Evidence Report/Technology Assessment 

Number 157 

Treatment of Primary and Secondary Osteoarthritis 

of the Knee 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0026 

Prepared by:

Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based 

Practice Center 

Chicago, Illinois 

Investigators 

David J. Samson, M.S. 

Mark D. Grant, M.D., M.P.H. 

Thomas A. Ratko, Ph.D. 

Claudia J. Bonnell, B.S.N., M.L.S. 

Kathleen M. Ziegler, Pharm.D. 

Naomi Aronson, Ph.D. 

AHRQ Publication No. 07-E012 

September 2007
This report is based on research conducted by the Blue Cross and Blue Shield Association 

Technology Evaluation Center Evidence-based Practice Center (EPC) under contract to the 

Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-

0026). The findings and conclusions in this document are those of the author(s), who are 

responsible for its content, and do not necessarily represent the views of AHRQ. No statement in 

this report should be construed as an official position of AHRQ or of the U.S. Department of 

Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied.
ii 

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Samson DJ, Grant MD, Ratko TA, Bonnell CJ, Ziegler KM, Aronson N. Treatment of Primary 

and Secondary Osteoarthritis of the Knee. Evidence Report/Technology Assessment No. 157 

(Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidencebased Practice Center under Contract No. 290-02-0026). AHRQ Publication No. 07-E012. 

Rockville, MD: Agency for Healthcare Research and Quality. September 2007.

None of the investigators has any affiliations or financial involvement that conflicts with 

the material presented in this report.
iii 

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, Ph.D., R.N. Capt. Ernestine Murray, R.N., M.A.S. 

Director, EPC Program EPC Program Task Order Officer 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

v 

Acknowledgments 

The research team would like to acknowledge the efforts of Maxine A. Gere, M.S., for general 

editorial assistance and program support; Carol Gold-Boyd for administrative support; and Tina 

Murray, R.N., M.A.S., Senior Health Policy Analyst, Agency for Healthcare Research and 

Quality Center for Outcomes and Evidence, for advice as our Task Order Officer. 

vii 

Structured Abstract

Objectives: Systematic review of outcomes of three treatments for osteoarthritis (OA) of the 

knee: intra-articular viscosupplementation; oral glucosamine, chondroitin or the combination; 

and arthroscopic lavage or debridement. 

Data Sources: We abstracted data from: 42 randomized, controlled trials (RCTs) of 

viscosupplementation, all but one synthesized among six meta-analyses; 21 RCTs of 

glucosamine/chondroitin, 16 synthesized among 6 meta-analyses; and 23 articles on arthroscopy. 

The search included foreign-language studies and relevant conference proceedings. 

Review Methods: The review methods were defined prospectively in a written protocol. We 

sought systematic reviews, meta-analyses, and RCTs published in full or in abstract. Where 

randomized trials were few, we sought other study designs. We independently assessed the 

quality of all primary studies. 

Results: Viscosupplementation trials generally report positive effects on pain and function 

scores compared to placebo, but the evidence on clinical benefit is uncertain, due to variable trial 

quality, potential publication bias, and unclear clinical significance of the changes reported. 

 The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), a large (n=1,583), highquality, National Institutes of Health-funded, multicenter RCT showed no significant difference 

compared to placebo. Glucosamine sulfate has been reported to be more effective than 

glucosamine hydrochloride, which was used in GAIT, but the evidence is not sufficient to draw 

conclusions. Clinical studies of glucosamine effect on glucose metabolism are short term, or if 

longer (e.g., 3 years), excluded patients with metabolic disorders. 

 The best available evidence for arthroscopy, a single sham-controlled RCT (n=180), showed 

that arthroscopic lavage with or without debridement was equivalent to placebo. The main 

limitations of this trial are the use of a single surgeon and enrollment of patients at a single 

Veterans Affairs Medical Center. 

 No studies reported separately on patients with secondary OA of the knee. The only 

comparative study was an underpowered, poor-quality trial comparing viscosupplementation to 

arthroscopy with debridement. 

Conclusions: Osteoarthritis of the knee is a common condition. The three interventions 

reviewed in this report are widely used in the treatment of OA of the knee, yet the best available 

evidence does not clearly demonstrate clinical benefit. Uncertainty regarding clinical benefit can 

be resolved only by rigorous, multicenter RCTs. In addition, given the public health impact of 

OA of the knee, research on new approaches to prevention and treatment should be given high 

priority. 

ix 

Contents 

 

Executive Summary.........................................................................................................................1 

Evidence Report.............................................................................................................................7 

Chapter 1. Introduction ...................................................................................................................9 

 Burden of Illness........................................................................................................................9 

 Clinical Management.................................................................................................................9 

 Pathophysiology...................................................................................................................9 

 Classification......................................................................................................................10 

 Diagnosis............................................................................................................................10 

 Treatment ...........................................................................................................................11 

 Interventions Addressed in This Report ............................................................................11 

 Key Questions for This Systematic Review ............................................................................15 

Chapter 2. Methods.......................................................................................................................17 

 Peer Review .............................................................................................................................17 

 Study Selection Criteria ...........................................................................................................17 

 Types of Studies.................................................................................................................19 

 Types of Participants..........................................................................................................19 

 Types of Interventions .......................................................................................................19 

 Types of Outcomes ............................................................................................................20 

 Pain and Function Measurement Issues.............................................................................21 

 Search Strategy and Review ....................................................................................................23 

 Search Strategy ..................................................................................................................23 

 Search Screen.....................................................................................................................23 

 Data Extraction and Analysis...................................................................................................24 

 Data Elements ....................................................................................................................24 

 Evidence Tables.................................................................................................................26 

 Assessment of Study Quality...................................................................................................26 

 Definition of Ratings Based on Criteria.............................................................................26 

 Primary RCTs and Quasi-Experimental Studies................................................................26 

 Systematic Reviews and Meta-Analyses ...........................................................................27 

 Case Series.........................................................................................................................30 

Chapter 3. Results and Conclusions..............................................................................................33 

 Part I: Intra-Articular Hyaluronan Effectiveness and Harms .................................................33 

 Literature Overview...........................................................................................................33 

 Results, Part I: Key Questions 1 and 2 .............................................................................33 

 Adverse Events ..................................................................................................................54 

 Supplementary Analyses Performed by the Evidence-Based Practice Center ..................55 

 Summary and Appraisal.....................................................................................................58 

 Results, Part I: Key Question 3 (Subgroup Analyses)......................................................63 

 Results, Part I: Key Question 4 (Comparative Outcomes) ...............................................64 

Conclusions: Part I............................................................................................................64 
x 

 Part II: Glucosamine/Chondroitin Effectiveness and Harms..................................................65 

Literature Overview...........................................................................................................66 

Results, Part II: Key Questions 1 and 2 ............................................................................67 

Results, Part II: Key Question 3 (Subgroup Analyses)...................................................104 

Results, Part II: Key Question 4 (Comparative Outcomes)............................................105 

Conclusions: Part II.........................................................................................................106 

 Part III: Arthroscopy Effectiveness and Harms....................................................................108 

 Literature Overview.........................................................................................................108 

 Results, Part III: Key Questions 1 and 2.........................................................................108 

 Results, Part III: Key Question 3 (Subgroup Analyses) .................................................135 

 Results, Part III: Key Question 4 (Comparative Outcomes)...........................................137 

 Conclusions: Part III .......................................................................................................139 

Chapter 4. Discussion and Future Research ...............................................................................141 

Minimal Clinically Important Improvement in Pain and Function Should be the 

Measure of Success for all Trials.....................................................................................142 

 Unpublished Studies Should be Made Available as Full-Text Publications .........................142 

 The Pitfalls of Meta-Analysis Should be More Widely Recognized and Acknowledged.....142 

 Specific Research Recommendations....................................................................................143 

References....................................................................................................................................147 

List of Acronyms/Abbreviations..................................................................................................157 

Figures 

Figure 1. Systematic review process ...........................................................................................18 

Figure 2. QUOROM flow diagram .............................................................................................24 

Figure 3. Oxman and Guyatt rating.............................................................................................28 

Figure 4. Forest plot of hylan G-F 20 studies reporting VAS pain at 5 to 13 

weeks—weight-bearing or WOMAC (95% confidence intervals)..............................59 

Tables 

Table 1. U.S. FDA-approved hyaluronan products and product information statements..........12 

Table 2. Carey and Boden case series quality assessment tool..................................................31 

Table 3. Radiographic classification and grade in included viscosupplement RCTs ................34 

Table 4. Number of participants randomized and reported in abstracts, unpublished 

and published RCTs of hyaluronan-based products ....................................................36 

Table 5. Outcome measures pooled in viscosupplementation meta-analyses relevant 

to Key Questions 1 & 2................................................................................................36 

Table 6. Viscosupplementation RCTs addressing Key Questions.............................................37 

Table 7. Overview quality assessment questionnaire ratings of viscosupplementation 

meta-analyses...............................................................................................................39 

Table 8. Characteristics of study-level viscosupplementation meta-analyses ...........................41 

Table 9. Overall result for pain from Lo, LaValley, McAlindon, et al. (2003) .........................43 
xi 

Table 10. Overall results for pain with activity and function for non-G-F 20 

hyaluronans (non-cross-linked) from Wang, Chen, Huang, et al. (2004)....................45 

Table 11. Subgroup results for non-cross-linked hyaluronans ....................................................45 

Table 12. Pooled visual analog scale results for rest and activity pain from Arrich, 

Piribauer, Mad, et al. (2005) ........................................................................................46 

Table 13. Pooled results joint function from Arrich, Piribauer, Mad, et al. (2005).....................47 

Table 14. Pooled visual analog scale pain change from Modawal, Ferrer, Choi, 

et al. (2005) ..................................................................................................................47 

Table 15. Pooled visual analog scale pain change for high-quality RCTs from Modawal, 

Ferrer, Choi, et al. (2005).............................................................................................48 

Table 16. Pooled visual analog scale results for rest and weight-bearing pain from 

Bellamy, Campbell, Robinson, et al. (2006)................................................................49 

Table 17. Pooled Western Ontario and McMaster Osteoarthritis Index pain results from 

Bellamy, Campbell, Robinson, et al. (2006)................................................................49 

Table 18. Pooled Western Ontario and McMaster Osteoarthritis Index function results 

from Bellamy, Campbell, Robinson, et al. (2006).......................................................49 

Table 19. Pooled Lequesne Index results from Bellamy, Campbell, Robinson, et al. (2006).....49 

Table 20. Pooled global assessment results from Bellamy, Campbell, 

Robinson, et al. (2006).................................................................................................50 

Table 21. Numbers needed to treat for various outcomes from Bellamy, Campbell, 

Robinson, et al. (2006).................................................................................................51 

Table 22. Results of sensitivity analyses for Bellamy, Campbell, Robinson, et al. 

(2006) 5–13 week pain.................................................................................................56 

Table 23. Summary pain result closest to 8–12 weeks and key characteristics 

of study-level viscosupplementation meta-analyses....................................................60 

Table 24. Results by subgroups from Altman and Moskowitz (1998) ........................................63 

Table 25. Summary description of meta-analyses of glucosamine and chondroitin 

in knee osteoarthritis....................................................................................................67 

Table 26. Additional RCTs not included in glucosamine and chondroitin meta-analyses..........67 

Table 27. Oxman and Guyatt method quality evaluation of glucosamine and 

 chondroitin meta-analyses ........................................................................................69 

Table 28. Methodologic characteristics of glucosamine and chondroitin meta-analyses............71 

Table 29. Primary randomized trials included in glucosamine meta-analyses............................73 

Table 30. Primary randomized trials included in chondroitin meta-analyses..............................74 

Table 31. Clinical outcomes in RCTs of glucosamine that meet protocol selection criteria.......76 

Table 32. Clinical outcomes in RCTs of chondroitin that meet protocol selection criteria.........76 

Table 33. Clinical outcomes in RCTs of glucosamine plus chondroitin that 

 meet protocol selection criteria.................................................................................77 

Table 34. Baseline characteristics of randomized trials of glucosamine that meet 

protocol selection criteria.............................................................................................78 

Table 35. Baseline characteristics of randomized trials of chondroitin treatment 

that meet protocol selection criteria.............................................................................81 

Table 36. Baseline characteristics of randomized trials of glucosamine plus chondroitin 

treatment that meet protocol selection criteria.............................................................83 

Table 37. Quality ratings of randomized trials of glucosamine that meet protocol 

selection criteria...........................................................................................................84
xii 

Table 38. Quality ratings of randomized trials of chondroitin that meet protocol 

selection criteria...........................................................................................................85

Table 39. Bjordal, Klovning, Ljunggren, et al. (2006) meta-analysis clinical outcomes ............86 

Table 40. Towheed, Maxwell, Anastassiades, et al. (2006) meta-analysis outcomes .................87 

Table 41. Towheed, Maxwell, Anastassiades, et al. (2006) sensitivity and subgroup 

analyses for pooled composite pain measurement.......................................................88 

Table 42. Poolsup, Suthisisang, Channark, et al. (2005) meta-analysis clinical outcomes .........89 

Table 43. Richy, Bruyere, Ethgen, et al. (2003) meta-analysis clinical outcomes ......................90 

Table 44. Leeb, Schweitzer, Montag, et al. (2000) meta-analysis clinical outcomes..................91 

Table 45. McAlindon, LaValley, Gulin, et al. (2000) meta-analysis clinical outcomes..............92 

Table 46. McAlindon, LaValley, Gulin, et al. (2000) sensitivity analyses for pooled 

composite pain measurement.......................................................................................92 

Table 47. Key health outcomes of all randomized patients in GAIT ..........................................94 

Table 48. GAIT patients with mild pain (WOMAC pain score 125–300) ..................................95 

Table 49. Outcomes from Michel, Stucki, Frey, et al. (2005) .....................................................96 

Table 50. Outcomes from Uebelhart, Malaise, Marcolongo, et al. (2004) ..................................97 

Table 51. Outcomes from Das and Hammad (2000) ...................................................................98 

Table 52. Outcomes from Herrero-Beaumont, Roman, Trabado, et al. (2007; GUIDE) ............99 

Table 53. Results of Rotta-related studies meeting protocol selection criteria .........................101 

Table 54. Adverse events associated with glucosamine treatment in placebo-controlled 

RCTs that meet protocol selection criteria.................................................................102 

Table 55. Adverse events associated with chondroitin treatment in placebo-controlled 

RCTs that meet protocol selection criteria.................................................................103 

Table 56. GAIT Patients with moderate-to-severe pain (WOMAC pain score 301–400).........105 

Table 57. Arthroscopy placebo-controlled RCT, sample selection ...........................................109 

Table 58. Arthroscopy placebo-controlled RCT, interventions.................................................109 

Table 59. Arthroscopy placebo-controlled RCT, patient characteristics...................................110 

Table 60. Arthroscopy placebo-controlled RCT, outcome assessment .....................................110 

Table 61. Arthroscopy placebo-controlled RCT, study quality assessment ..............................111 

Table 62. Arthroscopy placebo-controlled RCT, results ...........................................................112 

Table 63. Arthroscopy non-placebo RCTs, sample selection....................................................114 

Table 64. Arthroscopy non-placebo RCTs, patient characteristics............................................114 

Table 65. Arthroscopy non-placebo RCTs, interventions..........................................................115 

Table 66. Arthroscopy non-placebo RCTs, study quality..........................................................115 

Table 67. Arthroscopy non-placebo RCTs, results....................................................................116 

Table 68. Arthroscopy quasi-experimental study, sample selection..........................................117 

Table 69. Arthroscopy quasi-experimental study, patient characteristics .................................117 

Table 70. Arthroscopy quasi-experimental study, interventions ...............................................117 

Table 71. Arthroscopy quasi-experimental study, study quality ...............................................118 

Table 72. Arthroscopy quasi-experimental study, results..........................................................118 

Table 73. Arthroscopy administrative database, further surgery results....................................120 

Table 74. Arthroscopy administrative database, adverse event results......................................120 

Table 75. Arthroscopy case series, sample selection.................................................................122 

Table 76. Arthroscopy case series, patient characteristics.........................................................124 

Table 77. Arthroscopy case series, treatments...........................................................................126 

Table 78. Arthroscopy case series, study quality.......................................................................127 
xiii 

Table 79. Arthroscopy case series, validated outcome scales ...................................................129 

Table 80. Arthroscopy case series, Hospital for Special Surgery rating....................................129 

Table 81. Arthroscopy case series, patient global change assessment.......................................130 

Table 82. Arthroscopy case series, patient global result assessment.........................................131 

Table 83. Arthroscopy case series, symptom/function improvement........................................132 

Table 84. Arthroscopy case series, further surgery....................................................................133 

Table 85. Arthroscopy case series, adverse events ....................................................................134 

Table 86. Arthroscopy non-placebo RCTs, sample selection....................................................137 

Table 87. Arthroscopy non-placebo RCTs, patient characteristics............................................137 

Table 88. Arthroscopy non-placebo RCTs, interventions..........................................................138 

Table 89. Arthroscopy non-placebo RCTs, study quality..........................................................138 

Table 90. Arthroscopy non-placebo RCTs, results....................................................................138 

Table 91. Future Research Recommendations for Osteoarthritis of the 

Knee---EPICOT Framework......................................................................................144 

Appendixes 

Appendix A: Exact Search Strings 

Appendix B: List of Excluded Studies 

Appendix C: Evidence Tables 

Appendix D: Technical Expert Panel and Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/oaknee/oaknee.pdf. 

 1

Executive Summary 

Osteoarthritis (OA) affects about 21 million people in the United States. By age 65, the 

majority of the population has radiographic evidence of osteoarthritis and 11 percent have 

symptomatic OA of the knee. This is a systematic review of three treatments for OA of the knee: 

intra-articular injections of viscosupplements; oral glucosamine, chondroitin, or the combination; 

and, arthroscopic lavage and debridement. The key questions are: (1) effectiveness and harms in 

primary OA of the knee, (2) in secondary OA of the knee, (3) in subpopulations, and (4) 

comparison of the three interventions. 

Methods 

The review methods were defined prospectively in a written protocol. A technical expert 

panel provided consultation. The draft report was also reviewed by other experts and 

stakeholders. 

We sought systematic reviews, meta-analyses, and RCTs published in full or in abstract that 

reported on one or more of the interventions among patients with primary or secondary 

osteoarthritis of the knee; and reported at least one outcome of interest. Primary outcomes were 

pain, function, quality of life and adverse effects. 

Our search had no language restrictions and used these electronic databases: 

• MEDLINE® (through March 29, 2007) 

• EMBASE (through March 16, 2006) 

• Cochrane Controlled Trials Register (through November 27, 2006). 

EMBASE was updated with abbreviated searches through November 27, 2006. Additional 

sources were 2004–2006 conference proceedings of the American Association of Orthopedic 

Surgeons (AAOS), American College of Rheumatology (ACR) and the Osteoarthritis Research 

Society International (OARSI). Product inserts of U.S.-marketed viscosupplements were 

consulted. 

There were few RCTs on arthroscopy or comparative outcomes, so we also sought 

nonrandomized comparative trials and, for arthroscopy, administrative database analyses and 

case series (n>50). Because several comprehensive systematic reviews with meta-analyses on 

viscosupplementation and glucosamine/chondroitin had been published, we focused on detailed 

review of existing meta-analyses, supplemented by primary studies where necessary. 

Of 1,842 citations, 451 articles were retrieved and 98 selected for inclusion: 

• Six meta-analyses (N=41 trials) and one additional trial of viscosupplementation 

• Six meta-analyses (N=16 trials) and five additional trials of glucosamine/chondroitin 

• 23 articles on arthroscopy. 
 2

A single reviewer screened citations for article retrieval; citations judged as uncertain were 

reviewed by a second reviewer. The same procedure was used to select articles for inclusion in 

the review. A single reviewer performed data abstraction and a second reviewed the evidence 

tables for accuracy. However, study quality was appraised by dual independent review. All 

disagreements were resolved by consensus. 

The quality of RCTs and quasi-experimental studies were assessed using the general 

approach developed by the U.S. Preventive Services Task Force (Harris, Helfand, Woolf, et al. 

2001). Assessment of the quality of systematic reviews and meta-analyses were guided by a 

quality rating method reported by Oxman and Guyatt (1991). The framework proposed by Carey 

and Boden (2003) was used to assess the quality of case series. 

Results 

Viscosupplementation

Effectiveness and Harms in Primary OA of the Knee. Results from 42 trials (N=5,843), 

all but one synthesized in various combinations in six meta-analyses, generally show positive 

effects of viscosupplementation on pain and function scores compared to placebo. However, the 

evidence on viscosupplementation is accompanied by considerable uncertainty due to variable 

trial quality, potential publication bias, and unclear clinical significance of the changes reported. 

The pooled effects from poor quality trials were as much as twice those obtained from higher 

quality ones. Pooled results from small trials (<100 patients) showed effects up to twice those of 

larger trials, a finding consistent with selective publication of underpowered positive trials. 

Among trials of viscosupplementation, those that have not been published in full text comprise 

approximately 25 percent of the total patient population. 

Most RCTs reported results as mean changes in pain and function. Interpreting the clinical 

significance of pooled mean effects from the meta-analyses is difficult; mean changes do not 

quantify proportions responding. Numbers needed to treat cannot be calculated from mean 

changes. It would be more informative to report response rate, i.e., comparison of the proportion 

of patients achieving a clinically important improvement. 

Trials of hylan G-F 20, the highest molecular weight cross-linked product, generally reported 

larger effects than other trials. 

Minor adverse events accompanying intra-articular injections are common, but the relative 

risk accompanying hyaluronan injections over placebo appears to be small. Pseudoseptic 

reactions associated with hyaluronans appear relatively uncommon, but can be severe. 

Differences in Outcomes Among Subpopulations. Four RCTs were identified examining 

any of the specified subgroups. None examined race/ethnicity, disease duration, or prior 

treatment. In one trial, randomization was stratified by disease severity; all other subgroup 

results were obtained in post-hoc analyses. There was no evidence for differential effects 

according to subgroups defined by age, sex, primary/disease, body mass index/weight, or disease 

severity. One positive post-hoc subgroup analysis found greater efficacy among older 

individuals with more severe disease, but was not confirmed in a subsequent trial. 
 3

Glucosamine, Chondroitin, Alone or in Combination 

Effectiveness and Harms in Primary OA of the Knee. The best evidence comes from the 

Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT; Clegg, Reda, Harris, et al., 2006), 

a large (n=1,583), good quality, NIH-funded, multicenter RCT. GAIT compared glucosamine 

hydrochloride, chondroitin sulfate, or the combination of these agents, with placebo or celecoxib 

in patients with primary osteoarthritis of the knee. After 24 weeks of treatment, intention-to-treat 

analysis showed no significant difference in symptomatic relief between glucosamine 

hydrochloride, chondroitin sulfate, or glucosamine hydrochloride plus chondroitin sulfate 

compared to placebo. Substantiating this result was that celecoxib, the active control, was 

effective. 

Six study-level meta-analyses (MAs) assessed glucosamine or chondroitin in OA of the knee. 

All but one of the MAs reported statistically significant differences between treatment and 

placebo. However, these MAs had limitations in the quality of the primary studies that were 

pooled. Limitations of the primary literature included small study size, inclusion of studies that 

assessed joints other than knee, and failure to report intent to treat analysis. In general, the MAs 

did not perform adequate quality appraisal of the primary studies. 

Glucosamine sulfate has been reported to be more effective than glucosamine hydrochloride, 

however, the evidence is not sufficient to draw conclusions. A subgroup analysis in the largest 

MA (Towheed, Maxwell, Anastassiades, et al., 2006) significantly favored glucosamine sulfate. 

The results of GUIDE (Herrero-Beaumont, Roman, Trabado, et al., 2007), a European placebocontrolled RCT (n=318), sponsored by Rotta, a glucosamine sulfate manufacturer, report 

favorable results for glucosamine sulfate. While the overall results of GAIT show no benefit, in 

the subgroup of knee OA patients with moderate-to-severe pain at baseline, the combination of 

glucosamine hydrochloride and chondroitin sulfate significantly improved pain. Together, this 

evidence suggests an independent trial of glucosamine sulfate would be useful to definitively 

establish whether there is benefit. 

In general, adverse events with glucosamine or chondroitin treatment were no greater than 

placebo. There has been some concern from in vitro and preclinical studies that glucosamine 

supplementation could have a deleterious effect on glucose metabolism and glycemic control. 

However, available clinical studies are short-term, or if longer (e.g., 3 years), excluded patients 

with metabolic disorders. 

Differences in Outcomes Among Subpopulations. GAIT found that glucosamine plus 

chondroitin produced a statistically and clinically significant improvement of pain in patients 

with moderate-to-severe OA of the knee. Although the effect of celecoxib treatment in a similar 

group of patients was not statistically significant, the magnitude and direction of the response 

were consistent with clinical benefit. The nonsignificant statistical result in the celecoxib arm 

may be a function of insufficient power due to the small number of patients. Although this 

subgroup analysis was not explicitly prespecified in the GAIT protocol, the stratified 

randomization by disease severity yields statistically valid comparisons. A trial of glucosamine 

sulfate would be useful to definitively establish whether there is benefit. 

Arthroscopic Lavage and Debridement 

Effectiveness and Harms in Patients With Primary OA. The best available evidence, a 

single placebo-controlled RCT, found arthroscopic lavage with or without debridement was not 
 4

superior to placebo. The evidence base does not definitively show that arthroscopy is no more 

effective than placebo. However, additional high-quality RCTs would be necessary to refute the 

existing trial, which suggests equivalence between placebo and arthroscopy. 

