The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis

Andrew Concoff, Parag Sancheti, Faizan Niazi, Peter Shaw, Jeffrey Rosen, Andrew Concoff, Parag Sancheti, Faizan Niazi, Peter Shaw, Jeffrey Rosen

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Intra-articular hyaluronic acid (IA-HA); Knee; Osteoarthritis (OA).

Conflict of interest statement

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

Andrew Concoff: Honorarium received for Ferring Pharmaceuticals advisory board.

Parag Sancheti: None.

Faizan Niazi: Paid employee of Ferring Pharmaceuticals.

Peter Shaw: Paid employee of Ferring Pharmaceuticals.

Jeffrey Rosen: Honorarium received for Ferring Pharmaceuticals, Flexion, and Novartis advisory boards. Honorarium received for OrthoGenrx sales force lecture.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Screening process. Legend: IA-HA: Intra-articular hyaluronic acid, RCT: Randomized controlled trial, OA: Osteoarthritis
Fig. 2
Fig. 2
Efficacy of IA-HA injections closest to 3-months
Fig. 3
Fig. 3
Efficacy of IA-HA injections closest to 6-months
Fig. 4
Fig. 4
Total number of participants experiencing a treatment-related serious adverse event
Fig. 5
Fig. 5
Subgroup analysis of the efficacy of IA-HA by total dose administered
Fig. 6
Fig. 6
Total number of participants experiencing a treatment-related adverse event
Fig. 7
Fig. 7
Risk of bias summary

