IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS

Review of Physiology Modifiers: Hyaluronan, Polysulfated , and Tiludronate

Chris E. Kawcak, DVM, PhD, Diplomate ACVS, ACVSMR

Author’s address: Equine Orthopaedic Research Center, College of Veterinary Medicine and Bio- medical Sciences, Colorado State University, Fort Collins, CO 80523; e-mail: ckawcak@colostate. edu. © 2011 AAEP.

1. Introduction leading to a decrease in post-injury trauma,7 and to Physiology modifiers, including hyaluronan, poly- have a positive effect when combined with cortico- sulfated glycosaminoglycana, and tiludronateb, are steroids such as with triamcinolone or methylpred- 8,9 meant to influence the cells within the musculosk- nisolone acetate. However, in vitro studies have eletal system. In this review, the general mecha- shown mixed results in the face of corticosteroids, as nisms of actions and indications are reviewed. one study showed little effect of hyaluronan on methylprednisolone acetate–induced articular carti- 10 2. Hyaluronan lage matrix catabolism, and another showed that exogenous hyaluronan in combination with cortico- Hyaluronans have been used and studied in horses steroids decreased the proteoglycan release typical and humans since the 1970s. Most hyaluronan 11 preparations are a 1% concentration with a molecu- of corticosteroid administration alone. lar size of anywhere between 500,000 and 6,000,000 There has also been some indication that molecu- 1 lar weight may have an influence on the efficacy of Daltons. Hyaluronan has been shown to interact 2 with the CD44 receptor to modulate cell prolifera- hyaluronan. One in vitro study showed that low- tion, migration, and gene expression. It has also and medium-molecular-weight hyaluronan actually been shown to decrease proinflammatory mediators increased inflammation, whereas high-molecular- and pain-producing neuropeptides that are common weight hyaluronan decreased inflammation. This in the joint and lead to disease.2,3 In vitro, hyaluro- was shown to occur via binding to the CD44 receptor nan has shown a positive effect on chondrocyte mor- and led to the conclusion that CD44 receptor may 12 phology in articular cartilage explants,4 it modulate inflammation via hyaluronan mass. stimulated proteoglycan synthesis in both chondro- Santangelo et al.13 showed that hyaluronan was pro- cyte and articular cartilage explant cultures,5 and it tective of lipopolysaccharide-induced fibroblast has also been shown to decrease prostaglandin E2 changes in vitro and that high-molecular-weight (PGE2) by synoviocytes in a lipopolysaccharide- hyaluronan had a greater effect than low-molecular- stimulated model.6 Hyaluronan has also been weight compounds. Although in vitro studies have shown to reduce shear strain after injury, probably shown an effect of molecular weight, variable effects