No other study besides Moseley, O’Malley, Petersen, et al. (2002) addressed the potential 

contribution of placebo effects to apparent improvement in outcome after arthroscopy. The 

primary limitations of the Moseley, O’Malley, Petersen, et al. (2002) trial are lack of details 

describing the patient sample, the use of a single surgeon, and enrollment of patients at a single 

Veterans Affairs Medical Center. These concerns call into question the generalizability of this 

trial’s findings. Since OA of the knee affects a large population, uncertainty about arthroscopy’s 

effectiveness should be resolved with further well-conducted and well-reported RCTs. 

Major methodologic shortcomings in non-placebo RCTs, an administrative database analysis 

and case series preclude resolution of uncertainties raised by the trial of Moseley, O’Malley, 

Petersen, et al. (2002). 

Evidence on the harms after arthroscopic lavage and debridement comes primarily from an 

administrative database analysis and case series reports. Potential harms include infection, 

prolonged drainage from arthroscopic portals, effusion, hemarthrosis and deep vein thrombosis. 

To determine whether the risk of such harms is acceptable, it is important to establish whether 

the effectiveness of arthroscopic lavage and debridement surpasses placebo. 

Differences in Outcome Among Subpopulations. Subgroup analyses for mechanical 

symptoms, alignment and OA stage were performed in the Moseley placebo-controlled RCT. 

No differences in results were observed within subgroups. Subgroup analyses were also 

performed in a quasi-experimental study, an administrative database and several case series. In 

these studies, different outcomes were observed according to age, presence of mechanical 

symptoms, and severity of OA. However, since these studies did not include placebo controls, it 

cannot be concluded that arthroscopy has greater effectiveness in specific patient subgroups. 

All Interventions 

Effectiveness and Harms in Secondary OA of the Knee. We identified no studies that 

enrolled patients with only secondary OA of the knee, or that reported separately on secondary 

OA of the knee. 

Comparison of Interventions. We did not find any direct comparative studies in which 

glucosamine, chondroitin, or glucosamine plus chondroitin were compared with arthroscopy or 

viscosupplementation to treat OA of the knee. A single, small, underpowered, poor quality trial 

found no difference in outcome measures comparing intra-articular hyaluronan to arthroscopy 

and debridement over a 1-year followup. 

Discussion and Future Research 

OA of the knee is a common condition and the three interventions reviewed in this report are 

widely used in the treatment of OA of the knee. Yet the best available evidence reports that 

glucosamine/chondroitin and arthroscopic surgery are no more effective than placebo. The 

Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (n=1,583) found that neither 

glucosamine hydrochloride, chondroitin sulfate nor the combination was superior to placebo and 

that all were inferior to celecoxib. The double blind randomized controlled trial by Moseley, 

O’Malley, Petersen, et al. (2002, n=180) found that arthroscopic lavage with or without 
 5

debridement was not superior to sham arthroscopy. Results from 42 RCTs, all but one of which 

were synthesized in various combinations in six meta-analyses, generally show positive effects 

of viscosupplementation on pain and function scores compared to placebo. However, the 

evidence on viscosupplementation is accompanied by considerable uncertainty due to variable 

trial quality, potential publication bias, and unclear clinical significance of the changes reported. 

For viscosupplementation, higher-quality trials are in the minority and show smaller effects; 

there are numerous patients lost to follow-up, and a substantial portion of studies (25 percent of 

total patients) have not been published as full articles. The clinical significance of reported 

changes in pain and function scores is uncertain, as almost all studies compare only mean 

difference between arms. Although the overall pooled estimate suggests that hylan G-F 20 may 

have a larger effect than other hyaluronans, whether this represents a meaningful clinical effect 

or limitations in the quality and completeness of study reporting is unknown. A rigorous RCT 

that showed strong evidence of improvement in pain and function would be necessary to 

conclude that viscosupplementation is beneficial. 

While the overall results of GAIT show no benefit, a subgroup analysis found that the 

combination of glucosamine hydrochloride and chondroitin sulfate significantly improved pain 

in patients with moderate-to-severe OA of the knee. Although this subgroup analysis was not 

explicitly prespecified in the GAIT protocol, the stratified randomization by disease severity 

yields statistically valid comparisons. The nonsignificant statistical result in the celecoxib arm in 

the same patient subgroup may be a function of insufficient power. Given the small number of 

patients in the moderate-to-severe subgroup, and the large number of such patients in the general 

population, a further trial can be justified. However, these subgroup results do not override the 

overall results of GAIT, which must stand unless confirmed in a rigorous RCT. 

The existing evidence does not definitively show that arthroscopic lavage with or without 

debridement is no more effective than placebo. However, additional placebo-controlled RCTs 

showing clinically significant advantage for arthroscopy would be necessary to refute the 

Moseley results, which show equivalence between placebo and arthroscopy. The recently 

published Spine Patient Outcomes Research Trial (SPORT) offers an alternative study design 

that could be informative, a rigorous RCT comparing surgery to conservative management, 

rather than sham (Weinstein, Tosteson, Lurie, et al., 2006). 

Overall, our recommendations for future research reach beyond the specific treatments 

addressed in this report, and are intended broadly to improve the quality of research and 

reporting on interventions for osteoarthritis of the knee. However, our population is aging, there 

is increasing prevalence of obesity, and increasing burden of knee osteoarthritis, together with 

inconsistent evidence regarding disease treatments. Given the public health impact, research on 

new approaches to prevention and treatment should be given high priority. 

Minimally Clinically Important Improvement in Pain and Function Should be the 

Measure of Success for All Trials. Clinically meaningful results require outcome measures 

establishing that patients experience improvement that is important to them—meaningful 

clinically important improvement. The range of magnitude of improvement clinically important 

to patients has been estimated for VAS pain and WOMAC measures, while to a lesser degree for 

the Lequesne Index (see Methods). Common measures and intervals for measurement will 

produce a more robust body of cumulative evidence and improve the ability to compare and pool 

results among trials. 

Unpublished Studies Should be Made Available as Full Text Publications. Among RCTs 

of viscosupplementation, those that have not been published in full text comprise approximately 
 6

25 percent of the total patient population. Several meta-analyses of glucosamine report that trials 

of the Rotta product, glucosamine sulfate, show outcomes superior to trials of glucosamine 

hydrochloride; yet key trials have not been published as full-text studies. Existing studies should 

be published in full. And all trials should be registered at inception at ClinicalTrials.gov along 

with anticipated date for full release of results. 

The Pitfalls of Meta-Analysis Should be More Widely Recognized and Acknowledged. 

Our evidence report draws heavily on six study-level meta-analyses of glucosamine/chondroitin 

and five of viscosupplementation. While we used a validated instrument to appraise the quality 

of the systematic reviews, the instrument does not address the question of when meta-analysis is 

appropriate to a systematic review. Meta-analysis is a technique with underlying assumptions 

that may or may not hold when a particular collection of results are pooled. Furthermore, metaanalyses may fail to convey the real uncertainty and potential bias accompanying pooled 

estimates. 

Uncertainty in the magnitude of effects pooled is influenced by factors intrinsic to the 

underlying trials. Among these are variable patient characteristics, trial characteristics, and the 

indication that a few trial results were outliers and influential on pooled estimates. The metaanalyses frequently reported high inter-trial heterogeneity. Random effects models were used in 

the face of high heterogeneity, but a consequence is to increase the influence of smaller trials on 

the pooled results. The meta-analyses did not address a threshold question, one that has not been 

clearly resolved by practitioners of meta-analysis: when is heterogeneity too high to justify 

pooling trial results. A related concern is the practice of reporting on multiple outcome measures 

and time intervals, which may be represented by a small portion of studies, thus potentially 

introducing bias. 

Conclusions 

Osteoarthritis of the knee is a common condition. The three interventions reviewed in this 

report are widely used in the treatment of OA of the knee, yet the best available evidence does 

not clearly demonstrate clinical benefit. Uncertainty over clinical benefit can be resolved only 

by rigorous, multicenter RCTs. In addition, given the public health impact of OA of the knee, 

research on new approaches to prevention and treatment should be given high priority. 
Evidence Report

9 

Chapter 1. Introduction 

This is a systematic review of three treatments for osteoarthritis (OA) of the knee: intraarticular injections of viscosupplements; oral glucosamine, chondroitin or the combination; and, 

arthroscopic lavage and debridement. The key questions are: (1) effectiveness and harms in 

primary OA of the knee, (2) in secondary OA of the knee, (3) in subpopulations, and (4) 

comparison of the three interventions. This section outlines the burden of illness and clinical 

management of osteoarthritis of the knee, the interventions of interest and uncertainties, and 

overviews key questions to be addressed. 

Burden of Illness 

According to the U.S. Centers for Disease Control and Prevention (CDC), an estimated 22 

percent of adults (46 million) in the United States have doctor-diagnosed arthritis (Centers for 

Disease Control and Prevention, 2006). Earlier figures suggest approximately 11 percent of the 

population 64 years and older has symptomatic OA of the knee (Manek and Lane, 2000). 

Symptoms of OA typically begin after age 40 and progress slowly, with radiographic evidence of 

the disease present in the majority of the population by 65 years of age and in approximately 80 

percent of the population age 75 years and older. OA of the knee is more common in women 

than in men, with risk factors that include obesity, previous knee injury or surgery, and 

occupational bending and lifting (Felson, 2006; Centers for Disease Control and Prevention, 

2005). 

Loss of joint function as a result of OA overall is a major cause of work disability and 

reduced quality of life. The CDC estimates that osteoarthritis and related arthritic conditions 

cost the U.S. economy nearly $81 billion per year in direct medical care, with indirect expenses 

of about $47 billion that include lost wages and production (Centers for Disease Control and 

Prevention, 2004). CDC figures further estimate the total annual direct cost of OA and related 

conditions per person is approximately $1,752. 

Clinical Management 

Pathophysiology 

The term “osteoarthritis” refers to a heterogeneous group of joint disorders, usually signaled 

by symptoms of pain and stiffness. It involves both destructive and reparative metabolic 

processes, with a variety of biochemical triggers in addition to mechanical injury of the joint 

(Mandelbaum and Waddell, 2005). It is thought that inflammation does not play a primary role 

in osteoarthritis, although it may be present. When inflammation occurs, it is generally mild 

(Hochberg, Altman, Brandt, et al., 1995b). The pathogenesis of OA is not fully understood, 

although multiple contributing factors are recognized including genetic, environmental, 

metabolic, and biomechanical factors (Kraus, 1997). 

Although OA eventually involves all joint structures, it begins with damage and progressive 

degradation of articular hyaline cartilage structure and function (chondropenia), typically in a 
10 

nonuniform, focal manner (Felson, 2006). As chondropenia progresses in localized areas, stress 

increases across the entire joint, further damaging and eroding cartilage. In areas with fullthickness cartilage loss, abnormal remodeling and attrition of subarticular bone commences, 

typically accompanied by growth of osteophytes. Synovitis, ligamentous laxity, and periarticular 

muscle weakness may also occur, eventually leading to joint tilting and malalignment. 

Malalignment is a risk factor for joint failure, hastening structural deterioration of the joint by 

increasing local loading forces. 

The symptoms of OA result from abnormal stresses on the weight-bearing joints or normal 

stresses on weakened joints, becoming progressively worse and more frequent with age. The 

typical joints involved with osteoarthritis include the large, weight-bearing joints such as the hip 

and knee, as well as selected smaller joints in the hands, feet, and spine. 

Classification 

Osteoarthritis may be broadly categorized as primary (idiopathic) or secondary. According 

to the American Academy of Orthopaedic Surgeons, primary OA of the knee can be defined as a 

process in which articular degeneration occurs in the absence of an obvious underlying 

abnormality (American Academy of Orthopaedic Surgeons, 2004). Secondary OA of the knee is 

often the result of injury (trauma) or repetitive motion such as found in certain occupations. It 

can also result from congenital conditions and underlying diseases, including include systemic 

metabolic diseases, endocrine diseases, bone dysplasias, and calcium crystal deposition diseases. 

Secondary OA is more likely to manifest itself at an earlier age than primary OA, and may be an 

initial clue to the presence of a potentially dangerous and treatable systemic disease. While there 

is rationale for identifying two separate categories of OA, making a distinction between them 

does not alter clinical practice and therapeutic choices. 

Diagnosis 

The diagnosis of osteoarthritis is established using a combination of clinical information 

derived from history, physical examination, radiologic, and laboratory evaluation. An algorithm 

of diagnostic criteria for osteoarthritis of the knee has been proposed by the American College of 

Rheumatology (ACR) (Altman, Asch, Bloch, et al., 1986). A diagnosis of OA of the knee is 

defined as presenting with pain, and meeting at least five of the following criteria: 

• Patient older than 50 years of age 

• Less than 30 minutes of morning stiffness 

• Crepitus (noisy, grating sound) on active motion 

• Bony tenderness 

• Bony enlargement 

• No palpable warmth of synovium 
11 

• Erythrocyte sedimentation rate (ESR) <40 mm/hr 

• Rheumatoid factor <1:40 

• Noninflammatory synovial fluid. 

The presence of clinical symptoms of OA does not always correlate well with the degree of 

abnormality seen on radiographs. It has been noted that approximately 40 percent of patients 

who have severe X-ray findings report no symptoms, and conversely, patients with clinical 

symptoms may show no significant radiological changes (Balint and Szebenyi, 1996; Davis, 

Ettinger, Neuhaus, et al., 1992; Claessens, Schouten, van den Ouweland, et al., 1990). 

Treatment 

Treatment for OA of the knee aims to alleviate pain and improve function in order to mitigate 

reduction in activity (American College of Rheumatology, 2000; Felson, 2006). However, most 

treatments do not modify the natural history or progression of OA, and thus are not considered 

curative. Nonsurgical modalities include education, exercise, weight loss, and various 

supportive devices; acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) such as 

ibuprofen; nutritional supplements (glucosamine and chondroitin); and, intra-articular 

viscosupplements. 

Guidelines for the medical management of osteoarthritis emphasize the role of both 

nonpharmacologic and pharmacologic therapies (American College of Rheumatology, 2000; 

Jordan, Arden, Doherty, et al., 2003). Initial management involves nonpharmacologic therapies, 

including education, exercise, various appliances and braces, and weight reduction. 

Acetaminophen is recommended as first-line pharmacologic therapy. If pain relief is inadequate 

with acetaminophen, analgesic-dose NSAIDs may be used (e.g., ibuprofen, naproxen). If 

symptom response to a lower NSAID dosage is inadequate, higher, anti-inflammatory, doses 

may be used. Intra-articular corticosteroid injection may be considered when relief from 

NSAIDs is insufficient or the patient is at risk from gastrointestinal adverse effects. Injection of 

corticosteroids is frequently limited to three to four times per year per joint because of concern 

about the possibility of progressive cartilage damage through repeated injection in the weightbearing joints (Neustadt, 1992). 

If symptom relief is inadequate with conservative measures, invasive treatments may be 

considered. Operative treatments for symptomatic OA of the knee include arthroscopic lavage 

and cartilage debridement, osteotomy, and, ultimately, total joint arthroplasty (Day, 2005). 

Surgical procedures intended to repair or restore articular cartilage in the knee, including 

abrasion arthroplasty, microfracture techniques, autologous chondrocyte implantation, and 

others, are appropriate only for younger patients with focal cartilage defects secondary to injury 

(Clarke and Scott, 2003). 

Interventions Addressed in This Report 

 Intra-Articular Injections of Hyaluronic Acid Preparations. As shown in Table 1, five 

hyaluronan-based products are approved, all as class 3 devices, via U.S. Food and Drug 
Table 1. U.S. FDA-approved hyaluronan products and product information statements 

Product Regarding Treatment 

Course 

Regarding Minimum # of 

Injections 

Regarding Other Joints Regarding Re

Hyalgan

® (sodium 

hyaluronate); Fidia Pharmaceutical Original PMA date: 5/28/97 MW: 0.5–0.73 million Da 

“A treatment cycle consists of five injections given at weekly intervals. Some patients may experience benefit with three injections given at weekly intervals.” 

“The effectiveness of a single treatment cycle of less than 3 injections has not been established.” 

“The safety and effectiveness of the use of Hyalgan

® in joints 

other than the knee have not been established.” 

“Adverse experience dcontain no evidence of retreatment with Hyalg

severity of adverse everepeat treatment cyclethat reported for a singHyalgan

® is the only hy

demonstrated safety in open-label trial in whiccycle of 5 weekly inject

months. 

Synvisc

® (hylan G-F 

20); Genzyme Corporation Original PMA date: 8/08/97 MW: 6 million Da (hylan A) 

“Synvisc

® is administered 

by intraarticular injection once a week (one week apart) for a total of three injections.” 

“The effectiveness of a single treatment cycle of less than three injections of Synvisc

® has not been 

established.” 

“The safety and effectiveness of Synvisc

® in locations other 

than the knee and for conditions other than osteoarthritis have not been established.” 

“The reactions seemed Synvisc

® was injected 

set of injections than w

as a first set of injectio

Supartz

® (sodium 

hyaluronate); Seikagaku Corporation Original PMA date: 1/24/01 MW: 0.62–1.17 million Da 

“Supartz

® is administered 

by intraarticular injection once a week (one week apart) for a total of 5 injections.” 

“The effectiveness of a single treatment cycle of less than 5 injections has not been established.” 

“The safety and effectiveness of the use of Supartz

® in joints 

other than the knee have not been established.” 

“The safety and effectivcycles of Supartz

® hav

12
Table 1. U.S. FDA-approved hyaluronan products and product information statements (continued) 

Product Regarding Treatment 

Course 

Regarding Minimum # of 

Injections 

Regarding Other Joints Regarding R

Orthovisc

® (sodium 

hyaluronate), Anika Therapeutics, Inc. Original PMA date: 2/04/04 MW: 1–2.9 million Da 

“Orthovisc

® is injected into 

the knee joint in a series of intraarticular injections one week apart for a total of three or four injections.” 

The effectiveness of a single treatment cycle of less than 3 injections has not been established. Pain relief may not be seen until after the third injection. 

“The safety and effectiveness of the use of Orthovisc

® in joints 

other than the knee have not been established.” 

“The effectiveness has more than one course 

Euflexxa

® (sodium 

hyaluronate), Ferring Pharmaceuticals Original PMA date: (approved under the name Nuflexxa) MW: 2.4–3.6 million Da 

“A dose of 2 ml is injected intraarticularly into the affected knee at weekly intervals for three weeks, for a total of three injections.” 

N/R “Safety and 

effectiveness of injection in conjunction with other intraarticular injectables, or into joints other than the knee has not been studied.” 

“The safety and effecttreatment cycles of EUestablished.” 

Da: Daltons; MW: molecular weight; PMA: premarket approval

13
14 

Administration (FDA) premarketing application (PMA) approval. These products vary by 

molecular weight, with Hyalgan®, Supartz®, and Orthovisc® on the lower to mid-range end (0.5–

0.73 mDa, 0.6–1.2 mDa, and 1–2.9 mDa, respectively) and Synvisc® on the upper end with a 

much greater molecular weight related to its cross-linked nature. Synvisc® actually comprises 

two components (thus, the name “hylan gel-fluid 20”): (1) hylan A, which is a viscoelastic fluid 

with an average molecular weight of 6 mDa, and (2) hylan B, a hydrated gel, for which a 

molecular weight cannot be measured. For comparison, the molecular weight of hyaluronan in 

normal synovial fluid is about 0.2–0.5 mDa (Peyron, 1993). 

 Glucosamine and Chondroitin. Glucosamine is an aminomonosaccharide which is the 

principal component of O-linked and N-linked glycosaminoglycans, which comprise the matrix 

of all connective tissues, including cartilage (Biggee and McAlindon, 2004; Matheson and Perry, 

2003; Hauselmann, 2001; Deal and Moskowitz, 1999). This compound historically has been 

derived by extraction of chitin, a component of crustacean shells, although is also is produced 

through fermentation of a vegetarian source. Chondroitin sulfate is a glycosaminoglycan with a 

polymerized disaccharide base linked to a sulfate moiety, and is a component of proteoglycans of 

articular cartilage. It is usually derived from bovine trachea, although other sources such as 

ovine or porcine trachea and shark cartilage are used. The mechanisms of action of these 

compounds are unknown, but it is speculated they may promote maintenance and repair of 

cartilage. 

In the United States, glucosamine hydrochloride or sulfate and chondroitin sulfate are 

considered dietary supplements available in over-the-counter (OTC) products, which may vary 

substantially in content and purity from what is stated on the label (McAlindon, 2003). In 

European Union countries, glucosamine sulfate and chondroitin sulfate are regulated as 

prescription drugs. A number of clinical trials with positive outcomes either used glucosamine 

sulfate manufactured by an Italian firm, Rotta Research Laboratorium, or were financially 

supported by Rotta. It has been hypothesized that Rotta glucosamine sulfate has greater efficacy 

than the hydrochloride salt, and that the formulation is a key factor in trial outcome (Altman, 

Abramson, Bruyere, et al., 2006; Hochberg, 2006; McAlindon, 2003). Oral administration of 

glucosamine sulfate can increase serum and synovial fluid sulfate levels, whereas sodium sulfate 

does not. Absorbed sulfate is then used in the synthesis of proteoglycans and metabolic 

intermediates like coenzyme A and glutathione that are important for chondrocyte metabolism. 

 Arthroscopy. The term “arthroscopy” is often used collectively in reference to individual 

minimally invasive surgical procedures, joint lavage and articular debridement, which are 

performed using fine needles and an arthroscope (Gidwani and Fairbank, 2004; Gunther, 2001). 

Arthroscopic lavage is a palliative measure in which intra-articular fluid is aspirated and the joint 

is washed out, removing inflammatory mediators, debris, or small loose bodies from the 

osteoarthritic knee. Articular debridement involves removal of cartilage or meniscal fragments, 

but also can include cartilage abrasion, excision of osteophytes and synovectomy. Debridement 

is intended to improve symptoms and joint function in patients with mechanical symptoms such 

as locking or catching of the knee. Because lavage and debridement are often performed at the 

same time, it is difficult to attribute the success or failure of arthroscopy to a specific procedure. 
15 

Key Questions for This Systematic Review 

This systematic review of the literature will address the following questions regarding 

managing patients with OA of the knee with three interventions: intra-articular injections of 

viscosupplements; oral glucosamine and chondroitin; and, arthroscopic lavage and debridement. 

1. What are the clinical effectiveness and harms of each intervention in patients with 

primary OA of the knee? 

2. What are the clinical effectiveness and harms of each intervention in patients with secondary 

OA of the knee? 

3. How do the short-term and long-term outcomes of each intervention differ by the following 

subpopulations: age, race/ethnicity, gender, primary or secondary OA, disease severity and 

duration, weight (body mass index), and prior treatments? 

4. How do the short-term and long-term outcomes of each intervention compare for the 

treatment of primary OA of the knee; and secondary OA of the knee? 

17 

Chapter 2. Methods 

This report is a systematic review of the effectiveness of three technologies to treat 

osteoarthritis (OA) of the knee: intra-articular hyaluronan injections (viscosupplements), enteral 

glucosamine and chondroitin given alone or in combination, and arthroscopic lavage and 

debridement. This chapter describes the search strategies used to identify literature; criteria and 

methods used for selecting eligible articles; methods for data abstraction; methods for quality 

assessment; and, finally, the process for technical expert advice and peer review. 

The methods of this review are generally applicable to all Key Questions. However, as 

noted, there were variations in specific aspects of the methods as necessary to satisfy 

requirements of each question. 

Peer Review 

A technical expert panel provided consultation for the systematic review and reviewed the 

draft report. The draft report was also reviewed by 12 external reviewers, including invited 

clinical experts and stakeholders (Appendix D*). Revisions were made to the draft report based 

on reviewers’ comments. 

Study Selection Criteria 

This Evidence Report takes a tiered approach to evidence of the effectiveness of the three 

key interventions. The primary focus is on whether interventions have beneficial effects 

exceeding those of a comparative placebo. We first determined whether existing systematic 

reviews and meta-analyses adequately addressed the Key Questions and whether they identified 

all relevant primary studies. If additional primary studies are found, this Evidence Report 

integrates their findings with systematic reviews and meta-analyses. If evidence from 

randomized, placebo-controlled trials (RCTs) clearly shows benefits beyond placebo, then 

comparisons between these interventions and other active interventions would be relevant. 

 The diagram in Figure 1 describes how reviewers proceeded through this systematic review, 

beginning with applying study selection criteria to literature search results. Further steps 

included data extraction and summary (see Data Extraction and Analysis), quality assessment 

(see Assessment of Study Quality), and finally evidence synthesis and interpretation. 

Assessment of the quality of RCTs and meta-analyses is an important part of how we conducted 

this review; however, interpretation of the body of evidence for a particular class of interventions 

entailed more than that. Quality assessment informed the critical appraisal of the results and 

conclusions of meta-analyses, but rating classes did not give a complete picture of the strength of 

the body of evidence. Beyond quality ratings, we explored the methodologic strengths and 

weaknesses of RCTs and meta-analyses, inquired whether meta-analyses addressed the clinical 

importance of treatment effects, and assessed how well meta-analyses attempted to explain 

hetereogeneity of effects. All of these activities contributed to interpreting the overall strength of 

the evidence and determining whether conclusions could be drawn with respect to key questions. 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
Figure 1. Systematic review process 

Extraction and summary descriptionof RCTs

Quality assessment of MAsQuality assessment of RCTs

Crtical appraisal of MA results/conclusions, focusing ono methodologic strengths and 

weaknesses of RCTS and MAs

o whether MAs addressed 

clinical importance of treatment effects and

o whether MAs attempted to 

explain heterogeneity of effects by • study quality• sample sizes• sample characteristics• intervention subtype• industry involvement

Extraction and summary descriptionof MAs

Identification of meta-analyses (MAs) meeting study selection criteriaIdentification of randomized controlled trials (RCTs) meeting study selection criteria

Literature

18search
19 

Types of Studies 

We sought systematic reviews, meta-analyses, RCTs, including abstracts of unpublished 

placebo-controlled RCTs, examining the clinical effectiveness of one or more of the 

interventions of interest among patients with primary or secondary OA of the knee; and reporting 

at least one outcome of interest. 

