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Results of studies of systemic treatments for patients with osteoarthritis indicate significant positive effects on biomarkers that may be associated with disease progression but no significant effects on joint-space narrowing.
ABSTRACT: Systemic treatments for patients with osteoarthritis (OA) have been shown to have significant positive effects on biomarkers that may be associated with OA disease progression. Acetaminophen currently is recommended as a first-line treatment. NSAIDs are among the most widely used medications. Coxibs were developed to decrease GI toxicity while providing pain relief at least equivalent to that with nonselective NSAIDs. Tramadol and stronger opioids are recommended for the management of moderate to severe pain related to OA. Injection of corticosteroids is effective for symptomatic treatment, but there is no evidence to support disease-modifying activity. There is limited evidence to indicate that early intervention with intra-articular hyaluronic acid may have disease-modifying chondroprotective activity and positive effects on biomarkers associated with disease progression.
Results of studies of systemic treatments for patients with osteoarthritis (OA) indicate significant positive effects on biomarkers that may be associated with disease progression but no significant effects on joint-space narrowing. Licofelone, which is still in clinical trials, has been shown to significantly reduce cartilage volume loss over time, as demonstrated by MRI in patients with knee OA.
Intra-articular injection of corticosteroids is effective for symptomatic treatment of patients who have knee OA with synovitis, but there is no evidence to support disease-modifying activity for these agents. In contrast, there is limited evidence from clinical trials supporting the view that early intervention with intra-articular hyaluronic acid (IAHA) may have radiologically demonstrable disease-modifying chondroprotective activity in patients with OA and positive effects on biomarkers that may be associated with disease progression.
This is the third article in a 3-part series on managing early knee OA. In this series, we review clinical results for nonpharmacological and pharmacological treatments for patients with OA and summarize data related to their potential for altering disease progression. Such information is limited, but it may help clinicians select treatments for patients who have early OA.
In the first part ("Managing Knee Osteoarthritis: Rationale for Early Treatment," http://www.musculoskeletalnetwork.com/osteoarthritis), we described the relationships among molecular changes, structural damage, and disease progression and the rationale for early treatment and defining disease modification. The second article ("Managing Knee Osteoarthritis: Self-Help and Nonpharmacological Interventions," http://www.musculoskeletalnetwork.com/osteoarthritis) discussed self-help and nonpharmacological interventions. In this third article, we will provide an overview of systemic pharmacotherapy, including acetaminophen, NSAIDs and selective cyclooxygenase (COX)-2 inhibitors, licofelone, diacerein, tramadol and other opioid analgesics, and calcitonin, as well as intra-articular treatments, including corticosteroids and hyaluronates.
Searches of studies for all therapies were carried out using PubMed. Searches for each treatment were focused on citations that included information on "disease modification," "biomarkers," "joint space," "inflammation," and "cytokines."
This agent currently is recommended as a first-line treatment for patients with OA.1,2 However, meta-analyses of clinical trial results indicate modest or no significant benefit compared with placebo in patients with this condition.3,4
Acetaminophen use also has been associated with an increased risk of GI events and liver damage,5-9 as well as increased blood pressure.10 In 2009, an FDA panel recommended lowering dosing recommendations for acetaminophen because of toxicity concerns.11
There is no evidence that acetaminophen has significant disease-modifying activity in OA. However, acetaminophen may decrease the severity of synovitis and reduce effusion.12 In our clinical experience, up to 2000 mg/d of acetaminophen has a positive effect and may reduce the need for NSAIDs.
Nonselective NSAIDs/selective COX-2 inhibitors
NSAIDs are among the medications most widely used in the United States and worldwide.13 In patients with OA, nonselective NSAIDs have been shown to be significantly superior to placebo or acetaminophen for decreasing pain and stiffness and improving function.3,4 However, the limitations of conventional NSAIDs--a high risk of GI adverse events, such as ulcers, bleeding, and death7,14,15; destabilization of blood pressure; adverse effects on renal function; and an increased risk of cardiovascular events--are well known.16,17 We recommend that if possible, NSAIDs be used intermittently, particularly in patients with diabetes mellitus who are at high risk for nephropathy, to decrease the risk of adverse events.
