Abstract
To compare the efficacy of intra-articular administration of platelet-rich plasma (PRP), hyaluronic acid (HA), corticosteroids (CS), and nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis. This retrospective study analyzed 205 knees of 150 patients with Kellgren–Lawrence grade 2 to 3 knee osteoarthritis treated between 2016 and 2021. Patients received intra-articular injections of PRP, HA, CS, or NSAIDs. Visual analog scale (VAS) pain scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and Kellgren–Lawrence grades were assessed at baseline and final follow-up (6–12 months). All groups showed significant improvements in the VAS and WOMAC scores from baseline to the final follow-up. PRP demonstrated the greatest pain reduction (3.2 point VAS decrease) and functional improvement (20-point WOMAC decrease). HA provided moderate but consistent benefits to the patients. The CS showed rapid early improvement that diminished over time. NSAIDs showed minimal improvement. Radiographic progression was minimal in all the groups. No major adverse events were observed. PRP offered the most sustained improvement in pain and function in knee osteoarthritis, followed by that of HA. CS provide short-term relief but have limited long-term benefits. NSAIDs were the least effective treatment. These findings support a tailored approach to knee osteoarthritis treatment, using PRP and HA as promising options for long-term management. The datasets generated and/or analyzed during the current study are not publicly available but can be obtained from the corresponding author upon reasonable request. The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.Level of evidence: Diagnostic Level 3 (retrospective cohort study).
Keywords: corticosteroids, hyaluronic acid, knee osteoarthritis, platelet-rich plasma
1. Introduction
Knee osteoarthritis is a prevalent degenerative joint disorder that seriously affects the quality of life due to pain, stiffness, and limited mobility.[1] To date, many intra-articular treatments have been attempted for symptom relief and functional improvement, including platelet-rich plasma (PRP), hyaluronic acid (HA), corticosteroids (CS), and oral nonsteroidal anti-inflammatory drugs (NSAIDs). These treatments aim to reduce inflammation, restore joint lubrication, and modify the disease course.[2]
PRP is an autologous blood product containing extremely high levels of growth factors that induce healing and tissue repair. Recently, PRP has gained increasing attention as an alternative treatment for knee osteoarthritis (OA). Several studies have reported improvements in pain and function, although the preparation methods and dosing remain variable.[3,4] The United States in 1997, the Food and Drug Administration acted as a viscosupplement to restore the viscoelastic properties of synovial fluid, thereby improving joint lubrication and function.[5] Although the evidence regarding its efficacy is mixed, HA remains one of the most common options for mild-to-moderate OA.[2]
CS have been widely used to transiently alleviate OA symptoms owing to their potent anti-inflammatory effects.[6] However, long-term prescriptions are limited by concerns regarding cartilage damage following repeated administration.[7] NSAIDs are well known for the treatment of pain; however, during chronic use, adverse gastrointestinal and cardiovascular effects are of concern. To minimize such systemic risks, intra-articular administration of NSAIDs has been considered.[8]
The outcomes of these treatments are typically assessed using the visual analog scale (VAS) to measure pain intensity and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to assess pain, stiffness, and physical function.[9,10] Additionally, radiographic assessment using the Kellgren–Lawrence (KL) grading system provides a standardized assessment of joint degeneration severity.[11,12]
There is no consensus among orthopedic surgeons regarding the efficacy of intra-knee injections or the optimal choice of treatment. Therefore, this retrospective study aimed to compare the efficacy of PRP, HA, CS, and NSAIDs in patients with knee OA by analyzing the VAS and WOMAC scores and KL staging at the last follow-up. This study provides a detailed comparison of the clinical and radiographic outcomes in patients with knee OA.
2. Materials and methods
2.1. Study design
This retrospective cohort study aimed to evaluate the clinical and radiological outcomes of patients diagnosed with stages 2 and 3 gonarthrosis who were treated at Şanliurfa Mehmet Akif İnan Training and Research Hospital between January 2016 and December 2021. This study was approved by the Clinical Research Ethics Committee of the Harran University Faculty of Medicine (Approval No. HRÜ/24.11.27, August 5, 2024). The requirement for informed consent was waived due to the retrospective design of the study.
Patients aged > 40 years with a diagnosis of KL grade 2 and 3 knee osteoarthritis and symptoms persisting for at least 1 year were included in the study. Patients were followed up regularly for at least 1 year.
Patients with KL grade 2 and 3 knee osteoarthritis with at least 1 year of symptoms and at least 1 year of follow-up were included in the study. Patients with systemic rheumatological diseases, such as rheumatoid arthritis; those who did not return for follow-up; those with a history of knee surgery; those with a history of intra-knee injections; those with a meniscal root tear on magnetic resonance imaging; those with neoplasia; those with a body mass index (BMI) >40; and those with cognitive dysfunction were excluded from the study.
2.2. Treatment groups
Participants were divided into 4 treatment groups based on the type of intra-articular injection received.
