Visco-supplementation in patients with knee osteoarthritis: temporal trend of benefits assessed by metaregression

Dario Maratea, Valeria Fadda, Sabrina Trippoli, Andrea Messori

Appendix A - Supplementary material posted on the web

This Appendix includes:

-Table A1: Complete bibliographies for the 68 studies included in our analysis.

-Table A2: Software and technical details of our analysis.

-Table A3: Regression equations.

-Figure A1: Proportion meta-analysis of effect size.

Table A1. Complete bibliographies for the 68 results included in our analysis.
  1. Personal communication (Rydell, 1972) described in: Peyron JG, Balazs EA. Preliminary clinical assessment of Na-hyaluronate injection into human arthritic joints. Pathol Biol (Paris). 1974;22:731-6.
  1. Shichikawa K, Igarashi M, Sugawara S, Iwasaki Y. Clinical evaluation of high molecular weight sodium hyaluronate (SPH) on osteoarthritis of the knee—a multi-center well controlled comparative study. Jpn J Clin Pharmacol Therapeut. 1983;14:545-58.
  1. Shichikawa K, Maeda A, Ogawa N. [Clinical evaluation of sodium hyaluronate in the treatment of osteoarthritis of the knee]. Ryumachi. 1983;23:280-90.
  1. Bragantini A, Cassini M, de Bastiani G, Perbellini A. Controlled single-blind trial of intra-articularly injected hyaluronic acid (Hyalgan) in osteo-arthritis of the knee. Clin Trials J. 1987;24:333-40.
  1. Grecomoro G, Martorana U, Di Marco C. Intra-articular treatment with sodium hyaluronate in gonarthrosis: a controlled clinical trial versus placebo. Pharmatherapeutica. 1987;5:137-41.
  1. Dixon AS, Jacoby RK, Berry H, Hamilton EB. Clinical trial of intraarticular injection of sodium hyaluronate in patients with osteoarthritis of the knee. Curr Med Res Opin. 1988;11:205-13.
  1. Ghirardini M, Betelemme L, Fatti F. Impiego intraarticolare di acido ialuronico estrattivo de orgoteina sia separatamente che in associazione in pazienti affetti da gonartrosi in fase sinovitica [Abstract]. Reumatismo. 1990;42:132.
  1. Russell IJ, Michalek JE, LawrenceVA, Lessard JA, Briggs BT, May GS. A randomized, placebo (PL) and no-intervention (NI) controlled, trial of intraarticular (IA) 1% sodium hyaluronate (HA) in the treatment of knee osteoarthritis (OA) [Abstract B94]. Arthritis Rheum. 1992;35(Suppl):S132.
  1. Dougados M, Nguyen M, Listrat V, Amor B. High molecular weight sodium hyaluronate (hyalectin) in osteoarthritis of the knee: a 1 year placebocontrolled trial. Osteoarthritis Cartilage. 1993;1:97-103.
  1. Moreland LW, Arnold WJ, Saway A, Savory C, Sikes D. Efficacy and safety of intra-articular hylan G-F 20 (Synvisc), a viscoelastic derivative of hyaluronan, in patients with osteoarthritis of the knee [Abstract]. Arthritis Rheum. 1993; 36(Suppl 9):165.
  1. Puhl W, Bernau A, Greiling H, Ko¨pcke W, Pfo¨rringer W, Steck KJ, et al. Intra-articular sodium hyaluronate in osteoarthritis of the knee: a multicenter, double-blind study. Osteoarthritis Cartilage. 1993;1:233-41.
  1. Cohen MA, Shiroky JB, Ballachey ML, Neville C, Esdaile JM. Doubleblind randomized trial of intra-articular (I/A) hyaluronate in the treatment of osteoarthritis of the knee [Abstract 62]. Arthritis Rheum. 1994;37(Suppl 6):R31.
  1. Creamer P, Sharif M, George E, Meadows K, Cushnaghan J, Shinmei M, et al. Intra-articular hyaluronic acid in osteoarthritis of the knee: an investigation into mechanisms of action. Osteoarthritis Cartilage. 1994;2:133-40.
  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;53:529-34.
  1. Scale D, Wobig M, Wolpert W. Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res Clin Exp. 1994;55: 220-32.*
  1. Adams ME, Atkinson MH, Lussier AJ, Schulz JI, Siminovitch KA, Wade JP, et al. The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage. 1995;3:213-25.
  1. Carrabba M, Paresce E, Angelini M, Re KA, Torchiana EEM, Perbellini A. The safety and efficacy of different dose schedules of hyaluronic acid in the treatment of painful osteoarthritis of the knee with joint effusion. Eur J Rheumatol Inflamm. 1995;15:25-31.
  1. Corrado EM, Peluso GF, Gigliotti S, De DC, Palmieri D, Savoia N, et al. The effects of intra-articular administration of hyaluronic acid on osteoarthritis of the knee: a clinical study with immunological and biochemical evaluations. Eur J Rheumatol Inflamm. 1995;15:47-56.
  1. Guler M, Kuran B, Parlar D, Guler M, Saglam H, Yapici S, et al. Clinical trial of intra-articular injection of hyaluronic acid in patients with osteoarthritis of the knee [Abstract]. Presented at X National Rheumatology Congress, Pamukkale-Denizli, Turkey, 29 October–3 November 1996.
