivo, PRP may promote chondrocyte proliferation and differentiation. The available data are somewhat conflicting regarding potential effects on synovial cells and angiogenesis modulation. PRP probably exerts an early anti-inflammatory effect, which may be chiefly mediated by inhibition of the NF-B pathway, a hypothesis that requires confirmation by proof-of-concept studies. It is far too early to draw conclusions about the efficacy of PRP as a treatment for hip osteoarthritis. The only randomized trial versus hyaluronic acid showed no significant difference in effects, and no placebo-controlled trials are available. Most of the randomized trials in knee osteoarthritis support a slightly greater effect in alleviating the symptoms compared to visco-supplementation, most notably at the early stages of the disease, although only medium-term data are available. Many uncertainties remain, however, regarding the best administration regimen. Serious adverse effects, including infections and allergies, seem rare, although post-injection pain is more common than with other intra-articular treatments for osteoarthritis. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Osteoarthritis is the most common of all joint diseases and exacts a heavy economic toll due to its high prevalence in the general population and potential for causing progressive disability [1]. To date, the pharmacological armamentarium for osteoarthritis is confined to symptomatic treatments, whose goal is to diminish functional impairments and pain severity. No drugs have been proven capable of inducing clinically relevant chondro-protective effects [2]. Platelet-rich plasma (PRP) was initially used to improve outcomes of dental implant procedures. In recent years, the musculoskeletal effects of PRP have been the focus of considerable interest, most notably in sports medicine and orthopedics [3–5].
∗ Corresponding author. Département de rhumatologie, hôpital universitaire de Dijon, Bocage Central, 14, rue Paul-Gaffarel, 21079 Dijon, France. E-mail address: [email protected] (P. Ornetti).
PRP is autologous plasma enriched in platelets, which can release a host of mediators and growth factors when activated by exogenous agents [6–8]. Numerous clinical trials are under way to determine whether PRP alleviates osteoarthritis symptoms when administered locally either during surgical procedures (application of PRP gel during orthopedic surgery) or as in situ injections (e.g., at sites of tendinopathy or within muscle or cartilage lesions). The results of these trials are conflicting [3,5]. Despite the wealth of recent publications, many uncertainties persist regarding the use of PRP to treat disorders of bone and cartilage [9]. A key issue is the variability in the composition of PRP [10,11]. The platelet concentration in PRP varies 5-fold across studies (from 300,000/mm3 to over 1,500,000/mm3 ). These variations are ascribable to differences in donors, collected blood volumes, agents used for platelet activation (thrombin or calcium chloride), number of centrifugations, and whether the product obtained is frozen. They obviously constitute a major obstacle
http://dx.doi.org/10.1016/j.jbspin.2015.05.002 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
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to comparisons and also limit the validity of study results, since neither the in vitro nor the clinical results can be generalized to all PRP preparations [10,12]. In addition, widely variable intraarticular injection schedules are used, although most of them are patterned after those advocated for other intra-articular treatments for osteoarthritis (e.g., corticosteroid or hyaluronic acid), in the absence of pharmacological evidence to support this practice. Additional uncertainties stem from the presumed biological effects of PRP once introduced into the joint cavity. The release by the activated platelets of large numbers of soluble mediators such as growth factors and cytokines results in complex interactions that vary across tissues (cartilage, fibrocartilage, subchondral bone, and synovial membrane) [13]. Furthermore, PRP may exert different effects on a given tissue (e.g., presence or absence of pro-anabolic or anti-inflammatory effects) depending on the concentrations of specific mediators or on the presence of leukocytes in the preparation [7,8]. Nevertheless, this new therapeutic option may hold theoretical appeal in osteoarthritis. PRP therapy involves the direct introduction within the joint of an autologous product that may be capable of limiting the inflammatory response and promoting healing over a fairly long period [4,6]. These theoretical considerations provide a rationale for investigating PRP as a treatment for cartilage disorders, including focal lesions and the diffuse damage seen in osteoarthritis [9,14]. The objective of this article is to review current data on the use of PRP to treat osteoarthritis with the goal of better defining the potential role for PRP within the fairly limited pharmacological armamentarium. 