RCTs had to be published either as articles in any language or English-language abstracts (if 

the study was only presented as an abstract). No minimum number of patients per study arm was 

required for RCTs. Because there were few RCTs available to address arthroscopy and Key 

Question 4 (comparative outcomes), we sought additional study designs. For arthroscopy, we 

also sought English-language articles of nonrandomized comparative trials (i.e., quasiexperimental studies), administrative database analyses, and case series with samples of 50 or 

more. For Key Question 4, we sought randomized and nonrandomized comparative studies. 

Studies were excluded if no outcome of interest to this review was reported. Studies were 

also excluded if the patient population of interest was fewer than 80 percent of included patients, 

or, alternatively, results for the patient population of interest were not separately reported. When 

multiple reports were available for the same study, it was counted as a single trial and outcome 

data from the report with the longest followup were used. 

Types of Participants

 The populations of interest are patients with primary or secondary OA of the knee, as defined 

by the American Academy of Orthopaedic Surgeons (American Academy of Orthopaedic 

Surgeons, 2004): 

• Primary osteoarthritis of the knee is a process in which articular degeneration occurs in the 

absence of any obvious underlying abnormality (unknown cause); and 

• Secondary OA is often the result of injury (trauma) or repetitive motion in certain 

occupations, but it can also result from congenital conditions and systemic metabolic 

diseases, endocrine diseases, bone dysplasias, and calcium crystal deposition diseases. 

 Subpopulations of interest include: age, race or ethnicity, sex, disease severity and duration, 

weight (body mass index), and prior treatments 

Types of Interventions 

Glucosamine or Chondroitin. 

• Enteral (i.e., orally administered) glucosamine (sulfate or hydrochloride) given alone 

• Enteral chondroitin given alone 

• Enteral glucosamine and chondroitin given in combination. 
20 

 Glucosamine is given orally at 1,500 mg daily, usually as a single dose, or divided into two 

or three doses. Chondroitin is administered orally, usually a total of 800 to 1,200 mg daily, or in 

divided doses. At minimum, treatment duration is 1 to 3 months, and may be continued 

indefinitely if the patient experiences improvement. 

 Intra-Articular Injections Hyaluronan Preparations. The first group of products, derived 

from sodium hyaluronate, is the most commonly used viscosupplement in RCTs and is followed 

by hylan G-F 20 as the next most common class. Additionally, unapproved non-animal stabilized 

hyaluronic acid (NASHA) derived from streptococci has been used in two RCTs (Altman, 

Akermark, Beaulieu, et al., 2004; Pham, Le Henanff, Ravaud, et al., 2004). One trial (Petrella, 

DiSilvestro, Hildebrand, et al., 2002) administered a hyaluronan that is not approved by the U.S. 

Food and Drug Administration (FDA). Intra-articular injections performed in RCT protocols 

were most often weekly for 3 to 5 weeks, although different schedules also were used. 

 Arthroscopy. Studies were selected if arthroscopic treatment of OA involved lavage with or 

without debridement, and debridement was not specifically required to include procedures 

beyond nonabrasion chondroplasty and removal of loose bodies. Thus, studies were excluded if 

they focused only on arthroscopic meniscectomy or abrasion chondroplasty, for example. 

Types of Outcomes 

Primary Outcomes. The primary outcomes of interest are: 

• Pain severity or intensity 

• Self-reported physical function 

• Patient global assessment 

• Quality of life. 

Secondary Outcomes. Secondary outcomes of interest include: 

• Need for or time to total knee replacement or other surgeries. 

• Concomitant analgesic use. 

Harms or Adverse Effects. Any adverse events reported, including: 

• Hyaluron Preparations. Local: injection site redness, edema, pain, joint swelling, joint 

stiffness, worsened osteoarthritis, infection, pseudoseptic reactions. Systemic: severe acute 

inflammatory reaction or pseudosepsis, anaphylaxis, arthralgias, rash, urticaria, back pain, 

headache. 

• Glucosamine and Chondroitin. Alterations in blood glucose, hypersensitivity reactions, and 

local gastrointestinal toxicities. 
21 

• Arthroscopy. Infection, prolonged drainage from arthroscopic portals, effusion, hemarthrosis 

and deep vein thrombosis. 

Pain and Function Measurement Issues 

 Instruments. Pain and function should be measured by instruments with established validity 

and reliability. Although results are frequently reported as mean change in the intervention 

compared to control arms, this is not the preferred method of measuring outcomes. More 

informative, is a comparison of response, that is the proportion of patients achieving an 

improvement that is established representing a minimum clinically important improvement. 

(Tubach, Wells, Ravaud, et al., 2005). 

 Among established instruments, pain severity may be assessed by a visual analog scale 

(VAS) or a numeric rating scale (NRS) or from a subscale included in a knee-specific validated 

OA instrument. The horizontal 100-mm VAS has a left-hand or 0-mm endpoint labeled “no 

pain” and a right-hand or 100-mm endpoint usually labeled with a statement such as “extreme 

pain” or “pain as bad as it could possibly be.” While the amount of improvement required may 

not be definitively established (Tubach, Ravaud, Baron et al. 2005; Pham, van der Heijde, 

Altman, et al. 2004), the best available estimates for OA of the knee are between 20 and 40 

percent improvements have been used in hyaluronan and glucosamine/chondroitin trials 

(Nuestadt et al. 2005, Altman et al. 2004, Clegg et al). A clinically significant change in VAS 

score depends on the baseline pain (Campbell and Patterson, 1998). For example, in knee OA an 

absolute 20 mm or 40 percent relative reduction in VAS pain score could be considered a 

minimal clinically important improvement (MCII) (Tubach, Wells, Ravaud, et al., 2005) and 

define clinically meaningful response. Accordingly, a decrease of 10–12 mm may be clinically 

significant from a baseline of 25 mm, while a reduction of 20–31 mm may be necessary to 

achieve a clinically significant reduction for patients with high baseline pain (e.g., VAS 75–100 

mm). 

 Among 2 widely used OA instruments, the Western Ontario and McMaster University 

Osteoarthritis Index (WOMAC, McConnell, Kolopack, and Davis, 2001; Bellamy, Buchanan, 

Goldsmith, et al., 1988) evaluates 3 dimensions, pain, stiffness, and physical function with 5, 2, 

and 17 questions, respectively. WOMAC assesses pain using either the sum of scores from 5 

items or the VAS. WOMAC outcomes can be based on the total, or a subset score. A 20- to 40-

percent reduction in the WOMAC pain subscore is a positive response criterion for pain used in 

knee OA studies and represents achieving a MCII (Tubach, Wells, Ravaud, et al., 2005). 

 Another commonly used OA instrument is the Lequesne Index, a validated numerical scale in 

which points are assessed for various levels of pain, distance walking, and ability to perform 

activities of daily living (Lequesne, Mery, Samson, et al., 1987). It sums scores from 5 

adjectival items, producing scores ranging from 1 to 24 points. The severity of handicap related 

to the knee can be categorized by point score: mild (1–4 points); moderate (5–7 points); severe 

(8–10 points); very severe (11–13 points); and extremely severe (>14 points) (Bellamy, 1993). 

What constitutes a MCII is likely approximately 20 percent (Bellamy, 1993). 

 Physical function may be appraised through reported difficulty performing specific daily 

activities affected by knee OA (Bellamy, Buchanan, Goldsmith, et al., 1988; Lequesne, Mery, 

Samson, et al., 1987). Patient global assessment (generally defined as the “patient's assessment 

of overall disease activity or improvement”) can be assessed by VAS, NRS, or other specific 

instruments (Pham, van der Heijde, Altman, et al. 2004). The MCII for patient global 
22 

assessment on a 100 mm VAS has been suggested to be 18 mm, or a relative improvement of 40 

percent. 

 Both generic measures and disease-specific quality of life (QOL) measures may be relevant 

(Salaffi, Carotti, and Grassi, 2005) assessing disease impact. The SF-36 and Arthritis Impact 

Measurement Scales (Meenan, 1986) are acceptable scales to assess the impact of osteoarthritis 

on QOL. 

 Pooled Outcome Measures. Meta-analyses may pool outcome measures using the metric of 

the original scale, or a metric related to it. 

The “weighted mean difference” (WMD) combines (pools) differences between treatment 

and control from multiple trials on the scale of the original instrument. It can be reported as 

either a difference between treatment and control at some followup time or a difference in 

change scores. While intuitive to interpret as a difference or difference in change for some 

outcome measure, the WMD has doe not define proportions achieving a MCII or response (Senn 

1997, page 226; Tubach, Ravaud, Giraudeau 2005). 

“Relative risks” (or the approximately equal odds ratio) can be pooled for dichotomous 

outcome measures (e.g., patient global assessment and adverse events). It is a ratio comparing 

the outcome probability among treated compared placebo groups. The relative risk clearly 

conveys increased risk, but does not directly reflect clinical benefit in terms of response unless a 

comparison of meaningful clinical response rates. 

“Sums of differences” in outcome measures between treatment and placebo groups (e.g., pain 

and function) over the course of a study can also be pooled. The measure is expressed as a 

percentage reflecting how much greater relief is provided by treatment compared to placebo. 

Although commonly used in pain research, the measure does not have direct clinical meaning 

with respect to response. 

“Standardized effect sizes” expressed as differences or differences in change, standardized by 

their variability (divided by the standard deviation) can also be pooled. Standardized effect sizes 

are typically used when scales pooled have different metrics (e.g., a 0- to 100-mm VAS and a 

25-point WOMAC scale). The clinical meaning of standardized effect sizes when different 

scales are pooled and variability differs across studies is difficult to intuit. While small, medium, 

and large referents corresponding to 0.3, 0.5 and 0.8, respectively, were suggested by Cohen 

(1988), they pertain to sample size calculations not clinical meaning, and were qualified 

substantially.*

 Others have pointed out problematic aspects of standardized effect sizes 

including: incomparability across studies (Rothman and Greenland, 1998) and that studies with 

identical results may appear to differ (Greenland, Schlesselman, Criqui, 1986). Most 

importantly, one cannot infer individual response Senn (1997).†

 

 

*

 “For each statistical test’s ES [effect size], the author proposes, as a convention, ES values to serve as operational definitions 

the qualitative adjectives ‘small,’ ‘medium,’ and ‘large.’ This is an operation fraught with many dangers: The definitions are 

arbitrary, such qualitative concepts as “large” are sometimes understood as absolute, sometimes as relative; and thus they run a 

risk of being misunderstood...” (Cohen, 1988, page 12.) 

†

 “The probability associated with an effect size calculates the probability of observing such a superiority [of treatment A over 

B]. However, to know whether a given patient will be better off treated with A or B, or even to know what proportion of patients 

will be better off is quite another matter. No simple comparison of means whether scaled by the standard deviation or not can 

answer this question.” (Senn 1997, page 226.) 
23 

Search Strategy and Review 

Search Strategy 

Electronic Databases. The following databases were searched for citations. The full search 

strategy is displayed in Appendix A*

. The search was not limited to English-language 

references; however, foreign-language references without abstracts were disregarded. 

• MEDLINE® (through March 29, 2007) 

• EMBASE (through March 16, 2006) 

• Cochrane Controlled Trials Register (through November 27, 2006). 

EMBASE was updated with abbreviated searches through November 27, 2006. 

Additional Sources of Evidence. The Technical Expert Panel and individuals and 

organizations providing peer review were asked to inform the project team of any studies 

relevant to the key questions that were not included in the draft list of selected studies. 

 We examined the bibliographies of all retrieved articles for citations to any RCT that was 

missed in the database searches. In addition, we sought RCTs published in conference 

proceedings and abstracts from the American Association of Orthopaedic Surgeons (AAOS), 

American College of Rheumatology (ACR) and the Osteoarthritis Research Society International 

(OARSI) over the past 2 years. We also consulted product inserts of U.S.-marketed 

viscosupplement products.

Search Screen 

Search results were stored in a ProCite® database. Using the study selection criteria for 

screening titles and abstracts, a single reviewer marked each citation as either: (1) eligible for 

review as full-text articles, (2) ineligible for full-text review, or (3) uncertain. Citations marked 

as uncertain were reviewed by a second reviewer and resolved by consensus opinion, with a third 

reviewer to be consulted if necessary. Using the final study selection criteria, review of full-text 

articles was conducted in the same fashion to determine inclusion in the systematic review. Of 

1,842 citations, 451 articles were retrieved and 98 selected for inclusion (Figure 2). Records of 

the reason for exclusion for each paper retrieved in full-text, but excluded from the review, were 

kept in the ProCite® database (see Appendix B*, Excluded Studies). 

 

*

 Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm 
24 

Figure 2. QUOROM flow diagram 

Data Extraction and Analysis 

Data Elements 

The data elements below were abstracted, or recorded as not reported, from intervention 

studies. Data elements to be abstracted were defined in consultation with the Technical Expert 

Panel. 

1,842 articles

identified on

literature searches

1,391 articles

excluded on review

of titles and abstracts

451 full-text 

articles retrieved

98 articles met study

selection criteria

353 articles excluded

after full review

hyaluranon:

106 articles

glucosamine/

chondroitin:

57 articles

arthroscopy:

190 articles

hyaluranon:

48 articles

glucosamine/

chondroitin:

27 articles

arthroscopy:

23 primary 

study articles

6 metaanalysis

articles

in metaanalyses:

41 primary 

study 

articles

not in 

metaanalyses:

1 primary

study 

article

6 metaanalysis

articles

in metaanalyses:

16 primary

study 

articles

not in 

metaanalyses:

5 primary

study

articles
25 

Data elements from intervention studies (RCTs and quasi-experimental studies) include: 

• Critical features of the study design (for example, patient inclusion/exclusion criteria, 

number of participants, allocation method (including concealment), use of blinding) 

• Patient characteristics (age, gender, race/ethnicity, body weight, primary or secondary 

disease. disease duration) 

• Measures of disease severity 

• Treatment protocols (for example, dose, frequency, duration, extent of arthroscopic surgery, 

other prior and concurrent treatments) 

• Patient monitoring procedures (for example, followup duration and frequency, outcome 

assessment methods) and 

• The specified key outcomes and data analysis methods 

• Results 

• Funding source. 

Data elements from systematic reviews and meta-analyses include: 

• Use of a protocol 

• The study question (patients, interventions/comparisons, outcomes) 

• Literature search strategy 

• Study inclusion/exclusion criteria 

• Data extraction methods 

• Assessment of study quality 

• Methods of data synthesis/analysis 

• Funding source. 

 Data elements from case series include: 

• Clinical question 

 

• Enrollment of patients (consecutive or otherwise) 
26 

• Whether a single-center or multicenter study 

• Patient selection criteria and sample characteristics 

• Intervention 

• Length of followup 

• Validated outcome measures and independence or blinding of outcome assessment 

• Statistical analyses 

• Results. 

Evidence Tables 

Templates for evidence tables were created in Microsoft Excel® and Microsoft Word®. One 

reviewer performed primary data abstraction of all data elements into the evidence tables, and a 

second reviewer reviewed articles and evidence tables for accuracy. Disagreements were 

resolved by discussion, and if necessary, by consultation with a third reviewer. When small 

differences occurred in quantitative estimates of data from published figures, the values obtained 

by the two reviewers were averaged. 

Assessment of Study Quality 

Definition of Ratings Based on Criteria

 In consultation with the AHRQ Task Order Officer and Technical Expert Panel, the general 

approach to grading evidence developed by the U.S. Preventive Services Task Force (Harris, 

Helfand, Woolf, et al. 2001) were applied to primary studies. The quality of the abstracted 

studies was assessed by two independent reviewers. Discordant quality assessments were 

resolved with input from a third reviewer, if necessary. 

Primary RCTs and Quasi-Experimental Studies

 The quality of RCTs and quasi-experimental studies were assessed on the basis of the 

following criteria: 

• Initial assembly of comparable groups: adequate randomization, including concealment and 

whether potential confounders (e.g., other concomitant care) were distributed equally among 

groups 

• Maintenance of comparable groups (includes attrition, crossovers, adherence, contamination) 
27 

• Important differential loss to followup or overall high loss to followup 

• Measurements: equal, reliable, and valid (includes masking of outcome assessment) 

• Clear definition of interventions 

• All important outcomes considered 

• Analysis: adjustment for potential confounders, intention-to-treat analysis. 

 

Definition of Ratings Based on Above Criteria. The rating of intervention studies 

encompasses the three quality categories described here:

• Good: Meets all criteria: Comparable groups are assembled initially and maintained 

throughout the study (followup at least 80 percent); reliable and valid measurement 

instruments are used and applied equally to the groups; interventions are spelled out clearly; 

all important outcomes are considered; and appropriate attention is given to confounders in 

analysis. In addition, for RCTs, intention-to-treat analysis is used. 

• Fair: Studies were graded “fair” if any or all of the following problems occur, without the 

fatal flaws noted in the “poor” category below: In general, comparable groups are assembled 

initially but some question remains whether some (although not major) differences occurred 

with followup; measurement instruments are acceptable (although not the best) and generally 

applied equally; some but not all important outcomes are considered; and some but not all 

potential confounders are accounted for. Intention-to-treat analysis is done for RCTs. 

• Poor: Studies were graded “poor” if any of the following fatal flaws exists: Groups 

assembled initially are not close to being comparable or maintained throughout the study; 

unreliable or invalid measurement instruments are used or not applied at all equally among 

groups (including not masking outcome assessment); and key confounders are given little or 

no attention. For RCTs, intention-to-treat analysis is lacking. 

Systematic Reviews and Meta-Analyses

 Assessment of the quality of systematic reviews and meta-analyses were guided by a quality 

rating method reported by Oxman and Guyatt (1991; Overview Quality Assessment 

Questionnaire).*

 Oxman and Guyatt tool results in a quality score, based on the answers to ten 

questions that provide information on the content of a review in terms of how it was conducted, 

as follows: 

 

* Our original protocol included analysis of the quality of meta-analysis reporting according to the QUOROM (Moher, Cook, 

Eastwood, et al., 1999). However, we have not included this analysis because QUOROM was not generally available or in 

widespread use when the earlier meta-analyses were published.
28 

1. Were the search methods used to find evidence on the primary question(s) stated? 

2. Was the search for evidence reasonably comprehensive? 

3. Were the criteria used for deciding which studies to include in the overview reported? 

4. Was bias in the selection of studies avoided? 

5. Were the criteria used for assessing the validity of the included studies reported? 

6. Was the validity of all the studies referred to in the text assessed using appropriate criteria? 

7. Were the methods used to combine the findings of the relevant (to reach a conclusion) 

reported?*

8. Were the findings of the relevant studies combined appropriately relative to the primary 

question of the overview? 

9. Were the conclusions made by the author(s) supported by the data and/or analysis reported in 

the overview? 

10. What was the overall scientific quality of the overview? Use the following scoring scale: 

Figure 3. Oxman and Guyatt Rating 

Flaws 

Extensive Minor 

Major Minimal 

1 2 3 4 5 6 7 

 

 The following guidelines are used to apply the Oxman and Guyatt rating: 

Question 1: Literal interpretation. 

Question 2: For a search to be considered comprehensive the methods used to perform the 

search should include searching for unpublished material as well as multiple 

medical databases (at least EMBASE and MEDLINE®). If only published 

material was searched for, the search should be marked “partially.” A look 

through bibliographies, conference proceedings, or trial registries is deemed 

adequate as a search for unpublished literature. The search must not be limited to 

the English language. 

 

*

 Our original protocol included analysis of the quality of meta-analysis reporting according to the QUOROM (Moher, Cook, 

Eastwood, et al., 1999). However, we have not included this analysis because QUOROM was not generally available or in 

widespread use when the earlier meta-analyses were published. 
29 

Question 3: Should specify defining population, intervention, principal outcomes, and study 

design to be “yes;” if only 2 or 3 of these are noted, it should be scored “partially” 

here. 

Question 4: Must be “yes” on 2 and 3 and dual review to be “yes” here; if “no” on 2 or 3 must 

be “no” here; if “partially” or “can’t tell” on 2 and 3 then must be the same here. 

Question 5: Must use some cited validity tool for “yes” here. 

Question 6: Scales used must be appropriately applied to study type for “yes” here. 

Question 7: An appropriate pooling method and test for heterogeneity must be described for 

“yes” here; were “partially” if a pooling method but no heterogeneity testing 

method is specified. 

Question 8: If no attempt has been made to combine findings, and no statement is made 

regarding the inappropriateness of combining findings, check “no.” If a summary 

(general) estimate is given anywhere in the abstract, the discussion, or the 

summary section of the paper, and it is not reported how that estimate was 

derived, mark “no,” even if there is a statement regarding the limitations of 

combining the findings of the studies reviewed. If in doubt, mark “can’t tell.” To 

determine whether it is appropriate to use random or fixed effects model, the 

study should address the question of how much heterogeneity would be 

considered (addressing clinical and statistical aspects of heterogeneity). 

Question 9: If 8 is “no,” 9 must be “no.” If 8 is “can’t tell,” 9 must be “can’t tell.” For an 

overview to be scored as “yes” on Question 9, data (not just citations) must be 

reported that support the main conclusions regarding the primary question(s) that 

the overview addresses. 

Question 10: The overall scientific quality should be based on the answers to the first 9 

questions. The following guidelines can be used to assist with deriving a 

summary score: if the “can’t tell” option is used one or more times on the 

preceding questions, a review is likely to have minor flaws at best, and it is 

difficult to rule out major flows (i.e., a score ≤4). If the “no” option is used on 

Questions 2, 4, 6, or 8, the review is likely to have major flaws (i.e., a score of ≤3, 

depending on the number and degree of the flaws). 

It should be noted that a new quality assessment tool for systematic reviews and metaanalyses was recently developed (Shea, Grimshaw, Wells, et al., 2007). It was based, in part, on 

the work of Oxman and Guyatt, but differs in significant ways. In particular, the Oxman and 

Guyatt tool does not adequately address whether quality concerns of the underlying literature 

were incorporated into conclusions. The tool by Shea, Grimshaw, Wells, et al. (2007) more 

clearly assesses whether conclusions took appropriate account of the quality of included studies 

and the potential for publication bias. The recently developed tool was unavailable during the 

time when ratings of meta-analyses were performed for this evidence report. 
30 

Case Series

 The quality of included case series was assessed based on a set of study characteristics 

proposed by Carey and Boden (2003, Table 2), as follows: 

• Clearly defined question 

• Well-described study population 

• Well-described intervention 

• Use of validated outcome measures 

• Appropriate statistical analyses 

• Well-described results 

• Discussion and conclusion supported by data 

• Funding source acknowledged. 
Table 2. Carey and Boden case series quality assessment tool 

Clearly Defined 

Question 

Well-Described 

Study 

Population

*

Well-Described 

Intervention 

Use of Validated 

Outcome 

Measures 

Appropriate 

Statistical 

Analysis 

Well-Described 

Results 

Discussio

Conclusio

Supported 

Data 

Question should be appropriate to study design; should not be stated in terms of effectiveness; best when focused; 

Case definition (diagnostic criteria); type of criteria (clinical, radiographic); whether criteria used before (reference); explicit inclusion/ exclusion criteria; includes standard information (age; sex; socioeconomic status; stage and duration of disease; comorbidities; n; time to accrual; exclusions and reasons; loss to followup; refusal) 

Sufficiently clear that another center could replicate study; if not identified in detail, should provide references; cointerventions should be described in reasonable detail 

Reference to previous validation; ideally individual assessing patient’s outcome should be masked to specific intervention; alternatively, assessor who is not in direct employ of clinical office; standardized length and intervals of observation and of sufficient duration to be clinically meaningful; justification for the duration of followup 

Statistical tests and power calculations aimed at improvement over time; prepost analysis should take into account paired nature of data; comparisons with historical controls should take into account differences in cointerventions between time periods; attention to nonspecific effects and inability to distinguish procedure’s effect from spontaneous improvement; avoids overreliance on those variables showing improvement; analysis should address multiple comparisons 

Utilize only validated outcome measures; description of adequacy of followup (number lost to followup, number who switch to another provider or pursue other treatments, number who die from other causes); [adaptation: inclusion of both potentially beneficial outcomes (symptom/ function/ quality of life) and adverse events] 

Conclusion should be supported by data in the awhere other information iused to buttrconclusions, should be explicitly staand referenclimitations shbe made expdescription ospecific next research ste(e.g., need foRCT, details RCT) [adaptation: element disregarded] 

*OA criteria noted; minimum set of characteristics: age, sex, disease duration and preop severity described. 

31

33 

Chapter 3. Results and Conclusions 

Part I: Intra-Articular Hyaluronan Effectiveness and Harms 

Literature Overview 

 Five study-level meta-analyses comparing intra-articular hyaluronans with placebo (e.g., 

arthrocentesis and saline injection) for osteoarthritis (OA) of the knee have been published. One 

patient-level meta-analysis of a single product was also identified.*

 The quality of the metaanalyses was appraised with a validated tool (Oxman and Guyatt, 1991; Oxman, Guyatt, Singer, 

et al., 1991)—the Overview Quality Assessment Questionnaire. 