  1. Lohmander LS, Dale´n N, Englund G, Ha¨ma¨la¨inen M, Jensen EM, Karlsson K, et al. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomised, double blind, placebo controlled multicentre trial. Hyaluronan Multicentre Trial Group. Ann Rheum Dis. 1996;55:424-31.
  1. Kalay S. The effectiveness of intra-articular hyaluronic acid treatment in primary gonarthrosis [Specialization thesis]. Ankara, Turkey: Ministry of Health, Republic of Turkey; 1997.
  1. Listrat V, Ayral X, Patarnello F, Bonvarlet JP, Simonnet J, Amor B, et al. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cartilage. 1997;5:153-60.
  1. Schneider U, Miltner O, Graf J, Thomsen M, Niethard FU. [Mechanism of action of hyaluronic acid in gonarthrosis of both knee joints in a right/left comparison. Study with dynamometry, oxygen partial pressure, temperature and Lequesne score]. Z Orthop Ihre Grenzgeb. 1997;135:341-7.
  1. 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;25:2203-12.
  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;20:410-23.
  1. Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford). 1999;38:602-7.
  1. Seikagaku Corporation. Summary of safety and effectiveness data: Sodium hyaluronate. Bethesda, MD: U.S. Food and Drug Administration; 2001. Accessed at on 27 February 2012.**
  1. Ardic¸ F, Bolulu D, Topuz O, Cubukc¸u S. Efficacy of intra-articular hyaluronic acid injections in knee osteoarthritis [Abstract 75]. Ann Rheum Dis. 2001; 60(Suppl 1):232.
  1. Bunyaratavej N, Chan KM, Subramanian N. Treatment of painful osteoarthritis of the knee with hyaluronic acid. Results of a multicenter Asian study. J Med Assoc Thai. 2001;84 Suppl 2:S576-81.
  1. Caracuel MA, Mun˜oz-Villanueva MC, Escudero A, Veroz R, Frias G, Vacas J, et al. Effects of joint lavage and hyaluronic acid infiltration in patients with osteoarthritis of the knee [Abstract 91]. Ann Rheum Dis. 2001;60(Suppl):236.
  1. Dickson DJ, Hosie G, English JR; Primary Care Rheumatology Society OA Knee Study Group. A double-blind, placebo-controlled comparison of hylan G-F 20 against diclofenac in knee osteoarthritis. J Clin Research. 2001;4:41-52.
  1. Hizmetli S, Kocagil S, Kaptanoglu E, Elden H, Nacitarhan V. The efficacy and safety of intra-articular hyaluronic acid in osteoarthritis of the knee: a prospective, double-blind trial. Pamphlet provided at the European League Against Rheumatism, 3rd Annual European Congress of Rheumatology, Stockholm, Sweden, 12–15 June 2002.
  1. Karlsson J, Sjo¨gren 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; 41:1240-8.
  1. Miltner O, Schneider U, Siebert CH, Niedhart C, Niethard FU. Efficacy of intraarticular hyaluronic acid in patients with osteoarthritis—a prospective clinical trial. Osteoarthritis Cartilage. 2002;10:680-6.
  1. Petrella RJ, DiSilvestro MD, Hildebrand C. Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med. 2002;162: 292-8.
  1. Raynauld JP, Torrance GW, Band PA, Goldsmith CH, Tugwell P, Walker V, et al; Canadian Knee OA Study Group. A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results. Osteoarthritis Cartilage. 2002;10:506-17.
  1. Bayramog˘lu M, Karatas¸ M, Cetin N, Akman N, So¨zay S, Dilek A. Comparison of two different viscosupplements in knee osteoarthritis—a pilot study. Clin Rheumatol. 2003;22:118-22.
  1. Jubb RW, Piva S, Beinat L, Dacre J, Gishen P. 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;57:467-74.
  1. Kahan A, Lleu PL, Salin L. Prospective randomized study comparing the medicoeconomic benefits of Hylan GF-20 vs. conventional treatment in knee osteoarthritis. Joint Bone Spine. 2003;70:276-81.
  1. Tetik S, Ones K, Tetik C. Efficacy of intra-articular Hylan G-F 20 on osteoarthritis of the knee. The Pain Clinic. 2003;15:459-66.
  1. Tsai CL, Chang CC, Chen SC, Beinat L, Piva S. Treatment of knee osteoarthritis in Asian population with an intra-articular hyaluronan of MW500–730 KDa [Abstract P333]. Osteoarthritis Cartilage. 2003;11(Suppl A):119.
  1. Altman RD, Akermark C, Beaulieu AD, Schnitzer T; Durolane International Study Group. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2004;12:642-9.
  1. Day R, Brooks P, Conaghan PG, Petersen M; Multicenter Trial Group. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31:775-82.
  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;63:1611-7.
  1. Wu HB, Du JY, Yang SH, Shao ZW, Xiong XQ. [Evaluation on the effects of hyaluronan combined with different dosages of celecoxib for relieving pain and ankylosis induced by knee osteoarthritis]. Zhongguo Linchuang Kangfu. 2004;8: 5491-3.
  1. Cubukc¸u D, Ardic¸ F, Karabulut N, Topuz O. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clin Rheumatol. 2005;24:336-41.
