Effects of platelet-rich plasma on the clinical outcomes and cartilage thickness in patients with knee osteoarthritis

Abstract

BACKGROUND:

The interest in biological treatments that have the potential to modify cartilage biology has gradually increased in recent years.

OBJECTIVE:

The aim of our study was to investigate the effects of intra-articular platelet-rich plasma (IA-PRP) injections on the femoral cartilage thickness, pain, functional status, and quality of life of patients with knee osteoarthritis.

METHODS

: A total of 71 patients (109 knees) with knee osteoarthritis who were administered IA-PRP injections twice with two-week intervals were included in this study. The resting and activity pain values measured using a Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, the Lequesne index scores, and the quality of life scores measured using Short Form-36 (SF-36) were recorded before treatment and at 1 month, 3 months, and 6 months after treatment. The femoral cartilage thickness was measured via ultrasonography before treatment, and at 3-month and 6-month follow ups. Obtained results were analyzed by the Wilcoxon signed rank test.

RESULTS:

The mean age of the patients was 47.4 $\pm$ 10.4 years old. The resting and activity pain scores were significantly decreased at 1-month, 3-month and 6-month follow ups when compared to the pre-injection values ( $p<$ 0.05). Significant reductions were found in the Lequesne index and WOMAC pain, stiffness, and function scores at 1, 3, and 6 months ( $p<$ 0.05), while a significant increase was detected in the third month scores when compared to the first month. Significant improvements were determined in the physical functioning, physical role, pain, general health, and emotional role sub-scores during the 6-month period ( $p<$ 0.05). However, there was no significant difference with regard to the cartilage thickness at the follow ups ( $p>$ 0.05).

CONCLUSIONS:

The results of our study indicated that the IA-PRP injections improved the pain, stiffness, physical functioning, and quality of life of knee osteoarthritis patients; however, they did not seem to affect the cartilage thickness during the 6-month follow up period.

Keywords

Cartilage intra-articular injection knee osteoarthritis platelet-rich plasma

1. Background

Osteoarthritis (OA) is a chronic disease that is characterized by cartilage degeneration, and it can impair the functional status and daily living activities of these patients. An effective pharmacological treatment is not currently available, and the treatments have focused on reducing pain [1]. Therefore, intra-articular (IA) biological treatments that have the potential to modify the cartilage biology have gained importance in recent years.

Platelet-rich plasma (PRP) has been shown to modulate cartilage regeneration, and it has the potential to slow down OA progression, in addition to reducing pain and improving function [2]. Although the PRP mechanism of action is unclear in OA cases, it has been reported to stimulate stem cell migration, proliferation, and differentiation, provide joint homeostasis and lubrication, and reduce pain by reducing inflammation and synovial membrane angiogenesis [3]. PRP, which is obtained from autologous blood, is composed of highly concentrated activated platelets in a low plasma volume that leads to the release of many mediators and growth factors that are important for tissue healing and regeneration [3, 4]. When the effects of PRP on cartilage degeneration were analyzed, it was seen to inhibit the inflammatory process induced by interleukin-1 beta and to reduce the activation of the nuclear factor kappa B pathway, which play important roles in OA pathogenesis [5]. Additionally, animal studies have reported that IA-PRP injections influenced cartilage regeneration, and they had preventive effects against OA [6, 7].

IA-PRP has been shown to have short to medium term effectiveness for improving pain and function in OA [8]. However, it seems that a consensus is not currently available about the recommendations for PRP injections in symptomatic knee OA [1]. While some systematic reviews have indicated different outcomes for IA-PRP injections due to the patient selection, PRP preparation, and heterogeneous application methods, it has been shown to yield better outcomes for pain and functional recovery when compared to hyaluronic acid (HA) treatments and placebos [2, 9, 10, 11]. Despite the presence of studies investigating the efficiency of PRP in knee OA patients, and those making comparisons with other IA injection methods, only a limited number of studies investigating its effect on the cartilage thickness were encountered in the literature [12, 13, 14]. Therefore, the aim of this study was to evaluate the effects of IA-PRP on the pain severity, functional status, quality of life, and femoral cartilage thickness in patients with knee OA.