 These meta-analyses included outcome measures from 41 relevant randomized, controlled 

trials (RCTs). One additional placebo-controlled trial (Rolf, Engstrom, Ohrvik, et al., 2005) 

identified by our literature search†

 was not included in any meta-analysis (42 trials, therefore, 

included in this review). RCTs pooled by the meta-analyses overlap considerably; their 

quantitative results and limitations also overlapped. Owing to the broad scope of the metaanalyses, they were judged to effectively capture existing evidence and formed the primary basis 

for evaluating hyaluronans’ effectiveness. Important details relevant to the evidence, or 

inconsistently reported in the meta-analyses, were abstracted from the primary literature (e.g., 

sample size and power calculations, use of intention-to-treat or per protocol analyses, industry 

involvement, quality appraised according to our protocol). 

Results, Part I: Key Questions 1 and 2 

 Outline. Because this chapter reports results from different perspectives, its organizational 

structure is outlined to guide the reader: 

• Study populations included in RCTs comprising the meta-analyses described 

• Application of the Overview Quality Assessment Questionnaire to the five study-level metaanalyses 

• Relevant detailed results from the meta-analyses 

• Trials not pooled or included in the meta-analyses 

• Adverse events 

 

*

 The patient-level meta-analysis combines individual patient data while the study-level meta-analyses combine results from 

individual trials. 

†

 A recent trial, Petrella and Petrella (2006) comparing two hyaluronan dosing regimens, was excluded because there was no 

comparison group only given placebo. 
34 

• Supplementary analyses performed by the Evidence-based Practice Center 

– Sensitivity analyses 

– Publication bias 

– Hylan G-F 20 

• Summary and appraisal. 

 Study Populations. Characteristics of participants included in the 42 RCTs varied 

(Appendix C*

, Tables IA, IB). Mean ages ranged from 45 to 72 years. Females represented 

between 28 and 100 percent of participants. In 24 RCTs, 60 percent or more were female. Only 

two RCTs (Dahlberg, Lohmander, Ryd, et al., 1994; Rolf, Engstrom, Ohrvik, et al., 2005) 

specified including individuals with secondary OA of the knee (both due to trauma). Fifteen 

RCTs stated that only individuals with primary OA of the knee were included, while in 25 either 

no distinction was reported or information was unavailable (e.g., unpublished studies and 

abstracts). No trial reported including individuals with OA of the knee secondary to systemic or 

congenital conditions. 

Radiological disease grade of knees studied varied. The most common classification applied 

was Kellgren and Lawrence (1957) (in 18 RCTs). Schemes developed by Altman, Asch, Bloch, 

et al. (1986), Larsen, Dale, and Eek (1977), and Ahlback (1968) were also used. Table 3 

displays the range of radiographic grades included (not unspecified in 18 RCTs or 45 percent). 

Table 3. Radiographic classification and grade in included viscosupplement RCTs 

Classification and Grade RCTs 

Kellgren-Lawrence 0-4 1 

Kellgren-Lawrence 1–2 1 

Kellgren-Lawrence 1–3 1 

Kellgren-Lawrence 1–4 3 

Kellgren-Lawrence 2–3 5 

Kellgren-Lawrence 2–4 7 

Ahlback 0–3 1 

Ahlback 1–2 2 

Altman 1–3 1 

Larsen 1–4 1 

Larsen 2–4 1 

Unreported or Unavailable 18 

Total 42 

Mean baseline pain measured by visual analog scale (VAS) with movement was reported 19 

RCTs ranging from 44 to 79 mm in hyaluronan study arms and 42 to 80 mm among placebo 

study arms. The variability of the baseline pain measurements in trials spanned standard 

deviations from 5.5 to 31. When reported, mean disease duration varied from 1.2 to 22 years. 

Patient samples included in RCTs were therefore heterogeneous with respect to age, sex, 

knee radiographic grade, and baseline pain, reflecting varied patient selection among RCTs. 

 Randomized Controlled Trials. The conduct and quality of the 42 RCTs varied in a 

number of aspects including (see also Appendix C*

, Tables IB–IF): 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
35 

• Quality ratings according to our protocol for 37 evaluable RCTs were “good” for nine, “fair” 

for 16, and 12 rated “poor” (five were not evaluable). 

• Sample sizes ranged from 12 to 408 with a mean of 141 and median 102. 

• Power calculations were reported in 19 RCTs. Mean sample size in these RCTs was 204 

compared to 60 for the 16 RCTs without those calculations in published manuscripts. 

• Trial duration ranged from 4 to 52 weeks with a mean of 23 and median 20 weeks; 11 were 

fewer than 10 weeks in duration. 

• Intention-to-treat results were the primary analytical results reported in 17 RCTs (40 

percent); 16 (38 percent) reported per protocol analyses; the analytical approach was either 

unclear or not reported in 9 (21 percent)—e.g., some unpublished studies. 

• Losses to follow-up or drop-outs ranged from 0 to 50 percent with nine RCTs reporting 20 

percent or greater loss to follow-up. 

• Blinding was reportedly double in 35 RCTs. 

• Reported industry involvement included funding of 23 RCTs, providing statistical analyses 

for eight, and in eight, an industry member was a co-author. 

The RCTs in this review consist of 41 trials included in the meta-analyses and one RCT 

(Rolf, Engstrom, Ohrvik, et al., 2005) identified in our literature search. Of the RCTs included 

in meta-analyses, 33 have been published as articles, five as abstracts (Russell, Michalek, 

Lawrence, et al., 1992; Moreland, Arnold, Saway, et al., 1993; Cohen, Shiroky, Ballachey, et al., 

1994; Guler, Kuran, Parlar, et al., 1996; Tsai, Chang, Chen, et al., 2003), and three were 

unpublished (Table 4). In addition, an unpublished and unreported trial was identified in the 

Orthovisc® package insert as OAK 9801.*

 Trials not published in full text comprise 

approximately 25 percent of the total patient population. 

In summary, there is variability in trial characteristics including study quality, sample size 

and power calculations, duration, use of intention-to-treat analysis, losses to follow-up, funding, 

and industry involvement. The known extent of unpublished data includes a large number of 

individuals. Results from at least one trial (OAK 9801) appear unreported in any form. 

 

*

http://www.orthovisc.com/content/xhtml_backgrounders/orthovisc.us_tld/orthovisc.us_eng/Orthovisc_Package_Insert.pdf (last 

accessed 10/29/06). “The effectiveness of ORTHOVISC® for the treatment of osteoarthritis of the knee was evaluated in three 

main studies; two randomized, controlled, double-blind multicenter studies (OAK9501 and OAK2001) that involved unilateral 

treatment, and one study (OAK9801) that involved bilateral treatment. Because bilateral treatment confounded the assessment of 

effectiveness of the OAK9801 study, the effectiveness data are summarized for the OAK9501 and OAK2001 studies. Safety data 

for all three studies are reported...”
36 

Table 4. Number of participants randomized and reported in abstracts, unpublished and published RCTs of 

hyaluronan-based products 

 Trial Sample Size* Result (+/–) 

Russel et al., 1992 210 – 

Moreland et al., 1993 94 – 

Cohen et al., 1994 39 ?‡

Guler et al., 1996 30 + 

Tsai et al., 2003† 200 + 

Abstract only 

Subtotal (% of Total) 573 (9.8) 

France, 1995 254 – 

U.K., 1996 231 ? 

Hizmetli et al., 1999 50 + 

OAK 9801 382 ?§

Unpublished 

Subtotal (% of Total) 917 (15.7) 

Published All Participants (% of Total) 4,353 (74.5) 

Total 5,843 (100) 

* Sample size reported here are patients (not knees) randomized. 

†

 Bellamy, Campbell, Robinson, et al. (2006) refer to as Lin 2004, “in-house publication” 

‡

 As reported in Lo, LaValley, McAlindon, et al. (2003) 95% CI included unity; Wang, Chen, Huang, et al. (2004) suggested 

benefit; abstract notes no statistically significant difference at any time points for pain, WOMAC, or global assessment. 

§

 Results presumably negative given language in package insert (see footnote). Not mentioned by Bellamy, Campbell, 

Robinson, et al. (2006) who obtained a number of results from manufacturers. 

 Overview of the Meta-Analyses. The six meta-analyses were published between 2003 and 

2006—five study- and one patient-level (Strand, Conaghan, Lohmander, et al., 2006). Each 

pooled different outcomes measures relevant to Key Questions 1 and 2 as outlined in Table 5. 

Table 5. Outcome measures pooled in viscosupplementation meta-analyses relevant to Key Questions 1 & 2 

Lo 

et al., 

2003 

Wang 

et al., 

2004 

Arrich 

et al., 

2005 

Modawal 

et al., 

2005 

Bellamy 

et al., 

2006 

Strand 

et al., 

2006 

Pain X X X X X 

Physical Function X X X 

Patient Global Assessment X 

WOMAC (Composite) X 

Lequesne Index (Composite) X X 

There was considerable overlap of RCTs included in the meta-analyses (Table 6). Some 

differences can be attributed to publication chronology. Of the study-level meta-analyses 

Modawal, Ferrer, Choi, et al. (2005) pooled results from the fewest RCTs while Bellamy, 

Campbell, Robinson, et al. (2006) the most. Strand, Conaghan, Lohmander, et al. (2006) being a 

patient-level meta-analysis of a single product pooled results from five RCTs. 

Quality Assessment of the Study-Level Meta-Analyses. Methodologic quality is an important 

consideration in synthesizing evidence pooled by the meta-analyses. As outlined in the Methods 

chapter, the Overview Quality Assessment Questionnaire (Oxman and Guyatt, 1991; Oxman, 
37 

Table 6. Viscosupplementation RCTs addressing Key Questions 

Trial 

Lo et al., 

2003 

Wang et al.,

2004 

Arrich et 

al., 2005 

Modawal et 

al., 2005 

Bellamy et 

al., 2006 

Strand et 

al., 2006 

Shichikawa et al. 1983a 

Shichikawa et al. 1983b 

Bragantini et al. 1987 

Grecomoro et al. 1987 

Dixon et al. 1988 * 

Russell et al. 1992 

Dougados et al. 1993 

Moreland et al, 1993 

Puhl et al. 1993 

Cohen et al. 1994 

Creamer et al. 1994 

Dahlberg et al. 1994 

Henderson et al. 1994 

Scale et al. 1994 ** 

Carrabba et al. 1995 

Corrado et al. 1995 

Formiguera & Esteve * 

France 1995 

Guler et al. 1996 

Lohmander et al. 1996 ** 

U.K. 1996 

Wu et al. 1997 * 

Altman & Moskowitz 1998 

Dickson & Hosie 1998† † 

Wobig et al. 1998 * 

Hizmetli et al. 1999 

Huskisson & Donnelly 

Brandt et al. 2001 *** 

Bunyaratavej et al. 2001 *** 

Dickson et al. 2001† †

Tamir et al. 2001 * 

Karlsson et al. 2002 

Petrella et al. 2002 

Jubb et al. 2003 

Pham et al. 2003‡ ‡ 

Tsai et al. 2003 

Altman et al. 2004 *** 

Cubukcu et al. 2004 

Day et al. 2004 

Pham et al. 2004‡ ‡

Neustadt et. al. 2005 *** 

Sezgin et al. 2005 

Rolf et al. 2005 

Kotevoglu et al. 2006 

(42 trials; 41 included 

in meta-analyses) 22 20 17 9 32 5 

Shaded boxes indicate included in a meta-analysis, bolded RCTs are unpublished, italicized RCTs are abstracts not 

subsequently published; † or ‡ represent abstract and subsequent publications; although listed twice for to reflect what 

was included in meta-analysis, they are the same studies and therefore included only once in the total. 

* Included for adverse events, but not in any pooled efficacy result. 

** Identified in search, but data "could not be used" for any outcome other than adverse events. 

*** Included in systematic review, but data not used in a pooled by-class result. 
38 

Guyatt, Singer, et al., 1991) was used to appraise meta-analysis quality.* Descriptions of the 

ratings provide insight into their basis and potential implications. Although summaries are 

presented, they should not be interpreted reflecting the potential validity of conclusions from any 

meta-analysis. Rather, the quality ratings are but one element of the overall evidence evaluation 

and synthesis. 

Application of the Overview Quality Assessment Questionnaire found one meta-analysis to 

have minimal flaws, one minor, and three major flaws (Table 7). The primary flaws identified 

included not searching EMBASE and language restrictions. Only one meta-analysis (Bellamy, 

Campbell, Robinson, et al., 2006) included any RCTs (n=2) published in a non English language. 

However, the two studies (Shichikawa, Igarashi, Sugawara, et al., 1983 Shichikawa, Maeda, and 

Ogawa, 1983) were both 5 weeks in duration and assessed pain using a 4-point scale (no 

symptom, mild, moderate, severe). Therefore, while language limitation affected numerical 

ratings, implications for results of any meta-analysis results are minimal. Conclusions were 

judged supported by the data in one meta-analysis, partially in three, and unsupported in one 

(summarized in Appendix C†, Table IJ). 

In summary, based on the methodologic appraisal and quality, these meta-analyses form a 

substantive body of evidence and basis from which to evaluate the efficacy of hyaluronans for 

OA of the knee. 

Characteristics of the Study-Level Meta-Analyses. Comparative characteristics of the studylevel meta-analyses are detailed in Table 8. Study inclusion criteria differed among them as did 

pain and function effect measures combined. Bellamy, Campbell, Robinson, et al. (2006)‡

 and 

Arrich, Piribauer, Mad, et al. (2005) pooled the mean difference at follow-up (weighted mean 

difference); assuming equal baseline pain measurements this measure reflects difference in 

change. Modawal, Ferrer, Choi, et al. (2005) pooled the calculated difference in change directly 

(reporting a weighted mean difference). Lo, LaValley, McAlindon, et al. (2003) pooled the 

difference in change standardized by standard deviation. Wang, Chen, Huang, et al. (2004) 

pooled effects as a percentage reduction compared to placebo. 

 The treatment of time relative to the potential longitudinal nature of effects also differed 

among the study-level meta-analyses. Lo, LaValley, McAlindon, et al. (2003) examined effect at 

the time of likely maximum benefit (2 to 3 months post-injection) (Kirwan, 2001); Wang, Chen, 

Huang, et al. (2004) possible benefit over entire studies (discussed in detail later); Arrich, 

Piribauer, Mad, et al. (2005), Modawal, Ferrer, Choi, et al. (2005), and Bellamy, Campbell, 

Robinson, et al., (2006) pooled effects for various periods following administration. Pooling of 

functional differences, when reported, differed similarly. 

Model selection was dictated by the degree of heterogeneity—random-effects models were 

generally used. Meta-regressions were performed in three meta-analyses (Wang, Chen, Huang, 

et al., 2004; Arrich, Piribauer, Mad, et al., 2005; Modawal, Ferrer, Choi, et al., 2005) exploring a 

variety of factors with study quality examined in each. Two of the five study-level metaanalyses reported funnel plot asymmetry (Lo, LaValley, McAlindon, et al., 2003; Modawal, 

Ferrer, Choi, et al., 2005), two did not (Wang, Chen, Huang, et al.; 2004; Arrich, Piribauer, Mad, 

 

* Strand, Conaghan, Lohmander, et al. (2006) was not rated because the questionnaire is not validated for patient-level metaanalyses.

† Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm

‡ Bellamy, Campbell, Robinson, et al. (2006) also pooled outcome measures in other manners, but for pain primarily as a posttest weighted mean difference.
Table 7. Overview quality assessment questionnaire ratings of viscosupplementation meta-analyses 

Item Rating Lo et al., 2003 Wang et al., 2004 Arrich et al., 2005 Modawal e1. Were the search methods used to find evidence (original research) on the primary question(s) stated? 

z Clearly stated z Clearly stated z Clearly stated z Clearly s

2. Was the search for evidence reasonably comprehensive? 

| Did not include 

EMBASE, but did search Cochrane Registry

| English language only; did search Cochrane Registry

z Searched 4 electronic databases; Cochrane Registry; limited to English and German

| RestricteEnglish, did include EMBdid search CRegistry

3. Were the criteria used for deciding which studies to include in the overview reported? 

z Clearly stated z Clearly stated

 Defining 

populations not explicitly defined

z Defining populationsinterventionoutcomes, adesign spec

4. Was bias in the selection of studies avoided? 

| Due to lack of 

EMBASE search--i.e. no on Q2

| Language and lack of unpublished literature—no on Q2.

 Because partial 

Q3; language restriction; no test for publication bias

| English la

restriction 

5. Were the criteria used for assessing the validity of the included studies reported? 

z Applied stated 

criteria although minimal

z Used 28-point validated check list

z Employed stated 

criteria: reporting treatment allocation; blinding; intention-totreat analysis

z Chalmers 

6. Was the validity of all studies referred to in the text assessed using appropriate criteria (either in selecting studies for inclusion or in analyzing the studies that are cited)? 

z Each trial rated z Each trial rated z Each trial rated z Each tria

7. Were the methods used to combine the findings of the relevant studies (used to reach a conclusion) reported? 

z Yes  Partially or can't tell |- No

z Random-effects models

z Random-effects 

models when heterogeneity present

z Random-effects 

models

z Random-models

39
Table 7. Overview quality assessment questionnaire ratings of viscosupplementation meta-analyses (continued) 

Item Rating Lo et al., 2003 Wang et al., 2004 Arrich et al., 2005 Modawal e

8. Were the findings of the relevant studies combined appropriately relative to the primary question the overview addresses? 

z Random effects 

models accounting for heterogeneity

z Random effects 

models accounting for heterogeneity

z Random effects models accounting for heterogeneity

z Random 

models accfor heteroge

9. Were the conclusions made by the author(s) supported by the data and/or analysis reported in the overview? 

z Yes  Partially or can't tell |- No 

 Due to Q2

 Did not define a 

clinical meaning for SPID (sum of pain intensity difference) etc; English only

z Generally cogent synthesis of results; well conducted metaanalysis 

| Due to no incorrect Eginterpretatio

10. How would you rate the scientific quality of the overview? 

“Flaws”: 1 extensive 2 3 major 4 5 minor 6 7 minimal 

3 

Due to Q2 

3 

Due to Q2 

5 

Due to Q3 and Q4 

3 

Due to Q

40
Table 8. Characteristics of study-level viscosupplementation meta-analyses 

 Lo et al., 2003 Wang et al., 2004 Arrich et al., 2005 Modawal et al., 2005 

General inclusion criteria 

Single- or double-blind 

IA placebo-controlled 

RCTs, at least 3 

injections, <50% 

dropout, >2 months f/u 

Single or double blind 

placebo controlled 

RCTs 

Single or double blind 

placebo controlled 

RCTs 

Double blind placebo 

controlled RCTs 

Pain and function outcome(s) compared to placebo 

Pain: Global knee or 

walking or WOMAC pain 

or Lequesne or during 

non-walking activities 

Pain with and without 

activities 

Joint function 

Pain at rest 

Pain during or after 

exercise 

Joint function 

Knee pain (VAS) during 

activity or rest 

Pain effect measure SMD Pain Change Sum of Pain Intensity Differences WMD Pain Difference at Follow-up WMD Pain Change Other pooled effect measures 

Sum of Functional 

Intensity Differences SMD Joint Function 

Time "8 to 12 weeks" All time points/area under the curve 2–6, 10–14, 22–30 weeks 1, 5–7, 8–12, 15–22 weeks Model selection random effects random & fixed effects random effects random effects 

Trial quality assessment Intention-to-treat analysis/dropout rate 28-point checklist (Downs and Black 1998) Allocation concealment; intention-to-treat analysis; Binding Chalmers 

Comment on trial quality 

7/22 intention-to-treat 

data available 

Mean dropout 12.4% 

(0-40.3) 

Mean score 17 (9–25) 

(maximum possible 28) 

Trial quality considered 

“unsatisfactory” Mean .70/1 (.44–.80) 

Heterogeneity

Test used Cochran's Q Cochran's Q (only non-cross linked) Cochran's Q 

I

2

Cochran's Q 

Galbraith Plot 

Result(s) p<.001 

Multiple values reported, 

all significant except for 

ASFID% 

Pain at rest I2 94% 

Pain after or during 

 exercise I2 81% 

Joint function I2 66% 

Heterogeneity 

evident in plot; 

Q (p<.001) at time 

points examined 

41
Table 8. Characteristics of study-level viscosupplementation meta-analyses (continued)

 Lo et al., 2003 Wang et al., 2004 Arrich et al., 2005 Modawal et al., 2005 

Meta-regression 

Factors explored — 

Only for non-crosslinked: quality, 

publication year, 

molecular weight, mean 

age, trial duration, 

sample size 

Allocation concealment

Blinded outcome 

assessment 

intention-to-treat 

analysis 

Pain type, 

medication (HA vs. 

hyaluronan G-F20), 

trial quality, week 

Sensitivity analysis Yes Yes Yes Yes Funnel plot/bias 

Funnel Plot 

(asymmetric) 

Egger Test 

(p=.07) 

Funnel Plots 

(symmetric) 

Regression methods 

Egger Test; "could not 

detect” 

Egger Test 

(p=.096) 

Included studies 22 RCTs 20 RCTs 22 RCTs 9 RCTs Industry sponsored 77% 65% not reported 73% † I2 A measure of overall variability ranging from 0% to 100% ‡ Bellamy examined other outcomes not a part of this report's protocol § Based on notes reported for RCTs ASFID: adjusted sum of function index differences; f/u: followup; HA: hyaluronic acid; IA: intra-articular; RR: relative risk; SMD: standardized mean differe

VAS: visual analog scale; WMD: weighted mean difference; WOMAC: Western Ontario and McMaster Osteoarthritis Index 

42
43 

et al., 2005), and Bellamy, Campbell, Robinson, et al. (2006) did not report those results (funnel 

plot asymmetry is later examined in supplementary analyses). 

Summary. The approaches and characteristics of the five study-level meta-analyses provide 

different perspectives of the evidence. Supplementing results by relevant elements of included 

RCTs, the meta-analyses permit broad synthesis of the evidence. 

 Individual Meta-Analyses. Lo, LaValley, McAlindon, et al., 2003. Only pain outcome 

measures were pooled in this meta-analysis. MEDLINE® and Cochrane Controlled Trials 

Registry were searched from 1966 through February 2003, supplemented by hand searches of 

trial bibliographies and abstracts relevant scientific meetings. Randomized single- or doubleblinded, placebo-controlled trials published in English and non-English languages were eligible 

for inclusion. RCTs were included if at least 3 intra-articular hyaluronan injections were 

administered, an intra-articular placebo was used, drop-out rate was less than 50 percent, and 

pain was reported using at least one of following instruments (in order of decreasing 

precedence): 

1. Global knee pain score (VAS or Likert scale) 

2. Knee pain on walking (VAS or Likert scale) 

3. WOMAC Index 

4. Lequesne Index 

5. Knee pain during activities other than walking (VAS or Likert scale). 

From 57 RCTs identified results from 22 were pooled. Because different outcome measures 

were combined, standardized mean differences in change* were pooled—the mean difference in 

pain change from baseline between treated and placebo groups divided by the pooled standard 

deviation. If pain was reported between 2 and 3 months following initial treatment that measure 

was included. Otherwise, pain measures were obtained from assessments occurring between 1 to 

2 and 3 to 4 months. 

Trial quality was characterized by reporting of an intention-to-treat analysis and drop-out 

rates. An intention-to-treat analysis was defined as “(1) it was characterized by its investigators 

as such and there was an attempt to analyze data from all randomized participants, or (2) there 

was no dropout (even if the analysis was not specifically described as intent-to-treat).” When 

intention-to-treat data were not published the authors attempted to obtain it. 

The overall pooled standardized mean difference in change (Table 9) was -0.32 and 

accompanied by significant heterogeneity. 

Table 9. Overall result for pain from Lo, LaValley, McAlindon, et al. (2003) 

Time Week "8–12" 

Standardized Mean Difference (Change) -0.32 

95% CI -0.47 to -0.17 

Heterogeneity (Cochran Q) p<.001 

Trials Included 22 

CI: confidence interval 

 

*

 A standardized effect size for difference in change from baseline. 
44 

When the three RCTs of hylan G-F 20 were excluded, the pooled standardized mean 

difference diminished to -0.19 (95 percent confidence interval (CI): -0.27 to -0.10) with no 

evidence of heterogeneity (Cochran Q p=.58). The authors judged two of these three RCTs 

outliers (Scale, Wobig, and Wolpert, 1994; Wobig, Dickhut, Maier, et al., 1998). With the 

possible exception of hylan G-F 20, there was no indication of an association between product 

molecular weight and effect magnitude. 

The pooled effect estimate from unpublished RCTs (-0.07; 95 percent CI: -0.28 to 0.15) and 

significant the Egger Test (p=.07) were interpreted as supporting publication bias. Nine of the 

RCTs were judged to have attempted an intention-to-treat analysis and three other analyses 

viewed as intention-to-treat owing to complete follow-up. Dropout rates in the pooled studies 

ranged from 0 to 40.3 percent. 

Wang, Chen, Huang, et al., 2004. Pain (with or without activities) and functional outcome 

measures reported by VAS, WOMAC scores, Lequesne Index, or MODEMS (Musculoskeletal 

Outcomes Data Evaluation and Management Scale), and adverse events were pooled. 

MEDLINE®, EMBASE, Cochrane Controlled Trials Registry, and EMBASE were searched 

from 1966 to December 2001 for randomized single- or double-blinded, placebo-controlled 

trials. Hand searching was performed of relevant publications and bibliographies reviewed. 

Unpublished literature was not searched. Only English-language RCTs were considered. 

Reported outcome measures for pain or function were required. From 665 identified articles, 

results from 20 were pooled. Trial quality was appraised using a 28-point checklist developed by 

Downs and Black (1998). 