There is no evidence that NSAID treatment can slow radiographic disease progression in patients with knee OA, and in one study, indomethacin treatment significantly accelerated joint-space narrowing.18 Study results for naproxen and diclofenac have indicated that they can down-regulate the plasminogen activator/plasmin system and gelatinase expression during the early stage of knee OA.19,20
Results from one study showed that ibuprofen has no significant effects on serum cartilage oligomeric matrix protein or urinary C-telopeptide of type II collagen (CTX-II) levels in patients with knee OA.21 In another trial, however, ibuprofen significantly decreased urinary CTX-II levels during knee OA flares.22 In a study of 90 patients with knee OA, nimesulide-but not ibuprofen-significantly decreased urinary CTX-II and serum levels of matrix metalloproteinase (MMP)-3 and MMP-13.23
COX-2 inhibitors, or coxibs, were developed to decrease GI toxicity while providing pain relief at least equivalent to that with nonselective NSAIDs. Clinical trial results have demonstrated effectiveness of these agents in achieving both goals. However, the GI benefit of coxibs was decreased in patients who also were receiving low-dose aspirin.24-28
Coxibs also may be associated with cardiorenal adverse events.17 Clinical trial results for celecoxib in patients with knee OA showed no significant effect on the progression of joint-space narrowing.29 However, studies of celecoxib, valdecoxib, rofecoxib, and etoricoxib have indicated that each of these agents can down-regulate the plasminogen activator/plasmin system and gelatinase expression during the early stage of knee OA.20
This agent--a combination 5-lipoxygenase and COX inhibitor--and naproxen were found to be equally effective in reducing symptoms in patients with knee OA.30 However, licofelone also significantly reduced cartilage volume loss over time, as demonstrated by MRI. Licofelone still is in the approval process.
This agent and its active metabolite rhein have been shown to inhibit interleukin-1 in a dose-dependent manner, thus down-regulating inflammatory pathways involved in OA that are stimulated by this cytokine.31 In a meta-analysis of results from 19 clinical trials, diacerein was significantly more effective than placebo and equivalent to NSAIDs in relieving symptoms of knee OA.32,33 Diacerein also showed a carryover effect; significant analgesic-sparing actions persisted for up to 3 months after treatment.
Diacerein is well tolerated, with the most common adverse events involving the GI system.32-34 The agent has no significant effect on progression of joint-space narrowing in knee OA.35,36 However, the Chondromodulating Effect of Diacerein in OA of the Hip study showed that diacerein significantly slows joint-space narrowing compared with placebo in patients with hip OA.37 Three trials currently under way are aimed at gaining approval for diacerein in the United States.
Tramadol and Other Opioid Analgesics
Tramadol and stronger opioids are recommended for the management of moderate to severe pain related to OA.38 A meta-analysis of clinical trial results showed that tramadol or tramadol plus acetaminophen decreases pain intensity and improves function in patients with OA.39
Adverse events associated with tramadol and other opioid analgesics include constipation, delirium, excessive sedation, an increased risk of gait disturbance and falls, and respiratory and circulatory depression.40,41 Also, diversion and abuse of opioids are concerns.42,43 There is no evidence that these agents modify disease progression in patients with OA.
Oral calcitonin has been shown to significantly decrease type II collagen neoepitope, CTX-II, and MMP-13 levels in patients with knee OA, but there is no evidence that it alters radiological disease progression.44 The treatment currently is being evaluated in clinical trials.
In a meta-analysis of 28 studies (1973 patients), intra-articular corticosteroids were more effective than intra-articular saline for pain reduction and patients' global assessment at 1 week after injection.45 There also was evidence of significant pain reduction with intra-articular corticosteroids at 2 and 3 weeks after injection but no evidence to support functional improvement at these time points. At 4 to 24 weeks after injection, there was no evidence that intra-articular corticosteroids had any significant effects on pain or function.
Potential complications of intra-articular corticosteroid injection include intra-articular and periarticular calcification, cutaneous atrophy, cutaneous depigmentation, osteonecrosis, rapid destruction of the femoral head, acute synovitis, Charcot arthropathy, tendinopathy, Nicolau syndrome, and joint dislocation.46 Joint infection may occur but is rare.
There is no evidence to indicate that intra-articular corticosteroid injection modifies the course of disease in patients with OA.47 However, intra-articular methylprednisolone acetate reduced the number of inflammatory cells, including macrophages, lymphocytes, and mast cells, in the synovium of patients with knee OA.48 Intra-articular corticosteroids are used to manage acute joint effusion in patients with knee OA. Intra-articular corticosteroid injection is effective in this patient subgroup, in which other injectables, such as IAHA, are contraindicated.