1. What is platelet-rich plasma? 1.1. Regulatory framework The use of autologous platelet products administered by local injection has been authorized in France since the Bioethics Law was passed on August 7, 2004, an amendment to which was introduced in 2007. The French Healthcare Product Safety Agency (ANSM, previously named AFSSAPS) defines PRP as a labile blood product prepared only from autologous material and administered only by local injection. The use of PRP can be a component of standard care. No special expertise is required to use PRP, in contrast to other platelet concentrates. When PRP therapy was first introduced in sports medicine, it was classified among performance enhancers based on its non-negligible growth factor content. In January 2011, the World Anti-Doping Agency removed PRP from the list of banned performance enhancers, and the use of PRP has been allowed by the International Olympic Committee, two changes that have contributed to the rapid development of PRP therapy in sports medicine [12]. 1.2. Background, composition, and nomenclature From a practical viewpoint, about 30 ready-to-use kits are available to facilitate the preparation of PRP from autologous blood without necessarily having to involve a hospital laboratory. The only legal requirement is the use of an accredited centrifuge that complies with European standards. Depending on the preparation method, PRPs may contain up to 10 times the normal platelet concentration, although in most studies the platelet concentration was increased 3-fold to 6-fold [15]. Once separated from the erythrocyte supernatant, the platelet concentrate is activated (with thrombin or calcium chloride) to induce the release of the largest possible amount of mediators. The panel of released mediators, or secretome, can contain up to 800 protein components [10,16].
Table 1 Platelet growth factors present in platelet-rich plasma (PRP), with their main effects. Growth factors
Role in the joint
Transforming growth factor beta (TGF)
Regulates collagen production and proteoglycan synthesis Promotes chondrocyte proliferation and differentiation Stimulates angiogenesis Regulates the release of other growth factors Inhibits the pro-inflammatory NF-B pathway Stimulates angiogenesis Increases angiogenesis and blood vessel permeability Promotes endothelial cell proliferation Increases angiogenesis Promotes fibroblast and osteoblast proliferation and differentiation Regulates collagen production and proteoglycan synthesis Inhibits the pro-inflammatory NF-B pathway Stimulates osteoblast and chondrocyte proliferation and differentiation Stimulates the production of extracellular matrix Promotes chondrocyte and mesenchymatous stem cell differentiation Stimulates chondrocyte proliferation Stimulates hyaluronic acid production by synovial cells Increases angiogenesis Stimulates angiogenesis Promotes chondrocyte differentiation Promotes platelet adhesion
Hepatocyte growth factor (HGF) Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF)
Insulin-like growth factor (IGF)
Fibroblast Growth Factor-2 (FGF)
Connective tissue growth factor (CTGF)
The main components include growth factors (Table 1), soluble mediators involved in resolution of the inflammatory response (interleukin-1 receptor antagonist [IL-1-RA], IL-4, IL-8, IL-10, arachidonic acid metabolites, and others), pro-inflammatory mediators (IL-1, IL-6, TNF, alpha-2-macroglobulin, and others), and mediators that modulate angiogenesis and coagulation [17]. Some PRPs also contain various amounts of cells belonging to the leukocyte lineage (L-PRP) and capable of producing metalloproteinases and free radicals that exert deleterious effects on the joint and may increase the risk of post-injection pain. Nevertheless, L-PRP may exert beneficial anti-microbial effects at the injection site [18]. The variability of the cell composition of PRP has prompted the development of an international classification system, known as PAW [19] and based on three characteristics: the absolute platelet count, rated from low (P1) to high (P4, more than 4-fold the normal count); the manner in which platelet activation is induced; and the presence or absence of white blood cells. When comparing the results of clinical studies, the PAW classification must be taken into account to avoid drawing incorrect conclusions. 