Next Round on Hyaluronic Acid: Better Even Than Acetaminophen?

Jan 15, 2015

A new meta-analysis deems intra-articular hyaluronic acid considerably more effective than nonsteroidal anti-inflammatory drugs for knee arthritis pain. An expert on osteoarthritis ponders the implications.

The potential benefit of intra-articular hyaluronic acid (IAHA) has become increasingly controversial since the 2013 recommendations of the American Association of Orthopedic Surgeons (AAOS) that they not be used for osteoarthritis of the knee.1  The AAOS based its recommendations on processing of data from selected published studies using a statistical method that required a minimally clinically important improvement (MCII), as described by Tubach and associates.2

In contrast, Bannuru and associates have found intra-articular hyaluronic acid to be quite effective, using a different statistical method that uses indirect comparisons, a network meta-analysis.3 As described in an editorial, network meta-analysis "allows investigators to quantify the relative effectiveness of common treatments compared with each other and with placebo, which offers a good metric for establishing relative efficacy.”4

In this latest analysis, IAHA had the highest effect size (0.63) compared to oral placebo, almost 1.5 times that of naproxen (0.38) and 3.5 times that of acetaminophen (0.18), which surprisingly had the lowest effect size. The authors of the study point out that an “integrated [intra-articular] placebo effect may contribute to the superiority of IAHA to nonsteroidal anti-inflammatory drugs.

This issue needs clarification.  Perhaps the answer will come in part from the increasing data that intra-articular hyaluronic acid delays the need for knee replacement surgery.5,6

A delay in the need for surgery has important clinical and economic implications, and would also address the Food and Drug Administration's desire to have joint replacement as a hard outcome in disease-modifying trials for osteoarthritis.


1. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition.J Am Acad Orthop Surg. 2013; Sep;21(9):571-576. doi: 10.5435/JAAOS-21-09-571.

2.  Tubach F, Ravaud P, Martin-Mola E et al. Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: Results from a prospective multinational study.Arthritis Care Res 2012; 64:1699-1707. doi: 10.1002/acr.21747.

3.  Bannuru RR, Schmid CH, Kent DM et al.Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Ann Intern Med. 2015;162:46-54. doi: 10.7326/M14-1231.

4.  Mandl LA and Losina E. Relative efficacy of knee osteoarthritis treatments: are all placebos created equal?Ann Intern Med. 2015;162:71-2. doi: 10.7326/M14-2636.

5.  Abbott T, Altman RD, Dimeff R et al.Do Hyaluronic Acid Injections Delay Total Knee Replacement Surgery? ACR 2013 Program Book (Suppl):308 Abstract 2139

6. Mar J, Romero JM, Arrospide A, et al. [Cost-analysis of viscosupplementation treatment with hyaluronic acid in candidate knee replacement patients with osteoarhritis] Rev Esp Cir Ortop Traumatol. 2013;57:6-14. doi: 10.1016/j.recot.2012.08.006. [Article in Spanish]