A single outcome estimated over each trial’s duration was pooled. The measure was 

intended to assess efficacy with respect to pain and functional outcomes—“efficacy scores.” The 

scores were obtained for pain and functional scales by: 

1. Calculating the average difference between each consecutive time point 

2. Dividing the average difference by the time between the those time points 

3. Repeating the calculation for all consecutive time points and summing results. 

The method estimates the area under the “pain intensity difference-versus-time curve.” Finally, 

the estimate is divided by the maximum scale of pain intensity multiplied by the trial duration 

and expressed as percentage—the SPID% or SFID% (sum of pain or functional intensity 

differences as a percentage). Two related estimates were also calculated and pooled as: 

1. Averages: ASPID% and AFID% (sum of pain or functional intensity differences divided by 

the baseline intensity multiplied by trial duration) 

2. Peak differences: Peak PID% and Peak FID% (maximum pain or functional intensity 

differences divided the maximum of the scale). 

Table 10 displays pooled results for activity pain and function. Functional measures were 

pooled separately for hylan G-F 20 and other hyaluronans. 
45 

Table 10. Overall results for pain with activity and function for non-G-F 20 hyaluronans (non-cross-linked) 

from Wang, Chen, Huang, et al. (2004) 

Pain with Activities Function (Non-Cross-Linked) 

Pooled Measure* SPID% ASPID% Peak PID% SFID% ASFID% Peak FID% 

Estimate 7.9% 13.4% 9.9% 5.3% 11.7% 8.2% 

95% CI 4.1 to 11.7 5.5 to 21.3 4.8 to 15.0 2.1 to 8.5 6.3 to 16.2 3.8 to 12.6 

Heterogeneity† 84% (I2

) 83% (I2) 91% (I2) p=.33 (Q) p=.23 (Q) p<.001 (Q) 

Trials included 17 15 16 NR NR NR 

* See text for definitions of Pooled Measures 

† Q reported only for functional measures. I2 calculated from data presented when possible. 

(A)SFID: (adjusted) sum of function index differences; (A)SPID: (adjusted) sum of pain index differences; CI: confidence interval; 

FID; function index differences; PID: pain index differences; 

Pooled estimates were higher for the 3 RCTs of hylan G-F 20 (Dickson and Hosie, 1998 

[later published as Dickson, Hosie, and English, 2001]; Scale, Wobig, and Wolpert, 1994; 

Wobig, Dickhut, Maier, et al., 1998): SPID%, 23.6 percent; ASPID%, 34.8 percent; peak PID%, 

27.1 percent; SFID% 21.9 percent; ASFID%, 38.3 percent; PEAK FID%, 26.8 percent (no 

confidence intervals accompanied estimates). 

Subgroup analyses and meta-regressions were reported for the non-G-F 20 hyaluronans. 

However, results were not always consistent for the three endpoints. Table 11 displays subgroup 

findings reporting a suggested difference only when results were consistent for all three outcome 

measures examined (SPID%, ASPID%, Peak PID%). Qualitative results are displayed because 

these analyses must be considered hypothesis generating. 

Table 11. Subgroup results for non-cross-linked hyaluronans 

Subgroup Result 

Blinding Single > Double* 

Centers Single Center* > Multicenter 

Intention-to-treat analyses ITT Analyses* ? Per Protocol 

Age Mean Age <65* > Mean Age >65* 

Disease stage Less Advanced > Advanced 

Effusion as inclusion criteria Effusion ? No Effusion 

Sample size <100* > >100 

Escape analgesics allowed Not Allowed > Allowed 

Funding Non Industry* > Industry 

* Indicates significant Cochran Q for at least 2 of the 3 outcome measures—i.e., heterogeneity 

in pooled result. 

> indicates effect larger in subgroup; ? inconsistent for the 3 outcome measures 

Significant associations with trial results were found in meta-regressions for: (1) mean 

patient age for ASPID% without activities only; (2) publication year for SPID% functioning; and 

(3) trial quality, mean patient age, and sample size for ASFID% functioning. No association 

between molecular weight and outcome measures was found. Of the 54 regression coefficients 

tested, five were statistically significant. 

Funnel plots using sample size for the ordinate (vertical axis) were not consistent with 

publication bias. The authors commented indirectly on the overall methodologic quality of the 

primary literature stating that allocation concealment was unclear in all RCTs and more high 

quality trials are needed. The mean quality score on the rating system used was 19 points 

(maximum 28) (Downs and Black, 1998, Pendleton, Arden, Dougados, et al., 2000). 
46 

Major adverse events were documented in three of 1002 knees treated with non G-F 20 

hyaluronans (severe swelling, vasculitis, and a hypersensitivity reaction); one patient from 139 

knees treated with hylan G-F 20 experienced an acute painful local reaction. The pooled relative 

risk of minor adverse events for all hyaluronan products was 1.2 (95 percent CI: 1.01 to 1.41). 

Arrich, Piribauer, Mad, et al. (2005). Outcomes examined in this meta-analysis included 

pain at rest and during or after activities (VAS), joint function (WOMAC, Lequesne Index, 

subjective VAS rating, time for 40-meter walk), and adverse events. MEDLINE®, EMBASE, 

CINAHL, BIOSIS, and the Cochrane Controlled Trials Registry were searched from inception 

through April, 2004 for randomized single- or double-blinded, placebo-controlled trials 

published with English or German abstracts. Either pain at rest, during or after movement, joint 

function, or adverse event reporting was required. From 1,159 articles identified 22 were 

included—data from 17 trials reporting pain and/or joint function outcome measures were 

pooled; for adverse events outcomes from the 5 additional trials were included. 

Outcome measures were pooled separately for four time periods: weeks 2 to 6, 10 to 14, 22 

to 30, and 44 to 60. VAS pain was pooled as a weighted mean difference for each period. 

Different functional outcome measurement scales reported required pooling standardized effect 

sizes. Comparative adverse event risk was pooled as a relative risk. Trial quality was 

characterized by adequacy of allocation concealment, use of intention-to-treat analyses, and 

blinding. 

Table 12 displays pooled pain results. 

Table 12. Pooled visual analog scale results for rest and activity pain from Arrich, Piribauer, Mad, 

et al. (2005) 

 Rest During/After Exercise 

Weeks 2–6 2–6 10–14 22–30 

Weighted mean difference VAS (100mm) -8.7 mm -3.8 mm -4.3 mm -7.3 mm 

95% CI -17.2 to -0.2 -9.1 to 1.4 -7.6 to -0.9 -11.8 to -2.4 

 Heterogeneity (I2) 94% 81% 0% 0% 

Trials included 9 9 5 4 

When rest pain measures were pooled from trials not using intention-to-treat analyses or 

when allocation concealment absent or unclear, the weighted mean difference was 15.6 mm 

lower (i.e., greater effect magnitude favoring hyaluronans); in unblinded trials the weighted 

mean difference was 13.6 mm lower (favoring hyaluronans). The large value of I2

 for activity 

pain at 2 to 6 weeks was attributed to Henderson, Smith, Pegley, et al. (1994) in which pain 

increased among those with more advanced disease receiving hyaluronans. Excluding the trial 

diminished I2

 to 20 percent while yielding a similar pooled weighted mean difference (-4.2 mm, 

95 percent CI: -7.5 to -0.8). The authors noted that trial quality did not influence the pooled 

estimates for pain during or after exercise, but only a single trial was judged high quality. 

Pooled results for joint function are displayed in Table 13. Similar to the rest pain results, 

unclear or absent allocation was accompanied by larger effect sizes during the first two time 

periods. 
47 

Table 13. Pooled results joint function from Arrich, Piribauer, Mad, et al. (2005) 

Joint Function 

Weeks 2–6 10–14 22–30 

Standardized mean difference 0.0 -0.11 -0.16 

95% CI -0.23 to 0.23 -0.31 to 0.09 -0.16 to 0.13 

Heterogeneity (I2) 66% 59% 62% 

Trials included 9 7 5 

Sensitivity analyses were performed for all pooled outcomes at weeks 2 to 6 and 10 to 14 

were including only RCTs reporting adequate allocation concealment, blinded outcome 

assessment, and intention-to-treat analyses. According to the report, “[N]o significant effect in 

favour of the intervention” was found. There was no association between molecular weight and 

effect size in meta-regressions. Adverse events, typically minor, were more common with 

hyaluronans than with placebo (pooled relative risk 1.08; 95 percent CI; 1.01 to 1.15). No 

evidence of publication bias was reported using regression methods, except possibly for the 

studies reporting adverse events (publication of trials reporting adverse events was more 

frequent). 

Modawal, Ferrer, Choi, et al., 2005. The meta-analysis pooled only pain outcome measures 

reported on a VAS scale. MEDLINE®, and the Cochrane Controlled Trials Registry were 

searched from 1965 to August, 2004 for randomized double-blind, placebo-controlled Englishlanguage RCTs. Reference lists of included articles and reviews were also searched. From 

1,872 articles identified 9 were included. Studies reporting pain as part of the WOMAC were 

excluded. Pain measures during activity or at rest were extracted and pooled (although which 

studies and at what time periods contributed activity or rest pain measures was not specified). 

The mean difference between treatment and placebo in change from baseline pain was 

pooled for four time periods: weeks 1, 5 to 7, 8 to 12, and 15 to 22. Adverse event rates were not 

summarized. Trial quality was assessed using the method of Chalmers, Smith, Blackburn, et al. 

(1981) (maximum score of 1.0)—those scoring 0.75 or lower were considered low quality. 

Table 14 displays the pooled results. 

Table 14. Pooled visual analog scale pain change from Modawal, Ferrer, Choi, et al. (2005) 

Pain with activity or rest 

Weeks 1 5–7 8–12 15–22 

Weighted mean difference VAS change (100mm) -4.4 mm -17.6 mm -18.1 mm -4.4 mm 

95% CI -7.2 to -1.1 -28.0 to -7.5 -29.9 to -6.3 -24.1 to 15.3 

 Heterogeneity (I2*) 92% 92% 95% 94% 

Trials Included 9 6 6 3 

* I2 calculated from Q and accompanying df (degrees of freedom). 

Heterogeneity examined with Galbraith plots was consistent with the I2 values calculated. 

Excluding the four low-quality trials diminished the pooled effect magnitudes considerably 

(Table 15). 
48 

Table 15. Pooled visual analog scale pain change for high-quality RCTs from Modawal, Ferrer, Choi, 

et al. (2005) 

Pain with activity or rest 

Weeks 1 5–7 8–12 15–22 

Weighted Mean Difference VAS Change (100mm) 1.0 mm -7.2 mm -7.1 mm -4.4 mm 

95% CI -1.2 to 3.2 -12.0 to -2.4 -11.3 to -3.0 -24.1 to 15.3 

 Heterogeneity (I2*) 83% 0 9% 94% 

Trials Included 7 2 6 3 

* I2 calculated from Q and accompanying df (degrees of freedom). 

In meta-regressions, trial quality and hylan G-F 20 were associated with significantly better 

outcomes at 5 to 7 and 8 to 12 weeks; poor trial quality was associated better outcomes at other 

time periods although statistically significant only at week 1. Potential publication bias was 

assessed using Egger test (p=.096) (time period not specified) which the authors stated was “not 

statistically significant...suggesting that there is no publication bias.” 

Bellamy, Campbell, Robinson, et al., 2006.*

 Outcomes examined relevant to our protocol 

included pain at rest and with activity, WOMAC function, Lequesne Index, patient global 

assessment, and adverse events. The literature search included MEDLINE® (to the first week of 

January 2006); EMBASE, PREMEDLINE, and Current Contents to July 2003; the Cochrane 

Central Register of Controlled Trials; specialized journals and reference lists of identified 

randomized controlled trials; and pertinent review articles to December 2005. Single- or doubleblinded randomized controlled trials with placebo or other comparators were eligible; no 

language restrictions were imposed. From 76 trials identified, 32 in the meta-analysis were 

placebo-controlled comparisons. Outcome measures from 30 RCTs were pooled in some 

manner. Trial quality was assessed using the Jadad scale (Jadad, 1996). 

Outcome measures were pooled separately for four time periods: weeks 1 to 4, 5 to 13, 14 to 

26, and 45 to 52. Unadjusted post-test scores were pooled (Bellamy, Campbell, Robinson, et al., 

2006; page 5)—the difference between treatment and placebo at follow-up. VAS pain and 

Lequesne Index scores were pooled as weighted mean differences; WOMAC pain and function 

as standardized mean differences; patient global assessment and adverse events as relative risks. 

Both by-product and by-class results were reported. While Bellamy, Campbell, Robinson, et 

al. (2006) emphasize the by-product results, we focus on by-class results for both clinical and 

methodologic reasons. Rationale for by-product results is based on the premise that “...these 

products differ in their MW [molecular weight], concentration, treatment schedules, and mode of 

production...” However, with the exception of hylan G-F 20, none of the preceding metaanalyses found outcomes differing by molecular weight. Thus, there is potential for spurious 

subgroup findings with multiple individual product analyses. Of the more than 850 forest plots 

presented, only 38 combine results from more than 3 trials. Accordingly, we focus on by-class 

results. 

Table 16 displays pooled results for VAS pain at rest and with weight-bearing comparing 

hyaluronans to placebo.†

 

 

*

 As of this writing, this review has been re-issued as a 627-page version, Bellamy, Campbell, Robinson, et al., (2007) without an 

updated literature review. The date of the most recent substantive amendment is the same in both documents—February 21, 

2006. 

†

 One trial included in these pooled results (Wobig, Bach, Beks, et al., 1999) was not strictly a placebo comparison. However, 

removing it did not alter any result materially when results were replicated.
49 

Table 16. Pooled visual analog scale results for rest and weight-bearing pain from Bellamy, Campbell, 

Robinson, et al. (2006) 

Rest Weight-Bearing Weeks 1–4 1–4 5–13 14–26 45–52 

Weighted mean difference VAS (100mm) -3.5 mm -7.7 mm -13.0 mm -9.0 mm -2.6 mm 

95% CI -9.2 to 2.1 -11.3 to -4.1 -17.8 to -8.2 -14.8 to -3.2 -7.4 to 2.2 

 Heterogeneity (I2) 80% 80% 82% 77% 0% 

Trials included 9 20 16 8 3 

The magnitude of pooled effect estimate was greatest at 5 to 13 weeks and lower thereafter—

the critical caveat being that trials and outcome measures from different patients were pooled at 

different periods. The degree of heterogeneity among trials was large at all periods except weeks 

45 to 52 where only 3 trials were included. 

WOMAC pain was pooled as a standardized mean difference because different pain scale 

metrics were used as allowed in the instrument (Table 17). 

Table 17. Pooled Western Ontario and McMaster Osteoarthritis Index pain results from Bellamy, Campbell, 

Robinson, et al. (2006) 

 WOMAC Pain 

Weeks 1–4 5–13 14–26 

Standardized mean difference -1.2 -1.0 -1.0 

95% CI -1.9 to -0.5 -1.6 to -0.5 -1.8 to -0.3 

 Heterogeneity (I2) 88% 88% 80% 

Trials included 6 6 3 

Pooled standardized mean differences were lower than -1.0 during each period and 

magnitudes appeared similar over time. Heterogeneity among trials was large (I2 values 80 to 88 

percent). 

Pooled WOMAC function standardized mean differences (Table 18) were similar to the 

WOMAC pain results. 

Table 18. Pooled Western Ontario and McMaster Osteoarthritis Index function results from Bellamy, 

Campbell, Robinson, et al. (2006) 

 WOMAC Physical Function 

Weeks 1–4 5–13 14–26 

Standardized mean difference -1.0 -0.9 -0.8 

95% CI -1.6 to -0.4 -1.3 to -0.4 -1.4 to -0.2 

 Heterogeneity (I2) 85% 84% 70% 

Trials included 6 6 3 

Lequesne Index (pain and function composite ranging 0 to 24) scores were pooled from up to 

five trials for the four time periods (Table 19). 

Table 19. Pooled Lequesne Index results from Bellamy, Campbell, Robinson, et al. (2006) 

 Lequesne Index 

Weeks 1–4 5–13 14–26 45–52 

Weighted Mean Difference -0.8 -1.4 -0.1 -1.1 

95% CI -1.5 to -0.2 -2.0 to -0.7 -0.8 to 0.9 -2.7 to 0.5 

 Heterogeneity (I2) 44% 16% 6% NA 

Trials Included 5 4 3 1 
50 

There was less heterogeneity than for the WOMAC results. However, estimates at 1 to 4 and 

5 to 13 weeks included results from 40 patients twice in the trial finding the largest benefit 

(Carrabba, Paresce, Angelini et al., 1995). 

Patient global assessment was pooled as the relative risk of improvement (Table 20). 

Table 20. Pooled global assessment results from Bellamy, Campbell, Robinson, et al. (2006) 

 Patient Global Assessment 

Weeks 1–4 5–13 14–26 45–52 

Relative risk of improvement 1.1 1.1 1.0 1.0 

95% CI 0.9 to 1.4 0.9 to 1.4 0.7 to 1.5 0.8 to 1.2 

 Heterogeneity (I2) 58% 60% 70% 30% 

Trials included 5 6 4 2 

 Although lower than in previous results, heterogeneity was still generally high. There was no 

evidence that patient-reported global improvement differed with treatment during any time 

period—all relative risks were indistinguishable from unity 

While few studies reported responder rates from intention-to-treat analyses, Bellamy, 

Campbell, Robinson, et al. (2006) reported number needed to treat (NNT) for some outcomes 

(Table 21). They varied in both magnitude and direction (negative indicates placebo better). 

Only NNTs derived from Altman, Akermark, Beaulieu, et al. (2004), and possibly Brandt, Block, 

Michalski, et al. (2001) are well anchored to response defined by attaining some minimal 

clinically important improvement. 

The systematic review did not directly examine any potential relationship between product 

molecular weight and efficacy. However, results from studies of hylan G-F 20 were separately 

analyzed. At 5 to 13 weeks, the pooled weighted mean difference in VAS measured pain from 

four trials was -22.5 mm (95 percent CI: -35.2 to -9.7; I2 = 82.9%). One trial included in the 

estimate was not strictly a placebo comparison (Wobig, Dickhut, Maier, et al., 1998). 

Potential publication bias was not analyzed although discussed: “In an attempt to address 

potential publication bias, we have searched abstract books, as well as published manuscripts, 

corresponded with manufacturers, and contacted investigators in the search for additional 

information or unpublished studies” (Bellamy, Campbell, Robinson, et al., 2006; page 46). 

Sensitivity analyses or meta-regressions exploring heterogeneity of pooled estimates were not 

reported. Mean trial quality on the Jadad scale was 3.7 (range 2 to 5). 

The pooled relative risk of local reactions for hylan G-F 20 (5 trials) was 1.9 (95 percent CI: 

0.51 to 7.3, 5 trials) and other hyaluronans 1.6 (95% CI: 0.54 to 5.6, 5 trials). Adverse events 

were otherwise reported primarily as relative risks from individual trials. 

Strand, Conaghan, Lohmander, et al., 2006. Strand, Conaghan, Lohmander, et al. (2006) 

conducted a patient-level meta-analysis for a single outcome—the Lequesne Index. Patient data 

(N=1,155) were obtained from five double-blind placebo-controlled randomized controlled trials 

included in a premarketing approval application for Supartz® (18 trials were included in the 

application). The five trials were conducted in Germany, Sweden, U.K., France, and Australia. 

Three have been published (Day, Brooks, Conaghan, et al., 2004; Puhl, Bernau, Greiling, et al., 

1993; Lohmander, Dalen, Englund, et al., 1996). 
51 

Table 21. Numbers needed to treat for various outcomes from Bellamy, Campbell, Robinson, et al. (2006) 

Trial Weeks NNT 

Number of Patients Improved 

1–4 100 

Lohmander et al., 1996 5–13 Infinity 

14–26 7.1 

Shichikawa et al., 1983a (5-week trial) 1–4 5 

Shichikawa et al., 1983b (5-week trial) 1–4 11 

Puhl et al., 1993 5–13 10 

Brandt et al., 2001 14–26 20 

 Number of Patient Clinical Failures

14–26 11 Karlsson et al., 2002 

45–52 6.7 

 WOMAC Pain 40% Relative; 5-point Absolute (20-point scale) 

1–4 14 

Altman et al., 2004 5–13 -33* 

14–26 -33* 

 WOMAC Pain >5-point Improvement (20-point scale)

Brandt et al., 2001 >5-Point 14–26 5.9 

 Patient Global Assessment (Number Improved)

Corrado et al., 1995 1–4 -2.3 

Creamer et al., 1994 1–4 11.1 

Sala et al., 1995 1–4 -6.7 

Corrado et al., 1995 5–13 -10 

Sala et al., 1995 5–13 -2.9 

Henderson et al., 1994 14–26 25 

Huskisson et al., 1999 14–26 -3.1 

* Sign incorrectly reported in Bellamy, Campbell, Robinson, et al. (2006, page 194; 

2007, page 194) 

Participants received three to five weekly intra-articular hyaluronan or placebo injections and 

were followed at least 3 months. They were assessed at weeks 5 and 13 in all trials, week 9 in 

four, and weeks 17, 20, and/or 25 in three trials. Four trials included individuals aged 40 years 

and older; the other aged 50 years and older (Lohmander, Dalen, Englund, et al., 1996). 

Lequesne Index score was the primary outcome in three RCTs. Intention-to-treat analyses were 

used and missing data imputed by carrying the last observation forward. Both fixed- and 

random-effects models were examined. Trial quality was assessed by Jadad scale. 

Analyses included 1,155 participants (619 treated, 536 placebo). Dropout rates were 10.2 

and 14.6 percent in treated and placebo arms respectively. The highest drop out rates occurred in 

the unpublished U.K. trial—28.3 and 40.9 percent in hyaluronan and placebo groups. No 

significant baseline differences were noted within the overall sample. 

Longitudinal mixed-effects models (random effects) were fitted to the data with some 

differences between the fixed- and random-effects models. In both, a significant treatment effect 

was seen; the treatment by time interaction was not significant in the fixed-effects model and 

reached p=.06 in the random effects one. 

In a fixed-effects model the mean improvement in Lequesne Index was -2.74 and -2.16 in the 

placebo group (difference of -0.58, 95 percent CI: -0.95 to -0.20); in a random-effects model -

2.68 and -2.00 (difference of -0.68, 95 percent CI: -0.79 to -0.56). When analyses were 
52 

conducted for individual trials, treatment effects were statistically significant in two. Results 

were sensitive to model specification in two trials. For one, (Puhl, Bernau, Greiling, et al., 1993) 

the fitted mixed-effects model showed no treatment difference (p=.55), while the original 

publication reported a statistically significant difference in Lequesne Index scores at the end of 

follow-up (p=.005 at 14 weeks). No participant-level random-effects models were examined. 

Adverse events were noted in 1.8 and 3.2 percent of the hyaluronan and placebo groups. 

Trials Not Pooled or Included in Meta-Analyses. Two RCTs identified by Bellamy, 

Campbell, Robinson, et al. (2006) were not pooled—one trial of a non-animal stabilized 

hyaluronan (NASHA) (Altman, Akermark, Beaulieu, et al., 2004) and the other Neustadt, 

Caldwell, Burnette, et al. (2005) (see Appendix C*, Tables IB–IG). These RCTs were not 

included in other meta-analyses owing to recent publication dates. 

Altman, Akermark, Beaulieu, et al., 2004. The trial randomized 347 participants in a 

placebo-controlled double-blind 26-week multicenter trial across 18 sites in the United States, 

Canada, and Sweden. Treatment and placebo groups were comparable at baseline. Mean 

participant age was approximately 63 years; 55 percent were female; and 35 percent had prior 

knee surgery; knees with Kellgren-Lawrence radiographic grades 2 to 4 were enrolled. A single 

NASHA (60 mg) or saline placebo injection was administered to 172 or 174 participants, 

respectively. The primary outcome was response defined as a reduction in WOMAC pain score 

(20-point scale) >40 percent with an absolute 5-point improvement. Following the baseline 

exam, participants were assessed at weeks 2, 6, 13, and 26. 

Trial quality was rated “good.” There were no differences in response rates between 

treatment and placebo arms at any of the time points examined in either intention-to-treat or per 

protocol analyses. In a post-hoc analysis of the subgroup with only knee OA (62 percent), a 

significant difference was found at week 6 (42.1 versus 27.5 percent) but at no other time point. 

This trial used clearly defined responder criteria (Dougados, Nguyen, Listrat, et al., 2000) 

and found no evidence for a beneficial effect of NASHA. The post-hoc subgroup finding of a 

single difference was inconsistent with the overall result. 

Neustadt, Caldwell, Burnette, et al., 2005. At 24 sites in the United States and Canada, 372 

participants were randomized in a placebo-controlled, double-blind, 22-week trial. Treatment 

and placebo groups were comparable at baseline. The mean age of participants was 60 years; 52 

percent were female; those with Kellgren-Lawrence radiographic grades 2 to 3 were enrolled. 

The trial had three arms with four weekly intra-articular injections: (1) four hyaluronan 

injections, (2) three hyaluronan injections followed by arthrocentesis, and (3) four 

arthrocenteses. The primary outcome was response defined as a 20 percent relative and a 50-mm 

absolute improvement on WOMAC pain at weeks 8, 12, 16, and 22. Baseline characteristics of 

the intention-to-treat sample were not reported, only those of the “evaluable population.” This 

subgroup was defined as participants receiving all four injections, attending at least one followup visit, and without protocol deviation (n=336 or 90 percent of those randomized). Intention-totreat analyses were not reported. 