NOTES

AAEP PROCEEDINGS ր Vol. 57 ր 2011 111 IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS have also been shown due to differences in concen- 3. Polysulfated tration of hyaluronan regardless of the molecular PSGAGs have shown beneficial effects in vitro. 14 weight. Although in vitro studies have shown Specifically, they have been shown to stimulate pro- that molecular weight imparts variable effects on teoglycan synthesis,30 increase collagen and glycos- joints, the same has not been shown in vivo. Spe- aminoglycan synthesis in vitro,31 and decrease cifically, several clinical studies have shown no sig- PGE2 release in response to lipopolysaccharide in a nificant differences between the administration of synoviocyte model.6 However, the results have high-or low-molecular-weight hyaluronan.15–17 been variable in in vivo studies. PSGAG has been Although there is no difference, all of these studies shown in vivo to have no significant effect compared have shown significant improvement with exoge- with controls in an osteochondral defect model of the nous hyaluronan administration. middle carpal joint.20 However, Frisbie et al.18 Several in vivo studies have also been performed, have shown that exogenously administered PSGAG evaluating the efficacy of exogenous hyaluronan on decreased synovial effusion, subintimal fibrosis, and joints. Frisbie et al.18 showed that in an osteochon- synovial membrane vascularity in an osteochondral 19 dral fragment model, exogenously administered fragment model. In addition, Gaustad et al. showed that PSGAG decreased lameness in compar- hyaluronan significantly reduced the histologic evi- 32 dence of articular cartilage fibrillation, therefore im- ison to placebo. However, Todhunter et al. showed that in an articular cartilage healing model, parting more of a protective effect on the articular PSGAG administration decreased healing ability. cartilage than thought before. In addition, 19 Although in vivo effects appear to be variable, a Gaustad et al. showed that hyaluronan decreased survey of equine clinicians showed that PSGAGs are lameness at an effect greater than placebo adminis- perceived to be moderately effective and even better tration. However, exogenously administered than hyaluronan for subacute lesions.33 However, hyaluronan had no significant effects on an osteo- hyaluronan was perceived to be better than PSGAG chondral defect model of the middle carpal joint in the acute stages of joint disease.33 compared with controls.20 Exogenous hyaluronan Overall, PSGAGs appear to be clinically beneficial has also been shown to be beneficial when given for management of joint disease in horses, and re- systemically. Kawcak et al.21 showed that intrave- cent evidence supports its use for reducing synovitis. nous administration of hyaluronan resulted in de- creased lameness in an osteochondral fragment 4. Tiludronate model as well as reduced inflammatory signs within Bisphosphonate compounds are meant to inhibit os- the synovial membrane and decreased synovial fluid teoclastic function and to have a mild anti-inflam- total protein and PGE2 concentrations. Overall, matory effect. Tiludronate has been used in horses the in vivo effect of exogenous hyaluronan has been over the last 10 years. Although it was initially good; however, in humans, the rate of local reaction given at 0.1 mg/kg daily for 10 days, it has now been after administration of intra-articular hyaluronan shown to be effective at a single 1.0 mg/kg dose. appears to be variable and at times fairly high (7% This is typically diluted in a 1-liter bag of saline to 53%).22–26 There are no reports indicating the given over 30 minutes. Most clinicians will pre- reaction rate of horses to exogenously administered medicate with a dose of flunixin meglumine because hyaluronan; however, there has been a case report of in one early study, mild colic was seen in a low 34 severe reaction within 10 hours after of percentage of horses. An in vivo experimental hyaluronan.27 study showed that in horses with osteopenia in- Exogenous hyaluronan has also been produced in duced by lower-limb cast application, those horses an oral form. Although there is some concern about treated with tiludronate had significant reduction in bone resorption, therefore leading to the conclusion absorption and efficacy, Bergin et al.28 showed that that it had a protective effect on sparing bone den- in 24 yearlings with hock osteochondritis desiccans sity in this model.35 Otherwise, three clinical stud- treated with 100 mg of oral hyaluronan per day for ies have led to the justification for the use of 30 days, effusion was significantly reduced com- tiludronate in clinical situations. Deniox et al.36 pared with those that were not treated. Therefore, showed that tiludronate administration improved there is some indication that administration of oral lameness in horses with navicular disease, espe- hyaluronan can be efficacious. In a small clinical 29 cially in those with an acute history of lameness study, Carmona et al. showed a trend for exoge- development. In addition, Coudry et al.37 showed nous oral hyaluronan to reduce effusion. that administration of tiludronate in horses with Overall, exogenous hyaluronan has been shown to osteoarticular lesions of the thoracolumbar verte- be efficacious for use in treating horses with joint brae significantly improved dorsal flexibility in disease and appears useful for reducing articular those horses that were treated. In addition, Gough cartilage fibrillation. However, large-scale clinical et al.38 showed that administration of tiludronate in studies on the efficacy of hyaluronans for prevention addition to a strict exercise regimen improved of disease are lacking. horses with clinical evidence of bone spavin.