1.3. Precautions for use No absolute medical contraindications to the use of PRP therapy have been identified [3]. The use of autologous blood to prepare PRP eliminates all risk of incompatibility and of transmission of blood borne microorganisms [15]. However, few studies have assessed changes over time in PRP contents depending on storage duration and conditions (freezing) [10]. In addition, as PRP contains growth factors, which may have effects on carcinogenesis, an often cited precaution consists in avoiding PRP injection in the vicinity of malignant or dysplastic tissues. Furthermore, non-steroidal anti-inflammatory drugs inhibit platelet function and consequently should not be applied near or at the injection site within 48 hours to 1 week of the injection [20]. The absence of reported serious adverse events may seem reassuring, given the broad spectrum of situations in which PRP is
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now used to treat osteoarticular conditions. A surprising fact, however, is the absence of reported cases of septic arthritis, which is a well-known complication of intra-articular injections, although anti-microbial effects of PRP have been suggested [18,21]. The most often reported adverse effect is pain, which seems more common after intra-articular injection of PRP than of corticosteroids or hyaluronic acid [7,9] and correlates with the platelet concentration [20]. The routine use of ultrasound guidance to ensure proper needle position before injecting PRP has been recommended [22]. 2. Key data in osteoarthritis Fig. 1 indicates the main components of PRP after activation of the platelet pool. The concentrate of soluble mediators released by activated platelets interacts with the various tissues involved in the osteoarthritis process (cartilage, synovial membrane, synovial fluid, and subchondral bone). However, given the large number of mediators and complexity of the interactions, elucidating the exact effects is difficult both in vitro and in vivo. 2.1. Chondrocytes and extracellular matrix In most of the available in vitro studies, PRP promoted the proliferation of animal or human chondrocytes [23–28]. This effect may depend on the platelet concentration [20]. A similar mitogenic effect has been demonstrated on cultured fibrocartilage cells from menisci and on mesenchymatous stem cells [14,26,29]. In addition, PRP may promote the recruitment of mesenchymatous stem cells, their adhesion, and their differentiation toward a chondrocyte phenotype [27,28,30,31]. An anabolic effect of chondrocytes on proteoglycan and collagen type II synthesis was found in some studies, both in vitro and in animal models [24,32], but not in others [26,28]. Few data are available on the duration of these effects on chondrocytes [27]. Studies in some animal models of osteoarthritis suggest a short-term decrease in the rate of cartilage loss [33,34]. Longer-term studies in larger samples are needed to confirm these results. 2.2. Synoviocytes and synovial fluid Published data about potential PRP effects on the synovial membrane are considerably less numerous and more conflicting. Osteoarthritis is characterized by active cross-talk between the cartilage and synovial membrane [35]. A significant increase in the production of hyaluronic acid by type B synoviocytes has been reported after the addition of PRP during knee arthroplasty for osteoarthritis [36]. PRP may also promote the production by synoviocytes of hepatocyte growth factor (HGF), which is known to limit the inflammatory response within the synovial membrane [36–38]. In these studies, the production by synoviocytes of procatabolic enzymes such as MMP1 and MMP3 was not increased. In contrast, other studies documented significant increases in the production of several metalloproteinases (MMP1 and MMP9) and pro-inflammatory cytokines (TNF, IL-6, and IL-1) by the synovial membrane [39]. 2.3. Angiogenesis and joint inflammation PRP contains proangiogenic growth factors (VEGF, PDGF, TGF, and FGF) that may play a role in the healing process after damage to several tissue types (e.g., tendons and muscle fibers) [17,30]. Uncontrolled angiogenesis, however, can exert deleterious effects in osteoarthritis by contributing to perpetuate the inflammatory process, most notably via the effects of VEGF and TGF. In several in vitro studies, neither VEGF nor TGF levels increased in response to PRP [36,38]. This limited angiogenic effect despite the presence