  1. Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis Rheum. 2005; 53:812-20.
  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;32:1928-36.
  1. Sezgin M, Demirel AC, Karaca C, Ortancil O, Ulkar GB, Kanik A, et al. Does hyaluronan affect inflammatory cytokines in knee osteoarthritis? Rheumatol Int. 2005;25:264-9.
  1. Kotevoglu N, Iyibozkurt PC, Hiz O, Toktas H, Kuran B. A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatol Int. 2006;26:325-30.
  1. Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol. 2006;33:951-6.
  1. Atay T, Aslan A, Baydar ML, Ceylan B, Baykal B, Kirdemir V. [The efficacy of low- and high-molecular-weight hyaluronic acid applications after arthroscopic debridement in patients with osteoarthritis of the knee]. Acta Orthop Traumatol Turc. 2008;42:228-33.
  1. Blanco FJ, Ferna´ndez-Sueiro JL, Pinto-Tasende JA, Ferna´ndez-Lo´pez JC, Ramallal M, Freire A, et al. Intra-articular hyaluronan treatment of patients with knee osteoarthritis waiting for replacement surgery. Open Arthritis J. 2008;1:1-7.
  1. Heybeli N, Doral MN, Atay OA, Leblebiciog˘lu G, Uzu¨mcu¨gil A. [Intraarticular sodium hyaluronate injections after arthroscopic debridement for osteoarthritis of the knee: a prospective, randomized, controlled study]. Acta Orthop Traumatol Turc. 2008;42:221-7.
  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;37:142-50.
  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;27:975-81.
  1. Altman RD, Rosen JE, Bloch DA, Hatoum HT, Korner P. A doubleblind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an openlabel safety extension (the FLEXX trial). Semin Arthritis Rheum. 2009;39:1-9.
  1. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17:152-60.
  1. Baraf HS, Strand V, Hosokawa H, Akahane O, Lim S, Yaguchi M. Effectiveness and safety of a single intraarticular injection of gel-200, a new crosslinked formulation of hyaluronic acid [HA] in the treatment of symptomatic osteoarthritis [OA] of the knee [Abstract 326]. Osteoarthritis Cartilage. 2009; 17(Suppl 1):S174.
  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;22:1-9.
  1. Petrella RJ, Decaria JE, Wolfe D, Chesworth B, Shapiro S, Montero- Odasso M. The effect of hyaluronic acid on gait in knee osteoarthritis patients: preliminary results for a randomized, double-blind, placebo controlled study [Abstract 375]. Ann Rheum Dis. 2009;68(Suppl 3):479.
  1. Chevalier X, Jerosch J, Goupille P, van Dijk N, Luyten FP, Scott DL, 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;69:113-9.
  1. Jørgensen A, Stengaard-Pedersen K, Simonsen O, Pfeiffer-Jensen M, Eriksen C, Bliddal H, 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;69:1097-102.
  1. Kosuwon W, Sirichatiwapee W, Visanuyotin T, Jeeravipoolvarn P, Laupattarakasem W. An efficacy study on cartilage volume by MRI findings in patient with knee osteoarthritis between 25 mg of sodium hyaluronate (2.5 ml) to placebo [Abstract 370]. Ann Rheum Dis. 2010;69(Suppl 3):267.
  1. Kul-Panza E, Berker N. Is hyaluronate sodium effective in the management of knee osteoarthritis? A placebo-controlled double-blind study. Minerva Med. 2010;101:63-72.
  1. Huang TL, Chang CC, Lee CH, Chen SC, Lai CH, Tsai CL. Intraarticular 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.
* The trials by Scale et al. 1994 is cited twice: as Scale et al, 1994 A and Scale et al., 1994 B (see figure 1 in the review by Rutjes et al.)
** The trial by Seikagaly et al 2001 is cited twice: as Seikagalu U.K., 2001 and as Seikagaku France, 2001 (see figure 1 in the review by Rutjes et al.)
Table A2: Software and technical details of our analysis.
Our analysis was based on the use of specific software for meta-analysis (Open Meta-Analyst
version 4.16.12 Tufts University url and multivariate statistics (Spss SPSS Statistics for Windows, Version 21.0, Armonk NY).
For the purpose of our analysis, each study was assigned to a specific calendar year represented by the publication date. In our proportion meta-analyses, rates were subjected to natural logarithm transformation and then back-transformed to avoid negative values in the 95% confidence intervals.
Table A3. Regression equations.
The regression equations shown in Figure 1 are the following:
EFFECT-SIZE = -94.726 + 0.0469 x YEAR
Figure A1: Proportion meta-analysis of differences in pain intensity.
Legend to Figure A1. Data and graphs of the "traditional" meta-analyses of proportion, the material of which was included in our metaregressions. Differences in pain intensity expressed as effect size were the end-point of these analyses that.

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