2. Methods

The data from 120 patients who were administered IA-PRP knee injections at the Outpatient Clinic of the Istanbul Physical Therapy Rehabilitation Research and Training Hospital between April and June of 2016 were analyzed. Seventy one patients (109 knees) who met the inclusion criteria were included in the study. The inclusion criteria were as follows: chronic (minimum of 3 months) symptomatic knee pain, cartilage degeneration findings, a knee OA Kellgren-Lawrence score of 2 or 3 on an anteroposterior knee X-ray, administered IA-PRP to unilateral/bilateral knees, and having completely filled out assessment forms. The exclusion criteria were as follows: over 65 years old or younger than 30 years old, a Kellgren-Lawrence score of 1 or 4, a history of an IA injection or a significant trauma during the last 3 months, other severe meniscus or ligament injuries that could lead to knee pain, a history of knee surgery, the presence of severe effusion in the knee, the presence of inflammatory joint disease, a hematological disease, an infection, immune suppression, or the use of anticoagulant or antiaggregant medications. All the participants provided written informed consent before enrollment, and the study protocol was approved by the Istanbul Bakirkoy Sadi Konuk Training and Research Hospital Ethics Committee (approval number 2016/09/09) in conformity with the Declaration of Helsinki.

The data from the patients who were evaluated before the injection and one month after the injection were analyzed. In addition, third and sixth month controls were conducted prospectively. The sociodemographic characteristics and the resting and activity pain statuses measured using a Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Lequesne index and the quality of life scores measured using the Short Form Health Survey 36 (SF-36) were recorded before the PRP injection and at the 1-month, 3-month, and 6-month follow ups. The femoral cartilage thickness was measured using ultrasonography (USG) before the PRP injection and at the 3-month and 6-month follow ups.

For the preparation of the 3–4 ml of PRP with a concentration of 8–10 times the average normal value, 2 ml of an anticoagulant was added to a 20 ml syringe, and then, 18 ml of blood was drawn from the patient. After the first centrifugation at 3,000 rpm for 3–4 mins, the plasma layer and the red blood cell (RBC) layer were separated. The fastened PRP kit was put on the centrifuge for a second centrifugation in order to enrich the concentrated platelets at 3,250 rpm for 4–6 mins, and then, the PRP layer was slowly removed from the upper part using a 10 ml syringe with a needle, leaving 4 ml in the lower part. An exogenous factor was not used for the activation process, but the platelets were allowed to be in direct contact with the joint collagen in order to help the activation. The platelet concentration of the PRP obtained was also evaluated using laboratory measurements, and the PRP was shown to have more than 1,250,000 platelets/ml.

Each PRP injection was applied to the patello-femoral joint space with a 20 G needle using a lateral approach while the patient was in a supine position by the same physiatrist under sterile conditions twice with a two-week interval. One ml of an anesthetic solution, which was obtained by preparing 1 ml of lidocaine and 4 ml of saline in a 5 ml syringe, was injected in a routine position and backflow was observed. Then, 3 ml of IA-PRP was administered while the needle was in the IA space. The patients were instructed not to apply heat or cold compresses and not to use non-steroidal anti-inflammatory drugs after the injection. They were not given any activity restrictions with the exception of a restriction of severe activities of the lower extremities for 24 hours after the injection.

3. Outcome measures

The distal femoral cartilage thickness was evaluated using a MyLab series USG device (Esaote Biomedica, Italy) and high resolution 7–12 MHz linear probe by the same experienced clinician who was blinded to the clinical data. The patient was kept in a prone position, with his or her knee in full flexion and ankle in a neutral position, when evaluating the distal femoral cartilage, and the probe was placed on the lateral margin of the patella in an axial position. The femoral cartilage was observed as anechogenic between hyperechogenic bone cortex and suprapatellar fat. The distance between the fine hyperechogenic line on cartilage surface of the synovial space and the sharp hyperechogenic line on the bone surface was measured as the cartilage thickness. Three (mid-point) measurements were taken from each affected knee as follows: lateral condyle, intercondylar area and medial condyle [15, 16].

