The online version of this article (https://doi.org/10.1186/s12891-017-1897-2) contains supplementary material, which is available to authorized users.
Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens.
We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline.
Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2–4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = −0.76; −0.98 to −0.53, 95% CI, P < 0.00001, and SMD = −0.36; −0.63 to −0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2–4 injection subgroups.
Overall, 2–4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2–4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.
Additional file 2: Figure S1. Funnel plot analysis of studies investigating efficacy of IA-HA injections closest to 3-months. (DOCX 18 kb)
American Academy of Orthopaedic Surgeons Academy, AAOS. Treatment of Osteoarthritis of the Knee Evidence-Based Guideline 2 nd Edition. Adopted by the American Academy of Orthopaedic Surgeions Board of Directors. Am Acad Orthop Surg Board Dir. 2013:973.
American College of Rheumatology. Position Statement. Subject: Intra-Articular Hyaluronic Acid Injection in Osteoarthritis of the Knee. Available at https://www.rheumatology.org/Portals/0/Files/Viscosupplementation.pdf. Accessed September 26, 2017.
Bruyère O, Cooper C, Pelletier J, et al. A consensus statement on the European Society for Clinical and Economic Aspects of osteoporosis and osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis—from evidence-based medicine to the real-life setting. Semin Arthritis Rheum. 2016;45(4):S3–S11. CrossRefPubMed
Altman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E. Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee. Am J Sports Med. Nov 17 2015.
Coe R. Effect Size Calculator. http://www.cem.org/effect-size-calculator. Published 2016.
Review Manager (RevMan) Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Altman RD, Rosen JE, Bloch DA, Hatoum HT, Korner PA. Double-blind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an open-label safety extension (the FLEXX trial). Semin Arthritis Rheum. 2009;39(1):1–9. CrossRefPubMed
Brandt KD, Block JA, Michalski JP, Moreland LW, Caldwell JR, Lavin PT. Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC study. Group. 2001;
Day R, Brooks P, Conaghan PG, Petersen MA. Double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular Hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31(4):775–82. PubMed
Henderson EB, Smith EC, Pegley F, Blake DR. Intra-articular injections of 750 kD hyaluronan in the treatment of osteoarthritis: a randomised single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy. Ann Rheum Dis. 1994;53(8):529–34. CrossRefPubMedPubMedCentral
Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford). 1999;38(7):602–7. CrossRef
Karlsson J, Sjögren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford). 2002;41(11):1240–8. CrossRef
Navarro-Sarabia F, Coronel P, Collantes E, et al. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011;70(11):1957–62. CrossRefPubMedPubMedCentral
Neustadt D, Caldwell J, Bell M, Wade J, Gimbel J. Clinical effects of intraarticular injection of high molecular weight hyaluronan (Orthovisc) in osteoarthritis of the knee: a randomized, controlled, multicenter trial. J Rheumatol. 2005;32(10):1928–36. PubMed
Petrella RJ, Petrella MA. Prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol. 2006;33(5):951–6. PubMed
Pham T, Le Henanff A, Ravaud P, Dieppe P, Paolozzi L, Dougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004;63(12):1611–7. CrossRefPubMedPubMedCentral
Puhl W, Bernau A, Greiling H, et al. Intra-articular sodium hyaluronate in osteoarthritis of the knee: a multicenter, double-blind study. Osteoarthr Cartil Osteoarthr Res Soc. 1993;1:233–41. CrossRef
Scale D, Wobig M, Wolpert W. Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res. 1994;55(3):220–32. CrossRef
Strand V, Baraf HSB, Lavin PT, Lim S, Hosokawa HA. Multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthr Cartil. 2012;20(5):350–6. CrossRefPubMed
Tamir E, Robinson D, Koren R, Agar G, Halperin N. Intra-articular hyaluronan injections for the treatment of osteoarthritis of the knee: a randomized, double blind, placebo controlled study. Clin Exp Rheumatol. 2001;19(3):265–70. PubMed
van der Weegen W, Wullems JA, Bos E, Noten H, van Drumpt RAM. No difference between intra-articular injection of hyaluronic acid and placebo for mild to moderate knee osteoarthritis: a randomized, controlled, double-blind trial. J Arthroplast. 2015;30(5):754–7. CrossRef
Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis – meta-analysis. Osteoarthr Cartil.
Bauer C, Niculescu-Morzsa E, Jeyakumar V, Kern D, Späth S, Nehrer S. Chondroprotective effect of high-molecular-weight hyaluronic acid on osteoarthritic chondrocytes in a co-cultivation inflammation model with M1 macrophages. J Inflamm. 2016;13(1)
Block J, Miller L. US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2013;57 https://doi.org/10.4137/cmamd.s12743.
Pham T, van der Heijde D, Altman RD, et al. OMERACT-OARSI initiative: osteoarthritis research society international set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2004;12(5):389–99. CrossRef
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