Efficacy and Safety of Intra-Articular Injection of Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

 LIUYi ¹ , Aili·Rehei ¹ , YANGDe-sheng ¹ , YEYuan-zheng ² ,  CAOLi ³

1. Department of Pediatric Surgery, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China;
2. Department of Cardiac Function, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China;
3. Department of Joint Surgery, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China;

Corresponding author：

CAOLi, Email: xjbone@21cn.com

Keywords：

Hyaluronic acid; Knee osteoarthritis; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20160180

Video：

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Objective To systematically evaluate the efficacy and safety of intra-articular injection of hyaluronic acid for knee osteoarthritis. Methods Databases including PubMed, EMbase, The Cochrane Library (Issue 1, 2016), WanFang Data, CBM, and CNKI were searched to collect randomized controlled trials (RCTs) about intra-articular injection of hyaluronic acid for knee osteoarthritis from inception to February 2016. The meta-analysis was conducted using RevMan 5.3 software. Results A total of 17 RCTs involving 4 070 patients were included. The results of metaanalysis showed that: there were no significant differences in WOMAC pain scores (7 weeks: MD=-0.01, 95%CI -0.46 to 0.44, P=0.98; 13 weeks: MD=-0.01, 95%CI -0.46to 0.43, P=0.95; 26 weeks: MD=0.32, 95%CI -0.04 to 0.67, P=0.08), stiffness scores (7 weeks: MD=0.10, 95%CI -0.26 to 0.45, P=0.59; 13 weeks: MD=0.24, 95%CI -0.11 to 0.60, P=0.17; 26 weeks: MD=0.06, 95%CI -0.09 to 0.22, P=0.42), and life function scores (7 weeks: MD=-0.20, 95%CI -0.75to 0.36, P=0.49; 13 weeks: MD=-0.02, 95%CI -0.57 to 0.52, P=0.93; 26 weeks: MD=0.30, 95%CI -0.07 to 0.67, P=0.11) between the hyaluronic acid group and the control group in 7-, 13- and 26 weeks. However, the hyaluronic acid group was superior to the control group in 50-step test (MD=-0.49，95%CI -7.36 to -3.61，P<0.000 01). Conclusion Current evidence suggests that intra-articular injection of hyaluronic acid has better effect than control treatment for pain at movement. However, due to the limited quantity of the included studies, the above conclusion still need to be verified by more high quality studies．

Citation： LIUYi, Aili·Rehei, YANGDe-sheng, YEYuan-zheng, CAOLi. Efficacy and Safety of Intra-Articular Injection of Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2016, 16(10): 1183-1191. doi: 10.7507/1672-2531.20160180 Copy

1.	Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med, 2006, 354(8): 841-848.
2.	Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage, 2010, 18(4): 476-499.
3.	Mcalindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. IEEE Trans Aerosp Electron Syst, 2014, 22(3): 363-388.
4.	Rutjes A, Jüni P, Costa B, et al. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med, 2012, 157(3): 180-191.
5.	Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration. 2011. Available at: www.cochrane-handbook.org.
6.	Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol, 1998, 25(25): 2203-2212.
7.	Altman RD, Rosen JE, Bloch DA, et al. A 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.
8.	Arden NK, Åkermark C, Andersson M, et al. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin, 2014, 30(2): 279-286.
9.	Baltzer A, Moser C, Jansen SA, et al. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage, 2008, 17(2): 152-160.
10.	Chevalier X, Jerosch J, Goupille P, et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis, 2010, 69(1): 113-119.
11.	Day R, Brooks P, Conaghan PG, et al. A 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): 775-782.
12.	Huang TL, Chang CC, Lee CH, et al. Intra-articular injections of sodium hyaluronate (Hyalgan^{^®}) in osteoarthritis of the knee. a randomized, controlled, double-blind, multicenter trial in the asian population. BMC Musculoskelet Disord, 2011, 12(1): 221-221.
13.	Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology, 1999, 38(7): 602-607.
14.	Jubb RW, Piva S, Beinat L, et al. A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. Int J Clin Pract, 2003, 57(6): 467-474.
15.	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, 2002, 41(11): 1240-1248.
16.	Lundsgaard C, Dufour N, Fallentin E, et al. Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial. Scand J Rheumatol, 2008, 37(2): 142-150.
17.	Neustadt D, Caldwell J, Bell M, et al. 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): 1928-1936.
18.	Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intra-articular hyaluronic acid for osteoarthritis of the knee. J Rheumatol, 2006, 33(5): 951-956.
19.	Pham T, Henanff AL, Ravaud P, et al. 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): 1611-1617.
20.	Strand V, Baraf HS, Lavin PT, et al. A 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. Osteoarthritis Cartilage, 2012, 20(5): 350-356.
21.	Weegen WV, Wullems JA, Bos E, et al. No Difference Between Intra-Articular Injection of Hyaluronic Acid and Placebo for Mild to Moderate Knee Osteoarthritis: A Randomized, Controlled, Double-Blind Trial. J Arthroplasty, 2014, 30(5): 754-757.
22.	Zhang Q, Zhang T. Effect on Pain and Symptoms of Aspiration Before Hyaluronan Injection for Knee Osteoarthritis: A Prospective, Randomized, Single-blind Study. Am J Phys Med, 2015, 1977(260): 1-15.
23.	Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol, 1974, 22(8): 731-736.
24.	Altman RD, Schemitsch E, Bedi A. Assessment of Clinical Practice Guideline Methodology for the Treatment of Knee Osteoarthritis with Intra-Articular Hyaluronic Acid. Semin Arthritis Rheum, 2015, 45(2): 132-139.
25.	Reid MC. Viscosupplementation for osteoarthritis: a primer for primary care physicians. Adv Ther, 2013, 30(11): 967-986.
26.	Migliore A, Granata M. Intra-articular use of hyaluronic acid in the treatment of osteoarthritis. Clin Interv Aging, 2008, 3(2): 365-369.
27.	Wang F, Xijing HE. Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis. Exp Ther Med, 2015, 9(2): 493-500.

1. Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med, 2006, 354(8): 841-848.
2. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage, 2010, 18(4): 476-499.
3. Mcalindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. IEEE Trans Aerosp Electron Syst, 2014, 22(3): 363-388.
4. Rutjes A, Jüni P, Costa B, et al. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med, 2012, 157(3): 180-191.
5. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration. 2011. Available at: www.cochrane-handbook.org.
6. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol, 1998, 25(25): 2203-2212.
7. Altman RD, Rosen JE, Bloch DA, et al. A 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.
8. Arden NK, Åkermark C, Andersson M, et al. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin, 2014, 30(2): 279-286.
9. Baltzer A, Moser C, Jansen SA, et al. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage, 2008, 17(2): 152-160.
10. Chevalier X, Jerosch J, Goupille P, et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis, 2010, 69(1): 113-119.
11. Day R, Brooks P, Conaghan PG, et al. A 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): 775-782.
12. Huang TL, Chang CC, Lee CH, et al. Intra-articular injections of sodium hyaluronate (Hyalgan^{^®}) in osteoarthritis of the knee. a randomized, controlled, double-blind, multicenter trial in the asian population. BMC Musculoskelet Disord, 2011, 12(1): 221-221.
13. Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology, 1999, 38(7): 602-607.
14. Jubb RW, Piva S, Beinat L, et al. A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. Int J Clin Pract, 2003, 57(6): 467-474.
15. 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, 2002, 41(11): 1240-1248.
16. Lundsgaard C, Dufour N, Fallentin E, et al. Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial. Scand J Rheumatol, 2008, 37(2): 142-150.
17. Neustadt D, Caldwell J, Bell M, et al. 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): 1928-1936.
18. Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intra-articular hyaluronic acid for osteoarthritis of the knee. J Rheumatol, 2006, 33(5): 951-956.
19. Pham T, Henanff AL, Ravaud P, et al. 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): 1611-1617.
20. Strand V, Baraf HS, Lavin PT, et al. A 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. Osteoarthritis Cartilage, 2012, 20(5): 350-356.
21. Weegen WV, Wullems JA, Bos E, et al. No Difference Between Intra-Articular Injection of Hyaluronic Acid and Placebo for Mild to Moderate Knee Osteoarthritis: A Randomized, Controlled, Double-Blind Trial. J Arthroplasty, 2014, 30(5): 754-757.
22. Zhang Q, Zhang T. Effect on Pain and Symptoms of Aspiration Before Hyaluronan Injection for Knee Osteoarthritis: A Prospective, Randomized, Single-blind Study. Am J Phys Med, 2015, 1977(260): 1-15.
23. Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol, 1974, 22(8): 731-736.
24. Altman RD, Schemitsch E, Bedi A. Assessment of Clinical Practice Guideline Methodology for the Treatment of Knee Osteoarthritis with Intra-Articular Hyaluronic Acid. Semin Arthritis Rheum, 2015, 45(2): 132-139.
25. Reid MC. Viscosupplementation for osteoarthritis: a primer for primary care physicians. Adv Ther, 2013, 30(11): 967-986.
26. Migliore A, Granata M. Intra-articular use of hyaluronic acid in the treatment of osteoarthritis. Clin Interv Aging, 2008, 3(2): 365-369.
27. Wang F, Xijing HE. Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis. Exp Ther Med, 2015, 9(2): 493-500.

Chinese Journal of Evidence-Based Medicine

Efficacy and Safety of Intra-Articular Injection of Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review

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