Figure 1.

Changes in WOMAC and Lequesne index scores from the baseline to first, third and sixth months. WOMAC, Western Ontario and McMaster Universities Arthritis.

The average pain levels during activity and at rest over the previous week were evaluated using a VAS score between 0 and 10, where 0 indicated no pain and 10 indicated the worst pain [17]. The pain, functional status, and quality of life were evaluated using self-administered questionnaires. The pain, stiffness, and physical functions were evaluated using the WOMAC, which is among the most commonly used knee OA assessment tools. The patients replied to questions in three sections using a 0–4 Likert scale, the scores of each section were summed, and the WOMAC severity index score was calculated. Higher scores indicated worse pain, stiffness, and functional limitations [18]. The Lequesne index is an OA severity index that indicates inflammation, pain, physical performance, and functional insufficiency in 3 sections. Each item is scored as 0 (no difficulty), 1 (difficulty with movement), or 2 (difficulty without movement). The maximum score is 24, which is composed of the sum of the three sections [19, 20]. The SF-36 is a self-assessment questionnaire that is usually used for the assessment of the quality of life. The form is composed of 8 sections, with a total of 36 questions. The eight sections include physical functioning, role limitations, emotional limitations, energy, mental wellness, social functioning, bodily pain, and overall health [21, 22]. The scores vary between 0 (poor) and 100 (good). Turkish reliability and validity studies of the assessment tools are available [23, 24, 25].

For the descriptive statistics of the data, the mean, standard deviation, median, minimum, maximum, frequency and ratio values were used. The normality of distribution was determined by the Kolmogorov-Smirnov test. Since there was not a normal distribution in all variables at the baseline and/or follow up measures we preferred to use nonparametric tests in all statistical analyses to avoid any bias in the interpretation of the results. Wilcoxon signed rank test ( $\alpha=$ 0.05) was used for analysis of dependent variables. All analyses were conducting using IBM SPSS Statistics for Windows version 22.0 (IBM Corp., Armonk, NY, USA).

4. Results

The mean age of the patients was 47.4 $\pm$ 10.4 years old (range 35–65 years), 64.8% ( $n=$ 46) of the patients were females, 58.5% of the patients had grade 2 OA, and 41.5% had grade 3 OA. The mean body mass index was 29.2 $\pm$ 4.9 kg/m ${}^{2}$ .

The mean resting pain scores evaluated using the VAS before the PRP injection and 1, 3, and 6 months after the injection were 2.0 $\pm$ 2.3, 0.8 $\pm$ 1.4, 0.8 $\pm$ 1.4, and 0.7 $\pm$ 1.2, respectively. The mean activity pain scores evaluated with the VAS before the PRP injection and 1, 3, and 6 months after the injection were 4.8 $\pm$ 2.1, 2.7 $\pm$ 1.9, 2.5 $\pm$ 1.8, and 2.3 $\pm$ 1.9, respectively. The resting and activity pain scores were significantly decreased 1, 3, and 6 months after the injection when compared to the pre-injection values ( $p=$ 0.000). Statistically significant differences were not detected in the resting pain scores at the third month follow up when compared to the first month follow up values ( $p=$ 0.533) and at the sixth month follow up when compared to the third month values ( $p=$ 0.499). Similarly, there were no significant differences at the third month when compared to the first month values ( $p=$ 0.093) and at the sixth month when compared to the third month in terms of the activity pain ( $p=$ 0.076).

Significant improvements were found in the WOMAC pain, stiffness, and physical functioning scores at the 1-month, 3-month, and 6-month follow ups when compared to the pre-injection values ( $p=$ 0.000), and a significant increase was indicated in the scores for the third month when compared to the scores for the first month ( $p<$ 0.05). In addition, significant differences were not detected in the sixth month when compared to the third month scores for the WOMAC pain ( $p=$ 0.772), stiffness ( $p=$ 0.088), and physical functioning ( $p=$ 0.117). Significant decreases were found in the Lequesne index scores at the 1-month, 3-month, and 6-month follow ups when compared to the pre-injection values ( $p=$ 0.000) and in the third month scores when compared to the first month ( $p=$ 0.000); however, a significant difference was not detected in the sixth month scores when compared to the third month ( $p=$ 0.117) (Fig. 1).

