A Randomized Trial of Intra-articular Injection Therapy for Knee Osteoarthritis

Abstract

Background: Intra-articular injections are widely used for conservative treatment of knee osteoarthritis (OA). However, rigorous data are lacking regarding the comparative therapeutic effectiveness of these injections.

Purpose: The aim of this study was to compare clinical outcomes after intra-articular injections of glucocorticoid, hyaluronic acid, platelet-rich plasma (PRP), or placebo in patients with mild or moderate OA of the knee.

Materials and methods: In a double-blinded, placebo-controlled, single-center trial, we randomly assigned knees with early- to middle-stage knee OA (Kellgren-Lawrence grade 1-3) to an intra-articular injection with one of these substances: glucocorticoid, hyaluronic acid, PRP, or placebo. Primary outcome was pain reduction within 6 months after the injection, assessed with the numeric rating scale (NRS; range, 0-100). Secondary outcome parameters included WOMAC scores, Tegner Activity Scale, knee mobility, and adverse events. Finally, a linear mixed-effects model was calculated and corrected for possible patient and covariate effects.

Results: One hundred twenty knees (30 knees per treatment group) in 95 patients (41 female) were included in the final analysis. The median age of patients was 60 years (interquartile range, 54.0-68.0). There was no evidence that the drug effects of primary and secondary outcome parameters differed over time. The median pain at baseline was 32.5 (interquartile range, 15.00-50.00) on NRS. The changes in pain level during the first 6 months compared with baseline were small (within ±5 points on NRS), whereas the intrapatient variability was large between -20 and +20 points. Secondary outcome parameters did not differ significantly among the groups. Kellgren-Lawrence grade did not have a statistically significant effect on pain reduction ( P = 0.61).

Conclusions: There is no evidence that knee injections with glucocorticoid, PRP, or hyaluronic acid have superior short- or long-term effects in patients with low pain level at baseline and early- to middle-stage knee OA when compared with placebo.

Trial registration: ClinicalTrials.gov NCT02776514.

FIGURE 1

Trial enrollment, randomization, and follow-up numbers. Note: n = number of knees; 4 knees of 4 different patients had to be replaced due to dropout within the first 3 months after injection. Follow-up numbers are not shown for all follow-up time points in order to avoid an unwieldy figure. Most common reasons for failed inclusion criteria were Kellgren-Lawrence grade IV, anticoagulant therapy, and immunosuppressive therapy.

FIGURE 2

Primary outcome (A and B) and secondary outcomes (C–F). Panel A shows the difference in pain on NRS compared with baseline based on the linear mixed-effects model (LMM). Negative difference indicates pain reduction. Predicted values are created by setting all predictors other than drug and time point to a given value. The graph shows the expected effects for “an average patient” when we control for all other predictors in the model. Note: Confidence intervals for the predicted values are not reported as currently there is no satisfactory way to compute them for LMMs. Nevertheless, Supplementary Table S2, http://links.lww.com/RLI/A779, does report the estimated post hoc contrasts along with standard errors and P values. Panel B demonstrates the difference in pain versus pain at baseline in all knees. The blue line represents the “smoother line.” The effect of baseline value is very clear and strong. Those having low baseline values (eg, 0) won't show any improvement (see left-hand side of this graph). Note that the effect here does not seem to be linear. Therefore, this effect was implemented into the prediction model as a quadratic effect. Panel C shows the difference in pain (WOMAC pain: total) compared with baseline based on the LMM. Negative difference indicates pain reduction. Panel D demonstrates the difference in stiffness (WOMAC stiffness: total) compared with baseline based on the LMM. Negative difference indicates improvement of stiffness; positive difference indicates worsening of stiffness. E, The difference in physical function (WOMAC physical function: total) compared with baseline based on the LMM is shown is panel E. Negative difference indicates improvement of physical function. Panel F shows the difference in Tegner Activity Scale compared with baseline based on the LMM. Positive difference indicates increase in level of activity.