112 2011 ր Vol. 57 ր AAEP PROCEEDINGS IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS Overall, the administration of tiludronate appears 14. Sanchez Lazaro JA, Granado PC, Del Sol MG, et al. The role to be beneficial for these specific clinical conditions. of different hyaluronic acids in the articular cartilage of rab- bit. Open Orthop J 2010;4:44–47. 5. Discussion 15. Karatosun V, Unver B, Gocen Z, et al. Comparison of two hyaluronan drugs in patients with advanced of Overall physiology modifiers appear to be clinically the . A prospective, randomized, double-blind study with useful for joint disease. Although general applica- long term follow-up. Clin Exp Rheumatol 2005;23:213–218. tion guidelines for these products can be taken from 16. Lee PB, Kim YC, Lim YJ, et al. Comparison between high the literature, a personalized treatment program is and low molecular weight hyaluronates in knee osteoarthritis usually used by different practitioners. Hyaluro- patients: open-label, randomized, multicentre clinical trial. J Int Med Res 2006;34:77–87. nans and PSGAGs are used both as preventatives 17. Tikiz C, Unlu Z, Sener A, et al. Comparison of the efficacy of and for treatment of joint disease. Most practitio- lower and higher molecular weight viscosupplementation in ners probably use hyaluronans for synovitis and PS- the treatment of hip osteoarthritis. Clin Rheumatol 2005; GAGs for more chronic conditions when articular 24:244–250. cartilage damage is involved. However, when the 18. Frisbie DD, Kawcak CE, McIlwraith CW, et al. Evaluation literature is reviewed, they appear to have effects in of polysulfated glycosaminoglycan or sodium hyaluronan ad- ministered intra-articularly for treatment of horses with ex- both situations. Understanding of tiludronate use perimentally induced osteoarthritis. Am J Vet Res 2009;70: is still growing, and many more conditions appear to 203–209. be anecdotally responding well to this treatment. 19. Gaustad G, Larsen S. Comparison of polysulphated glycos- aminoglycan and sodium hyaluronate with placebo in treat- References and Footnotes ment of traumatic arthritis in horses. Equine Vet J 1995; 1. Balazs EA. Viscosupplementation for treatment of osteoar- 27:356–362. thritis: from initial discovery to current status and results. 20. Barr AR, Duance VC, Wotton SF, et al. Influence of intra- Surg Technol Int 2004;12:278–289. articular sodium hyaluronate and polysulphated glycosami- 2. Ghosh P, Guidolin D. Potential mechanism of action of in- noglycans on the biochemical composition of equine articular tra-articular hyaluronan therapy in osteoarthritis: are the surface repair tissue. Equine Vet J 1994;26:40–42. effects molecular weight dependent? Semin Arthritis 21. Kawcak CE, Frisbie DD, Trotter GW, et al. Effects of intra- Rheum 2002;32:10–37. venous administration of sodium hyaluronate on carpal joints 3. Moreland LW. Intra-articular hyaluronan () in exercising horses after arthroscopic surgery and osteo- and hylans for the treatment of osteoarthritis: mechanisms chondral fragmentation. Am J Vet Res 1997;58:1132–1140. of action. Arthritis Res Ther 2003;5:54–67. 22. Conrozier T, Chevalier X. Long-term experience with hylan 4. Bolt DM, Ishihara A, Weisbrode SE, et al. Effects of triam- GF-20 in the treatment of knee osteoarthritis. Expert Opin cinolone acetonide, sodium hyaluronate, amikacin sulfate, Pharmacother 2008;9:1797–1704. and mepivacaine hydrochloride, alone and in combination, on 23. Cohen MM, Altman RD, Hollstrom R, et al. Safety and morphology and matrix composition of lipopolysaccharide- efficacy of intra-articular sodium hyaluronate (Hyalgan) in a challenged and unchallenged equine articular cartilage ex- randomized, double-blind study for osteoarthritis of the an- plants. Am J Vet Res 2008;69:861–867. kle. Foot Ankle Int 2008;29:657–663. 5. Frean SP, Abraham LA, Lees P. In vitro stimulation of 24. Huskin JP, Vandekerckhove B, Delince P, et al. Multicen- equine articular cartilage proteoglycan synthesis by hyaluro- tre, prospective, open study to evaluate the safety and effi- nan and carprofen. Res Vet Sci 1999;67:183–190. 6. Frean SP, Lees P. Effects of polysulfated glycosaminoglycan cacy of hylan G-F 20 in knee osteoarthritis subjects and hyaluronan on prostaglandin E2 production by cultured presenting with pain following arthroscopic meniscectomy. equine synoviocytes. Am J Vet Res 2000;61:499–505. Knee Surg Sports Traumatol Arthrosc 2008;16:747–752. 7. Wong BL, Kim SH, Antonacci JM, et al. Cartilage shear 25. Migliore A, Tormenta S, Massafra U, et al. Intra-articular dynamics during tibio-femoral articulation: effect of acute administration of hylan G-F 20 in patients with symptomatic joint injury and tribosupplementation on synovial fluid lubri- hip osteoarthritis: tolerability and effectiveness in a large cation. Osteoarthritis Cartilage 2010;18:464–471. cohort study in clinical practice. Curr Med Res Opin 2008; 8. Schaefer EC, Stewart AA, Durgam SS, et al. Effects of so- 24:1309–1316. dium hyaluronate and triamcinolone acetonide on glucosami- 26. Witteveen AG, Giannini S, Guido G, et al. A prospective noglycan metabolism in equine articular chondrocytes multi-centre, open study of the safety and efficacy of hylan treated with interleukin-1. Am J Vet Res 2009;70:1494– G-F 20 (Synvisc) in patients with symptomatic ankle (talo- 1501. crural) osteoarthritis. Foot Ankle Surg 2008;14:145–152. 9. Yates AC, Stewart AA, Byron CR, et al. Effects of sodium 27. Kuemmerle JM, Uhlig H, Kofler J. Severe acute inflamma- hyaluronate and methylprednisolone acetate on proteoglycan tory reaction (SAIR) of the fetlock joint after intraarticular metabolism in equine articular chondrocytes treated with hyaluronate injection in a horse. Vet Comp Orthop Trauma- interleukin-1. Am J Vet Res 2006;67:1980–1986. tol 2006;19:236–238. 10. Doyle AJ, Stewart AA, Constable PD, et al. Effects of so- 28. Bergin BJ, Pierce SW, Bramlage LR, et al. Oral hyaluronan dium hyaluronate and methylprednisolone acetate on pro- gel reduces post operative tarsocrural effusion in the yearling teoglycan synthesis in equine articular cartilage explants. Thoroughbred. Equine Vet J 2006;38:375–378. Am J Vet Res 2005;66:48–53. 29. Carmona JU, Arguelles D, Deulofeu R, et al. Effect of the 11. Roneus B, Lindblad A, Lindholm A, et al. Effects of intra- articular corticosteroid and sodium hyaluronate injections on administration of an oral hyaluronan formulation on clinical synovial fluid production and synovial fluid content of sodium and biochemical parameters in young horses with osteochon- hyaluronate and proteoglycans in normal equine drosis. Vet Comp Orthop Traumatol 2009;22:455–459. joints. Zentralbl Veterinarmed A 1993;40:10–16. 30. Frean SP, Cambridge H, Lees P. Effects of anti-arthritic 12. Campo GM, Avenoso A, Campo S, et al. Differential effect of drugs on proteoglycan synthesis by equine cartilage. J Vet molecular size HA in mouse chondrocytes stimulated with Pharmacol Ther 2002;25:289–298. PMA. Biochim Biophys Acta 2009;1790:1353–1367. 31. Glade MJ. Polysulfated glycosaminoglycan accelerates net 13. Santangelo KS, Johnson AL, Ruppert AS, et al. Effects of synthesis of collagen and glycosaminoglycans by arthritic hyaluronan treatment on lipopolysaccharide-challenged fi- equine cartilage tissues and chondrocytes. Am J Vet Res broblast-like synovial cells. Arthritis Res Ther 2007;9:R1. 1990;51:779–785.