Table 1
SF-36 subgroup scores before and at 1, 3 and 6 months after treatment

	Baseline	1 month	3 months	6 months
Physical functioning	37.8 $\pm$ 23.1	53.8 $\pm$ 23.6*	64.1 $\pm$ 26.5*†	60.4 $\pm$ 41.8*†
Physical role	29.8 $\pm$ 36.7	48.9 $\pm$ 44.3*	56.2 $\pm$ 45.8*	55.7 $\pm$ 45.7*
Bodily pain	42.8 $\pm$ 21.1	58.5 $\pm$ 20.9*	60.5 $\pm$ 19.8*	60.1 $\pm$ 23.2*
General health	50.9 $\pm$ 11.6	55.3 $\pm$ 12.7*	56.4 $\pm$ 11.4*	53.0 $\pm$ 12.9*
Vitality	50.0 $\pm$ 13.1	48.4 $\pm$ 16.8	51.3 $\pm$ 10.2	48.7 $\pm$ 12.4
Social role	46.6 $\pm$ 14.9	44.4 $\pm$ 11.2	44.7 $\pm$ 10.5	43.9 $\pm$ 12.8
Emotional role	46.2 $\pm$ 43.5	67.0 $\pm$ 42.2*	81.7 $\pm$ 38.1*†	65.7 $\pm$ 47.4*†
Mental health	55.5 $\pm$ 12.9	53.4 $\pm$ 16.3	55.2 $\pm$ 11.0	52.2 $\pm$ 13.5

${}^{*}$ indicates significant values compared to pre-treatment period; †indicates significant values compared to the previous measurement. Wilcoxon signed rank test ( $\alpha=$ 0.05).

There were significant improvements over the 6-month period in the physical functioning, physical role, pain, general health, and emotional role scores; however, significant differences were not detected in the vitality, social role, and mental health subgroup scores. A significant improvement was found in the physical functioning subscale at the third month when compared to the first month ( $p=$ 0.000), and a significant reduction was shown in the sixth month assessment when compared to the third month ( $p=$ 0.010). Similarly, a significant improvement was found in the third month assessment when compared to the first month ( $p=$ 0.003), and a significant reduction was shown in the sixth month assessment when compared to the third month ( $p=$ 0.000) (Table 1).

As can be seen in Table 2, there was no significant difference at the 3-month and 6-month follow ups with regard to the cartilage thickness measurements conducted from the medial condyle, intercondylar space, and lateral condyle ( $p>$ 0.05).

Table 2

Distal femoral cartilage thickness values before and 6 months after the treatment

	Mean $\pm$ SD	$p^{{\dagger}}$
Cartilage thickness-MFC (mm)
Baseline	1.8 $\pm$ 0.2
3 months	1.8 $\pm$ 0.6	0.292
6 months	1.9 $\pm$ 0.2	0.108
Cartilage thickness-ICA (mm)
Baseline	2.1 $\pm$ 0.2
3 months	2.1 $\pm$ 0.2	0.673
6 months	2.2 $\pm$ 0.2	0.684
Cartilage thickness-LFC (mm)
Baseline	1.9 $\pm$ 0.2
3 months	1.9 $\pm$ 0.2	0.593
6 months	2.0 $\pm$ 0.2	0.063

ICA, intercondylar area; MFC, medial femoral condyle ; LFC, lateral femoral condyle; SD, standard deviation. † Wilcoxon signed rank test ( $\alpha=$ 0.05).

5. Discussion

The results of the present study indicated that the IA-PRP injection was effective for improving pain, stiffness, physical functioning, and the quality of life in knee OA patients; however, it did not seem to be effective on the cartilage thickness during the six months of follow up.