IAHA is a well-accepted treatment for patients with knee OA for whom pharmacological interventions have not been successful or who do not have extensive inflammation with synovitis.49 Osteoarthritis Research Society International and American College of Rheumatology guidelines recommend IAHA for the treatment of patients with knee OA.50,51 A Cochrane meta-analysis supported the use of IAHA injection for knee OA, indicating that the greatest improvements in symptoms and function occur between 5 and 13 weeks after treatment.45
In a meta-analysis of 7 studies that compared IAHA, corticosteroid, and placebo injection in a total of 606 patients, effect size favored IAHA over corticosteroids at 8, 12, and 26 weeks after treatment.52 Sensitivity analyses indicated that the superiority of IAHA extends across a range of patient subtypes. Combined analysis of results from clinical trials suggested that IAHA administration may have its greatest benefit in younger patients with early OA.
Results from one meta-analysis showed that patients 65 years or older and those with the most advanced stages of arthritic change (complete loss of joint space) are less likely to improve with IAHA therapy than younger patients with less advanced disease.53 It has been suggested that intervention with IAHA be initiated earlier in patients with OA to avoid cardiovascular, GI, and renal adverse events associated with NSAIDs and coxibs and to maximize IAHA efficacy.54
Hyaluronates have a generally acceptable safety profile; injection site reactions are the most frequently reported adverse events.55,56 Less common adverse events, such as pseudosepsis, have been associated with cross-linked and avian-derived hyaluronate agents and do not appear to be class-related.57
Results from several studies have provided evidence that IAHA may have disease-modifying actions. In a large randomized trial that assessed the disease-modifying effects of IAHA in knee OA, viscosupplementation compared with placebo significantly reduced the progression of joint-space narrowing in a subset of patients with a greater joint-space width at study entry.58 However, results from another 1-year study showed no significant effect of IAHA injection on joint-space narrowing in a cohort of 301 patients with knee OA.36 MRI results from 20 patients who received 3 weekly injections of IAHA into 1 or both knees (30 knees) indicated a significant improvement in patellofemoral joint cartilage after treatment.59
In an open-label study of 5 weekly injections of IAHA, both the cartilage and the synovial membrane showed improvement when measured 6 months after the injection.60 In 9 patients with Kellgren-Lawrence grade 2 OA, the thickness of the superficial amorphous cartilage layer increased significantly between the baseline and final evaluations. A significant reduction in the thickness of the synovial membrane and in the number of infiltrating mononuclear cells indicative of reduced inflammation in the synovium also was observed.
In a study in which patients were randomized to conventional therapy and then arthroscopically evaluated for severity of chondropathy, cartilage deterioration was observed in both control and intra-articular groups.61 However, it was significantly less in the IAHA group as measured by an investigator overall visual analog scale score and Socit Franaise d'Arthroscopie scoring. In another study of patients with symptomatic knee OA who were monitored for 2 years and evaluated with MRI, those who received 6 monthly IAHA injections without regard to symptoms had significantly better preservation of cartilage than patients in the control group (usual care without injections).62
IAHA injection has been shown to reduce levels of molecules thought to be involved in joint destruction in patients with knee OA. In one study, IAHA decreased the level of MMP-3 and the ratio of MMP-3 to tissue inhibitor of metalloproteinase-1 in the synovial fluid of patients with knee OA.63 However, in another study of patients with knee OA treated with IAHA, this intervention increased urinary CTX-II levels.64
Studies of IAHA-managed tissues from patients with knee OA have produced results suggesting potential for disease modification with this intervention. In a study of patients with early OA, administration of IAHA decreased levels of MMPs, urokinase-type plasminogen activator, and plasminogen activator inhibitor in chondral, meniscal, and synovial cultures.65
In a comparison of the effects of IAHA and methylprednisolone acetate on articular cartilage and the synovium in patients with OA, the number and aggregation of synoviocytes in IAHA-treated knees decreased.48 Both treatments reduced the number of inflammatory cells, including macrophages, lymphocytes, and mast cells. IAHA also significantly improved the compactness and thickness of the amorphous superficial cartilage layer 6 months after treatment compared with baseline.
In one study, the thickness of the superficial amorphous layer was significantly increased and chondrocyte density was significantly higher with IAHA than with intra-articular corticosteroids.66 The investigators favored using IAHA as an early intervention instrument for early arthritis, when it can have the highest success rate and, possibly, slow down loss of cartilage.
Systemic treatments have been shown to have significant positive effects on biomarkers that may be associated with OA disease progression. Injection of corticosteroids is effective for symptomatic treatment, but there is no evidence to support disease-modifying activity. Limited evidence indicates that early intervention with IAHA may have disease-modifying chondroprotective activity and positive effects on biomarkers associated with disease progression. The goals of future therapies will include not only pain reduction and function improvement but also early detection and early intervention.
