Surgeons have been using PRP to treat several orthopaedic conditions for many years . However, in the recent years it is used in the treatment of symptomatic knee OA by enhancing the regeneration of articular cartilage .
Our study showed the potency of a single injection of PRP on functional outcomes and cartilage repair in knee OA. The results of WOMAC, IKDC, VAS, and 6MWD proved significant improvement in the first-month itself compared to the baseline. These results were significant in the symptomatic and functional recovery for 6-months following PRP application. In the PRP group, all scores improved significantly from baseline to 1st month, followed by slight worsening (insignificant) at 3rd and 6th -month follow-up, and reasonable worsening (p < 0.002) at 12th month follow-up. However, the mean scores at 12 months were still significantly better than that at baseline (p < 0.002).
In the placebo group, although the improvement was noted at the 1st month, the values were not significant (p < 0.0354), and it could not be maintained at 3, 6, and 12-month follow-up. As compared to placebo, there were significantly evident benefits of PRP from the 1st month onward. Further significant differences between the two groups were noted after the study. This improvement was not significant (9% and 1%, respectively), over their baseline walking distances at 12 months in PRP and placebo group. The need for rescue medication was reduced by 54% (n = 24), in the PRP group and 83% (n = 36), in the placebo group.
Our study demonstrated no structural efficacy of PRP compared to placebo. Although it showed lower JSN in the PRP group, it would be safe to say that the PRP group had chondroprotective structural benefits in terms of better maintenance of JSW as an outcome measure.
Comparative analysis with related studies
We observed that the PRP application improved pain and clinical outcomes, which correlates with the results from other studies [30, 31, 32]. However, direct comparisons were difficult to make because of differences in platelet-separation techniques, the volume of blood used to obtain PRP, concentration factor, the absolute number of platelets injected, outcome scoring systems, and no standard structural efficacy criteria. Our study was unique as it addressed the adequate dose.
In a similar randomized study with PRP and HA treatment arms (49 patients and 50 patients in each arm respectively), IKDC score was significantly higher in the PRP group compared to the placebo group at 24 and 52 weeks (p = 0.003) but statistically lower VAS score in the PRP group than in the placebo group at 24 weeks (p < 0.0096) and 52 weeks (p < 0.0039) .
In a study carried out by Paterson on 23 patients, minor pain and swelling during the injection period were reported by two patients from the photo-activated PRP (PA-PRP) group. Significant improvements were demonstrated by the PA-PRP group in the VAS (p < 0.01) and KOOS (Knee injury and Osteoarthritis Outcome Score) scores (p < 0.05) at 12 weeks .
A similar study indicated a non-significant reduction in IKDC scores from 2 to 6 months, which significantly decreased at 12 months and then further decreased at 24 months. Although the absolute number of platelets injected was very small (6.5 million/knee), the response rate was good probably because of the patients being males with low BMI .
A single dose of PRP administered in 22 patients between the ages of 30 and 70 with grade 0–3 early knee OA was reported to have reduced pain score with high six months and one year functional and clinical scores from baseline. No conspicuous changes in MRI were found in at least 73% of the patients at one year . In comparison with this study, our study that included patients with advanced OA yielded better results.
A study reported by Patel et al. had the patient number and demography very similar to that in our study. They used 100 ml of blood to achieve platelet counts of 310,000/µl. The absolute count of 2385.6 million platelets injected per knee (variable and low compared to our study) demonstrated an equal benefit with single and double injections of WBC-filtered PRP. There was a significant improvement in all WOMAC scores within 2–3 weeks, with slight worsening at 6-month follow-up, without any influence of age, sex, and weight .
In six level I and II studies, four randomized controlled trials, and two prospective non-randomized studies (n = 577; mean age = 56.1 years) by Khoshbin et al., WOMAC and IKDC scores were shown to be significantly better with PRP than HA or NS injections (p < 0.001). Frequent side effects were reported in patients in the PRP group than in the HA group (p = .002). In our study, local undesirable effects were more in the placebo group .
