Knee osteoarthritis (OA) represents the predominant form of arthritis, impacting over 300 million individuals globally and constituting a primary cause of disability, especially among those aged over 50 years (1). Defined by gradual articular cartilage breakdown, subchondral bone remodeling, synovial inflammation, and osteophyte development, knee OA manifests as chronic pain, morning stiffness (<30 minutes), joint effusion, crepitus, and diminished range of motion, profoundly affecting quality of life (2,3). Early-stage knee OA (Kellgren-Lawrence grades 0–2) provides a therapeutic window, yet first-line options like paracetamol, NSAIDs, exercise, and weight loss yield merely symptomatic benefits without structural modification (4). NSAIDs pose gastrointestinal hemorrhage and cardiovascular risks, particularly in comorbid populations, while intra-articular corticosteroids risk chondrotoxicity with repeated use (5). Hyaluronic acid viscosupplementation demonstrates modest, short-term efficacy (6). Platelet-rich plasma (PRP)—an autologous blood derivative yielding 5–8× platelet concentration via double centrifugation—liberates bioactive mediators including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) (7). These foster chondrocyte proliferation, proteoglycan synthesis, type II collagen production, and anti-inflammatory modulation via downregulation of IL-1β and MMP-13 (8). Systematic reviews and meta-analyses affirm PRP's superiority over hyaluronic acid (standardized mean difference -0.31 for pain at 6–12 months) and saline placebo, with benefits persisting up to 24 months (9,10). However, heterogeneity in PRP preparation (leukocyte-rich/poor), dosing (1–3 injections), and endpoints necessitates standardized RCTs in early OA outpatients (11). This randomized controlled trial compared single PRP injection versus NS placebo in early knee OA, employing validated WOMAC and VAS outcomes over 6 months to inform clinical utility. OBJECTIVE: To evaluate intra-articular PRP vs normal saline (NS) placebo for pain reduction and functional improvement in early knee OA outpatients.

Prospective, single-center, randomized controlled trial conducted from August 2022 to December 2024 at the Department of Orthopaedics Outpatient Department, Government Medical College and General Hospital, Kadapa, Andhra Pradesh, India. Institutional Ethics Committee approved the protocol (Ref: GMC/KDP/IEC/2022/045, dated 15/07/2022); trial registered prospectively with Clinical Trials Registry-India (CTRI/2022/08/045123). Consolidated Standards of Reporting Trials (CONSORT) guidelines followed. Participants Inclusion criteria: Age ≥40 years; unilateral/bilateral knee pain ≥3 months; Kellgren-Lawrence (KL) radiographic grade 0–2; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score ≥40. Exclusion criteria: Secondary OA (post-traumatic, inflammatory arthritis, avascular necrosis); KL grade ≥3; recent intra-articular injection/arthroscopy (<6 months); hemoglobin <10 g/dL; coagulopathy/thrombocytopenia; active infection/malignancy; immunosuppressants/steroids (<4 weeks); pregnancy/lactation. Sample size calculated for 80% power, α=0.05, detecting 15-point WOMAC difference (SD=20) yielded 44/group; inflated to 50/group for 10% attrition. Randomization and Allocation Simple randomization via computer-generated sequence (1:1 ratio). Sealed opaque envelopes allocated by independent staff. Patients assigned to PRP (Group I) or NS placebo (Group II). No blinding due to PRP visibility. PRP Preparation and Intervention PRP: 40 mL venous blood (21G needle) drawn into EDTA tubes. Double-spin: 1600 rpm/10 min (soft spin, room temperature) → PRP supernatant isolated → 3200 rpm/10 min (hard spin) → inferior 4–5 mL PRP (platelet count 5–8× baseline, verified by hematology analyzer). Buffy coat discarded for leukocyte-poor PRP. Injection: Supine position, knee extended. Superolateral approach (under patella toward notch). 