PRP group: Patients who received an intra-articular T-lab autologous PRP kit (T-Biotechnology Laboratory, Bursa, Turkey) prepared by centrifugation of autologous blood. Approximately 20 mL of blood was collected under sterile conditions, and PRP was prepared according to the manufacturer’s instructions. Briefly, after blood collection, the tubes were centrifuged at 830 × g for 8 minutes. A 16 G needle connected to a 5 mL syringe was inserted into the tube and advanced into the buffy coat layer. PRP was collected by rotating the needle tip. After approximately 2 to 4 cc of PRP was collected from the first tube, the second tube was treated similarly (a total of 4–8 cc of PRP was collected). The collected solution was returned to the suspension tube and gently vortexed for 30 seconds to 1 minute.[13]
HA group: Patients treated with commercially available HA (Opticore 40 mg, 20%, 2 mL, Istem Medical Ltd, Turkey) injections.
CS group: Patients who received intra-articular CS injections (Betamethasone, Diprover 2 mg + 5 mg/mL; Haver Pharma Ltd, Turkey).
NSAID group: Patients administered oral NSAIDs.
The dose and frequency of injections followed standard institutional protocols. Data on the number of injections per patient, time between injections, and last follow-up visit were collected for analysis.
2.3. Data collection
Baseline demographic data, including age, sex, BMI, duration of knee OA, baseline activity levels (average daily steps), and concomitant analgesic use (weekly dose), were extracted from electronic medical records. Clinical outcomes were assessed using the following equation:
Visual analog scale (VAS) for pain (ranging from 0 = no pain to 10 = worst possible pain).
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) includes subscales for pain, stiffness, and physical function (0 = no symptoms; 96 = worst symptoms).
Kellgren–Lawrence (KL) grading system for radiographic assessment of OA severity (grades I–IV).
Pretreatment VAS and WOMAC scores were recorded at baseline, and the same outcomes were reassessed at the last follow-up, which occurred between 6 and 12 months posttreatment.
2.4. Statistical analysis
Data were analyzed using the IBM SPSS Statistics software (version 26.0; IBM Corp., Armonk). The normality of the data distribution was assessed using the Shapiro–Wilk test, and the homogeneity of variances was tested using Levene’s test before applying parametric analyses. Continuous variables, such as age, VAS, and WOMAC scores, were expressed as mean ± standard deviation and compared between groups using 1-way analysis of variance (ANOVA). A post hoc analysis was performed using Tukey’s test to determine the differences between the individual treatment groups. Categorical variables, such as KL grade progression and adverse event incidence, were analyzed using the Pearson chi-square test or Fisher’s exact test as appropriate.
To evaluate the potential influence of follow-up duration on clinical outcomes, the patients were stratified into 2 subgroups: those who were followed for 6 to 9 months and those who were followed up for 10 to 12 months. VAS and WOMAC scores at the final follow-up were compared within each treatment group using independent sample t-tests.
Minimal clinically important differences (MCID) were defined as a ≥1.5-point reduction in VAS and a ≥10-point reduction in WOMAC scores, based on prior literature.[14,15] The proportion of patients in each group who achieved the MCID threshold was calculated.
Paired t-tests were used to assess within-group differences between the pre- and posttreatment VAS and WOMAC scores. Statistical significance was set at P < .05.
Adverse events were monitored and recorded at each follow-up. Events were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0), including severity grading (grades 1–5).[16,17] Particular attention was paid to the joint-related complications (pain, swelling, and stiffness) and gastrointestinal symptoms in the NSAID group. Serious adverse events were defined as those that required hospitalization or permanent damage.
2.5. Outcome measures
The primary outcome measure was the change in the VAS and WOMAC scores from baseline to the last follow-up visit. The secondary outcome was a change in the KL grade, which reflects disease progression. The duration of symptom relief, defined as the time until significant worsening of VAS scores, was also evaluated.
3. Results
We retrospectively analyzed 205 knees from 150 patients (65 women and 85 men, including 55 bilateral cases). Patients were divided into 4 groups based on the treatment received: PRP, HA, CS, and NSAIDs. Baseline characteristics, including age, BMI, KL grade, baseline activity, and concomitant analgesic use, were comparable between the groups (Table 1).
Table 1.
Patient demographics and baseline characteristics.
| Characteristic | PRP (n = 60) | HA (n = 60) | CS (n = 45) | NSAID (n = 40) | P-valuee |
|---|---|---|---|---|---|
| Age (yr, mean ± SD) | 61.8 ± 6.9 | 62.4 ± 7.1 | 63.3 ± 6.5 | 62.1 ± 7.0 | .492 |
| Gender (M/F) | 32/28 | 33/27 | 22/23 | 21/19 | .678 |
| BMI (kg/m², mean ± SD) | 27.9 ± 3.1 | 28.2 ± 2.9 | 28.1 ± 2.8 | 28.0 ± 3.0 | .791 |
| Kellgren–Lawrence grade II | 37 (61.7%) | 38 (63.3%) | 28 (62.2%) | 25 (62.5%) | .932 |
| Kellgren–Lawrence grade III | 23 (38.3%) | 22 (36.7%) | 17 (37.8%) | 15 (37.5%) | .865 |
| Baseline activity (average steps/d) | 4200 ± 1100 | 4300 ± 1000 | 4100 ± 1200 | 4150 ± 1150 | .743 |
| Concomitant analgesic use (weekly) | 3.0 ± 1.2 doses | 3.2 ± 1.3 doses | 2.9 ± 1.1 doses | 4.0 ± 1.4 doses | .058 |
BMI = body mass index, CS = corticosteroids, F = female, HA = hyaluronic acid, kg = kilogram, M = male, m = meter, NSAID = nonsteroidal anti-inflammatory drug, PRP = platelet-rich plasma, SD = standard deviation.