References

    1. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2163–2196. doi: 10.1016/S0140-6736(12)61729-2.
    1. Cheng OT, Souzdalnitski D, Vrooman B, Cheng J. Evidence-based knee injections for the Management of Arthritis. Pain Med (United States) 2012;13(6):740–753. doi: 10.1111/j.1526-4637.2012.01394.x.
    1. Kosorok MR, Omenn GS, Diehr P, Koepsell TD, Patrick DL. Restricted activity days among older adults. Am J Public Health. 1992;82(9):1263–1267. doi: 10.2105/AJPH.82.9.1263.
    1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162(1):46–54. doi: 10.7326/M14-1231.
    1. Strand V, Conaghan PG, Lohmander LS, et al. An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the knee. Osteoarthr Cartil. 2006;14(9):859–866. doi: 10.1016/j.joca.2006.02.012.
    1. Altman RD, Manjoo A, Fierlinger A, Niazi F, Nicholls M. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet Disord. 2015;16:321. doi: 10.1186/s12891-015-0775-z.
    1. American Academy of Orthopaedic Surgeons Academy, AAOS. Treatment of Osteoarthritis of the Knee Evidence-Based Guideline 2nd Edition. Adopted by the American Academy of Orthopaedic Surgeions Board of Directors. Am Acad Orthop Surg Board Dir. 2013:973.
    1. American College of Rheumatology. Position Statement. Subject: Intra-Articular Hyaluronic Acid Injection in Osteoarthritis of the Knee. Available at . Accessed September 26, 2017.
    1. Trojian T, Concoff A, Joy S, Hatzenbuehler J, Saulsberry W, Coleman CAMSSM. Scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med. 2016;50(2):84–92. doi: 10.1136/bjsports-2015-095683.
    1. 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. doi: 10.1016/j.semarthrit.2015.11.010.
    1. McAlindon T, Bannuru R, Sullivan M, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil. 2014;22(3):363–388. doi: 10.1016/j.joca.2014.01.003.
    1. Moher D, Liberati A, Tetzlaff J, Altman D. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097.
    1. 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.
    1. Coe R. Effect Size Calculator. . Published 2016.
    1. Rutjes AWS, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157(3):180–191. doi: 10.7326/0003-4819-157-3-201208070-00473.
    1. Review Manager (RevMan) Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
    1. Lohmander L, Dalén N, Englund G, et al. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Ann Rheum Dis. 1996;55:424–431. doi: 10.1136/ard.55.7.424.
    1. Altman RD, Akermark C, Beaulieu AD, et al. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthr Cartil. 2004;12(8):642–649. doi: 10.1016/j.joca.2004.04.010.
    1. 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. doi: 10.1016/j.semarthrit.2009.04.001.
    1. Arden NK, Akermark C, Andersson M, Todman MG, Altman RDA. Randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin. 2014;30(2):279–286. doi: 10.1185/03007995.2013.855631.
    1. 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;
    1. 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. doi: 10.1136/ard.2008.094623.
    1. Creamer P, Sharif M, George E, et al. Intra-articular hyaluronic acid in osteoarthritis of the knee: an investigation into mechanisms of action. Osteoarthr Cartil. 1994;2(2):133–140. doi: 10.1016/S1063-4584(05)80063-9.
    1. 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):775–782.
    1. DeCaria JE, Montero-Odasso M, Wolfe D, Chesworth BM, Petrella RJ. The effect of intra-articular hyaluronic acid treatment on gait velocity in older knee osteoarthritis patients: a randomized, controlled study. Arch Gerontol Geriatr. 2012;55(2):310–315. doi: 10.1016/j.archger.2011.11.007.
    1. Diracoglu D, Vural M, Baskent A, Dikici F, Aksoy C. The effect of viscosupplementation on neuromuscular control of the knee in patients with osteoarthritis. J Back Musculoskelet Rehabil. 2009;22(1):1–9. doi: 10.3233/BMR-2009-0207.
    1. Dixon A, Jacoby R, Berry H, Hamilton E. Clinical trial of intra-articular injection of sodium hyaluronate in patients with osteoarthritis of the knee. Curr Med Res Opin. 1988;11(4):205–213. doi: 10.1185/03007998809114237.
    1. 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):529–534. doi: 10.1136/ard.53.8.529.
    1. Huang TL, Chang CC, Lee CH, Chen SC, Lai CH, Tsai CL. 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;12:221. doi: 10.1186/1471-2474-12-221.
    1. Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford) 1999;38(7):602–607. doi: 10.1093/rheumatology/38.7.602.
    1. Jorgensen A, Stengaard-Pedersen K, Simonsen O, et al. Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Ann Rheum Dis. 2010;69(6):1097–1102. doi: 10.1136/ard.2009.118042.
    1. 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):1240–1248. doi: 10.1093/rheumatology/41.11.1240.
    1. Kotevoglu N, Iyibozkurt PC, Hiz O, Toktas H, Kuran BA. Prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatol Int. 2006;26(4):325–330. doi: 10.1007/s00296-005-0611-0.
    1. Lundsgaard C, Dufour N, Fallentin E, Winkel P, Gluud C. 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. doi: 10.1080/03009740701813103.
    1. 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):1957–1962. doi: 10.1136/ard.2011.152017.
    1. 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):1928–1936.
    1. 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):951–956.
    1. Petrella RJ, Cogliano A, Decaria J. Combining two hyaluronic acids in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Clin Rheumatol. 2008;27(8):975–981. doi: 10.1007/s10067-007-0834-4.
    1. 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):1611–1617. doi: 10.1136/ard.2003.019703.
    1. 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;1:233–241. doi: 10.1016/S1063-4584(05)80329-2.
    1. Scale D, Wobig M, Wolpert W. Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res. 1994;55(3):220–232. doi: 10.1016/S0011-393X(05)80166-3.
    1. Sezgin M, Demirel A, Karaca C, et al. Does hyaluronan affect inflammatory cytokines in knee osteoarthritis? Rheumatol Int. 2005;25(4):264–269. doi: 10.1007/s00296-003-0428-7.
    1. 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):350–356. doi: 10.1016/j.joca.2012.01.013.
    1. 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):265–270.
    1. 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):754–757. doi: 10.1016/j.arth.2014.12.012.
    1. Wobig M, Dickhut A, Maier R, Vetter G. Viscosupplementation with Hylan G-F 20: a 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther. 1998;20(3):410–423. doi: 10.1016/S0149-2918(98)80052-0.
    1. 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.
    1. Trojian TH, Concoff AL, Joy SM, Hatzenbuehler JR, Saulsberry WJ, Coleman CIAMSSM. Scientific statement concerning Viscosupplementation injections for knee osteoarthritis. Clin J Sport Med. 2016;26(1):1–11. doi: 10.1097/JSM.0000000000000274.
    1. Zoboli AAC, de Rezende MU, de Campos GC, Pasqualin T, Frucchi R, de Camargo OP. Prospective randomized clinical trial: single and weekly viscosupplementation. Acta Ortop Bras. 2013;21(5):271–275. doi: 10.1590/S1413-78522013000500006.
    1. Greenwald RA. Oxygen radicals, inflammation, and arthritis: pathophysiological considerations and implications for treatment. Semin Arthritis Rheum. 1991;20(4):219–240. doi: 10.1016/0049-0172(91)90018-U.
    1. 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)
    1. Fioravanti A, Cantarini L, Chellini F, et al. Effect of hyaluronic acid (MW 500–730kDa) on proteoglycan and nitric oxide production in human osteoarthritic chondrocyte cultures exposed to hydrostatic pressure. Osteoarthr Cartil. 2005;13(8):688–696. doi: 10.1016/j.joca.2005.03.006.
    1. Gómez-Aristizábal A, Kim K, Viswanathan SA. Systematic study of the effect of different molecular weights of hyaluronic acid on mesenchymal stromal cell-mediated immunomodulation. PLoS One. 2016;11(1):e0147868. doi: 10.1371/journal.pone.0147868.
    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 10.4137/cmamd.s12743.
    1. Finnoff JT, Hall MM, Adams E, et al. American medical Society for Sports Medicine (AMSSM) position statement: interventional musculoskeletal ultrasound in sports medicine. PM R. 2015;7(2):151–168. doi: 10.1016/j.pmrj.2015.01.003.
    1. 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):389–399. doi: 10.1016/j.joca.2004.02.001.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit