Osteoarthritis (OA) affects more than 500 million people worldwide and has a rapidly increasing prevalence [1].
The progressive nature of the disease, characterized by articular cartilage degeneration, leads to debilitating pain and stiffness. Consequently, physical limitations have a significant impact on quality of life, preventing patients from participating in personal and professional activities [2]. Without disease-modifying therapy options, joint replacement is often the inevitable outcome, contributing to a substantial health and economic burden for both the patient and the healthcare system [34].
Current treatment options for knee OA focus on symptomatic control and minimizing risk factors for OA progression. Treatment typically consists of corticosteroid or hyaluronic acid (HA) injections combined with weight loss, activity modification, physical therapy, and nonsteroidal anti-inflammatory drugs (NSAIDs) [5]. However, adequate symptomatic relief is not always achieved, and pathophysiological cartilage changes continue progressing. The physical and economic burden of OA necessitates a better understanding of our current treatment options and innovative strategies for disease prevention. Orthobiologics, including PRP, may be an option to improve joint longevity due to their disease-modifying and regenerative potential [6].
Platelet-Rich Plasma
Platelet-rich plasma (PRP) is an autologous orthobiologic acquired through the centrifugation of whole blood, resulting in a higher concentration of platelets compared to whole blood [7]. Local delivery of PRP stimulates an immunological and inflammatory response to supplement physiological healing by releasing growth factors and cytokines [8-10]. Activated platelets release alpha granules, which contain platelet-derived growth factor (PDGF), transforming growth factor (TGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) [11]. Collectively, these are thought to facilitate the healing of injured tissue through angiogenesis, cellular migration, proliferation, and matrix deposition [9 12].
In addition to growth factors and cytokines, leukocytes are known to influence wound healing and tissue repair [7,13]. However, the pro-inflammatory and immunologic effects mediated by leukocytes may negate the effects of PRP by causing cell and tissue damage [14]. As a result, leukocyte-poor PRP (LP-PRP) is generally preferred for intraarticular treatment, although currently available literature is controversial in supporting the use of LP-PRP, or any type of PRP, for OA [15-17]. It is still debatable whether the pro-inflammatory effects of leukocytes overshadow the potential harm [14]. Similarly, it is important to recognize the negative impact of red blood cells (RBCs) on tissue healing with improper PRP preparation. Damaged RBCs lead to oxidative stress and ultimately increase cell apoptosis and cartilage degeneration [14,18]. Therefore, reducing or eliminating RBC content from the PRP formulation is essential prior to treatment.
Additive agents are used to activate PRP, most commonly by administering calcium chloride and/or thrombin [19]. Activated PRP causes the platelets to degranulate, and nearly 100% of the growth factors are released within 1 hour of activation [20]. A recent meta-analysis demonstrated that exogenously activated PRP is more effective in improving pain and function than non-activated PRP in patients with knee OA [21]. However, conflicting evidence suggesting less efficient wound healing has questioned whether rapid delivery of growth factors is ideal [22]. It remains unclear whether PRP should be activated.
Many commercial processing systems are available with substantial variability in the composition of the PRP produced. In addition, specific PRP preparations used across clinical studies are highly underreported, irreproducible based on the information provided, or differ considerably [23]. The absence of a standardized PRP protocol makes the therapeutic analysis between studies challenging [23,24]. The overall lack of consensus surrounding PRP preparations represents the necessity for further research to determine the optimal PRP formulation, platelet number, leukocyte count, activation status, and dosing regimen [11].
Clinical Application
PRP is commonly used as a conservative treatment option for mild to moderate knee OA. Several recent systematic reviews and meta-analyses have been performed comparing PRP to corticosteroid and HA injections. McLarnon and Heron reported superior outcomes of intraarticular PRP injections compared to corticosteroid injections for symptomatic knee OA, with three PRP injections being more effective than a single injection [25]. Singh et al. showed PRP was more efficacious than HA, but both injections provided statistically significant improvements in outcomes compared to the placebo group [26]. In a separate review, Tang et al. found PRP to be more effective than HA for both pain and function [27]. Belk et al. took it further and assessed LP-PRP compared to leukocyte-rich PRP (LR-PRP) [28]. A statistically significant improvement in patient-reported outcome scores was demonstrated with PRP over HA, while LP-PRP was associated with significantly better International Knee Documentation Committee (IKDC) scores than LR-PRP, though inconsistent data fails to support this in other studies [29]. Finally, Costa et al. reviewed 40 studies comparing PRP with HA, corticosteroid, and saline injections [30]. While PRP was as effective as, and in some cases more effective than, other therapies, they called into question the current level of evidence, high risk of bias, and methodological heterogeneity across studies.
Evidence supports both HA and PRP injections for knee OA, but the latest literature suggests that combining PRP with HA may be even more successful. A systematic review and meta-analysis by Karasavvidis et al. reported that HA combined with PRP demonstrated greater improvement in pain, function, and stiffness compared to HA alone [31]. The combined effect of PRP and HA was supported by Zhao et al., who demonstrated reduced pain and greater function after 12 months of follow-up compared to PRP alone [32]. These outcomes indicate a potential synergistic effect when given together. However, other studies do not corroborate these findings, demonstrating PRP alone provides similar outcomes [33-35]. Interestingly, combined therapy resulted in fewer adverse events and may have a better safety profile, supporting the utilization of combination therapy [33-35].
Summary
PRP is a promising management option for symptom modification in the setting of knee OA. Clinical studies have demonstrated the utility of PRP as a safe, resource-conscious, and efficacious treatment for knee OA, providing symptomatic relief and improved patient-reported outcomes. Sustained research efforts leading to an improved understanding of PRP preparations and the biological properties of the final composition can potentially change the landscape of OA treatment. A validated classification system and standardized reporting for cross-study comparability are essential in taking the next step forward. Sustained clinical improvement and the possibility for tissue healing continue to challenge the traditional approaches for limiting disease progression and improving joint longevity.
References
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