Prior to performing ANOVA, data normality and homogeneity of variance were evaluated. The Shapiro–Wilk test confirmed that the VAS pain scores (P = .214), WOMAC scores (P = .185), baseline daily step counts (P = .262), and weekly analgesic use (P = .195) were normally distributed across the treatment groups. Levene’s test indicated homogeneity of variance for the VAS scores (P = .482), WOMAC scores (P = .375), baseline daily step counts (P = .439), and analgesic use (P = .353). Therefore, parametric tests (ANOVA and Tukey’s post hoc test) were appropriate for between-group comparisons in this study.
3.1. Pain assessment (VAS)
The VAS pain score demonstrated a significant improvement across all groups when comparing the scores before treatment to those at the last control. The PRP group demonstrated a significant mean VAS reduction of 3.2 points (Cohen’s d = 2.78; P < 0,05), indicating a large clinical effect. The HA, CS, and NSAID groups showed progressively smaller effect sizes (2.10, 1.60, and 1.18, respectively), which aligned with clinical relevance. The HA group experienced a 2.8-point reduction in the last control (P < .05), whereas CS-treated patients showed an early rapid improvement, with a 4.0-point decrease at 1 month, although this effect was diminished by the last control (P < .01). NSAID-treated patients demonstrated the least improvement, with only a 1.5-point reduction in VAS scores (P = .05; Table 2). Stratified analysis revealed no statistically significant difference in VAS scores between the 6 and 9 month and 10 to 12-month follow-up subgroups in any treatment arm (all P > .05). These results suggest that follow-up duration did not substantially affect clinical outcomes (Table 3). The proportion of patients who achieved the MCID thresholds for VAS was highest in the PRP group (91.7%), followed by the HA (86.7%), CS (71.1%), and NSAID (57.5%) groups (Table 4).
Table 2.
VAS pain, WOMAC, and Kellgren–Lawrence grade progression (before treatment and last control).
| Outcome measure | Time point | PRP (n = 60) | HA (n = 60) | CS (n = 45) | NSAID (n = 40) | P-value |
|---|---|---|---|---|---|---|
| VAS pain score (mean ± SD) | Before treatment | 7.6 ± 1.2 | 7.5 ± 1.3 | 7.8 ± 1.1 | 7.6 ± 1.2 | .732 |
| Last control | 4.4 ± 1.1 | 4.7 ± 1.2 | 5.5 ± 1.4 | 5.9 ± 1.2 | .039* | |
| Cohen’s d | 2.78 | 2.10 | 1.60 | 1.18 | ||
| WOMAC score (mean ± SD) | Before treatment | 67 ± 9 | 69 ± 8 | 70 ± 10 | 68 ± 9 | .643 |
| Last control | 47 ± 9 | 49 ± 9 | 54 ± 10 | 58 ± 10 | .023* | |
| Cohen’s d | 2.22 | 2.11 | 1.60 | 1.05 | ||
| Kellgren–Lawrence Grade | No progression (%) | 55 (91.7%) | 53 (88.3%) | 35 (77.7%) | 29 (72.5%) | .079 |
| Progression (%) | 5 (8.3%) | 7 (11.7%) | 10 (22.3%) | 11 (27.5%) | .079 |
CS = corticosteroids, HA = hyaluronic acid, NSAID = nonsteroidal anti-inflammatory drug, PRP = platelet-rich plasma, SD = standard deviation, VAS = visual analog scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
*P < .05, statistically significant.
Table 3.
Stratified analysis of VAS and WOMAC scores according to follow-up duration (6–9 mo vs 10–12 mo) in each treatment group.
| Outcome (mean ± SD) | PRP (n = 60) | HA (n = 60) | CS (n = 45) | NSAID (n = 40) |
|---|---|---|---|---|
| VAS (6–9 mo) | 4.5 ± 1.0 | 4.8 ± 1.1 | 5.4 ± 1.2 | 5.8 ± 1.1 |
| VAS (10–12 mo) | 4.3 ± 1.2 | 4.6 ± 1.3 | 5.6 ± 1.6 | 6.0 ± 1.3 |
| P-value | .521 | .498 | .611 | .537 |
| WOMAC (6–9 mo) | 48 ± 8 | 50 ± 9 | 53 ± 10 | 57 ± 9 |
| WOMAC (10–12 mo) | 46 ± 9 | 48 ± 10 | 56 ± 11 | 59 ± 11 |
| P-value | .432 | .417 | .356 | .389 |
CS = corticosteroids, HA = hyaluronic acid, NSAID = nonsteroidal anti-inflammatory drugs, PRP = platelet-rich plasma, SD = standard deviation, VAS = visual analog scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
Table 4.
Proportion of patients achieving minimal clinically important difference (MCID) for VAS and WOMAC scores.
| Treatment group | VAS MCID ≥ 1.5 pts | WOMAC MCID ≥ 10 pts |
|---|---|---|
| PRP (n = 60) | 91.7% (55 patients) | 88.3% (53 patients) |
| HA (n = 60) | 86.7% (52 patients) | 83.3% (50 patients) |
| CS (n = 45) | 71.1% (32 patients) | 66.7% (30 patients) |
| NSAID (n = 40) | 57.5% (23 patients) | 55.0% (22 patients) |
| P-value | .006 | .008 |
CS = corticosteroids, HA = hyaluronic acid, MCID = minimal clinically important difference, NSAID = nonsteroidal anti-inflammatory drug, PRP = platelet-rich plasma, VAS = visual analog scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
3.2. Functional outcome (WOMAC)
The WOMAC scores showed significant improvements in all treatment groups from pretreatment to the last control. PRP-treated patients showed the greatest improvement, with a 20-point reduction in the WOMAC score (P < .01). The HA-treated patients exhibited a 15-point improvement over the same period. CS-treated patients displayed rapid early improvements, with a 20-point decrease at 1 month, and the effect was less pronounced at the final follow-up. The NSAID-treated patients showed the smallest improvement, with a 10-point reduction (P < .05; Table 2). Stratified analysis revealed no statistically significant difference in WOMAC scores between the 6 and 9 month and 10 to 12-month follow-up subgroups in any treatment arm (all P > .05). These results suggest that follow-up duration did not substantially affect clinical outcomes (Table 3).
The proportion of patients who achieved the MCID thresholds for WOMAC was highest in the PRP group (88.3%), followed by the HA (83.3%), CS (66.7%), and NSAID (55.0%) groups (Table 4).
3.3. Radiographic evaluation (Kellgren–Lawrence staging)
Radiographic evaluation using the KL grading system revealed that most patients remained stable within their original stages. However, some patients experience disease progression. In the PRP group, 4 patients (6.7%) progressed from grade II to III, and 1 patient (1.6%) progressed to grade IV. In the HA group, 5 patients (8.3%) progressed to grade III and 2 (3.3%) progressed to grade IV. The CS and NSAID groups showed higher rates of radiographic worsening, with 7 (15.5%) and 7 (17.5%) patients progressing from grade II to III and 3 (6.6%) and 4 (10%) progressing to grade IV, respectively. Despite these trends, the differences between the groups did not reach statistical significance (χ² = 6.79, P = .079; Table 5).
Table 5.
Radiographic Kellgren–Lawrence grade distribution before and after treatment
| KL grade | Time | PRP (n = 60) | HA (n = 60) | CS (n = 45) | NSAID (n = 40) |
|---|---|---|---|---|---|
| Grade I | Before | 0 | 0 | 0 | 0 |
| After | 0 | 0 | 0 | 0 | |
| Grade II | Before | 37 (61.7%) | 38 (63.3%) | 28 (62.2%) | 25 (62.5%) |
| After | 34 (56.7%) | 33 (55%) | 21 (46.7%) | 18 (45%) | |
| Grade III | Before | 23 (38.3%) | 22 (36.7%) | 17 (37.8%) | 15 (37.5%) |
| After | 25 (41.7%) | 25 (41.7%) | 21 (46.7%) | 18 (45%) | |
| Grade IV | Before | 0 | 0 | 0 | 0 |
| After | 1 (1.6%) | 2 (3.3%) | 3 (6.6%) | 4 (10%) |
CS = corticosteroids, HA = hyaluronic acid, KL = Kellgren–Lawrence, NSAID = nonsteroidal anti-inflammatory drugs, PRP = platelet-rich plasma.
3.4. Subgroup analysis based on body mass index (BMI) and Kellgren–Lawrence grade
To explore the influence of BMI on treatment efficacy, the patients were stratified into nonobese (BMI < 30 kg/m²) and obese (BMI ≥ 30 kg/m²) subgroups. In the PRP group, nonobese patients showed a greater reduction in VAS scores (mean change: 3.6 ± 1.0) than obese patients (2.7 ± 1.1, P = .031). Similarly, WOMAC scores improved more in nonobese individuals (22 ± 6) than in obese patients (17 ± 7, P = .028). A similar pattern was observed in the HA group (VAS: 3.3 vs 2.5, P = .044; WOMAC score: 20 vs 16, P = .039). No statistically significant differences were observed between the BMI groups in the CS (P = .218) and NSAID (P = .256) groups (Table 6).
Table 6.
Treatment efficacy by BMI and Kellgren–Lawrence grade (VAS and WOMAC change scores).
