To evaluate effectiveness, in terms of patient-reported outcome measures, of platelet-rich plasma (PRP) injections for knee osteoarthritis compared to placebo and other intraarticular treatments. PubMed, Cochrane Library, Scopus, Embase, Web of Science, as well as the gray literature were searched on January 17, 2020. Randomized controlled trials (RCTs) comparing PRP injections with placebo or other injectable treatments, in any language, on humans, were included. Risk of bias was assessed following the Cochrane guidelines; quality of evidence was graded using the GRADE guidelines. Thirty-four RCTs, including 1403 knees in PRP groups and 1426 in control groups, were selected. WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score favored PRP, with a statistically and clinically significant difference versus placebo at 12-month follow-up (P = 0.02) and versus HA (hyaluronic acid) at 6-month (P < 0.001) and 12-month (P < 0.001) follow-ups. A clinically significant difference favoring PRP versus steroids was documented for VAS (Visual Analogue Scale) pain (P < 0.001), KOOS (Knee Injury and Osteoarthritis Outcome Score) pain (P < 0.001), function in daily activities (P = 0.001), and quality of life (P < 0.001) at 6-month follow-up. However, superiority of PRP did not reach the minimal clinically important difference for all outcomes, and quality of evidence was low. The effect of platelet concentrates goes beyond its mere placebo effect, and PRP injections provide better results than other injectable options. This benefit increases over time, being not significant at earlier follow-ups but becoming clinically significant after 6 to 12 months. However, although substantial, the improvement remains partial and supported by low level of evidence. This finding urges further research to confirm benefits and identify the best formulation and indications for PRP injections in knee OA.

Background: Platelet-rich plasma (PRP) has emerged as a promising therapeutic intervention for knee osteoarthritis (OA), attracting substantial clinical and research attention. However, the clinical relevance of the treatment benefit remains controversial. Purpose: To evaluate the effectiveness of PRP compared with placebo in patients with knee OA in terms of minimal clinically important difference (MCID) and to investigate the possible influence of platelet concentration on the clinical outcome. Study Design: Meta-analysis. Level of evidence 1. Methods: The search was conducted on 5 databases (PubMed, Cochrane Library, Scopus, Embase, Web of Science) using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were randomized controlled trials comparing PRP and placebo injections to treat knee OA, written in the English language, with no time limitation. The effects were quantified at 1-, 3-, 6-, and 12-month follow-up points. Visual analog scale (VAS) for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were used, with subanalyses based on platelet concentration performed using a 1,000,000 ± 20% platelets/µL cutoff. The MCID values (VAS, 1.37; WOMAC, 6.4) were used to interpret clinical improvement. The articles’ quality was assessed using the Revised Tool for Risk of Bias in Randomized Trials and the Grading of Recommendations Assessment, Development and Evaluation guidelines. Results: Among the 5499 articles retrieved, 18 randomized controlled trials (1995 patients) were included. PRP presented statistically superior improvements in VAS and WOMAC scores compared with placebo at all follow-up points, exceeding the MCID at 3- and 6-month follow-up points for VAS and at all follow-up points for WOMAC. The subanalysis based on platelet concentration showed that high-platelet PRP provided clinically significant pain relief with the improvement exceeding the MCID compared with placebo at 3-, 6-, and 12-month follow-up points. In contrast, low-platelet PRP failed to offer a clinically perceivable benefit in terms of VAS score. WOMAC results showed that both products provided a clinically significant improvement at 3 and 6 months of follow-up. This benefit was maintained up to the 12-month follow-up in the high-platelet group but not in the low-platelet group, where the improvement compared with placebo did not reach statistical significance. Conclusion: This meta-analysis showed that PRP offered clinically relevant functional improvement at 1-, 3-, 6-, and 12-month follow-up points and pain relief at 3- and 6-month follow-up points compared with placebo for the treatment of knee OA. Platelet concentration was found to influence treatment efficacy, with high-platelet PRP providing superior pain relief and more durable functional improvement compared with low-platelet PRP.

To quantify the placebo effect of intraarticular injections for knee osteoarthritis in terms of pain, function, and objective outcomes. Factors influencing placebo effect were investigated. Meta-analysis of randomized controlled trials; Level of evidence, 2. PubMed, Web of Science, Cochrane Library, and grey literature databases were searched on January 8, 2020, using the string: (knee) AND (osteoarthritis OR OA) AND (injections OR intra-articular) AND (saline OR placebo). The following inclusion criteria were used: double-blind, randomized controlled trials on knee osteoarthritis, including a placebo arm on saline injections. The primary outcome was pain variation. Risk of bias was assessed using the RoB 2.0 tool, and quality of evidence was graded following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) guidelines. Out of 2,363 records, 50 articles on 4,076 patients were included. The meta-analysis showed significant improvements up to the 6-month follow-up: Visual Analogue Scale (VAS)-pain −13.4 mean difference (MD) (95% confidence interval [CI]: −21.7/−5.1; P < 0.001), Western Ontario and McMaster Osteoarthritis Index (WOMAC)-pain −3.3 MD (95% CI: −3.9/−2.7; P < 0.001). Other significant improvements were WOMAC-stiffness −1.1 MD (95% CI: −1.6/−0.6; P < 0.001), WOMAC-function −10.1 MD (95% CI: −12.2/−8.0; P < 0.001), and Evaluator Global Assessment −21.4 MD (95% CI: −29.2/−13.6; P < 0.001). The responder rate was 52% (95% CI: 40% to 63%). Improvements were greater than the “minimal clinically important difference” for all outcomes (except 6-month VAS-pain). The level of evidence was moderate for almost all outcomes. The placebo effect of knee injections is significant, with functional improvements lasting even longer than those reported for pain perception. The high, long-lasting, and heterogeneous effects on the scales commonly used in clinical trials further highlight that the impact of placebo should not be overlooked in the research on and management of knee osteoarthritis.