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of proangiogenic factors may be partly ascribable to the presence among the many mediators released by platelets of angiogenesis inhibitors such as platelet factor 4 and thrombospondin 1 [7,8]. The effects of PRP on synovial inflammation are complex and vary over time, as well as with the platelet concentration and presence or absence of leukocytes (L-PRP). Thus, some PRP components have pro-inflammatory effects, such as the cytokines IL-1 and TNF␣ and the proteins contained in alpha-granules (␣2macroglobulin and vitamin D binding protein) [8]. Nevertheless, most of the in vitro results support fairly prolonged blunting of the inflammatory response due, in particular, to a decrease in the deleterious pro-inflammatory effects of IL-1 [17,31,37]. This antiinflammatory effect may be chiefly ascribable to inhibition of the NF-B pathway, which is one of the key pathways involved in the pathogenesis of osteoarthritis [40,41]. This effect may be promoted by increased production by synoviocytes of insulin-like growth factor (IGF) and HGF, which are potent NF-B pathway inhibitors [36,42]. Many unresolved issues remain regarding the in vitro antiinflammatory effect of PRP. Further investigations are needed via both in vitro approaches and therapeutic trials in animals and humans [4,6,8]. 3. Clinical data in osteoarthritis The flurry of clinical trials performed over the last 5 years reflects the high level of interest in this new symptomatic treatment option. Most of these trials used an open-label design and focused on knee osteoarthritis. Few studies have been conducted in hip osteoarthritis (only two open-label trials and a single recent randomized trial, which compared PRP to hyaluronic acid [43–45]). 3.1. PRP therapy in hip osteoarthritis Two open-label studies in small samples (n = 20 and n = 40, respectively) are available [43,44]. In the first trial, patients with symptomatic hip osteoarthritis received three ultrasoundguided intra-articular injections of 5 mL of PRP 15 days apart. The PRP platelet count is not specified in the study report. Scores for pain and function (WOMAC and Harris) showed significant improvements after 3 months (P < 0.05) and smaller but still significant improvements after 12 months. Half the patients reported injection-related pain, which resolved within 48 h with analgesic therapy. The same investigators recently reported a randomized trial versus high-molecular-weight hyaluronic acid in a total of 100 patients. Each patient received three injections at 15-day intervals. The symptoms were similarly alleviated in both groups, with no significant superiority of PRP, despite the limited efficacy of hyaluronic acid in available studies of hip osteoarthritis. The second trial used a similar regimen of three injections separated by 1-week intervals but with a higher volume of 8 mL per injection. After 7 weeks and 6 months, the visual analog scale (VAS) pain score, WOMAC, and Harris score were determined. At the month-time point, 57% of patients exhibited a response defined as a greater than 30% decrease in the VAS pain score. Of the 11 non-responders, 10 belonged to the subgroup characterized by advanced radiological changes (Tonnis 3). Although the VAS pain score decreases were statistically significant after 7 weeks and 6 months, they were not clinically relevant (mean improvement < 15/100). A transient sensation of heaviness in the hip after the injections was a frequent complaint. One patient experienced a generalized cutaneous allergic reaction that resolved spontaneously [44]. In the only randomized controlled trial of PRP in hip osteoarthritis, which was published recently [45], 100 patients were allocated at random to PRP or high-molecular-weight hyaluronic acid. In both
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Fig. 1. Main components of platelet-rich plasma (PRP), with their potential effects on the osteoarthritis process.
groups, the patients received three ultrasound-guided injections 15 days apart. Significant improvements in pain (VAS score) and function (Harris score) were documented in both groups after 1 month then after 3 and 6 months. The improvements were less marked after 12 months but remained statistically significant compared to baseline. No differences were found between the two groups in any of the disease severity subgroups (Kellgren II to IV). This result should be interpreted in the light of randomized trials showing that hyaluronic acid is not superior over a placebo in hip osteoarthritis. Post-injection pain was twice as common with PRP as with hyaluronic acid (P < 0.05).