| Group | BMI < 30 (VAS WOMAC) | BMI ≥ 30 (VAS WOMAC) | P-value (VAS WOMAC) | KL II (VAS WOMAC) | KL III (VAS WOMAC) | P-value (VAS WOMAC) |
|---|---|---|---|---|---|---|
| PRP | 3.6 ± 1.0 22 ± 6 |
2.7 ± 1.1 17 ± 7 |
.031 .028 |
3.8 ± 0.9 24 ± 6 |
2.6 ± 1.1 16 ± 8 |
.019 .021 |
| HA | 3.3 ± 0.9 20 ± 5 |
2.5 ± 1.0 16 ± 6 |
.044 .039 |
3.5 ± 0.8 22 ± 5 |
2.7 ± 1.0 17 ± 7 |
.026 .034 |
| CS | 2.1 ± 1.2 15 ± 6 |
1.8 ± 1.3 13 ± 7 |
.218 .221 |
2.2 ± 1.1 16 ± 6 |
1.9 ± 1.3 14 ± 7 |
.231 .198 |
| NSAID | 1.6 ± 1.0 13 ± 5 |
1.4 ± 1.1 12 ± 5 |
.256 .267 |
1.7 ± 0.9 14 ± 5 |
1.5 ± 1.1 12 ± 6 |
.242 .238 |
BMI = body mass index, CS = corticosteroids, HA = hyaluronic acid, KL = Kellgren–Lawrence, NSAID = nonsteroidal anti-inflammatory drug, PRP = platelet-rich plasma, VAS = visual analog scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
Based on radiographic severity, the patients were stratified into KL grades II and III subgroups. In the PRP group, patients with KL grade II demonstrated significantly greater improvements in VAS (3.8 ± 0.9 vs 2.6 ± 1.1, P = .019) and WOMAC scores (24 ± 6 vs 16 ± 8, P = .021). The HA group showed similar results (VAS: 3.5 vs 2.7, P = .026; WOMAC score: 22 vs 17; P = .034). The differences between the CS and NSAID groups were not statistically significant (P > .05 for both VAS and WOMAC comparisons; Table 6).
3.5. Adverse events
No serious adverse events were observed in any group during the follow-up period. The most frequently reported events were mild-to-moderate joint pain and swelling in the PRP and HA groups and gastrointestinal discomfort in the NSAID group. These events were transient and conservatively managed. The detailed event rates and severity grades are summarized in Table 7.
Table 7.
Adverse events.
| Adverse event | PRP (n = 60) | HA (n = 60) | CS (n = 45) | NSAID (n = 40) | Severity grading | P-value |
|---|---|---|---|---|---|---|
| Transient joint pain | 6 (10%) | 9 (15%) | 3 (6.7%) | 0 | Mild (grade 1) | .204 |
| Joint swelling | 2 (3.3%) | 3 (5%) | 1 (2.2%) | 0 | Mild–moderate | .558 |
| Gastrointestinal discomfort | 0 | 0 | 0 | 4 (10%) | Moderate | .041* |
| Joint stiffness | 0 | 0 | 4 (8.9%) | 0 | Moderate | .013* |
| Serious adverse events | 0 | 0 | 0 | 0 | None-observed | – |
CS = corticosteroids, HA = hyaluronic acid, NSAID = nonsteroidal anti-inflammatory drugs, PRP = platelet-rich plasma.
*P < .05, statistically significant.
4. Discussion
The results of this retrospective study comparing intra-articular treatments – PRP, HA, CS, and NSAIDs – for knee osteoarthritis (OA)–provide important insights into the efficacy and potential limitations of each therapy. Each modality offers distinct benefits, and the findings highlight their varying effects on pain relief, functional improvement, and disease progression.
4.1. PRP: efficacy and mechanism
PRP demonstrated the most sustained improvement in both pain (VAS score reduction) and function (WOMAC score) at the last follow-up, which aligns with the growing body of evidence supporting its role in the management of OA. PRP is thought to modulate inflammation and promote tissue regeneration via growth factors, such as platelet-derived growth factor and transforming growth factor-beta, which may contribute to its longer-lasting effects than those of other treatments.[3] Our study showed a significant reduction in pain and functional scores over time, consistent with earlier studies that found PRP to be effective in reducing symptoms and improving the quality of life of patients with moderate knee OA.[18]
However, it is essential to note that while PRP appears to be effective in the medium-term, variability in PRP preparation methods (e.g., platelet and leukocyte contents) could affect clinical outcomes. Future studies should aim to standardize PRP formulations to reduce these inconsistencies.[4] Despite the lack of standardization, our findings support the use of PRP as a valuable treatment option, particularly for patients seeking long-term symptom relief without the risks associated with CS or NSAIDs use.
Although recent high-quality meta-analyses have reported a significantly greater clinical benefit of PRP over HA in the treatment of knee osteoarthritis, particularly in terms of long-term pain relief and functional improvement,[15] our study did not demonstrate a statistically significant difference between the PRP and HA groups. One possible explanation is that both treatments were effective in our cohort, and the relatively small sample size may have limited our ability to detect subtle differences. Additionally, variations in PRP preparation protocols, patient selection criteria, and OA severity across studies may contribute to heterogeneity in treatment responses. Nevertheless, our results are consistent with the broader literature showing that both PRP and HA are superior to CS and NSAIDs for sustained symptom relief in mild-to-moderate OA.
A 2024 systematic review and meta-analysis of 11 RCTs (n = 1023) confirmed that PRP + HA provides superior long-term outcomes in VAS (MD, −4.27, 95% CI, −4.96 to–3.58; P < .001) and WOMAC (MD, −1.77, 95% CI, −2.20 to −1.34; P < .001) compared with PRP alone.[19–21] Notably, combination therapy also showed a lower incidence of adverse events (RR, 0.41; 95% CI, 0.35–0.48; P < .001). A separate meta-analysis (2024) reported similar findings, with superior cartilage protection and symptom relief with PRP + HA at 12 months.[22]
Our study did not include a PRP + HA arm; however, the consistently better safety and efficacy outcomes reported in the literature suggest that combined protocols may offer enhanced benefits. Therefore, future trials comparing PRP monotherapy with PRP + HA combination therapy are strongly recommended.