Majority of the studies on the treatment of human degenerative cartilage lesions with PRP showed improved pain, stiffness, functional state, and no change in radiological outcomes. Among various biological treatment options being explored, PRP was selected because of being autologous, ease of processing, and being in extensive research for 20 years. An additional advantage of autologous venous blood over synthetic chemicals is that it eliminates the risk of allergic reactions and possible transmission of infections .
Clinically effective concentration of platelets was injected (approximately 1 million/µl) for an appropriate therapeutic result , that was achieved using various manual centrifugation techniques. Standardization and optimization are crucial for the preparation of PRP, failing of which could cause inconclusive therapeutic results. Platelet loss in the supernatant was minimized during standardization.
Growth factors – the healing promoters
The growth factors that are secreted by the platelets (within a time span of 10 min to 5–10 days) assist in various stages of the repair process . These growth factors have a direct effect on the physical and biomechanical properties of the joint, cartilage biosynthesis and degradation. In addition, they possess anti-inflammatory effects and a direct analgesic effect related to interaction with pain receptors . They enhance the synthesis of type II collagen and chondrocytes by stimulating the proliferation of chondrocytes and pluripotent mesenchymal stem cells. Also, they suppress inflammatory mediators such as interleukin-1, encourage matrix deposition, and slow down degeneration . The migratory ability of the proliferative cells is increased, which leads to better regenerating capability and slows down the natural progression of the disease. Hence, growth factors help stabilize cartilage homeostasis and promote the healing potential in the degenerating articular cartilage. They aid in articular cartilage repair and halt the degeneration process .
The placebo group also showed improvements over time in the treatment of pain, activities, and composite scores, but they were not significant due to the lubricating and shock-absorbing properties of HA . HA also downregulates the gene expression of OA-associated cytokines and regulates the suppressor T-cells for cell proliferation.
We preferred to use inactivated PRP since it increases proliferation of the mesenchymal stem cells fivefold , improves cartilage, and aids in bone formation. Activated PRP may inhibit chondrogenesis and osteogenesis in vivo and in vitro .
Use of leukocyte-depleted PRP, with less pro-inflammatory cytokines, avoids the activation of the NF-κB pathway, promotes growth and chondrogenesis in vivo, and yields better cartilage repair compared with PRP with leukocytes . The functional outcomes of leukocyte-poor PRP were better in comparison with PRP rich in leucocytes .
Our study delivers standard PRP processing with little variation. High level of consistency in absolute platelet counts would help in standardizing a dose for treatment. The study duration based on the previous personal data might have been too short of demonstrating any structural change in the knee. The significance of radiographic joint space narrowing measurements after only 2 or 3 years of follow-up is unclear in many study participants who have typical, slow-progressing disease.
MRI evaluation should have been more extensive with three-dimensional MOCART (magnetic resonance observation of cartilage repair tissue) to quantify the regeneration in cartilage following the treatment. Further MRI changes of cartilage 0.2 mm are too small to be consistently and reliably picked up. Also, a huge placebo response might operate quite independently and be sufficient to skew the results. Patients in study groups were adapted to improved diet and a healthy lifestyle, since good habits aid in overall improvement and quick convalescence. Patients' expectation that all potential treatments in the randomized protocol provide benefits may have resulted in placebo response. Although the use of rescue medication was greater in placebo and mineral groups during the study period, this may have masked the differences between positive benefits related to the treatment and placebo groups.
Since OA is a joint failure and not just cartilage tissue disorder, disease-modifying agents in OA treatment would more likely to succeed if they focused primarily on correcting the abnormal mechanics and then addressing the cartilage loss if needed . Moreover, since articular cartilage is not innervated, approximately 50% of the patients with radiological changes of OA are symptomatic; therefore, the treatment is based on symptoms rather than radiological changes. Even a successful CPA might have a minimal effect on symptoms, leading to patients being reluctant to adhere to a therapy that does not improve their symptoms .
The limitations of this study were its short duration (one year), lack of assessment for remnant effects after discontinuation of treatment, and limited sample size (50 patients/treatment arm). A study with longer treatment duration on a greater number of patients would be helpful to verify the treatment effect and explore the lack of significance.