Tools for Practice

#89 Viscosupplementation (Hyaluronic Acid or Hylan): Cushioning the Blow (To Your Wallet)?

Do injections of viscosupplements (hylan or hyaluronic acid) improve symptoms of knee osteoarthritis?

Research on viscosupplementation (hylan or hyaluronic acid) for knee osteoarthritis has frequently been of poor quality and has exaggerated effectiveness. The best evidence indicates no meaningful benefit (if any at all) with potential adverse events (including cost).

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At least 8 systematic reviews. Focus on the best and consider others.  Rutjes 2012:1 89 randomized controlled trials (RCTs) with 12,667 patients (mean age 63), median follow-up 16 years 
  • Reduction in pain (at 3 months), effect size -0.37 (-0.28 to -0.46) 
    • Just reached minimally important clinical benefit (-0.37 = 9 mm on 100 mm pain scale) 
  • But many issues, 
    • Higher quality studies (>100 patients, proper randomization, or blinded outcome assessor) found no clinically meaningful improvement in pain or function 
    • Publication bias: Negative trials less likely to be published. Five of 6 unpublished studies provided data and showed no effect. 
  • Adverse events increased 
    • Serious adverse events: Relative risk 1.41 (1.02-1.97) 
    • Dropouts due to adverse events: Relative risk 1.33 (1.01-1.74). 
Bannuru 2015:2  
  • Versus intra-articular placebo: Effect size -0.34 (-0.26 to -0.42)  
  • No difference versus intra-articular corticosteroid: Effect size -0.02 (+0.12 to -0.17) 
  • Large placebo effect (expectation bias) from intra-articular administration of medications, 
    • Intra-articular placebo versus oral placebo: Effect size -0.29 (-0.04 to -0.54). 
Six other systematic reviews3-8 (with between 7-76 RCTs each) found 
  • Similar results3,4 
  • No difference in patients reporting global improvement5 
  • Placebo injections similar to viscosupplementation6 
  • Clinically meaningful difference not discussed or rarely attained3-8 
  • Higher quality studies showed smaller benefit3,7 
  • Patients >65 years with more advanced radiographic osteoarthritis may be less likely to benefit.8 
  • While the conclusions of some systematic reviews are positive,5-8 these ignore clinically meaningful outcomes and/or include poor-quality, biased studies. 
  • Systematic review examining the timing of viscosupplementation effect9 
    • Peak effect at 8 weeks: effect size -0.34 (-0.02 to -0.67) for high-quality studies 
    • Still less than 0.37 minimally important clinical difference.1 
  • Systematic review comparing hylan to hyaluronic acid found no difference (except hylan may have more adverse events).10 
  • Viscosupplementation (1-3 injections) costs $285-500. 
updated aug 13 2016 by ricky

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  • Constance M Lebrun MD CCFP
  • G. Michael Allan MD CCFP

1. Rutjes AW, Jüni P, da Costa BR, et al. Ann Intern Med 2012;157:180-91.

2. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Ann Intern Med 2015;162:46-54.

3. Arrich J, Piribauer F, Mad P, et al. CMAJ 2005;172:1039-43.

4. Lo GH, La Valley M, McAlindon T, et al. JAMA 2003;290:3115-21.

5. Bellamy N, Campbell J, Robinson V, et al. Cochrane Database Sys Rev 2006;2:CD005321.

6. Medina JM, Thomas A, Denegar CR. J Fam Pract 2006;55:669-75.

7. Modawal A, Ferrer M, Choi HK, et al. J Fam Pract 2005;54:758-67.

8. Wang C-T, Lin J, Change C-J, et al. J Bone Joint Surg 2004;86-A:538-45.

9. Bannuru RR, Natov NS, Dasi UR, et al. Osteoarthritis Cartilage 2011;19:611-9.

10. Reichenback S, Blank S, Rutjes AWS, et al. Arthritis Rheumatism 2007;57:1410-8.

Authors do not have any conflicts of interest to declare.