Although it seems difficult to make a comparison between studies due to heterogeneous patient populations, the varying PRP amounts and concentrations, and the frequency and number of injections, the IA-PRP was shown to be effective for improving the pain and functional status of patients with knee OA [8]. Similar to our study, improvements were found in the pain, stiffness, and functional capacity, which were evaluated with the WOMAC, and in the quality of life, which was evaluated with the SF-36, in the sixth month assessment after a leucocyte-rich PRP injection in knee OA patients [26, 27]. Prospectively, significant improvements were shown in the pain reduction and functional improvement at 2, 6, and 12 months in studies conducted with double-spinning PRP in patients with knee OA [28, 29]. Similar to our study, PRP, which was applied using different procedures in knee OA, was seen to provide significant improvements in the pain, quality of life, and daily living activities at the 6 and 12-month follow ups [12, 13].

Previous clinical studies have indicated that IA-PRP is superior to IA saline, and with the exception of one study comparing it with IA-HA, PRP was shown to be significantly more favorable than HA at the 3–6-month and 6–12-month follow ups of knee OA patients with regard to pain, functioning, and the WOMAC scores [30, 31, 32, 33, 34, 35]. In a systematic review of overlapping meta-analyses, the post-injection improvement was reported to start at the second month, and it was maintained for up to one year when IA-PRP was compared with IA-HA or a placebo in terms of pain and function [36]. However, the effectiveness of the PRP began to decrease after the sixth month in randomized controlled studies of degenerative knee pathologies [37]. In our study, a significant improvement was detected in the assessment parameters at the 1, 3, and 6-month assessments, whereas a tendency toward worsening was seen in the third month values when compared to the first month. The IA-PRP duration of action may be dependent on the protocol applied, and better and longer term outcomes may be obtained in younger patients and in patients with early stage degeneration; these effects may also depend on time.

In a limited number of studies evaluating the influences of IA-PRP in knee OA patients, an improvement was detected in the quality of life evaluated using the SF-36 [26, 27, 38]. In our study, the quality of life was seen to improve during the early period, which was consistent with the clinical outcomes. The improvements in the physical functioning, physical role, pain, general health, and emotional role subscales during the early period were shown to continue at the third and sixth months. However, tendencies toward decreases were detected in the physical functioning and emotional role subscales, but significant improvements were not observed in the mental health and social role subscales.

The results of previous studies support the findings that PRP injections improve pain, function, and the quality of life over the short to medium term in knee OA, which is similar to the results of our study [13, 28, 29, 32, 34]. The short to medium term effectiveness of PRP suggests that the influences on pain, function, and stiffness may not be associated with an increase in the cartilage thickness. However, the long term outcomes indicate that higher scores continue during the first year, and that there is a significant reduction at the 24-month follow up with respect to the 12-month evaluation [34].

A consensus is not available regarding how frequently the PRP injections should be applied, which platelet concentration is more effective, and which preparation procedures should be preferred [36, 37]. In some studies, the injections were applied at four-week intervals in order for enough time to pass to alleviate the patient’s symptoms [12, 27], and several studies indicated that they performed weekly injections [14, 30, 35]. However, in some studies, the injections were performed at two-week intervals, such as in our study [28, 38]. Evidence is also limited regarding the optimal platelet concentration for the treatment of OA. Although some in vitro studies have indicated that more growth factor is released with higher platelet concentrations, the clinical outcomes are not yet clear [39]. Moreover, the total number of injections used in the studies varied from one to four, so the comparison of these studies was complicated [37]. In the study conducted by Patel et al. comparing the effects of one and two injections of white blood cell filtered PRP with a platelet count of 3 times the normal amount with a single saline injection in early knee OA, a single injection of PRP was shown to be as effective as two injections, and both groups were found to be superior over the placebo [31]. Particularly, the leukocyte amount is another issue of debate. The leukocyte count, as well as the platelet count, is known to be high in PRP obtained using a double-spinning procedure. While some studies have reported better outcomes with leukocyte-poor PRP, some others have proposed that leukocytes may be an important source of cytokines and enzymes, and that the double-spinning technique may be more effective than single-spinning due to the higher platelet concentrations [33, 37, 40, 41]. Despite the absence of exact data about the frequency and number of injections, the injections were applied twice or less, and a single-spinning approach has led to uncertainty about the treatment effects [37]. In light of these data, the double-spinning approach PRP was administered twice with a two-week interval in our study.