Trial quality was rated “fair.” In the “evaluable population,” there were no statistically 

significant differences in WOMAC pain at any time point. Greater improvement in patient 

global assessment was evident at weeks 8 through 16 in the four hyaluronan injection group 

compared to the other two groups. No difference was evident between the arthrocentesis and 

three hyaluronan injection arms. The primary responder outcome was not reported for the 

“evaluable population.” 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
53 

An “evaluable subgroup” with Kellgren-Lawrence grade 2 or 3 and contralateral knee 

WOMAC pain <150 mm (500 mm scale) was next analyzed (n=294, 79 percent of those 

randomized). When response was defined as a 20 percent improvement alone (not the primary 

specified outcome measure) the 4 hyaluronan injection group was superior to placebo at week 8 

(76 versus 62 percent, p=0.035), but at no other time point. The three hyaluronan injection group 

was not superior to placebo. Further post-hoc subgroup analyses examined 40 and 50 percent 

improvement response criteria finding higher response 40 percent response rates with four 

hyaluronan injections compared to placebo at all time points. 

The trial did not demonstrate benefit for the primary efficacy outcome and intention-to-treat 

analyses were not reported. A single statistically significant responder result was found 

examining two subgroups. Subgroups were apparently defined post-hoc and not analyzed 

according to the primary efficacy outcome.*

 

Trials Not Included in Any Meta-Analyses. Rolf, Engstrom, Ohrvik, et al., 2005. This 

double-blind placebo-controlled trial conducted at two centers in Sweden randomized 272 

participants aged 35 years and older (Appendix C†

, Tables IA-IG) with: 

1. Primarily unilateral OA of the knee 

2. Outerbridge grades I through III by arthroscopy performed more than 6 months before entry 

3. Pain >40 mm with walking, climbing or descending stairs, or weight bearing. 

Mean participant age was approximately 54 years; 40 percent were female; 39 percent had 

prior partial meniscectomies and 7 prior knee surgery; 43 percent of knees were classified 

Ahlback grade 0 and 64 percent grade 0 or 1. The trial included three arms: hylan G-F 20, 25 mg 

hyaluronan, or placebo (buffered saline) each administered once weekly for three weeks. 

Baseline characteristics in the three arms were comparable; two participants were nonCaucasian. Following the initial examination, participants were assessed at weeks 6, 12, 18, 26, 

38, and 52. The primary efficacy outcome was VAS pain during walking, stair climbing, or 

weight-bearing with the previous assessment provided to the subject. Response was defined 

being symptom free (VAS <20 mm) at week 26. Among secondary outcomes were Lequesne 

Index and patient assessment of overall response. Intention-to-treat analyses were performed 

without adjustments for multiple comparisons. 

Trial quality was rated “good.” At 26 weeks, 44 percent of the hylan G-F 20 arm were 

classified as responders compared to 30 percent in the placebo arm (p=.048) and 43 percent of 

the hyaluronan arm.‡

 Response rates were generally higher with active treatment at all time 

points, but other comparisons not statistically significant. There were no differences between 

arms in patient assessed overall treatment response (proportions reporting very good or good in 

the hylan G-F 20, hyaluronan, and placebo arms being 58, 62, and 52 percent respectively). At 

26 weeks the decrease in stiffness score was greater in hyaluronan compared to hylan G-F 20 

arm (-18.1 versus -10.5 mm, p=.015) and -13.7 mm in the placebo arm. No differences were 

 

*

 The potentially problematic nature of subgroups analyses is illustrated nicely in the subgroup analyses by Lohmander, Dalen, 

Englund, et al. (1996), followed by Karlsson, Sjogren and Lohmander (2002), as discussed in Results, Part I, Key Question 3 

(Subgroup Analyses). 

† Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm

‡

 P-values not reported were not calculable from data provided because a logistic regression model was employed including a 

parameter for center and possible center by treatment interaction.
54 

found for “the majority of other efficacy parameters...” including Lequesne Index. Adverse 

events were reported in 59 percent of the hylan G-F 20 arm, 60 percent of the hyaluronan arm 

and placebo arms (Appendix C*

, Table IH). Arthropathy was more frequent with the hyaluronan 

preparation (10 percent) compared to either hylan G-F 20 or placebo (3 percent each). 

This trial enrolled a young predominantly male sample with a goal to “halt the progression of 

early-stage chondral pathology to end-stage OA disease.” At 26 weeks, response to hylan G-F 

20 was significantly better than placebo, but there were few significant results among the many 

examined and no adjustment for multiple comparisons. 

Adverse Events 

Adverse event profiles reported in individual trials are shown in Appendix C*, Table IH, but 

were not consistent across trials. The most frequently reported events were local in nature 

including injection site pain or infection and local joint pain and swelling. When reported, 

adverse events appeared generally similar in frequency with either intra-articular hyaluronan or 

placebo. 

The meta-analyses examining adverse events described small relative increased risk. Wang, 

Chen, Huang, et al. (2004) reported a pooled relative risk for minor events of 1.2 (95 percent CI: 

1.01 to 1.41) and Arrich, Piribauer, Mad, et al. (2005) 1.08 (95 percent CI; 1.01 to 1.15). 

Bellamy, Campbell, Robinson, et al. (2006) estimated a pooled relative risk for local reactions 

accompanying hylan G-F 20 (five RCTs) of 1.9 (95 percent CI: 0.51 to 7.3, five RCTs) and other 

hyaluronans (5 RCTs) of 1.6 (95 percent CI: 0.54 to 5.6). 

Six articles or abstracts were identified addressing adverse event occurrence. Hamburger, 

Lakhanpal, Mooar, et al. (2003) reviewed hyaluronan product safety profiles from a MEDLINE®

search through July 2002 and the FDA Manufacturer and Device Experience Database 

(MAUDE).† The review noted rare occurrence of serious reactions to both Hyalgan® and hylan 

G-F 20. 

Waddell (2003) described adverse event rate accompanying hylan G-F 20 from a 

retrospective review in a single clinical practice. He reported a local adverse event rate of 2.1 

percent (82/3,931) per injection—1 percent (34/3,367) for those receiving a single course and 8.5 

percent (48/564) accompanying a second course. 

Maheu and Bonvarlet (2003) surveyed French rheumatologists to explore the occurrence of 

acute pseudoseptic arthritis post-hyaluronan injection—a severe hyaluronan-related adverse 

event reportedly uncommon. A questionnaire was sent to 81 rheumatologists of whom 26 

responded. Sixteen reported 33 cases or pseudoseptic arthritis, possibly more frequently 

associated hylan G-F 20. The authors concluded acute pseudoseptic arthritis is “not so rare.” 

Limitations of the survey included the absence of a denominator to quantify risk and the low 

survey response rate.‡

 

Kemper, Gebhardt, Meng, et al. (2005) reported a 5.3 percent adverse event rate 

accompanying hylan G-F 20 injections in 4,253 patients. Arthropathy was most common 

occurring in 3.1 percent of patients. The most severe event reported was a large effusion and 

synovitis in one patient. Those with previous hyaluronan treatments had a two-fold increased 

risk of adverse events. Lussier, Cividino, McFarlane, et al. (1996) reported adverse events 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm 

† Dr. Hamburger was a paid consultant to Sanofi-Synthelabo, manufacturer of Hyalgan®.

‡ The survey, funded by Forest Pharmaceuticals, was not subsequently published.
55 

among 336 patients receiving 1,537 injections of hylan G-F 20. Local adverse events occurred at 

a rate of 2.7 percent per injection and in 1 of 12 patients. 

Finally, a search of MAUDE for hyaluronan products (code MOZ) from January 1, 2005 

through January 1, 2007 identified 236 records reporting adverse events following knee 

injection. Nine reports mentioned pseudosepsis or pseudoseptic reaction—four associated with 

Synvisc® (hylan G-F 20), one with Euflexxa©, and four with Hyalgan®. In 85 adverse events 

patients were hospitalized. 

Generally, severe adverse events associated with hyaluronan-based products have been 

reported as uncommon in trials. In contrast, local minor adverse events appear common, 

although the risk appears not substantially different compared to placebo injection. The true risk 

of pseudoseptic reactions may be small, but one study suggests they could be more common than 

generally thought. 

Supplementary Analyses Performed by the Evidence-Based 

Practice Center 

We performed supplementary analyses to address three key issues: 

1. Heterogeneity—clinical and statistical 

2. Publication bias 

3. Hylan G-F 20. 

The majority of these analyses rely upon data abstracted by Bellamy, Campbell, Robinson, et 

al. (2006) which included the largest number of trials. However, trial quality ratings we 

performed and cited throughout this reported were used for all analyses. 

Clinical and Statistical Heterogeneity/Sensitivity Analyses. All study-level meta-analyses 

found high heterogeneity and appropriately employed random effects models. Four of the five 

identified hylan G-F 20 and trial quality issues as factors affecting pooled estimates. Using posttest VAS pain as the outcome at 5-13 weeks (Bellamy, Campbell, Robinson et al. 2006, 

Comparison 50, 16 pooled studies), we performed sensitivity analyses exploring factors 

suggested by the meta-analyses and our own review of evidence: 

• Trial quality (good/fair versus poor)*

• Hylan G-F 20 versus other hyaluronans 

• Sample size (<100 or >100) or reported power calculations (these attributes were correlated; 

differences according to sample size was found to explain more heterogeneity) 

• Industry involvement 

 

* Note, these were our trial quality ratings, not those performed by Bellamy, Campbell, Robinson, et al. (2006)
56 

• Use of rescue analgesia 

• Primary intention-to-treat analyses.*

The sensitivity of results to the trial characteristics was examined by fitting random effects 

models to subgroups and in meta-regressions. From subgroup analyses, Table 22 shows 

estimated effects were highly sensitive to study quality, use of hylan G-F 20, sample size, power 

calculations, and use of rescue analgesics but not industry involvement or primary intention-totreat analyses. However, heterogeneity remained high in almost all subgroups. 

Table 22. Results of sensitivity analyses for Bellamy, Campbell, Robinson, et al. (2006) 5–13 week pain 

 Random-Effects Model* 

Study or Sample 

Characteristic 

WMD VAS 

100 mm 

 

95% CI 

 

I

2

Study Good/Fair -8.8 -12.4 to -5.2 61.0% 

Quality Poor -23.2 -37.2 to -9.3 89.7% 

G-F 20 -20.8 -31.3 to -10.4 83.8% Hylan Others -9.3 -13.4 to -5.1 68.3% 

Sample < 100 -17.0 -20.8 to -13.2 26.3% 

Size > 100 -7.3 -14.6 to 0.4 89.2% 

Yes -12.8 -18.8 to -6.8 84.6% ITT 

No -13.5 -22.1 to -4.9 80.2% 

Power Yes -9.1 -16.5 to -1.8 86.5% 

Calculation No -16.2 -22.7 to -9.8 78.5% 

Rescue Yes -11.4 -16.3 to -6.6 82.5% 

Analgesia No -24.2 -34.6 to -13.7 38.1% 

Industry Yes -12.9 -18.5 to -7.3 85.4% 

Involvement No -13.7 -18.4 to -9.0 0.0%* 

*A fixed-effects model. 

Add P-values 

 Characteristics found to influence results next examined in a hierarchical Bayes linear model 

(DuMouchel, 1994) with a vague prior for τ

2† specified. Study quality and hylan G-F 20 were 

retained in the model based on these findings and conclusions from the meta-analyses. Of the 

remaining attributes, only sample size was found independent and statistically significant.‡

 In 

the model including study quality, use of hylan G-F 20, and sample size all were statistically 

significant (respective probabilities of .006, .049, and .01) and between-study variability in the 

model (τ

2

) was reduced by 38 percent. In the model pooled weighted mean differences in VAS 

pain varied from -3.0 mm (good/fair study quality, non G-F 20 hyaluronan, sample size >100) to 

-29.6 mm (poor study quality, hylan G-F 20, sample size <100). 

 Although analyses must be considered exploratory, in subgroup analyses and metaregressions results were sensitive to study characteristics and use of hylan G-F 20. Industry 

involvement had no effect on pooled estimates. While the use of rescue analgesia in subgroup 

analyses influenced results, it was not independent of study quality and use of hylan G-F 20 and 

 

* Is not independent of study quality ratings.

† τ2

 is a measure of between-trial heterogeneity. 

‡

 Metaregressions were replicated using STATA Version 9 metareg with consistent results—nearly identical point estimates, but 

not unexpectedly somewhat different confidence intervals and p-values. 
57 

only three trials did not allow rescue analgesia. Study quality, hylan G-F 20, and sample size 

were independently associated with the trial effects explaining a sizeable proportion of betweenstudy variability. 

Publication Bias. Three findings suggest the presence of publication bias: 

 

1. Funnel plot asymmetry 

2. Small trial bias 

3. Unpublished trials. 

 Funnel Plot Asymmetry. Two meta-analyses found funnel plot asymmetry (Lo, LaValley, 

McAlindon, et al., 2003; Modawal, Ferrer, Choi, et al., 2005); using sample size as the ordinate 

Wang, Chen, Huang, et al., (2004) suggested no evidence of asymmetry. Arrich, Piribauer, Mad, 

et al. (2005) found no evidence of publication bias while Bellamy, Campbell, Robinson et al. 

(2006) did not report examining potential publication bias. 

Funnel plots constructed with precision as the ordinate using data from Wang, Chen, Huang, 

et al. (2004) showed asymmetry for SPID% (p=0.038) and peak PID% (p=.015) although not for 

ASPID% (p=.56) which as an average measure could be anticipated.*

 In Bellamy, Campbell, 

Robinson et al. (2006), Egger tests calculated for pooled VAS pain at rest, 1 to 4 weeks, 5 to 13 

weeks, and 14 to 26 weeks yielded p-values of .9, <.001, .017, and .086, respectively.† While 

other factors could explain these test results (Lau, Ioannidis, Terrin, et al., 2006) those reported 

in the meta-analyses and those we performed are consistent with publication bias. 

 Small Trial Bias. An apparent small trial bias was noted by Wang, Chen, Huang, et al. 

(2004) and shown in our sensitivity analyses. The average size of trials reporting sample size 

calculations was 204 compared to 60 for those without. The effect magnitude in clearly 

adequately powered trials was 44 percent lower than in those not reporting sample size 

calculations—consistent with concluding positive underpowered studies were more often 

published than negative ones. 

 Unpublished Trials. A substantive body of unpublished literature including large trials exists 

(OAK9801, France 1995, UK 1996, Hizmetli, Kocagil, Kaptanoglu, et al.)—15.5 percent of all 

participants were included in studies unreported in either manuscript or abstract form; 9.7 

percent included in abstracts not subsequently published (Table 4). This size of this body of 

evidence is consistent with potential publication bias. 

 Hylan G-F 20. The five study-level meta-analysis suggested hylan G-F 20 has greater 

effects than other hyaluronans. To extend results from the meta-analyses and explore how the 

potential effect of hylan G-F 20 might differ, we examined pooled trial results further. 

Pooling. Eight trials of hylan G-F 20 assessed outcome measures at different time points 

using different instruments (Cubukcu, Ardic, Karabulut, et al., 2004; Dickson, Hosie, and 

English, 2001; Karlsson, Sjogren, and Lohmander, 2002; Kotevoglu, Iyibozkurt, Hiz, et al., 

2006; Moreland, Arnold, Saway, et al., 1993; Rolf, Engstrom, Ohrvik, et al., 2005; Scale, Wobig, 

and Wolpert, 1994; Wobig, Dickhut, Maier, et al., 1998). For consistency and to allow 

 

*

 Funnel plots for pooled functional outcome measures could not be replicated as trial-level data were not provided in the metaanalysis. 

†

 Only three studies were pooled at 45 to 52 weeks and a result was not calculated.
58 

comparison with other meta-analyses, we adopted the general approach taken by Bellamy, 

Campbell, Robinson, et al. (2006) pooling weighted mean differences between treatment and 

placebo arms at follow-up. Data extracted by Bellamy, Campbell, Robinson, et al. (2006) at 5 to 

13 weeks post-injection (near the time of maximum anticipated benefit) were used. 

Results from two trials could not be included in the pooled result. Follow-up in the 

Moreland, Arnold, Saway, et al. (1993) trial was limited to four weeks. Rolf, Engstrom, Ohrvik, 

et al. (2005) did not report a pain outcome measure amenable to pooling with the other trials. 

Five of the remaining six RCTs reported pain on a VAS scale (Dickson, Hosie, and English, 

[2001] as part of WOMAC 100-mm VAS). Cubukcu et al. (2006) assessed WOMAC pain on a 

20 point scale (which we rescaled to 100 for pooling). From Karlsson, Sjogren, and Lohmander 

(2002) only the hylan G-F 20 and placebo arms were included. Random-effects models were 

fitted in all but one instance due to heterogeneity. 

Results. Trial quality was rated as either “poor” (n=3) or “fair” (n=3). Intention-to-treat 

analyses were conducted three trials. Two trials reported no dropouts (Appendix C*

 Table IC), 

three between 24 and 29 percent, the dropout rate was not reported in one (Scale, Wobig, and 

Wolpert, 1994). Five trials were double blinded and one unblinded. 

Figure 4 displays the forest plot including six trials for pain at 5 to 13 weeks (WMD: -20.2 

mm, 95% CI: -29.5 to -10.9; random effects model, I2

 = 82 percent, Egger test p=0.76). Because 

of the notably larger effect magnitudes of the Scale, Wobig, and Wolpert, (1994) and Wobig, 

Dickhut, Maier, et al. (1998) trials, results were also pooled separately for the two trials and the 

remaining four. There was no evidence of heterogeneity in these two subgroups (I2 = 0, and 16 

percent respectively) and fixed effects models were fitted. The disparity between these 

subgroups is substantial. The Scale, Wobig, and Wolpert, (1994) and Wobig, Dickhut, Maier, et 

al., (1998) were pooled in four of the study-level meta-analyses and both rated of “poor” quality 

due to baseline imbalances and not accounting for covariate imbalances. 

These results can be summarized as follows: 

1. The pooled effect magnitude from the available hylan G-F 20 RCTs appears larger than for 

other hyaluronans. 

2. Due to trial quality, drop-out rates, heterogeneity, considerably larger effects in the Wobig, 

Dickhut, Maier, et al. (1998) and Scale, Wobig, and Wolpert (1994), and between-trial 

variability, the pooled effect estimate must be considered accompanied by greater uncertainty 

than reflected in the confidence interval. 

Summary and Appraisal 

 Table 23 displays results from the five study-level analyses for pain reduction compared to 

placebo nearest 8 to 12 weeks (the time of anticipated maximum effect). Although pooled 

results across meta-analyses are not directly comparable due to differing effect measures and 

trials pooled, each found a positive statistically significant overall effect. Pooled results from 

better quality trials were lower in magnitude (the result of Arrich, Piribauer, Mad, et al. (2005) 

was based on a single trial). Trials of hylan G-F 20 reported larger effects as did small size 

trials. 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
59 

Figure 4. Forest plot of hylan G-F 20 studies reporting VAS pain at 5 to 13 weeks—weight-bearing or 

WOMAC (95% confidence intervals) 

Weighted Mean Difference (VAS Pain)

-50 -40 -30 -20 -10 0 10

Pooled (Random Effects Model)

 

Kotevoglu 2005

Cubukcu 2004

Karlsson 2002

Dickson 2001

Wobig 1998

Scale 1994 (3 inj)

Scale 1994 (2 inj)

Kotevoglu 2005, Dickson 2001, 

Karlsson 2002, Cubucko 2004; 

Fixed Effects Model

Scale 1994, 

Wobig 1998;

Fixed Effects Model

*

* Pain in Cubukcu et al. (2004), reported on a 20 point scale was rescaled to 100 for these analyses.

 Drawing conclusions requires considering the clinical meaning of pooled results, strengths 

and limitations of the meta-analysis and trial evidence, heterogeneity in pooled results, potential 

publication bias, and the uncertainty contributed by each. 

Clinical Meaning. Important effects, regardless of statistical considerations, must be 

accompanied by a minimal clinically important improvement patients can identify. While the 

amount of improvement required may not be definitively established (Tubach, Ravaud, Baron et 

al., 2005; Pham, van der Heijde, Altman, et al., 2004), between 20 and 40 percent improvements 

have been used in recent hyaluronan trials (Nuestadt, Caldwell, Burnette, et al., 2005, Altman, 

Akermark, Beaulieu, et al., 2004). In this respect, pooled results from the meta-analyses are 

limited due to a primary literature not generally reporting results quantifying proportions 

responding or achieving likely minimal clinically important improvements for the various 

outcome measures. Few trials reported response rates and an insufficient number from which to 

draw conclusions or to combine. 
Table 23. Summary pain result closest to 8–12 weeks and key characteristics of study-level viscosupplementation meta-analyse

Lo et al., 

2003 

Wang et al., 

2004 

Arrich et al., 

2005 

Modawal et a

2005 

Trials pooled at 8-12 weeks 22 20 5 6 Sample size: mean (range)

*

134 (24-108) 117 (12-347) 250 (49-408) 181 (80-347

Total patients 2,927 2,345 1,251 1086 Pooled pain outcome cited† Hierarchy‡ With/without Activities During or After Exercise During Activity or Comparison/Effect Measure 

Difference in Change

(standardized) 

(effect size)

Differences

(in pain intensity summed) 

 (0-100%)

Difference 

(at follow-up) 

(mm VAS pain) 

Difference in Ch

(unstandardize

(mm VAS pain ch

 Overall pooled effect -0.32 7.9% -4.3 mm -18.1 mm cha

95% CI (-0.47 to -0.17) (4.1% to 11.7%) (-7.6 to -0.9) (-29.9 to -6.3

p Value <.001 NR .013 NR 

Sensitivity Analyses  Trial quality 

Good (+ Fair) NR -6.2 mm (-15.9 to 3.5)

**

-7.1 mm (-11.3 to 

Poor NR 

Reported NS in 

meta-regression§ NR NR 

 Trial size 

Large NR 3.6% (0.9 to 6.3) NR NR 

Small NR 6.0% (2.1 to 10.1) NR NR 

 Molecular weight 

G-F 20 NR 23.6% (CI not reported) -33.0 mm ( -50.5 

17.5)‡‡ 

Non G-F 20 -0.19 (-0.27 to -0.10) 5.4% (2.6 to 19.9) 

Did not include 

any G-F 20 trials -19.2 mm (-30.5 to 

*

 If not reported in the meta-analysis, figures calculated from original trial publications using patients randomized (not knees). † While Arrich et al. (2005) and Bellamy et al. (2006) pooled a similar effect measure, the other meta-analyses chose different approache

chapter. ‡ Pain reported from one of the following instruments in order of decreasing preference: global knee pain score; knee pain on walking; W

Index; knee pain during activities other than walking. § Also reported that elements characterizing studies of lower methodologic quality were associated with higher effect estimates. **

 Result from a single high quality trial. †† From supplementary EPC analyses; not reported in Bellamy et al. (2006). ‡‡ Calculated from meta-regression model also including study quality and pain with activity or at rest, not presented in publication. 

 60
Table 23. Summary pain result closest to 8–12 weeks and key characteristics of study-level viscosupplementation meta-analyse

Lo et al., 

2003 

Wang et al., 

2004 

Arrich et al., 

2005 

Modawal et al.

2005 

Heterogeneity 

I2 NR NR 0% 95% 

Other Cochran Q: P<.001 Cochran Q: p<.001

*

 Cochran Q: p<.0

Explored/Explained Yes/Yes† Yes/No NA/NA‡ Yes/Partially§ 

Results consistent with publication bias Yes No

**

 No Yes 

CI: confidence interval; NA: not applicable; NR: not reported; NS: not significant (p<.05); VAS: Visual Analog Scale. *

 For non-G-F 20 trials. 

† No significant heterogeneity restricting analyses to non G-F 20 trials. ‡ Found high heterogeneity for the 2-6 week result (I2 = 81%) explained by excluding Henderson, Smith, Pegley et al., 1994. § No statistical heterogeneity restricting to good quality studies. **

 Result varies for vertical axis used as noted later. 

†† Egger test on published data p=.017 

61
62 

 Strengths of the Meta-Analyses. Lo, LaValley, McAlindon, et al. (2003) attempted to acquire 

intention-to-treat data even if not reported, conducted sensitivity analyses supporting their 

conclusions, and were able to explain between-trial variability by excluding two outlier results. 

Wang, Chen, Huang, et al., (2004) reported extensive subgroup results and meta-regressions. 

Arrich, Piribauer, Mad, et al. (2005) examined effects at different time periods and carefully 

explored between-trial variability. Bellamy, Campbell, Robinson et al. (2006) examined the 

greatest breadth of literature. Strand, Conaghan, Lohmander, et al. (2006) was able to examine 

patient-level data. 

 Key Limitations of Meta-Analyses. Lo, LaValley, McAlindon, et al. (2003) reported a pooled 

standardized mean difference change in pain derived from 5 different types of pain measures 

(and scales) posing challenges for clinical interpretation—a referent minimal clinically important 

improvement for the pooled effect is not clear. The pooled effects reported by Wang, Chen, 

Huang, et al., (2004) reflect cumulative response (McQuay and Moore, 1988) but what constitute 

minimal clinically important improvement in the metrics is undefined. Arrich, Piribauer, Mad, et 

al. (2005) excluded some trials included in other meta-analyses (Table 8) stating data “could not 

be used” without clear explanation. For example, some trials reporting large effects with respect 

to pain (e.g., Scale, Wobig, and Wolpert, 1994; Wobig, Dickhut, Maier, et al., 1998) were not 

pooled. Modawal, Ferrer, Choi, et al. (2005) included few studies relative to the body of 

literature. Justification for excluding studies assessing VAS pain as part of WOMAC was not 

stated—although WOMAC pain is a composite of pain experienced during times and activities. 