1. Poitras S, Avouac J, Rossignol M, et al. A critical appraisal of guidelines for the management of knee osteoarthritis using Appraisal of Guidelines Research and Evaluation criteria. Arthritis Res Ther. 2007;9:R126.
2. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-162.
3. Towheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257.
4. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004;63:901-907.
5. GarcÃa RodrÃguez LA, HernÃ¡ndez-DÃaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12:570-576.
6. Larson AM, Polson J, Fontana RJ, et al; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42:1364-1372.
7. Rahme E, Barkun A, Nedjar H, et al. Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol. 2008;103:872-882.
8. Rahme E, Pettitt D, LeLorier J. Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum. 2002;46:3046-3054.
9. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296:87-93.
10. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med. 2007;167:394-399.
11. American Association for the Study of Liver Diseases. FDA Advisory Panel tightens controls on acetaminophen products. http://www.aasld.org/journals/Pages/FDATightensControls.aspx. Accessed September 7, 2012.
12. Brandt KD, Mazzuca SA, Buckwalter KA. Acetaminophen, like conventional NSAIDs, may reduce synovitis in osteoarthritic knees. Rheumatology (Oxford). 2006;45:1389-1394.
13. Gaziano JM. Nonnarcotic analgesics and hypertension. Am J Cardiol. 2006;97:10-16.
14. Lanas A, GarcÃa-RodrÃguez LA, Polo-TomÃ¡s M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009;104:1633-1641.
15. Straube S, TramÃ¨r MR, Moore RA, et al. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol. 2009;9:41.
16. Hennekens CH, Borzak S. Cyclooxygenase-2 inhibitors and most traditional nonsteroidal anti-inflammatory drugs cause similar moderately increased risks of cardiovascular disease. J Cardiovasc Pharmacol Ther. 2008;13:41-50.
17. Valat JP, Deray G, HÃ©loire F. Are there any differences in the cardiovascular tolerance between classical NSAIDs and coxibs? [in French]. Presse Med. 2006;35(suppl 1):25-34.
18. Huskisson EC, Berry H, Gishen P, et al. Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis. J Rheumatol. 1995;22:1941-1946.
19. Chu SC, Yang SF, Lue KH, et al. Naproxen, meloxicam and methylprednisolone inhibit urokinase plasminogen activator and inhibitor and gelatinases expression during the early stage of osteoarthritis [published correction appears in Clin Chim Acta. 2008;388:234]. Clin Chim Acta. 2008;387:90-96.
20. Yang SF, Hsieh YS, Lue KH, et al. Effects of nonsteroidal anti-inflammatory drugs on the expression of urokinase plasminogen activator and inhibitor and gelatinases in the early osteoarthritic knee of humans. Clin Biochem. 2008;41:109-116.
21. Petersen SG, Saxne T, Heinegard D, et al. Glucosamine but not ibuprofen alters cartilage turnover in osteoarthritis patients in response to physical training. Osteoarthritis Cartilage. 2010;18:34-40.
22. Gineyts E, Mo JA, Ko A, et al. Effects of ibuprofen on molecular markers of cartilage and synovium turnover in patients with knee osteoarthritis. Ann Rheum Dis. 2004;63:857-861.
23. Manicourt DH, Bevilacqua M, Righini V, et al. Comparative effect of nimesulide and ibuprofen on the urinary levels of collagen type II C-telopeptide degradation products and on the serum levels of hyaluronan and matrix metalloproteinases-3 and -13 in patients with flare-up of osteoarthritis. Drugs R D. 2005;6:261-271.
24. Brown TJ, Hooper L, Elliott RA, et al. A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling. Health Technol Assess. 2006;10:iii-iv, xi-xiii, 1-183.
25. Chen YF, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess. 2008;12:1-278, iii.
26. Dubois RW, Melmed GY, Henning JM, Bernal M. Risk of upper gastrointestinal injury and events in patients treated with cyclooxygenase (COX)-1/COX-2 nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and gastroprotective cotherapy: an appraisal of the literature. J Clin Rheumatol. 2004;10:178-189.
27. Lanas A, GarcÃa-RodrÃguez LA, Arroyo MT, et al; AssociaciÃ³n EspaÃ±ola de GastroenterologÃa. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006;55:1731-1738.
28. Moore RA, Derry S, McQuay HJ. Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk. BMC Musculoskelet Disord. 2007;8:73.
29. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58:3183-3191.
30. Raynauld JP, Martel-Pelletier J, Bias P, et al; Canadian Licofelone Study Group. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI. Ann Rheum Dis. 2009;68:938-947.