The effects of PRP were mostly evaluated using clinical outcomes in the studies investigating knee OA. Similar to our study, a significant increase was not detected in the cartilage thickness in the limited number of studies investigating the cartilage thickness conducted with a limited number of patients [12, 13]. A significant difference was not shown in the cartilage thickness, which was evaluated at sixth months, in the study by Sampson et al. conducted with small number of patients with a large age range, and in which the baseline radiological staging was not stated [12]. While improvements were obtained in the pain and functional assessments with the PRP, which was applied as a single dose of 6 ml in early stage knee OA, a structural difference was not seen with magnetic resonance imaging in 73% of the patients [13]. However, in a study investigating the effectiveness of PRP in advanced stage knee OA, a significant improvement was detected in the cartilage thickness, which was evaluated using USG at the third and sixth month follow ups. The mean age was higher than that in our study, and Kellgren-Lawrence stage 4 patients were included in that study [14].

PRP has several potential effects on cartilage repair and OA with the stimulation of chondral anabolism and the inhibition of the catabolic process through growth factors and cytokines [42, 43, 44, 45]. However, PRP was not seen to be effective on cartilage repair in all studies [8, 46]. PRP was shown to be effective on joint degeneration in previous clinical studies. Nonetheless, the rapid clinical response and limited effect over time suggest that IA-PRP may not be effective for cartilage regeneration. One should consider that the positive effects may act through different mechanisms; PRP does not target only cartilage, and it may be effective on all joint surfaces via several effects by enhancing the cell signaling cascade, given the tissue healing effects of synovites, meniscal cells, and mesenchymal stem cells [47]. Furthermore, PRP was reported to reduce synovial hyperplasia and to slow down the degenerative process by enabling symptomatic and functional improvement [31, 47]. In our study, not being able to show the effects of PRP on the cartilage thickness, although its clinical benefits were shown in the early period (such as one month) in knee OA patients, may be associated with the fact that PRP may not be directly effective on cartilage. Its clinical effects may act through different mechanisms, and the number of injections, frequency, and insufficient follow up period should be taken into consideration.

This prospective, cross-sectional study was designed to reflect the normal population based on the age, OA stage, and dominance of the female gender. However, the absence of a control group and the fact that the patients were not blinded were the limitations of our study. The placebo effect on pain, function, and stiffness in OA is known to be more evident in injection therapies [48]. Therefore, the placebo effect cannot be excluded because the application was not blinded. Despite the fact that there was no standardization in the preparation and composition of PRP in previous studies, the effect of PRP is seen to start during the early period and continue until the sixth month; however, the long term effects of IA-PRP on the pain, function, cartilage thickness, and quality of life should be followed up.

6. Conclusions

Our data suggested that IA-PRP was effective for reducing pain and improving the function and the quality of life of patients with knee OA. However, no significant change was observed in the distal femur cartilage thickness measured via USG over six months. Knee OA studies should be focused on treatment approaches that stimulate the cartilage healing process. Although IA-PRP was shown to be effective for reducing pain and improving the function and quality of life, its effects on cartilage should be evaluated using randomized controlled studies with longer follow up durations. Whether the effect of PRP is only symptomatic or whether it has the potential to modify OA may be revealed through enlightening the PRP mechanism of action. Moreover, further studies are required to determine the procedures that may improve the preparation and application of PRP, which is promising for the treatment of cartilage degeneration and OA.

Footnotes

Conflict of interest

None declared.

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Effects of platelet-rich plasma on the clinical outcomes and cartilage thickness in patients with knee osteoarthritis

Abstract

BACKGROUND:

OBJECTIVE:

METHODS

RESULTS:

CONCLUSIONS:

Keywords

1. Background

2. Methods

3. Outcome measures

Table 1 SF-36 subgroup scores before and at 1, 3 and 6 months after treatment

6. Conclusions

Footnotes

Conflict of interest

References

Table 1
SF-36 subgroup scores before and at 1, 3 and 6 months after treatment