Bellamy, Campbell, Robinson et al. (2006) did not explore between-trial variability, report 

sensitivity analyses, or and examine potential publication bias. The meta-analysis includes more 

than 850 forest plots, yet only 38 pool results from more than 3 trials. Strand, Conaghan, 

Lohmander, et al. (2006) reported a statistically significant difference but of small magnitude 

(-0.68 on the 24-point Lequesne Index). There was also inconsistency between mixed effects 

models reported from Puhl, Bernau, Greiling, et al. (1993) and the France (1995) trial, where the 

changes reported did not correspond with those in the package insert.*

 

 Key Limitations of Primary Literature. Trial quality was the fundamental limitation of the 

primary literature—noted in four of five study-level meta-analyses. The second key limitation 

was the lack of reported response rates from intention-to-treat samples. This limits applying 

results to individual patients. 

Heterogeneity among trials results was high for pooled outcome measures in all study-level 

meta-analyses; use of hylan G-F 20 and trial quality were found to influencing pooled effect 

magnitude and heterogeneity. Supplementary analyses suggested trial size also to account for 

some heterogeneity. 

Potential Publication bias was consistent with Egger test results in three of the metaanalyses (Lo, LaValley, McAlindon, et al., 2003; Modawal, Ferrer, Choi, et al., 2005; Bellamy, 

Campbell, Robinson et al., 2006), and in Wang, Chen, Huang, et al., (2004), dependent on the 

choice of ordinate. Lo, LaValley, McAlindon, et al. (2003) also reported larger effect sizes in 

unpublished trials. Small trial size was associated with larger effects and less often accompanied 

by sample size calculations; a substantial number of patients were participants in unpublished 

trials. This evidence supports the presence of publication bias. 

Uncertainty in reported estimates is therefore likely substantially greater than reflected in 

reported p-values and confidence intervals. Authors’ conclusions from the meta-analyses 

 

* The control group improved by -3.1 points but in meta-analysis mixed-model by -2.6. 
63 

(Appendix C*

, Table IJ) together with the Overview Quality Assessment Questionnaire finding 

four of the five study-level meta-analyses conclusions incompletely supported by the data and 

analyses presented highlight this uncertainty. Overall pooled estimates fail to incorporate 

potential publication bias, trial quality and size, and heterogeneity†

 apparent in the evidence. 

Results, Part I: Key Question 3 (Subgroup Analyses)

Four RCTs examined subgroups specified by our protocol including age, sex, 

primary/secondary OA of the knee, body mass index (BMI)/weight, and disease severity. None 

examined ethnicity, disease duration, or prior treatment. In one trial a subgroup comparison was 

preceded by stratified randomization. No other subgroup comparisons were prespecified—

results obtained in post-hoc analyses. 

Lohmander, Dalen, Englund, et al. (1996) noted the subgroup aged 60 to 75 years with 

Lequesne Index scores over 10 (worse disease severity) experienced greater reduction in VAS 

pain compared to placebo (-23 mm versus -7 mm respectively at 13 weeks). However, in a 

confirmatory trial (Karlsson, Sjogren, and Lohmander, 2002) no benefit was found for that 

subgroup. This was the only subgroup result tested in a confirmatory study. 

In a per-protocol analysis of mean reduction in VAS pain (100-mm scale) Altman and 

Moskowitz (1998) reported on age, sex, BMI, and disease severity subgroups (Table 24). 

Randomization was stratified by disease severity. Of note, the overall intention-to-treat result 

found mean pain reductions at 12 weeks of -23 and -24 mm in hyaluronan and placebo arms 

respectively (at 26 weeks, -18 mm and -24 mm, respectively). Although statistical testing of 

subgroup effects was not conducted, the considerable overlap of all subgroup confidence 

intervals indicates no significant differences by subgroups.‡

 

Table 24. Results by subgroups from Altman and Moskowitz (1998) 

 Mean Reduction Walking VAS 

Pain (mm) Compared to 

Placebo (and 95% CI; from 

figure) 

Age <65 -12.0 (-20 to -4) 

 >65 -5.5 (-16 to 6) 

Sex Women -17.0 (-17to 0) 

 Men -16.0 (-22 to -2) 

BMI < 30.5 -6.0 (-13 to 2) 

 > 30.5 -16.0 (-25 to -7) 

Disease Severity "Moderate" -6.0 (-12.5 to 1.5) 

 "Severe" -10.5 (-25 to 2.0) 

 KL2 -9.0 (-17 to -1) 

 KL3 -7.0 (-13 to 1) 

Dahlberg, Lohmander, Ryd, et al. (1994) reported no beneficial effect of hyaluronan in the 

presence of previous trauma (secondary disease). Henderson, Smith, Pegley, et al. (1994) 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm

† For example, taking into account the potential variability in heterogeneity present in the 5 to 13 week overall VAS pain estimate 

in Bellamy, Campbell, Robinson et al. (2006) would increase the width of the estimated 95 percent confidence interval from 

(-17.8 to -8.2) to (-19.8 to -6.2) or 42 percent (see Viechtbauer, 2006 for analytical details).

‡ Recognizing that confidence intervals can overlap as much as 29 percent and still be potentially significant (van Belle, 2002).
64 

concluded that “hyaluronan offers no significant benefit over placebo during a five week 

treatment period...” but also reported effects among those classified as Kellgren-Lawrence grade 

2 and grades 3–4—each with separate control groups. At 5 weeks, the VAS pain score in the 

Kellgren-Lawrence grade 2 hyaluronan arm improved -15.6 mm compared to -14.2 mm for 

placebo arm; in the Kellgren-Lawrence grade 3-4 hyaluronan arm -8.7 mm, compared to -18.0 

mm for placebo. Finally, Petrella, DiSilvestro, and Hildebrand (2002) reported no significant 

differences within subgroups defined by age, sex, and BMI but estimates were not stated. 

 Comment. There is no evidence of differential effect of intra-articular hyaluronan according 

to subgroups defined by age, sex, primary/secondary OA of the knee, BMI/weight, or disease 

severity. However, the subgroup evidence is limited. The single positive subgroup finding 

subsequently examined in a confirmatory RCT was not substantiated. 

Results, Part I: Key Question 4 (Comparative Outcomes)

The single study comparing the interventions of interest to this Evidence Report was 

conducted by Forster and Straw (2003). Forster and Straw (2003) randomized patients to 

arthroscopic lavage and debridement or intra-articular Hyalgan®. It should be noted that the 

Forster and Straw trial is the only study meeting selection criteria for this Evidence Report’s Key 

Question 4, concerning the comparative short-term and long-term outcomes of 

viscosupplements, glucosamine and chondroitin, or arthroscopic lavage and debridement. The 

trial by Forster and Straw will be discussed separately, in Results, Part III, Key Question 4. 

Conclusions: Part I 

1. What are the Clinical Effectiveness and Harms of Intra-Articular Hyaluronic 

Acid/Hyaluron Preparations Injections in Patients With Primary OA of the Knee? 

• Results from 42 trials (N=5,843), all but one synthesized in various combinations in six 

meta-analyses, generally show positive effects of viscosupplementation on pain and function 

scores compared to placebo. However, the evidence on viscosupplementation is 

accompanied by considerable uncertainty due to variable trial quality, potential publication 

bias, and unclear clinical significance of the changes reported. 

– The pooled effects from poor-quality trials were as much as twice those obtained from 

higher-quality ones. 

– There is evidence consistent with potential publication bias. Pooled results from small 

trials (<100 patients) showed effects up to twice those of larger trials consistent with 

selective publication of underpowered positive trials. Among trials of 

viscosupplementation, those that have not been published in full text comprise 

approximately 25 percent of the total patient population. 

– Interpreting the clinical significance of pooled mean effects from the meta-analyses is 

difficult; mean changes do not quantify proportions responding. Numbers needed to treat 

cannot be calculated from mean changes. 

• Trials of hylan G-F 20, the highest molecular weight cross-linked product, generally reported 

better results than other trials. 
65 

 

• Minor adverse events accompanying intra-articular injections are common, but the relative 

risk accompanying hyaluronan injections over placebo appears to be small. Pseudoseptic 

reactions associated with hyaluronans appear relatively uncommon but can be severe. 

2. What are the Clinical Effectiveness and Harms of the Interventions of Interest in 

Patients With Secondary OA of the Knee? 

• We identified no studies enrolling patients with only secondary disease, or that stratified 

randomization by primary and secondary disease. There is insufficient evidence to draw 

conclusions about treatment outcomes in patients with secondary disease. 

3. How do the Short-Term and Long-Term Outcomes of the Interventions of Interest 

Differ by the Following Subpopulations: Age, Race/Ethnicity, Gender, Primary or 

Secondary OA, Disease Severity and Duration, Weight (Body Mass Index), and Prior 

Treatments? 

• Four RCTs were identified examining any of the specified subgroups. None examined 

race/ethnicity, disease duration, or prior treatment. In one trial, randomization was stratified 

by disease severity; all other subgroup results were obtained in post-hoc analyses. There was 

no evidence for differential effects according to subgroups defined by age, sex, 

primary/disease, BMI/weight, or disease severity. One positive post-hoc subgroup analysis 

found greater efficacy among older individuals with more severe disease, but was not 

confirmed in a subsequent trial. 

4. How do the Short-Term and Long-Term Outcomes of the Interventions of Interest 

Compare for the Treatment of: Primary OA of the Knee; and Secondary OA of the Knee? 

 

• No trials were identified comparing intra-articular hyaluronan to glucosamine and/or 

chondroitin. A single, small, underpowered, poor quality trial found no difference in 

outcome measures comparing intra-articular hyaluronan to arthroscopy and debridement over 

a 1-year followup. There is insufficient evidence to draw conclusions regarding comparative 

efficacy of the interventions. 

Part II: Glucosamine/Chondroitin Effectiveness and Harms 

We used the results of study-level meta-analyses (MAs) and additional randomized 

controlled trials (RCTs) that were not included in the MAs to address the Key Questions of this 

Evidence Report on osteoarthritis (OA) of the knee. 
66 

Literature Overview 

 This section of the Evidence Report includes six MAs* and five RCTs not included in the 

MAs.†

 In this section, we provide a brief descriptive overview of the MAs and identify the 

additional RCTs. Our systematic review of the literature did not identify any patient-level MAs 

on these interventions. 

 Summary Description of Meta-Analyses. Six MAs comprising a total of 21 individual 

RCTs of glucosamine (total N=2,495) and 12 RCTs of chondroitin (total N=548) were published 

between 2000 and 2006 (Table 25). Four reported on glucosamine administered alone and three 

evaluated chondroitin administered alone. In one MA, the authors pooled data from primary 

studies of glucosamine and chondroitin (Richy, Bruyere, Ethgen, et al., 2003). Four of the MAs 

included RCTs with active controls; the balance utilized placebo controls. Two of the MAs used 

a pain measure as the primary clinical outcome (Bjordal, Klovning, Ljunggren, et al., 2006; 

McAlindon, LaValley, Gulin, et al., 2000). The other four MAs examined additional efficacy 

parameters such as function, radiographic effects on cartilage structure, and adverse events. The 

individual study composition of the MAs and RCT characteristics are presented in detail in the 

following section of this Evidence Report. 

 Additional Randomized Trials. Five randomized, double-blind, placebo-controlled trials 

that were not included in any of the MAs met our study selection criteria (Table 26). Most 

notable among these is a large (n=1,583) multicenter, five-arm, National Institutes of Health- 

(NIH-) sponsored study that evaluated the efficacy and safety of orally administered 

glucosamine, chondroitin, or both together versus an oral placebo or an active control (celecoxib) 

in patients with OA of the knee (Clegg, Reda, Harris, et al., 2006). Two RCTs compared the 

clinical efficacy and tolerability of orally administered chondroitin sulfate versus placebo 

(Michel, Stucki, Frey, et al., 2005; Uebelhart, Malaise, Marcolongo, et al., 2004). One study 

examined the efficacy of combination treatment with glucosamine and chondroitin versus 

placebo (Das and Hammad, 2000). These will be considered in detail in the following Results 

section.

 

* As the final Evidence Report was in press, we found a new meta-analysis on chondroitin (Bana, Jamard, Verrouil, et al., 2006). 

Published in a European annual journal, it found modest effects favoring chondroitin on VAS pain and Lequesne Index; however, 

it excluded many papers and provided very few details on how meta-analysis was performed. In particular, no information was 

offered on pooling methods, whether heterogeneity was assessed, whether publication bias was assessed, and whether 

heterogeneity was explored by subgroup/sensitivity analysis or meta-regression. The findings of this poor-quality meta-analysis 

do not conflict with the other meta-analyses included in this section and do not alter the conclusions of this Evidence Report.

†

 As the final Evidence Report was in press, an additional RCT of chondroitin sulfate was identified (Mazieres, Hucher, Zaim, et

al., 2007). For one of two primary outcomes, VAS pain on activity, there was significantly greater change in the chondroitin 

group (mean -26.2.sd 24.9) compared with the placebo group (mean -19.9, sd 23.5, p=.029). There was no significant difference 

in the other primary outcome, function on the Lequesne Index (p=.109). Three secondary outcomes significantly favored 

chondroitin and seven secondary outcomes did not differ between groups. This study does not change the conclusions of this 

Evidence Report.
67 

Table 25. Summary description of meta-analyses of glucosamine and chondroitin in knee osteoarthritis

Key 

Question(s) 

Addressed 

Included RCT 

Design 

No. of RCTs 

Included 

MA Author, (total pts) Outcomes Reported 

Year 

Industry 

Funding 

of MA 1 2 3 4 DB SB PC AC C G Pain Func Struc AEs 

Bjordal et 

al., 2006 NR X X X X X 

6 

(362) 

7 

(401) X 

Towheed et 

al., 2006 NR X X X X X NA 

20 

(2,596) X X X 

Poolsup et 

al., 2005 NR X X X NA 

2 

(414) X X X X 

Richy et al., 

2003 NR X X X X 

8 

(855) 

7 

(1,203) X X X X 

Leeb et al., 

2000 NR X X X X X 

7 

(703) NA X X X 

McAlindon 

et al., 2000 NR X X X X X 

9 

(799) 

6 

(1,118) X 

No. RCTs Pooled (Total in Literature) 12 21 

AC: active-controlled; AEs: adverse events; C: chondroitin; DB: double-blind; G: glucosamine; Func: function; NR: not reported; PC: 

placebo-controlled; pts: patients; SB: single-blind; Struc: structural; RCT: randomized controlled trial; 

Table 26. Additional RCTs not included in glucosamine and chondroitin meta-analyses 

Study No. Pts per Study Arm Outcomes Reported 

G C G/C Pl Act 

Duration 

(wks) Pain Func Struc AEs 

Herrero-Beaumont et al., 

2007 106 104 108 24 X X X 

Clegg et al., 2006 317 318 317 313 318 24 X X X 

Michel et al., 2005 150 150 104 X X X X 

Uebelhart et al., 2004 54 56 52 X X X X 

Das and Hammad, 2000 46 47 24 X X X X 

Act: active; AEs: adverse events; C: chondroitin; G: glucosamine; G/C: glucosamine plus chondroitin; Pl: placebo; Func: function; 

Struc: structural; wks: weeks 

Results, Part II: Key Questions 1 and 2 

 Detailed Description of the Meta-Analyses. Appendix C*, Table IIA presents a detailed 

summary of the meta-analyses. Primary literature for each MA was compiled through searches 

of electronic databases (e.g., MEDLINE®, EMBASE, Cochrane Controlled Trials Register, 

BIOSIS, HealthSTAR) using prespecified protocols. Searches generally started from the 

inception of each database, with a cutoff just prior to publication of the MA. Manual searches of 

meeting abstracts; scrutiny of reference lists of primary articles and other systematic reviews; 

and hand searches of selected journals were conducted to identify studies that eluded the 

systematic electronic searches. 

 Meta-Analysis Quality Evaluation. We used a validated method developed by Oxman and 

Guyatt to assess the quality of the MAs based on nine questions related to aspects of their 

composition, execution, and analysis. As shown in Table 27, quality scores ranged from 3 to 7. 

The quality ratings of three MAs appear limited primarily by flaws in the scope and methods of 

the literature search (Poolsup, Suthisisang, Channark, et al., 2005; Leeb, Schweitzer, Montag, et 

al., 2000; McAlindon, LaValley, Gulin, et al., 2000). In addition, as described in the Methods 

section, we performed quality ratings of the primary studies included in the MAs. 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
68 

 Meta-Analysis Methodologic Characteristics. As shown in Table 28, all MA authors 

tested for heterogeneity across studies. Heterogeneity was a factor in interpretation of results 

from 3 MAs (Towheed, Maxwell, Anastassiades, et al., 2006; Richy, Bruyere, Ethgen, et al., 

2003; McAlindon, LaValley, Gulin, et al., 2000). Meta-regression analysis revealed influences 

of drug type, patient selection criteria, and missing data in two MAs (Bjordal, Klovning, 

Ljunggren, et al., 2006; Towheed, Maxwell, Anastassiades, et al., 2006). Sensitivity analyses 

performed by four groups examined the impact of factors such as allocation concealment and 

trial heterogeneity on results (Bjordal, Klovning, Ljunggren, et al., 2006; Towheed, Maxwell, 

Anastassiades, et al., 2006; Richy, Bruyere, Ethgen, et al., 2003; McAlindon, LaValley, Gulin, et 

al., 2000). Publication bias possibly influenced the results of three MAs (Richy, Bruyere, 

Ethgen, et al., 2003; Leeb, Schweitzer, Montag, et al., 2000; McAlindon, LaValley, Gulin, et al., 

2000).

 Primary Study Composition of Meta-Analyses. Glucosamine. Table 29 shows the 

primary RCTs that composed the glucosamine MAs. The number of trials included in each MA 

ranged from two to 20. Some MAs overlap, but no two contain the same body of evidence. No 

single primary study was represented in all five of the MAs. Nineteen of 21 references were full 

articles and two were abstracts (Houpt, McMillan, Paget-Dellio, et al., 1998; Rovati, 1997). 

 One MA included primary studies that used a reference control, pooling them with studies 

that used placebo controls (Towheed, Maxwell, Anastassiades, et al., 2006). Glucosamine was 

administered orally in 17 RCTs and parenterally in four. Two MAs combined data from studies 

in which glucosamine was administered parenterally with those in which it was given orally 

(Towheed, Maxwell, Anastassiades, et al., 2006; McAlindon, LaValley, Gulin, et al., 2000). 

Seventeen studies reported at least 80 percent of patients had knee OA. Four RCTs did not 

specify the knee as the primary affected joint (Zenk, Helmer, Kuskowski, et al., 2002; 

D’Ambrosio et al. 1981; Crolle and D’Este, 1980; Drovanti, Bignamini, and Rovati, 1980). 

 To assess the MAs as a means to address the Key Questions of this Evidence Report, we 

applied study selection criteria outlined in the Methods chapter to the primary studies in each 

MA. Two MAs contained RCTs that do not match the criteria specified in our Evidence Report 

(Towheed, Maxwell, Anastassiades, et al., 2006; McAlindon, LaValley, Gulin, et al., 2000). Ten 

of 20 RCTs included by the MA by Towheed and colleagues (2006) are not relevant to the aims 

of this Report, as will be outlined in the Results section for each MA. However, Towheed, 

Maxwell, Anastassiades, et al. (2006) includes all 10 trials that we have determined are 

applicable to our Report, whereas Bjordal, Klovning, Ljunggren, et al. (2006) and Richy, 

Bruyere, Ethgen, et al. (2003) excluded 3 of the 10. 
Table 27. Oxman and Guyatt method quality evaluation of glucosamine and chondroitin meta-analyses 

Evaluation Criteria Bjordal et al., 2006 Towheed et al., 

2006 

Poolsup et al., 

2005 

Richy et al., 2003 Leeb et al.

Were the search methods used to find evidence (primary research) on the primary question(s) stated? 

Y - clearly stated Y - clearly stated Y - clearly stated Y - clearly stated Y - clearly 

Was the search for evidence reasonably comprehensive? 

Y - clearly stated, 

comprehensive, but 

language restricted to 

English, German, 

Scandinavian 

Y - clearly stated, 

comprehensive, no 

language 

restrictions 

N - did not specify 

language 

restrictions, did 

not seek 

unpublished data 

Y - clearly stated, 

comprehensive, no 

language 

restrictions 

P - sear

strategy 

specifie

langua

restrictio

unclear, s

unclea

Were the criteria used for deciding which studies to include in the overview reported? 

Y - clearly stated Y - clearly stated Y - clearly stated Y - clearly stated Y - clearly 

Was bias in the selection of studies avoided? 

Y - comprehensive 

search, published and 

unpublished data 

sought 

Y - comprehensive 

search, published 

and unpublished 

data sought 

N - Unpublished 

data not sought or 

included, 

language 

restrictions not 

specified 

Y - comprehensive 

search, published 

and unpublished 

data sought 

N - Unpub

data not so

include

langua

restriction

specifie

Were the criteria used for assessing the validity of the included studies reported? 

Y - numerical score 

provided according to 

Jadad et al. 

Y - quality scores 

provided according 

to Gotzsche and 

Jadad et al. 

Y - numerical 

score provided 

according to 

Jadad et al. 

Y - numerical score 

provided according 

to Jadad et al. 

Y – unclea

method c

Was the validity of all studies referred to in the text assessed using appropriate criteria (either in selecting studies for inclusion or in analyzing the studies that are cited)? 

Y - validated methods 

clearly stated 

Y - validated 

methods clearly 

stated 

Y - validated 

methods clearly 

stated 

Y - clearly stated in 

tables 

Y – clearly 

in table

69
Table 27. Oxman and Guyatt method quality evaluation of glucosamine and chondroitin meta-analyses (continued) 

Evaluation Criteria Bjordal et al., 2006 Towheed et al., 

2006 

Poolsup et 

al., 2005 

Richy et al., 2003 Leeb et al., 20

Were the methods used to combine the findings of the relevant studies (used to reach a conclusion) reported? 

Y - clearly stated Y - handling of 

dichotomous and 

continuous 

outcomes clearly 

stated 

Y - clearly 

stated 

Y - handling of 

dichotomous and 

continuous outcomes 

clearly stated 

Y – clearly stat

Were the findings of the relevant studies combined appropriately relative to the primary question the overview addresses? 

Y - clearly stated Y - clearly stated Y - only used 

2 studies 

because of 

very strict 

inclusion 

criteria 

P - combined data from 

studies of both 

compounds based on 

the absence of efficacy differences, also mixed 

in some data from hip pts 

Y - clearly stat

Were the conclusions made by the author(s) supported by the data and/or analysis reported in the overview? 

Y - analysis within 

parameters was 

adequate, but went 

further in putting 

results into a "clinical" 

context for pain 

perception 

Y - thorough 

analyses broken 

down according to 

outcomes scored 

and adverse events 

Y - but limited 

number of 

studies 

reduces the 

impact of the 

MA 

P - combined data from 

studies of both 

compounds based on 

the absence of efficacy 

differences, yet stated 

they were individually 

efficacious 

Y - authors state

only "suggests 

CS may be usef

OA". 

How would you rate the scientific quality of the overview?*

7 7 3 5 3 

Y: Yes; P: Partially or can't tell; N: No * 1&2: extensive flaws; 3&4: major flaws; 5&6: minor flaws; 7 minimal flaws 

70
Table 28. Methodologic characteristics of glucosamine and chondroitin meta-analyses 

Study Bjordal et al., 2006 Towheed et al., 2006 Poolsup et al., 2005 Richy et al., 2003 Leeb et al., 

2000 

Heterogeneity Assessed Yes Yes Yes Yes Yes Test used Cochran Q Chi-square Cochran Q Cochran Q 95% CIs of 

Glass scores 

Result Outcome measures during 

first 4 weeks of treatment were not heterogeneous GS Q = 1.3 CS Q = 1.8 (p>.05 for either) I

2 = 0 for both comparisons 

(due to critically low Q) 

For GS or GH vs. placebo: reduction in pain and LI scores were heterogeneous Pain:  I2 = 88.5% 

LI: I

2 = 89.4% 

Disease progression: Q=0.35 (p>.1) Pain: Q=0.003 (p>.1) WOMAC function: Q=0.0009 (p>.1) I

2 = 0 for all 

comparisons (due to critically low Q) 

Outcome measures including JSN (p=.95), LI (p=.68), WOMAC (p=.83), mobility (p=.73) showed no heterogeneity VAS pain likely heterogeneous as RE model was used to combine data (p value not provided) 

NR 

Meta-RegressionConducted Yes Yes NR NR NR Factors explored 

Drug types within the same class Patient selection criteria Missing data in ITT analyses 

Pain and function in studies that used Rotta Research Laboratorium preparation of glucosamine versus those that used nonRotta preparation(s) 

NR NR NR 

71
Table 28. Methodologic characteristics of glucosamine and chondroitin meta-analyses (continued) 

Study Bjordal et al., 2006 Towheed et al., 2006 Poolsup et al., 

2005 

Richy et al., 2003 Leeb et al. 