Our subgroup analyses revealed that patient-related factors, such as obesity and radiographic severity (KL grade), significantly influenced the clinical response to intra-articular injections. In the PRP and HA groups, nonobese patients (BMI < 30 kg/m²) experienced significantly greater improvements in both pain and function than obese individuals. For instance, in the PRP group, the VAS and WOMAC scores improved by 3.6 and 22 points in nonobese patients, whereas obese patients showed improvements of 2.7 and 17 points (P = .031 and 0.028, respectively). These findings are consistent with those of a recent large-scale meta-analysis by Luo et al,[23] which demonstrated that obesity attenuates the clinical efficacy of PRP in knee osteoarthritis due to systemic low-grade inflammation and increased biomechanical loading[24,25]
4.2. Hyaluronic acid: moderate but reliable
HA injections also significantly improved both pain and function, albeit slightly less than PRP. HA acts as a viscosupplement, restoring the viscoelastic properties of synovial fluid, which improves lubrication and reduces mechanical stress on the joint.[5] This mechanism of action explains the moderate but consistent results observed in our study, in which HA-treated patients showed significant improvement, particularly in the short-to medium-term.
While earlier meta-analyses have raised questions about the efficacy of HA compared to placebo,[2] our findings suggest that it remains a useful option for patients with mild-to-moderate OA who may not be candidates for more aggressive treatments such as PRP. Additionally, HA may be particularly valuable for patients seeking to delay more invasive interventions, such as knee replacement. However, the progression of the KL grade observed in some patients treated with HA suggests that although it may provide symptomatic relief, it may not halt the underlying degenerative process, a limitation that has been echoed in other studies.[26]
The high proportion of patients who achieved the MCID thresholds in the PRP and HA groups supports the clinical relevance of these therapies. These findings reinforce that the improvements observed were not only statistically significant but also meaningful from the patient’s perspective.
According to the 2019 OARSI guidelines, PRP and HA are conditionally recommended for patients with mild-to-moderate knee OA, whereas CS are recommended only for short-term symptom control owing to potential adverse effects. Our data are consistent with these recommendations, as PRP and HA showed the most favorable long-term outcomes and minimal adverse events.[2]
4.3. Corticosteroids: rapid but short-lived relief
CS demonstrated the most rapid reduction in pain, with significant improvements at 1 month after injection. This aligns with the well-documented anti-inflammatory effects of CS, which can rapidly reduce joint inflammation and pain.[7] However, our study also confirmed that the benefits of CS are short-lived, as pain relief and functional improvements are diminished by the last control, typically within 6 months. This transient effect limits the long-term utility of CS, particularly considering their potential adverse effects, such as cartilage damage and joint degradation, with repeated use.[6]
Current guidelines recommend the cautious use of intra-articular CS due to these concerns.[2] Our results further underscore the importance of balancing short-term symptomatic relief with potential long-term harm. CS may be best suited for acute flares or in patients who are unresponsive to other treatments; however, their role in long-term treatment remains unclear.
4.4. NSAIDs: minimal improvement and potential risks
NSAID injections provided the least improvement in both VAS and WOMAC scores, consistent with previous studies that have found NSAIDs to be less effective than intra-articular alternatives, such as PRP and HA.[6] The modest pain relief observed with oral NSAID therapy in our study may be attributed to their limited ability to address the mechanical and biological factors that drive OA progression. NSAIDs primarily target inflammation but do not offer the lubricating or regenerative benefits provided by PRP and HA.[27]
Additionally, gastrointestinal discomfort reported by 10% of patients treated with NSAIDs raises concerns regarding the systemic absorption of these drugs, even when administered intra-articularly. Given the risks associated with long-term NSAID use, including gastrointestinal and cardiovascular complications, their role in managing knee OA should be carefully considered, particularly in older patients and those with comorbidities.[28] NSAIDs may be better suited for patients requiring short-term relief who are at a low risk of complications; however, their use should be limited to patients seeking long-term symptom management.
Although CS and NSAIDs showed less pronounced subgroup differences and overall smaller effect sizes, the consistent pattern observed in the PRP and HA groups highlights the importance of patient selection. These results underscore the need for tailored treatment strategies that consider both BMI and radiographic OA severity to optimize the therapeutic efficacy.
4.5. Disease progression and radiographic findings
Radiographic progression, assessed using the KL grading system, was minimal in most groups. However, the PRP and HA groups showed a slight trend toward stabilization of joint degeneration, whereas the CS and NSAID groups showed a greater tendency toward disease progression. Although these findings were not statistically significant, they suggest that PRP and HA may protect against joint structural deterioration. This is consistent with the proposed disease-modifying properties of PRP and the biomechanical benefits of HA.[2,3]
While CS provide rapid symptomatic relief, their potential for cartilage degradation with repeated use has been highlighted in previous studies.[7] Our findings suggest that CS may accelerate disease progression in some patients, emphasizing the need for judicious use.
The lack of significant differences between the 6 and 9 month and 10 to 12-month subgroups suggests the temporal stability of treatment responses. This indicates that the treatment effects remained consistent over the mid-term follow-up period.