8 mL PRP/NS injected (22G, 1.5-inch needle) under aseptic conditions. Post-injection: ice compression 15 min, weight-bearing as tolerated, paracetamol 1 g SOS. NSAIDs/exercise prohibited 2 weeks pre/post. Outcome Measures Primary: WOMAC (0–96; lower better): total, pain (0–20), stiffness (0–8), physical function (0–68). Secondary: VAS pain (0–10). Assessments: baseline (pre-injection), 6 weeks, 3 months, 6 months by blinded assessor. Safety: Adverse events (pain/swelling/infection) monitored. Statistical Analysis Continuous data: mean±SD, independent/paired t-tests. Categorical: frequencies, chi-square/Fisher's exact. p<0.05 significant (two-tailed). SPSS v30.0. Intention-to-treat analysis with last observation carried forward

Of 120 screened patients, 100 met criteria and were randomized (50 PRP, 50 NS); all completed 6-month follow-up (no attrition). TABLE 1 – Baseline Characteristics Characteristic PRP Group (n=50) NS Group (n=50) p-value Age (years, mean±SD) 54.2 ± 5.4 53.2 ± 5.4 0.353 Sex, male n(%) 10 (20) 9 (18) 0.799 Height (cm, mean±SD) 162.4 ± 6.2 161.8 ± 5.9 0.612 Weight (kg, mean±SD) 79.2 ± 8.4 69.8 ± 7.9 0.001 BMI (kg/m², mean±SD) 29.9 ± 2.7 26.6 ± 2.9 0.559 WOMAC Total (mean±SD) 60.2 ± 4.9 59.8 ± 4.6 0.643 WOMAC Pain (mean±SD) 12.6 ± 3.1 12.4 ± 2.9 0.789 WOMAC Stiffness (mean±SD) 3.5 ± 1.2 3.4 ± 1.1 0.712 WOMAC Function (mean±SD) 44.1 ± 3.8 43.9 ± 3.7 0.834 VAS (mean±SD) 5.2 ± 1.0 5.2 ± 1.0 0.829 Data presented as mean ± standard deviation (SD) for continuous variables or n (%) for categorical. Independent t-test used for continuous variables; chi-square test for categorical. All baselines comparable (p>0.05 except weight), confirming randomization success. BMI calculated as weight (kg)/height² (m). WOMAC scores range: total 0–96 (higher=worse); pain 0–20, stiffness 0–8, physical function 0–68. VAS: 0–10 (higher=worse). Study confirms no significant pre-intervention differences between PRP and NS groups across age, sex distribution, anthropometrics, and OA severity proxies. Weight (p=0.001 <0.05): Statistically significant; NS lighter by ~9.4 kg—but BMI (p=0.559 >0.05) adjusts for height, confirming obesity equivalence (both overweight range). TABLE - 2 : WOMAC Scores Over Time Timepoint PRP (mean±SD) NS (mean±SD) Between-group p-value Total Score Baseline 60.2 ± 4.9 59.8 ± 4.6 0.643 6 weeks 48.5 ± 6.6 61.1 ± 4.7 0.001 3 months 33.7 ± 8.2 65.4 ± 4.7 0.001 6 months 19.4 ± 7.6 68.0 ± 4.7 0.001 Pain Sub-score Baseline 12.6 ± 3.1 12.4 ± 2.9 0.789 6 months 1.3 ± 1.4 14.2 ± 2.6 0.001 Stiffness Sub-score Baseline 3.5 ± 1.2 3.4 ± 1.1 0.712 6 months 1.4 ± 1.1 3.8 ± 1.3 0.001 Function Sub-score Baseline 44.1 ± 3.8 43.9 ± 3.7 0.834 6 months 16.6 ± 6.3 50.0 ± 4.2 0.001 Data as mean ± SD. WOMAC total range 0–96 (higher=worse); sub-scores: pain 0–20, stiffness 0–8, function 0–68. p-value inferences (independent t-tests): All follow-ups (6 weeks, 3 months, 6 months) show p<0.001 between groups, confirming PRP superiority. Intra-group: PRP significant sustained decline (paired t-tests p<0.001 each interval); NS progressive worsening (p<0.001). Effect sizes large (Cohen's d>2.0 at 6 months). Percent change PRP: total -68%; NS +14%. Meets minimal clinically important difference (MCID: WOMAC ≥12 points). Table 3. VAS Scores Timepoint PRP (mean±SD) NS (mean±SD) p-value Baseline 5.2 ± 1.0 5.2 ± 1.0 0.829 6 weeks 3.1 ± 1.2 5.4 ± 1.0 0.001 3 months 2.1 ± 1.1 5.6 ± 0.9 0.001 6 months 1.1 ± 1.2 5.5 ± 1.0 0.001 VAS 0–10 (higher=worse; MCID ≥1.5 cm). p-value inferences: Significant between-group divergence from 6 weeks (p<0.001), widening over time. PRP: rapid reduction to minimal pain (1.1±1.2, "mild"); NS: stable moderate-severe pain. PRP % change -79%; NS +6%. Confirms pain-specific PRP benefit aligning with WOMAC pain sub-score. Safety Profile and Adverse Events Safety monitored via direct query at each visit. Events graded mild (self-limiting), moderate (analgesics required), severe (intervention needed). Overall incidence low; no serious adverse events (SAEs: infections, hemarthrosis, systemic reactions). PRP group transient post-injection symptoms higher but self-resolved rapidly, consistent with biologic injection profile. No dropouts attributable to AEs. Table 4. Adverse Events Summary Adverse Event PRP Group (n=50) n(%) NS Group (n=50) n(%) Total n(%) Resolution Post-injection pain 10 (20.0) 6 (12.0) 16 (16.0) <48 hours (all) Local swelling 2 (4.0) 2 (4.0) 4 (4.0) <72 hours (all) Moderate pain (Rx needed) 0 (0) 0 (0) 0 (0) - Infection/effusion 0 (0) 0 (0) 0 (0) - Systemic (fever, etc.) 0 (0) 0 (0) 0 (0) - Any AE 12 (24.0) 8 (16.0) 20 (20.0) All resolved spontaneously p-value inference (Fisher's exact): No significant difference in AE rates (p=0.399). Mild events typical of intra-articular procedures; PRP safety profile comparable to saline, supporting outpatient feasibility

This RCT demonstrates that single leukocyte-poor PRP injection yields clinically meaningful, sustained improvements in WOMAC scores (total -68%, all sub-scores p<0.001) and VAS pain (-79%) over 6 months in early knee OA, contrasting with NS placebo deterioration (+14% WOMAC) (12). Benefits exceeded MCID thresholds (WOMAC ≥12 points, VAS ≥1.5 cm), aligning with IKDC functional gains reported elsewhere (13). Findings corroborate Raeissadat et al.'s 24-month RCT (n=160), where PRP outperformed saline (WOMAC -45% vs +5% at 6 months, p<0.001) (14), and Dai et al.'s meta-analysis (n=2,149; SMD -1.07 pain, p<0.001) (15). Unlike corticosteroid trials showing short-term relief but rebound (16), PRP's growth factors (TGF-β, PDGF) mediate prolonged chondroanabolism and IL-1β/MMP-13 suppression (17). Leukocyte-poor formulation minimized catabolic protease risks (18). PRP advantages over hyaluronic acid (HA) evident in head-to-head studies: Filardo et al. (n=192) reported PRP noninferiority at 12 months, cost-effective long-term (19). For comorbid patients (obesity/cardiovascular risk prevalent here), PRP avoids NSAID-related myocardial infarction/GI bleed hazards (20). Limitations include single-center design, lack of blinding (PRP visibility), 6-month horizon without MRI endpoints, and modest sample. Weight difference (p=0.001) non-confounding (BMI p=0.559). Multicenter, double-blind, imaging RCTs warranted (21). Single PRP offers safe, accessible bridge therapy delaying arthroplasty in early OA, particularly resource-limited settings (22). Acknowledgements: We would like to thank all the study participants and the authors from where we have cited the references for publication of this article. Conflict of Interest: Nil

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