Objective: The aim of this meta-analysis was to study the evidence on pain sensitization in knee osteoarthritis (OA), providing a quantitative synthesis of its prevalence and impact. Factors associated with pain sensitization were also investigated. Methods: Meta-analysis; PubMed (MEDLINE), Cochrane Central Register (CENTRAL), and Web of Science were searched on February 2021. Level I to level IV studies evaluating the presence of pain sensitization in patients with symptomatic knee OA, documented through a validated method (questionnaires or quantitative sensory testing), were included. The primary outcome was the prevalence of pain sensitization. Factors influencing the prevalence were also evaluated, as well as differences in terms of pain thresholds between knee OA patients and healthy controls. Results: Fifty-three articles including 7,117 patients were included. The meta-analysis of proportion documented a prevalence of pain sensitization of 20% (95% confidence interval [CI] = 16%-26%) with a significant heterogeneity of results ( I² = 89%, P < 0.001). The diagnostic tool used was the main factor influencing the documented prevalence of pain sensitization ( P = 0.01). Knee OA patients presented higher pain sensitivity compared with healthy controls, both in terms of local pressure pain threshold (standardized mean difference [SMD] = −1.00, 95% CI = −1.67 to −0.32, P = 0.007) and distant pressure pain threshold (SMD = −0.54, 95% CI = −0.76 to −0.31, P < 0.001). Conclusions: Knee OA pain presents features that are consistent with a significant degree of pain sensitization. There is a high heterogeneity in the reported results, mainly based on the diagnostic tool used. The identification of the best methods to detect pain sensitization is warranted to correctly evaluate and manage symptoms of patients affected by knee OA. Registration: PROSPERO CRD42019123347.

There is no agreement on the best treatment for displaced midshaft clavicle fractures (MCFs), which are currently addressed by nonoperative or surgical approaches. The aim of this meta-analysis was to compare fracture healing and functional outcome after surgical versus nonsurgical treatment of MCFs, to help specialists in deciding between these different strategies by providing a synthesis of the best literature evidence. Meta-analysis. A systematic research of the literature was performed in different online databases: PubMed, Web of Science, Cochrane library, and grey literature. PRISMA (Preferred Reporting Items for Systematic Meta-Analyses) guidelines were used. The risk of bias was evaluated with the Cochrane Collaboration’s “risk of bias” tool, and the quality of evidence was graded according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Randomized controlled trials investigating differences between surgery and nonoperative treatment for displaced MCFs were included. The primary outcome was the nonunion rate. Other outcomes analyzed were time to union and to return to activities, Constant score, and Disabilities of the Arm, Shoulder and Hand (DASH) index. Patients’ satisfaction, secondary operations, and complications were also recorded. Out of 832 records found, 14 randomized controlled trials with 1546 patients were included. A significantly lower risk ratio was found for nonunion (10%; 95% CI, 6%-18%, P < .001) favoring surgery. Time to union was 5.1 weeks shorter with surgery (P = .007). The complication rate (including the number of reinterventions) was higher in the surgical group (31.3% vs 20.5%, P < .001). Shoulder function at short-term follow-up was significantly better in the surgical group (DASH index mean difference = 4.0 points), while no statistical difference was found in the Constant score and in the DASH index at midterm follow-up (P = .41 and .80, respectively). At long-term follow-up, both shoulder functional scores were significantly better in the surgery group: the overall Constant score mean difference was 5.3 points (95% CI, 2.3-8.4 points; P < .001), and the DASH index mean difference was 4.3 points (95% CI, 0.2-8.4 points; P = .04). Surgical treatment of MCFs significantly reduces the nonunion rate and shortens the time to union as compared with the nonoperative approach and, despite a slightly higher incidence of complications, leads to better shoulder functional scores at short- and long-term follow-up. Further studies should address the clinical significance of the documented improvement.

Different profiles of pain progression have been reported in patients with knee osteoarthritis (OA), but the determinants of this heterogeneity are still to be sought. The aim of this systematic review was to analyze all studies providing information about knee OA pain trajectories to delineate, according to patients’ characteristics, an evidence-based evolution pattern of this disabling disease, which is key for a more personalized and effective management of knee OA. A literature search was performed on PubMed, Web of Science, Cochrane Library, and grey literature databases. The Cochrane Collaboration’s tool for assessing risk of bias was used, and a best-evidence synthesis was performed to define the predictors of pain evolution. Seven articles on 7747 patients affected by knee OA (mainly early/moderate) were included. Daily knee OA pain trajectories were unstable in almost half of the patients. In the mid-term, knee OA had a steady pain trajectory in 85% of the patients, 8% experienced pain reduction, while 7% experienced pain worsening. Low education, comorbidities, and depression were patient-related predictors of severe/worsening knee OA pain. Conversely, age, alcohol, smoking, pain coping strategies, and medications were unrelated to pain evolution. Conflicting/no evidence was found for all joint-related factors, such as baseline radiographic severity.