Radiographic disease severity also affects the treatment outcomes. Patients with KL grade II showed significantly better clinical responses to PRP and HA injections than those with KL grade III. In our cohort, PRP-treated patients with KL II experienced a VAS reduction of 3.8 and a WOMAC improvement of 24 points, whereas those with KL III had more modest changes (VAS, 2.6; WOMAC, 16; P = .019 and 0.021, respectively). These findings are consistent with those of a recent large-scale observational study by Kamada et al,[29] which concluded that patients with early to moderate osteoarthritis (KL I–II) demonstrated a more favorable response to biological therapies, likely due to preserved cartilage integrity and a more modifiable inflammatory environment.
Furthermore, the interaction between obesity and OA severity may be synergistic. In their OARSI guidelines, Bannuru et al.[2] emphasized that intra-articular injection outcomes are often diminished in patients with advanced OA, especially in those with metabolic comorbidities. Our findings support these clinical insights and suggest that biological therapies may be more appropriate in nonobese patients with early stage disease, whereas advanced OA cases may require alternative or adjunctive strategies.
Our findings demonstrated a favorable safety profile for all treatment modalities, with no serious adverse events reported. The minor adverse effects were consistent with those described in previous studies on intra-articular injections. The use of standardized severity grading (CTCAE) adds robustness to our safety assessment and enhances the generalizability of our findings.[16,17]
4.6. Limitations and future directions
This study had several limitations inherent to its retrospective design, including potential selection bias and reliance on existing medical records, which may have lacked detailed data on certain variables. Additionally, the follow-up period was relatively short for assessing long-term outcomes, particularly the structural progression of OA. Future prospective randomized controlled trials are needed to confirm these findings and explore the potential of combining therapies to optimize outcomes.
Moreover, while this study focused on VAS, WOMAC, and radiographic outcomes, future research should incorporate patient-reported outcomes and quality of life measures to better understand the broader impact of these treatments. Exploring the molecular mechanisms underlying the effects of PRP and HA on cartilage health may provide insights into their potential as disease-modifying agents for OA.
5. Conclusion
In summary, this study suggests that PRP offers the most sustained improvement in pain and function in patients with knee OA, followed by HA, which provides moderate but reliable symptomatic relief. CS are highly effective in the short-term but should be used with caution because of their limited duration of effect and the potential for adverse outcomes. NSAIDs offer the least improvement and carry the risk of systemic side effects, making them less desirable for long-term use. These findings support a tailored approach to knee OA treatment, with PRP and HA serving as promising options for long-term relief and disease stabilization.
Author contributions
Conceptualization: Yaşar Samet Gökçeoğlu.
Data curation: Yaşar Samet Gökçeoğlu, Metin Yapti.
Formal analysis: Felat Öncel.
Funding acquisition: Ali Levent.
Supervision: Yaşar Samet Gökçeoğlu, Sedat Demir.
Writing – original draft: Yaşar Samet Gökçeoğlu.
Validation: Metin Yapti.
Abbreviations:
- BMI
- body mass index
- CS
- corticosteroids
- HA
- hyaluronic acid
- KL
- Kellgren–Lawrence
- MCID
- minimal clinically important difference
- NSAID
- nonsteroidal anti-inflammatory drug
- PRP
- platelet-rich plasma
- VAS
- visual analog scale
- WOMAC
- Western Ontario and McMaster Universities Osteoarthritis Index
This study was approved by the Clinical Research Ethics Committee of the Harran University Faculty of Medicine (Approval No. HRÜ/24.11.27, August 5, 2024). The requirement for informed consent was waived due to the retrospective design of the study.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Gökçeoğlu YS, Yapti M, Öncel F, Levent A, Demir S. Comparative efficacy of intra-articular platelet-rich plasma, hyaluronic acid, corticosteroids, and NSAIDs for knee osteoarthritis: A retrospective cohort study. Medicine 2025;104:40(e44929).
This study has not been presented at any congress or scientific meeting and was not derived from a thesis.
Contributor Information
Metin Yapti, Email: sametorto@gmail.com.
Felat Öncel, Email: sametgokceoglu@istanbul.edu.tr.
Ali Levent, Email: yasarsametgokceoglu@yandex.com.
Sedat Demir, Email: ortopedi01@yandex.com.