3.2. PRP in knee osteoarthritis A literature review [9] identified over 20 open-label studies, often with several studies performed by the same groups. The results suggest efficacy in improving both pain and function. The many limitations of these studies include heterogeneity in the patient populations, differences in the PRP administration regimens (amount and concentration of the PRP preparation and number and spacing of the injections), and a follow-up duration usually no longer than 1 year. The only study that assessed potential structural effects of PRP on early knee osteoarthritis (Kellgren I or II) used a prospective open-label design and showed absence of cartilage damage progression detectable by magnetic resonance imaging in 73% of patients [46]. Nevertheless, the level of evidence from this study is low, given the small sample size of only 20 patients and the study design. A more accurate assessment of the risk/benefit ratio of PRP therapy in knee osteoarthritis requires an analysis confined to randomized controlled trials, of which seven have been published to date, including a Korean trial that is not assessable. Oddly enough, none of these trials compared PRP to
intra-articular corticosteroid therapy, which is among the standard symptomatic treatments for knee osteoarthritis. A single randomized controlled trial compared PRP to a placebo (intra-articular saline) [47]. This trial included 78 patients with bilateral osteoarthritis who were allocated at random to treatment of both knees with a single PRP injection, two PRP injections, or a single saline injection. Thus, full blinding was not feasible. The two PRP groups showed statistically significant and similar changes after 12 and 24 weeks in the primary outcome measure (VAS pain score) and secondary outcome measures (WOMAC domains). Pain exacerbation occurred only in the PRP groups and was more common when two injections were given (44% versus 22% with a single injection, P < 0.05). The unusual study design, single-center patient recruitment, limited statistical power, and absence of change in the placebo group call into question the authors’ conclusion that PRP is superior over a placebo. The occurrence of pain exacerbation in the placebo group of intraarticular therapy for knee osteoarthritis challenges the validity of the study design, particularly regarding blinding of the patients and evaluators. The five other randomized controlled trials compared PRP to hyaluronic acid. Each included about 100 patients. The study designs were similar regarding the measures of pain and function used to assess efficacy, as well as the PRP regimen (1-week interval between injections, as with hyaluronic acid). Differences occurred, however, in PRP preparation and composition, a fact that hinders comparisons and invalidates the results of a recent meta-analysis [48]. In the first study of PRP versus hyaluronic acid [49], 60 patients were allocated to each group (mean age, 66 years; Kellgren I to III) and received four injections of either PRP containing leukocytes (L-PRP) or hyaluronic acid. The WOMAC was administered after 4, 12, and 24 weeks. The symptoms improved significantly in both groups versus baseline and these improvements were significantly
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greater in the PRP group after 12 and 24 weeks. The between-group differences were greatest in the patients with severe structural damage (Kellgren III). In the second study [50], 55 patients in each group received three injections of PRP or hyaluronic acid 1 week apart. The KOOS, IKDC score, and motion range were determined after 2, 6, and 12 months. No significant difference was demonstrated between the two groups. An early symptomatic effect was noted in both groups and was sustained after 1 year. This improvement seemed greatest in the patients with early disease (Kellgren I or II) who were treated with PRP. Tolerance was slightly less satisfactory in the PRP group, in which a higher proportion of patients experienced post-injection pain. The third study [51] did not use random allocation. Instead, three centers recruited patients, and each center used one of the following treatments: PRP, low-molecular-weight hyaluronic acid, and high-molecular-weight hyaluronic acid. After 2 months, the VAS pain score and IKDC score were significantly improved in the PRP and low-molecular-weight hyaluronic acid groups compared to the high-molecular-weight hyaluronic acid group. After 6 months, the patients given PRP exhibited significantly greater symptom relief than did those in the two hyaluronic acid groups. Factors associated with a good response to PRP therapy were age < 50 years and limited structural damage. The fourth trial [52] included 176 patients allocated at random to hyaluronic acid or PRP (platelet concentration more than 5-fold the normal value). Both treatments were administered as three injections 1 week apart. The primary outcome measure was the proportion of patients with an at least 50% decrease in the WOMAC pain score after 24 weeks. The secondary outcome measures were the OARSI response rate, other WOMAC scores, and Lequesne index. The primary outcome measure showed a difference in favor of PRP of borderline significance (34% ± 38% vs. 21% ± 24% of responders, P = 0.05). No differences were found for any of the secondary outcome measures, including analgesic consumption. Finally, a randomized trial [53] compared 60 patients given PRP (4-fold the normal platelet concentration) to 60 patients given hyaluronic acid, with three injections 1 week apart in both groups. The VAS pain score and total WOMAC showed significantly greater improvements in the PRP group after 3 months, and this difference was sustained after 6 months. Post-injection pain was reported by 6 patients in the PRP group and resolved within 48 hours. The data on PRP therapy for osteoarthritis at other sites are more limited. The recent body of evidence consists chiefly of open-label studies in small numbers of patients. The only exception is a randomized controlled trial of PRP versus hyaluronic acid in 32 patients with osteochondral lesions of the tibiotalar joint [54]. The results suggest a greater effect of PRP in improving pain and function.