AAEP PROCEEDINGS ր Vol. 57 ր 2011 113 IN-DEPTH: CHOOSING JOINT THERAPIES FOR THE BEST RESULTS

32. Todhunter RJ, Minor RR, Wootton JA, et al. Effects of ex- 36. Denoix JM, Thibaud D, Riccio B. Tiludronate as a new ercise and polysulfated glycosaminoglycan on repair of artic- therapeutic agent in the treatment of navicular disease: a ular cartilage defects in the equine carpus. J Orthop Res double-blind placebo-controlled clinical trial. Equine Vet J 1993;11:782–795. 2003;35:407–413. 33. Caron JP, Kaneene JB, Miller R. Results of a survey of 37. Coudry V, Thibaud D, Riccio B, et al. Efficacy of tiludronate equine practitioners on the use and perceived efficacy of in the treatment of horses with signs of pain associated with polysulfated glycosaminoglycan. J Am Vet Med Assoc 1996; osteoarthritic lesions of the thoracolumbar vertebral column. 209:1564–1568. Am J Vet Res 2007;68:329–337. 34. Delguste C, Amory H, Guyonnet J, et al. Comparative phar- 38. Gough MR, Thibaud D, Smith RK. Tiludronate infusion in macokinetics of two intravenous administration regimens of the treatment of bone spavin: a double blind placebo-con- tiludronate in healthy adult horses and effects on the bone trolled trial. Equine Vet J 2010;42:381–387. resorption marker CTX-1. J Vet Pharmacol Ther 2008;31: 108–116. aPSGAG: Adequan, Luitpold Pharmaceuticals, P.O. Box 9001, 35. Delguste C, Amory H, Doucet M, et al. Pharmacological Shirley, NY 11967. effects of tiludronate in horses after long-term immobiliza- bTiludronate: Tildren, CEVA, 301 Route 17 North, Rutherford, tion. Bone 2007;41:414–421. NJ 07070.

114 2011 ր Vol. 57 ր AAEP PROCEEDINGS