References
- [1].Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64:465–74. [DOI] [PubMed] [Google Scholar]
- [2].Bannuru RR, Osani M, Vaysbrot E, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27:1578–89. [DOI] [PubMed] [Google Scholar]
- [3].Filardo G, Di Matteo B, Di Martino A, et al. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015;43:1575–82. [DOI] [PubMed] [Google Scholar]
- [4].Laudy AB, Bakker EW, Rekers M, Moen MH. Efficacy of platelet-rich plasma injections in osteoarthritis of the knee: a systematic review and meta-analysis. Br J Sports Med. 2015;49:657–72. [DOI] [PubMed] [Google Scholar]
- [5].Bowden DJ, Byrne CA, Alkhayat A, Eustace SJ, Kavanagh EC. Injectable viscoelastic supplements: a review for radiologists. AJR Am J Roentgenol. 2017;209:883–8. [DOI] [PubMed] [Google Scholar]
- [6].Conaghan PG, Hunter DJ, Cohen SB, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Joint Surg Am. 2018;100:666–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317:1967–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Scheuing WJ, Reginato AM, Deeb M, Kasman SA. The burden of osteoarthritis: Is it a rising problem? Best Pract Res Clin Rheumatol. 2023;37:101836. [DOI] [PubMed] [Google Scholar]
- [9].Kim MJ, Kang BH, Park SH, et al. Association of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with muscle strength in community-dwelling elderly with knee osteoarthritis. Int J Environ Res Public Health. 2020;17:2260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Longo UG, Papalia R, Campi S, et al. Evaluating the minimum clinically important difference and patient acceptable symptom state for the womac osteoarthritis index after unicompartmental knee arthroplasty. J Clin Med. 2023;12:7618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Biscaro RC, Ochoa PGG, Ocampos GP, Arouca MM, de Camargo OP, de Rezende MU. Self-Management Program (Parqve) improves quality of life in severe knee osteoarthritis. Acta Ortop Bras. 2022;30:e255939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Carli AB, Akarsu S, Tekin L, Saglam M, Kiralp MZ, Ozcakar L. Ultrasonographic assessment of the femoral cartilage in osteoarthritis patients with and without osteoporosis. Aging Clin Exp Res. 2014;26:411–5. [DOI] [PubMed] [Google Scholar]
- [13].Cakiroglu Y, Saltik A, Yuceturk A, et al. Effects of intraovarian injection of autologous platelet rich plasma on ovarian reserve and IVF outcome parameters in women with primary ovarian insufficiency. Aging (Albany NY). 2020;12:10211–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Concoff A, Rosen J, Fu F, et al. A comparison of treatment effects for non-surgical therapies and the minimum clinically important difference in knee osteoarthritis: a systematic review. JBJS Rev. 2019;7:e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Xu H, Shi W, Liu H, et al. Comparison of hyaluronic acid and platelet-rich plasma in knee osteoarthritis: a systematic review. BMC Musculoskelet Disord. 2025;26:236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. CTCAE versión 5.0. Evaluación de la gravedad de los eventos adversos dermatológicos de las terapias antineoplásicas. Actas Dermosifiliogr (Engl Ed). 2021;112:90–2. [DOI] [PubMed] [Google Scholar]
- [17].US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE). (No Title). 2017. Nov 27.
- [18].Di Matteo B, Filardo G, Kon E, Marcacci M. Platelet-rich plasma: evidence for the treatment of patellar and Achilles tendinopathy—a systematic review. Musculoskeletal Surg. 2015;99:1–9. [DOI] [PubMed] [Google Scholar]
- [19].Liu Q, Ye H, Yang Y, Chen H. The efficacy and safety of intra-articular platelet-rich plasma versus sodium hyaluronate for the treatment of osteoarthritis: Meta-analysis. PLoS One. 2025;20:e0314878. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Gupta A, Sharma SP, Potty AG. Combination of platelet-rich plasma and hyaluronic acid vs. platelet-rich plasma alone for treatment of knee osteoarthritis. Biomedicines. 2023;11:2759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Du D, Liang Y. A meta-analysis and systematic review of the clinical efficacy and safety of platelet-rich plasma combined with hyaluronic acid (PRP + HA) versus PRP monotherapy for knee osteoarthritis (KOA). J Orthop Surg Res. 2025;20:57. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- [22].Gao J, Ma Y, Tang J, Zhang J, Zuo J. Efficacy and safety of platelet-rich plasma and hyaluronic acid combination therapy for knee osteoarthritis: a systematic review and meta-analysis. Arch Orthop Trauma Surg. 2024;144:3947–67. [DOI] [PubMed] [Google Scholar]
- [23].Luo P, Xiong Z, Sun W, Shi L, Gao F, Li Z. How to choose platelet-rich plasma or hyaluronic acid for the treatment of knee osteoarthritis in overweight or obese patients: a meta-analysis. Pain Res Manag. 2020;2020:7587936. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Annaniemi JA, Pere J, Giordano S. The efficacy of platelet-rich plasma injection therapy in obese versus non-obese patients with knee osteoarthritis: a comparative study. J Clin Med. 2024;13:2590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Glinkowski WM, Gut G, Śladowski D. Platelet-rich plasma for knee osteoarthritis: a comprehensive narrative review of the mechanisms, preparation protocols, and clinical evidence. J Clin Med. 2025;14:3983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Cao F, Xu Z, Li X-X, et al. Trends and cross-country inequalities in the global burden of osteoarthritis, 1990-2019: a population-based study. Ageing Res Rev. 2024;99:102382. [DOI] [PubMed] [Google Scholar]
- [27].Steinmetz JD, Culbreth GT, Haile LM, et al. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5:e508–e22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Altman R, Hackel J, Niazi F, Shaw P, Nicholls M. . Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: a systematic review. Semin Arthritis Rheum. 2018;48:168–75. [DOI] [PubMed] [Google Scholar]
- [29].Kamada K, Matsushita T, Yamashita T, et al. Factors affecting the therapeutic effects of multiple intra-articular injections of platelet-rich-plasma for knee osteoarthritis. Asia Pac J Sports Med Arthrosc Rehabil Technol. 2024;38:43–8. [DOI] [PMC free article] [PubMed] [Google Scholar]