4. PRP to treat osteoarthritis: take-home messages Although the therapeutic armamentarium for osteoarthritis is still limited, a number of uncertainties persist regarding the potential benefits from extending it to PRP. These uncertainties have not yet been resolved by the growing body of clinical evidence about PRP therapy in osteoarthritis, as well as in focal cartilage lesions [4,9,20]. The available evidence does not support the use of PRP as a first- or second-line treatment for lower-limb osteoarthritis. On the regulatory front, commendable efforts have been made to develop an unequivocal international classification system [19], which is of considerable assistance for navigating what has been termed the “PRP jungle” [15]. This system serves to determine when differences in PRP preparations preclude comparisons between studies. The readiness shown by regulatory agencies to approve the use of this innovative product obtained from labile
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blood products without requiring the usual preclinical and clinical validation studies is somewhat surprising. A pharmacological rationale for using PRP to treat degenerative joint diseases is difficult to establish, given the large number of compounds released by activated platelets and the complexity of their effects, which vary not only with the target tissue, but also with the concentration [8]. Thus, the often-cited anti-inflammatory and visco-inducing effects of PRP have not been firmly established by in vitro studies. Proof-of-concept studies are needed to answer the many open questions about the rationale for using PRP to treat osteoarthritis. The available data are not sufficient to allow conclusions about the efficacy of PRP in hip osteoarthritis. The only randomized trial reported to date compared PRP to hyaluronic acid, and no studies have used a placebo as the comparator [43,44]. Most of the randomized trials in patients with knee osteoarthritis support a slightly better symptomatic effect compared to hyaluronic acid, at least in patients with early disease and within the limited study follow-ups (usually 6 months). However, the designs of these trials were not always well suited to the demonstration of non-inferiority, and caution is in order given the well-demonstrated strong placebo effect of intra-articular injections in osteoarthritis [55]. The safety data suggest low frequencies of serious adverse events, including infections and allergic reactions. Post-injection pain may be more common and more severe with PRP than with hyaluronic acid. Despite these gaps in knowledge, it would be inappropriate to discard a novel therapeutic option that complements established treatments for lower-limb osteoarthritis, particularly as new developments can be expected in the near future [56]. Rheumatologists should therefore direct sufficient interest to PRP therapy and participate in multicenter randomized clinical trials in large numbers of patients, which are needed to assess the potential usefulness of PRP therapy in osteoarthritis. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Guillemin F, Rat A-C, Roux CH, et al. The KHOALA cohort of knee and hip osteoarthritis in France. Joint Bone Spine 2012;79:597–603. [2] Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis. Osteoarthritis Cartilage 2010;18:476–99. [3] Smets F, Croisier J-L, Forthomme B. Applications cliniques du plasma riche en plaquettes (PRP) dans les lésions tendineuses : revue de la littérature. Sci Sports 2012;27:141–53. [4] Xie X, Zhang C, Tuan RS. Biology of platelet-rich plasma and its clinical application in cartilage repair. Arthritis Res Ther 2014;16:204. [5] Sheth U, Simunovic N, Klein G, et al. Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. J Bone Joint Surg 2012;94:298–307. [6] Andia I, Sánchez M, Maffulli N. Joint pathology and platelet-rich plasma therapies. Expert Opin Biol Ther 2012;12:7–22. [7] Anitua E, Sanchez M, Nurden AT, et al. New insights into and novel applications for platelet-rich fibrin therapies. Trends Biotechnol 2006;24:227–34. [8] Andia I, Maffulli N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 2013;9:721–30. [9] Zhu Y, Yuan M, Meng HY, et al. Basic science and clinical application of plateletrich plasma for cartilage defects and osteoarthritis: a review. Osteoarthritis Cartilage 2013;21:1627–37. [10] Malgoyre A, Bigard X, Alonso A, et al. Variabilité des compositions cellulaire et moléculaire des extraits de concentrés plaquettaires (platelet-rich plasma, PRP). J Traumatol Sport 2012;29:236–40. [11] Sundman EA, Cole BJ, Fortier LA. Growth factor and catabolic cytokine concentrations are influenced by the cellular composition of platelet-rich plasma. Am J Sports Med 2011;39:2135–40. [12] Fortier LA, Hackett CH, Cole BJ. The effects of platelet-rich plasma on cartilage: basic science and clinical application. Oper Tech Sports Med 2011;19:154–9. [13] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 2010;6:625–35.
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Please cite this article in press as: Ornetti P, et al. Does platelet-rich plasma have a role in the treatment of osteoarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.05.002