Mixed Treatment Comparisons for Nonsurgical Treatment of Knee Osteoarthritis

A Network Meta-analysis

David S. Jevsevar, MD, MBA; Peter B. Shores, MPH; Kyle Mullen, MPH; Danielle M. Schulte, MS; Gregory A. Brown, MD, PhD; Deborah S. Cummins, PhD


J Am Acad Orthop Surg. 2018;26(9):325-336. 

In This Article

Abstract and Introduction


Introduction: Knee osteoarthritis (KOA) is a significant health problem with lifetime risk of development estimated to be 45%. Effective nonsurgical treatments are needed for the management of symptoms.

Methods: We designed a network meta-analysis to determine clinically relevant effectiveness of nonsteroidal anti-inflammatory drugs, acetaminophen, intra-articular (IA) corticosteroids, IA platelet-rich plasma, and IA hyaluronic acid compared with each other as well as with oral and IA placebos. We used PubMed, EMBASE, and Cochrane Central Register of Controlled Trials to perform a systematic search of KOA treatments with no date limits and last search on October 7, 2015. Article inclusion criteria considered the following: target population, randomized controlled study design, English language, human subjects, treatments and outcomes of interest, ≥30 patients per group, and consistent follow-up. Using the best available evidence, two abstractors independently extracted pain and function data at or near the most common follow-up time.

Results: For pain, all active treatments showed significance over oral placebo, with IA corticosteroids having the largest magnitude of effect and significant difference only over IA placebo. For function, no IA treatments showed significance compared with either placebo, and naproxen was the only treatment showing clinical significance compared with oral placebo. Cumulative probabilities showed naproxen to be the most effective individual treatment, and when combined with IA corticosteroids, it is the most probable to improve pain and function.

Discussion: Naproxen ranked most effective among conservative treatments of KOA and should be considered when treating pain and function because of its relative safety and low cost. The best available evidence was analyzed, but there were instances of inconsistency in the design and duration among articles, potentially affecting uniform data inclusion.


Epidemiological research estimates that the lifetime risk of developing symptomatic knee osteoarthritis (KOA) is 45%.[1] Because of the shifting demographics with an increasing percentage of the US population older than 65 years, the burden of KOA will continue to increase.[2,3] Although a recent randomized controlled trial demonstrated that total knee replacement is more effective than nonsurgical treatment of end-stage KOA,[4] effective nonsurgical treatments are required to manage KOA until surgical intervention becomes medically necessary.

Strong evidence of clinical effectiveness supports the use of self-managed strengthening, low-impact aerobic exercises, and nonsteroidal anti-inflammatory drugs (NSAIDs).[5] Moderate evidence of clinical effectiveness supported the recommendation for weight loss in patients with a body mass index ≥25. Strong evidence supported the recommendation that viscosupplementation (intra-articular [IA] hyaluronic acid HA injections) was not clinically effective. This conclusion that IA HA injections do not provide clinically significant improvement is supported by two additional independent meta-analyses.[6,7] Medical evidence for the treatment effectiveness of IA corticosteroid injections and platelet-rich plasma (PRP) injections was inconclusive.[5]

An evidence-based method is needed to determine the relative effectiveness of NSAIDs, acetaminophen, IA corticosteroid injections, IA PRP injections, and IA HA injections compared with oral placebo and IA placebo. This network meta-analysis (NMA) of high-quality clinical trials attempts to provide that evidence. Although there is strong evidence for the use of NSAIDs, this NMA uses statistical ranking techniques to provide evidence regarding which of the most common NSAIDs are most probable to decrease pain and improve function in patients with KOA and whether this is a comparable effect to other common conservative treatments. The NSAID studies also provide an effective source of overlapping data to generate indirect comparisons needed to fill gaps in evidence for more inconclusive and/or conflicting evidence for treatments such as HA, PRP, and corticosteroids. A previous NMA of KOA treatments included low-quality clinical trials with poor randomization, poor allocation, and/or poor blinding.[8] Inclusion of low-quality clinical trials can bias the results of an NMA.[9]