Efficacy and safety of biologic agents for the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials

Background: We aimed to evaluate the efficacy and safety of biologic agents targeting three main cytokines, that is, nerve growth factor (NGF), interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha), for osteoarthritis (OA) treatment. Methods: Databases (PubMed, Embase, and Cochrane Library) and ClinicalTrials.gov were systematically searched for randomized placebo-controlled trials (RCTs) of biologic agents from inception to November 15, 2020. The outcomes were the mean change in pain, function scores, and the risk of adverse effects (AEs). Results: Out of the 28 studies with 29 RCTs (8555 individuals) included, biologic agents were superior to placebo in pain relief (standardized mean difference [SMD] = 0.28, 95% confidence interval [CI] = 0.17-0.38, p <0.001) and function improvement (SMD = 0.30, 95% CI = 0.18-0.43, p< 0.001). The incidence of any AEs (risk ratio [RR] = 1.09, 95% CI = 1.05-1.14, p<0.001) and discontinuations due to AEs (RR = 1.39, 95% CI = 1.05-1.83, p= 0.021) were higher following treatment with biologic agents while no significant difference was found in serious AEs. Subgroup analyses showed that NGF inhibitors provided superior pain relief (SMD = 0.36, 95% CI = 0.26-0.47, p<0.0011 and function improvement (SMD = 0.41, 95% CI = 0.30-0.51, p <0.001), whereas IL-1 inhibitors and TNF-alpha inhibitors did not. Meanwhile, NGF inhibitors increased the incidence of any AEs (RR = 1.12, 95% CI = 1.07-1.17, p <0.001) and discontinuations due to AEs (RR = 1.48, 95% CI = 1.07-2.06, p =0.018). IL-1 inhibitors and INF-alpha inhibitors showed no difference in safety compared with placebo. Conclusions: The efficacy and safety of biologic agents vary by mechanism of action. NGF inhibitors can relieve OA-related pain and improve function but involve safety concerns. IL-1 inhibitors and TNF-alpha inhibitors are relatively safe options but with limited efficacy.