31. Boileau C, Tat SK, Pelletier JP, et al. Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Res Ther. 2008;10:R71.
32. Bartels EM, Bliddal H, SchÃ¸ndorff PK, et al. Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis Cartilage. 2010;18:289-296.
33. Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis [published correction appears in Arch Intern Med. 2007;167:444]. Arch Intern Med. 2006;166:1899-1906.
34. Pelletier JP, Yaron M, Haraoui B, et al. Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group. Arthritis Rheum. 2000;43:2339-2348.
35. Fidelix TS, Soares BG, Trevisani VF. Diacerein for osteoarthritis. Cochrane Database Syst Rev. 2006(1):CD005117.
36. Pham T, Le Henanff A, 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;63:1611-1617.
37. Dougados M, Nguyen M, Berdah L, et al; ECHODIAH Investigators Study Group. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539-2547.
38. Schnitzer TJ. Update on guidelines for the treatment of chronic musculoskeletal pain. Clin Rheumatol. 2006;(25 suppl 1):S22-S29.
39. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol. 2007;34:543-555.
40. Cavalieri TA. Management of pain in older adults. J Am Osteopath Assoc. 2005;105(3 suppl 1):S12-S17.
41. Fine PG, Herr KA. Efficacy, safety, and tolerability of pharmacotherapy for management of persistent pain in older persons. Ann Long-Term Care. 2006;14:25-33.
42. Bloodworth D. Issues in opioid management. Am J Phys Med Rehabil. 2005;84(3 suppl):S42-S55.
43. Dickson DJ. Opioids for non-operable osteoarthritis and soft-tissue rheumatism. Arthritis Res Ther. 2005;7:193-194.
44. Csaki C, Mobasheri A, Shakibaei M. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1beta-induced NF-kappaB-mediated inflammation and apoptosis. Arthritis Res Ther. 2009;11:R165.
45. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005321.
46. Habib GS, Saliba W, Nashashibi M. Local effects of intra-articular corticosteroids. Clin Rheumatol. 2010;29:347-356.
47. McGarry JG, Daruwalla ZJ. The efficacy, accuracy and complications of corticosteroid injections of the knee joint. Knee Surg Sports Traumatol Arthrosc. 2011;19:1649-1654.
48. Pasquali Ronchetti I, Guerra D, Taparelli F, et al. Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan) and methylprednisolone acetate (Depomedrol) in osteoarthritis. Rheumatology (Oxford). 2001;40:158-169.
49. Jordan KM, Arden NK, Doherty M, et al; Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-1155.
50. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. http://www.rheumatology.org/practice/clinical/guidelines/oa-mgmt.asp. Accessed September 7, 2012.
51. 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;18:476-499.
52. Bannuru RR, Natov NS, Obadan IE, et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum. 2009;61:1704-1711.
53. Wang CT, Lin J, Chang CJ, et al. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee: a meta-analysis of randomized controlled trials. J Bone Joint Surg. 2004;86A:538-545.
54. Brzusek D, Petron D. Treating knee osteoarthritis with intra-articular hyaluronans. Curr Med Res Opin. 2008;24:3307-3322.
55. Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford). 1999;38:602-607.
56. Reichenbach S, Blank S, Rutjes AW, et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum. 2007;57:1410-1418.
57. Kelly MA, Kurzweil PR, Moskowitz RW. Intra-articular hyaluronans in knee osteoarthritis: rationale and practical considerations. Am J Orthop (Belle Mead NJ). 2004;33(2 suppl):15-22.
58. 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;57:467-474.
59. CubukÃ§u D, ArdiÃ§ 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;24:336-341.
60. Frizziero L, Govoni E, Bacchini P. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin Exp Rheumatol. 1998;16:441-449.
61. Listrat V, Ayral X, Patarnello F, et al. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cartilage. 1997;5:153-160.
62. Wang Y, Hall S, Hanna F, et al. Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet Disord. 2011;12:195.
63. Xu HT, Chen Y, Chen LK, et al. Effect of various intervention factors on MMP-3 and TIMP-1 level in synovial fluid in knee joints with osteoarthritis [in Chinese]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008;33:47-52.
64. Gonzalez-Fuentes AM, Green DM, Rossen RD, Ng B. Intra-articular hyaluronic acid increases cartilage breakdown biomarker in patients with knee osteoarthritis. Clin Rheumatol. 2010;29:619-624.
65. Hsieh YS, Yang SF, Lue KH, et al. Effects of different molecular weight hyaluronan products on the expression of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis. J Orthop Res. 2008;26:475-484.
66. Guidolin DD, Ronchetti IP, Lini E, et al. Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the effects of 500-730 kDa sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage. 2001;9:371-381.