(2000) 

Sensitivity analysis

** Yes – planned using 

same subgroups if Q values indicated heterogeneity was present, not necessary for GH/Gs or CS 

Yes - Pain, function, radiologic measures in studies with adequate allocation concealment 

NR Yes NR 

Funnel plot/publication bias 

NR NR NR Funnel Plot 

(asymmetric) 

Egger Test 

(p=.08) 

Yes 

Non-central t-distribution revealed a relativerror of about 30

Included studies and compounds assessed 

CS = 6 single- or double-blind placebocontrolled RCTs GS = 7 single- or double-blind placebocontrolled RCTs 

20 double-blind RCTs, GS/GH 

2 double-blind placebo-controlled RCTs of GS 

15 double-blind placebo-controlled RCTs of GS and CS 

7 double-blind placebo-controlleRCTs of CS 

Industry sponsored 

5 of 6 CS trials industry funded 

15/20 connected to Rotta to some degree 

NR in metaanalysis, but both studies were funded by Rotta 

NR in metaanalysis NR in meta- analysis 

CS: chondroitin sulfate; GS: glucosamine sulfate; GH: glucosamine hydrochloride; ITT: intent to treat; NR: not reported; RCT: randomized controlled t* If study subgroups examined eliminating those likely to influence or bias results 

72
Table 29. Primary randomized trials included in glucosamine meta-analyses 

Route of 

Administration

Type of Control 

Used 

Publication 

Type 

Meta-Ana

(Yea

Primary Study Study 

Design O P Pl Act 

>80% 

Knees Art Abs 

Bjordal 

(2006) 

Towheed 

(2006) 

Poolsup 

(2005) 

Cibere et al., 2004 DB X X X X X McAlindon et al., 2004 DB X X X X X X Usha and Naidu, 2004 DB X X X X X X Hughes and Carr, 2002 DB X X X X X X Pavelka et al., 2002 DB X X X X X X Zenk et al., 2002 DB X X NR X X Reginster et al., 2001 DB X X X X X X Rindone et al., 2000 DB X X X X X X Houpt et al., 1999 DB X X X X X X Houpt et al., 1998 DB X X X X Qiu et al., 1998 DB X X X X X Rovati, 1997 DB X X X X X Muller-Fassbender et al., 1994 DB X X X X X Noack et al., 1994 DB X X X X X X Reichelt et al., 1994 DB X (IM) X X X X Lopes Vaz, 1982 DB X X X X X D'Ambrosio et al., 1981 DB X (IV/IM) X NR X X Vajaradul, 1981 DB X (IA) X X X X Crolle and D'Este, 1980 DB X (IM/IA) X NR X X Drovanti et al., 1980 DB X X NR X X Pujalte et al., 1980 DB X X X X X X No. RCTs Pooled (Total 21 in Literature) 7 20 2 Abs: abstract; Act: active; Art: article; DB: double-blind; IA: intra-articular; IM: intramuscular; IV: intravenous; NR: not reported; O: oral; P: parentera

* Bold face type and shading indicates study that meets Evidence Report selection criteria (see Methods section) 

73
74 

 The MA by Poolsup, Suthisisang, Channark, et al. (2005) examined the effect of 

glucosamine on structural progression of OA of the knee. Only two RCTs report such data 

(Pavelka, Gatterova, Olejarova, et al., 2002; Reginster, Deroisy, Rovati, et al., 2001). The 

earliest MA includes only 3 RCTs that meet our selection criteria, but publication chronology 

may be the key factor in that situation (McAlindon, LaValley, Gulin, et al., 2000). The primary 

literature on glucosamine comprising the other three MAs is consistent with our selection criteria 

(Bjordal, Klovning, Ljunggren, et al., 2006; Poolsup, Suthisisang, Channark, et al., 2005; Richy, 

Bruyere, Ethgen, et al., 2003). 

 Chondroitin. Table 30 shows primary RCTs used in the MAs of chondroitin. The number of 

trials included in each MA ranged from six to nine. While there is overlap between the 

chondroitin MAs, the body of studies that composed each differs. Four RCTs were common to 

all of the MAs (Uebelhart, Thonar, Delmas, et al., 1998; Bucsi and Poor, 1998; Bourgeois, 

Table 30. Primary randomized trials included in chondroitin meta-analyses

Route of 

Administration 

Type of 

Control 

Used 

Publication

Type 

Meta-Analysis*

Primary (Year) 

Study Study 

Design O P Pl Act 

>80% 

Knees Art Abs 

Bjordal 

(2006) 

Richy 

(2003) 

Leeb 

(2000) 

McAlindon 

(2000) 

Mazieres 

et al., 

2001 

DB X X X X X X 

Bourgeois 

et al., 

1998 

DB X X X X X X X X 

Bucsi and 

Poor, 

1998 

DB X X X X X X X X 

Conrozier, 

1998 DB X X X X X X 

Pavelka et 

al., 1998 DB X X X X X X 

Uebelhart 

et al., 

1998 

DB X X X X X X X X 

Morreale 

et al., 

1996 

DB X X X X X X 

Conrozier 

and 

Vignon, 

1992 

DB X X X X 

L'Hirondel, 

1992 DB X X X X X X X 

Mazieres 

et al., 

1992 

DB X X X X X X X 

Rovetta, 

1991 DB X (IM) X X X X 

Kerzberg 

et al., 

1987 

DB/CO X 

(IM) X X X X 

No. RCTs Pooled (Total 12 in Literature) 6 8 7 9 

Abs: abstract; Act: active; Art: article; DB: double-blind; CO: crossover; IM: intramuscular; O: oral; P: parenteral; Pl: placebo; 

* Bold face type and shading indicates study that meets Evidence Report selection criteria (see Methods section) 
75 

Chales, Dehais, et al., 1998; Mazieres, Loyau, Menkes, et al., 1992). Eleven of 12 primary 

studies were full articles; one was an abstract (Pavelka, Bucsi, Manopulo, et al., 1998). 

 Three MAs included RCTs that used reference controls (Bjordal, Klovning, Ljunggren, et al., 

2006; Leeb, Schweitzer, Montag, et al., 2000; McAlindon, LaValley, Gulin, et al., 2000). 

Chondroitin was administered orally in ten trials and parenterally in two. One MA pooled data 

from RCTs that used either route (McAlindon, LaValley, Gulin, et al., 2000). Ten studies 

included only patients with OA of the knee. Two included patients with OA of the knee and of 

the hip (Conrozier and Vignon, 1992; Mazieres, Loyau, Menkes, et al., 1992). The latter 2 RCTs 

were pooled with OA of the knee patient data in one MA (Leeb, Schweitzer, Montag, et al., 

2000). 

 Our study selection criteria excluded primary studies from each of the four MAs. This is 

particularly evident with one MA of nine primary studies, five of which would be allowed by our 

criteria (McAlindon, LaValley, Gulin, et al., 2000). 

 Outcomes Measured in Randomized Trials That Meet Protocol Selection Criteria. A 

number of health outcomes reported in primary RCTs provide relevant information to address 

Key Questions 1 and 2. To facilitate this presentation, where appropriate we have included the 

studies from the MAs with the additional studies in the summary tables. 

 Glucosamine. As shown in Table 31, seven of 12 glucosamine studies used a component of 

the Western Ontario and McMaster (WOMAC) pain, function, stiffness, or total index. Four 

primary RCTs reported pain intensity measured using a visual analog scale (VAS). Lequesne 

Index was reported in four studies. Walking time was not used as a scoring criterion in any of 

the glucosamine RCTs. 

 Chondroitin. As shown in Table 32, health outcomes for patients treated with chondroitin 

were scored using the same measures as used for glucosamine trials. Lequesne Index or a VAS 

for pain was used in six of nine RCTs. The WOMAC index or a global assessment was scored in 

two studies. Walking time was reported in two RCTs. Two of the RCTs shown were not 

included in the MAs (Michel, Stucki, Frey, et al., 2005; Uebelhart, Malaise, Marcolongo, et al., 

2004). 

 Glucosamine Plus Chondroitin. Neither RCT shown in Table 33 was included in the MAs. 

In the most recent RCT (GAIT; Clegg, Reda, Harris, et al., 2006), the investigators used the 

WOMAC scale to score clinical response to therapy. However, the primary outcome measure 

was reported as a threshold, a positive response being defined as a 20 percent decrease in the 

summed score for the WOMAC pain subscale at 24 weeks of therapy. Key secondary outcomes 

reported in GAIT were the OMERACT-OARSI response rate and the proportion of patients who 

achieved a 50 percent decrease in the WOMAC pain score. The second RCT utilized the total 

WOMAC scale as the primary outcome, scoring as respondents subjects who demonstrated a 25 

percent decrease in that parameter. Both studies also scored other outcomes, as shown in Table 

33. 

 Baseline Characteristics of Randomized Trials That Meet Protocol Selection Criteria. 

Glucosamine. As shown in Table 34, all of the glucosamine RCTs considered in this report were 

double-blinded. Glucosamine was administered at 1,500 mg/day as the sulfate salt in eight trials. 

The same dose of the hydrochloride salt was used in only one study (Houpt, McMillan, Wein, et 

al., 1999). The formulation was unclear in two studies that used a dose of 1500 mg/day (Usha 

and Naidu, 2004; Rindone, Hiller, Collacott, et al., 2000). 
76 

Table 31. Clinical outcomes in RCTs of glucosamine that meet protocol selection criteria 

VAS Pain WOMAC 

Global 

Assessment Study 

Motion Rest Overall Pain Function Stiffness Total Phys Pat LI 

Walking 

Time 

Studies Included in Meta-Analyses 

McAlindon et al, 

2004 X X X X 

Usha and Naidu, 

2004 X X 

Hughes and 

Carr, 2002 X X X X X X 

Pavelka et al., 

2002 X X X X 

Reginster et al., 

2001 X X X X 

Rindone et al., 

2000 X X 

Houpt et al., 

1999 X X X X 

Rovati, 1997 X 

Noack et al., 

1994 X 

Pujalte et al. 

1980 X X 

Additional Studies not Included in Meta-Analyses 

HerreroBeaumont et al., 

2007 

 X X X X X X 

Clegg et al. , 

2006 X X X X X X 

LI: Lequesne Index; VAS: visual analog scale; WOMAC: Western Ontario and McMaster index; 

Table 32. Clinical outcomes in RCTs of chondroitin that meet protocol selection criteria 

VAS Pain WOMAC 

Global 

Assessment Study 

Motion Rest Overall Pain Function Stiffness Total Phys Pt LI 

Walking 

Time 

Studies Included in Meta-Analyses 

Mazieres et al., 

2001 X X X X X 

Bourgeois et al., 

1998 X X 

Bucsi and Poor, 

1998 X X X 

Conrozier, 1998 X 

Uebelhart et al., 

1998 X 

L’Hirondel, 1992 X X 

Additional Studies not Included in Meta-Analyses 

Clegg et al. 

(2006) X X X X X X 

Michel et al. 

(2005) X X X X 

Uebelhart et al. 

(2004) X X X 

LI: Lequesne Index; pt: patient; VAS: visual analog scale; WOMAC: Western Ontario and McMaster index; 
77 

Table 33. Clinical outcomes in RCTs of glucosamine plus chondroitin that meet protocol selection criteria 

VAS Pain WOMAC 

Global 

Assessment Study 

Motion Rest Overall Pain Function Stiffness Total Phys Pt LI 

Walking 

Time 

Clegg et al., 

2006 X X X X X X 

Das and 

Hammad, 2000 X X X 

LI: Lequesne Index; pt: patient; VAS: visual analog scale; WOMAC: Western Ontario and McMaster index; 
Table 34. Baseline characteristics of randomized trials of glucosamine that meet protocol selection criteria

*

Study Dose 

(Type) 

N 

Tx/Pl 

Mn 

Age 

Tx/Pl 

(yrs) 

Female 

Pts (%) 

Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl 

OA 

Diag†

OA 

Stage 

(%Tx/ 

%Pl) 

Mn Dis 

Duration 

Tx/Pl 

(yrs) 

Mn VAS 

Movement 

(mm) Tx/Pl 

Mn 

VAS 

Rest 

(mm) 

Tx/Pl 

Mn 

WOMAC 

Pain Tx/P 

M

WOM

Func

Tx/

Studies Included in Meta-Analyses

McAlindon et al., 2004 

1,500 

mg/day 

(GS) 

101/104 Rng 

<54-

95 

/ 

<54-

84 

57/71 

p=.04 

 31.0 ± 7.6/34.1 ± 9.0 p=.01 

? NR NR Likert 

8.8/9.1 

Like

4.2/

Usha and Naidu, 2004 

1,500 

mg/day 

(inferred 

GS) 

30/28 52/50 60/57 26.6/25.4 

(calculated) 

? K-L 

1-3 

most 

3.2/2.9 58/NR 

Hughes and Carr , 2002 

1,500 

mg/day 

(GS) 

40/40 All: 

62 

All: 68 NR ? K-L 

1 (all, 

9) 

2 (all 

31) 

3 (all 

37) 

4 (all 

23) 

All: 7.6 All: 60.7 All: 

35.0 

Likert 

All: 9.2 

Like

All: 3

Pavelka et al., 2002 

1,500 

mg/day 

(GS) 

101/101 61/64 79/76 25.7 ± 

2.1/25.7 ± 1.8 

1° K-L 

2 

(54/53) 

3 

(46/47) 

10.1/11.0 Likert 

6.6/6.3 

Like

21.

22

Reginster et al., 2001 

1,500 

mg/day 

(GS) 

106/106 66/66 75/78 27.3 ± 

2.6/27.4 ± 2.7 

1° K-L 

2 

(71/70) 

3 

(29/30) 

8.0/7.6 194.1/ 

172.2 

740.1/

78
Table 34. Baseline characteristics of randomized trials of glucosamine that meet protocol selection criteria

*

 (continued)

Study Dose 

(Type) 

N 

Tx/Pl 

Mn 

Age 

Tx/Pl 

(yrs) 

Female 

Pts (%) 

Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl 

OA 

Diag†

OA 

Stage 

(%Tx/ 

%Pl) 

Mn Dis 

Duration 

Tx/Pl 

(yrs) 

Mn VAS 

Movement 

(mm) Tx/Pl 

Mn 

VAS 

Rest 

(mm) 

Tx/Pl 

Mn 

WOMAC 

Pain 

Tx/Pl 

M

WO

Fun

Tx

Studies Included in Meta-Analyses (continued)

Rindone et al., 2000 

1,500 

mg/day 

(unclear) 

49/49 63/64 4/6 NR ? K-L 1 

(40/30) 

K-L 2 

(18/19) 

K-L 3 

(35/35) 

K-L 4 

(7/16) 

12/14 (0-10) 

6.4/6.4 

(0-10) 

3.9/3.6 

Houpt et al., 1999 

1,500 

mg/day 

(GH) 

58/60 64/65 64/60 NR 1° NR 8.3/8.3 Likert 

8.8/8.4 

Li

33

3

Rovati (1997) 

1,500 

mg/day 

(GS) 

NR NR NR NR ? NR NR NR 

(used LI)‡

NR NR N

Noack et al., 1994 

1,500 

mg/day 

(GS) 

126/126 55/55 59/62 26.6/26.2 

(calculated) 

1° NR All: rng 

<6 mo to 

>10 yr 

Pujalte et al., 1980 

1,500 

mg/day 

(GS) 

10/10 59/65 80/90 NR ? NR NR 

Additional Studies not Included in Meta-Analyses

HerreroBeaumont et al., 2007 [GUIDE] 

1,500 

mg/day 

(GS) 

106/108/104 GS: 

63.4 ± 6.9 Acet: 63.8 ± 6.9 Pl: 64.5 ± 7.2 

91/93/89 GS: 27.7 ± 

2.3 Acet: 27.9 ± 2.3 Pl: 27.6 ± 2.4 

1o K-L 2: 

50/56/50 K-L 3: 41/31/39 K-L 2/3: 9/12/11 

GS: 7.4 ± 6.0 Acet: 6.5 ± 5.3 Pl: 7.2 ± 5.8 

 GS: 7.8 

± 3.0 Acet: 8.0 ± 2.9 Pl: 7.9 ± 3.0 

GS: ± 11Ace29.4 11.0 Pl: 2± 10

*

 All values are mean ± SD unless otherwise noted; 

† ACR criteria; ‡ Outcomes are generally those that are denoted in the paper as being the primary study outcomes;Acet: acetaminophen; ACR: American College of Rheumatology; BMI: body-mass index; Dis: disease; GS: glucosamine sulfate; GH: glucosamine hyd

Lawrence criteria; LI: Lequesne Index; mn: mean; NR: not reported; Pl: placebo; rng: range; Tx: treatment; VAS: visual analog scale; WOMAC: WesterUniversities Osteoarthritis Index; 

79
80 

 The mean age of patients ranged between 50 and 66 years, with females comprising 4–90 

percent of the study samples. In nine of 11 trials, females made up 60 percent or more of the 

enrolled patients. Five RCTs of glucosamine reported on patients with primary OA according to 

ACR criteria. None of the glucosamine studies reported patients specifically with secondary 

OA. Six reports did not specify whether patients had primary or secondary OA. The mean 

duration of OA of the knee ranged from 6 months or less to more than 10 years. Most patients in 

the RCTs had Kellgren-Lawrence grade 2–3 OA of the knee. One study included subjects who 

had Kellgren-Lawrence grade 4 disease (Hughes and Carr, 2002). No significant differences 

were reported between the composition of the treatment and placebo groups or their baseline 

characteristics, with the exception of a slight variation in sex distribution and BMI reported in 

one study (McAlindon, Formica, LaValley, et al., 2004). 

 Chondroitin. All of the chondroitin studies considered in this report used a double-blind 

design. Table 35 shows that in single-agent RCTs, chondroitin was given as the sulfate salt at 

doses that varied from 200 mg daily to 1,200 mg/day. The mean age of patients ranged between 

57 and 67 years, with females comprising 33–84 percent of the study samples. Females made up 

60 percent or more of enrolled patients in 4 of 8 trials. Four RCTs of chondroitin reported on 

patients with primary OA according to ACR criteria. None of the studies reported patients 

specifically with secondary OA. In contrast, two included a mix of primary and secondary 

disease (Bucsi and Poor, 1998; Uebelhart, Thonar, Delmas, et al., 1998). Two reports did not 

specify whether patients had primary or secondary OA (Conrozier, 1998; L’Hirondel, 1992). 

The mean duration of OA of the knee ranged from 4 years to more than 10 years. Most patients 

in the RCTs had Kellgren-Lawrence grade 2–3 knee OA. 

 Glucosamine Plus Chondroitin. As shown in Table 36, in two RCTs, glucosamine was given 

as the hydrochloride salt in combination with chondroitin (Clegg, Reda, Harris, et al., 2006; Das 

and Hammad, 2000). One trial included patients with primary OA of the knee (Clegg, Reda, 

Harris, et al., 2006). The other RCT included a mix of primary and secondary disease (Das and 

Hammad, 2000). One trial included subjects who had Kellgren-Lawrence grade 4 disease. 

Other characteristics of these RCTs are comparable to those of the other trials that meet our 

selection criteria. 

 Quality of Randomized Trials That Meet Protocol Selection Criteria. The study quality 

of primary RCTs that met our protocol selection criteria was evaluated using a grading tool 

described in the Methods chapter of this Evidence Report. 

 Glucosamine. Table 37 shows that four glucosamine trials were judged as “good” quality, 

four were “fair,” and four were rated “poor.” The quality of one was not evaluable due to 

missing information (Rovati, 1997). Poor quality ratings were ascribed to a lack of allocation 

concealment and failure to use ITT analysis. The combination therapy trials that were not part of 

the MAs are included in this Table (Clegg, Reda, Harris, et al., 2006; Das and Hammad, 2000). 
Table 35. Baseline characteristics of randomized trials of chondroitin treatment that meet protocol selection criteria

*

Study 

Dose (Type) N Tx/Pl 

Mn Age Tx/Pl (yrs) 

Female Pts (%) Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl OA Diag†

OA Stage (%Tx/ %Pl) 

Mn Dis Duration Tx/Pl (yrs) 

Mn VAS Movement (mm) Tx/Pl 

Mn VAS Rest (mm) Tx/Pl 

Mn WOMAC Pain Tx/P 

Mn WOMAC Function Tx/Pl 

MWST

Studies Included in Meta-Analyses 

Mazieres et al., 2001 

1,000 mg/day (CS) 

63/67 67/67 71/78 29.2 ± 

5.1/28.9 ± 4.8 

1o K-L 

2 (59/54) 3 (41/46) 

NR 54.4/ 

53.0 

29.9/ 27.7 

 

Bourgeois et al., 1998 

Daily 1,200 mg/day (CS 4&6) 3X daily 400 mg/day (CS 4&6) 

Daily/3X daily//Pl 40/43/44 

63/63/64 65/79/84 NR 1o ACR 

All: 1-3 (100) 

By L,R 6,5/4,5/ 6,6 

 58/54/56 

Bucsi and Poor, 1998 

800 mg/day (CS) 

39/46 61/59 56/63 29.2/29.1 

(estimated) 

1o/2o K-L 

All: 1-3 (100) 

NR 56/56 

Conrozier, 1998 

800 mg/day (CS 4&6) 

All: 104 NR NR ? NR NR 

81
Table 35. Baseline characteristics of randomized trials of chondroitin treatment that meet protocol selection criteria

*

 (continue

Study 

Dose (Type) 

N Tx/Pl 

Mn Age Tx/Pl (yrs) 

Female Pts (%) Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl OA Diag†

OA Stage (%Tx/ %Pl) 

Mn Dis Duration Tx/Pl (yrs) 

Mn VAS Movement (mm) Tx/Pl 

Mn VAS Rest (mm) Tx/Pl 

Mn WOMAC Pain Tx/Pl 

Mn WOMAFunctTx/Pl 

Studies Included in Meta-Analyses (continued) 

Uebelhart et al., 1998 

800 mg/day (CS 4&6) 

23/23 60/57 48/56 25.5/27.2 

(estimated) 

1o/2o K-L 

1 (44/48) 2 (48/44) 3 (9/9) 

NR 56/64 

L’Hirondel, 1992 

1200 mg/day (CS) 

63/62 All: 63 32.6 NR ? NR NR (0-5) 

4.03/3.90 

 

Additional Studies not Included in Meta-Analyses 

Michel et al., 2005 

800 mg/day (CS 4&6) 

150/150 

62/63 51/52 27.7 ± 

5.2/28.1 ± 5.5 

1o K-L 

All: 1-3 (100) 

NR (0-10) 

2.5/2.7 

(0-10) 2.1/2.5 

Uebelhart et al., 2004 

800 mg/day (CS 4&6) 

54/56 63/64 80/82 NR 1o K-L 

1 (7/6) 2 (32/33) 3 (15/17) 

4.2/4.4 58.8/61.1 

*

All values are mean ± SD unless otherwise noted; 

†ACR criteria; 

ACR: American College of Rheumatology; BMI: body-mass index; CS: chondroitin sulfate; Dis: disease; K-L: Kellgren-Lawrence criteria; LI: Lequesne 

reported; Pl: placebo; rng: range; Tx: treatment; VAS: visual analog scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; 

82
Table 36. Baseline characteristics of randomized trials of glucosamine plus chondroitin treatment that meet protocol selection 

Study 

Dose (Type) N Tx/Pl 

Mn Age Tx/Pl (yrs) 

Female Pts (%) Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl OA Diag†

OA Stage  (%Tx/ %Pl) 

Mn Dis Duration Tx/Pl (yrs) 

Mn VAS Movement (mm) Tx/Pl 

Mn VAS Rest (mm) Tx/Pl 

Mn WOMAC Pain Tx/Pl 

Mn WOMAC Function Tx/Pl 

Mn WOMAStiffneTx/Pl 

Clegg et al., 2006 [GAIT] 

1,200 mg/day (CS) 

318/313 58/58 64/64 32.0 ± 

7.6/31.9 ± 7.3 

1o K-L 

2 (59/57) 

9.7/9.5 (0-500) 

235.3/ 237.1 

(0-1700) 778.9/ 765.8 

(0-200) 106.6/ 106.6 

Das and Hammad, 2000 

1,600 

mg/day 

(CS) 

46/47 64/66 72/78 30.5 ± 

1.0/30.2 ± 0.9 (SEM) 

1o/2o K-L 2/3 

(72/83) K-L 4 (28/17) 

5.6/7.4 

*

 All values are mean ± SD unless otherwise noted; 

† ACR criteria; ACR: American College of Rheumatology; BMI: body-mass index; CS: chondroitin sulfate; Dis: disease; K-L: Kellgren-Lawrence criteria; LI: Lequesne 

reported; Pl: placebo; rng: range; SEM: standard error of the mean; Tx: treatment; VAS: visual analog scale; WOMAC: Western Ontario and McMaster U

Index; 

83
84 

Table 37. Quality ratings of randomized trials of glucosamine that meet protocol selection criteria 

Study 

Initial 

Assembly 

of Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance of 

Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Studies Included in Meta-Analyses 

McAlindon et al., 

2004 N*

 Y Y Y Y Fair 

Usha and Naidu,, 

2004 N†

 N Y Y Y Poor 

Hughes and Carr, 

2002 Y Y Y Y Y Good 

Pavelka et al., 2002 Y N Y Y Y Fair 

Reginster et al., 

2001 Y N Y Y Y Fair 

Rindone et al., 

2000 Y Y Y Y N‡

 Poor 

Houpt et al., 1999 Y§ Y Y Y Y Good 

Rovati et al., 1997 NR** NR NR NR NR ? 

Noack et al., 1994 ? Y N Y N†† Poor 

Pujalte et al., 1980 N‡ N N Y N Poor 

Additional Studies not Included in Meta-Analyses 

Herrero-Beaumont 

et al., 2007 Y N Y Y Y Fair 

Clegg et al., 2006 Y Y Y Y Y Good 

Das and Hammad, 

2000§§ Y Y Y Y Y Good 

*

 Did not report allocation concealment specifically, but Internet-based protocol should have sufficed; statistically significant (p<.05) 

differences in sex (71% female in placebo group versus 57% in glucosamine group); NSAID use (87% versus 74% in placebo 

versus glucosamine group); BMI (34.1 versus 31.0 in placebo versus glucosamine group) †

 Group characteristics not reported extensively, in particular OA grade; no mention of allocation concealment, although ITT 

analysis was specified 

‡

 No ITT analysis or description of allocation concealment; specifically analyzed data on completers only §

 Patients recruited to study via newspaper advertisement, self-reporting at least “moderate” knee pain, so may not be comparable 

to typical OA population 

** Abstract that does not present sufficient data to determine a quality rating 

†† Described as double-blind design, but did not mention allocation concealment, used “responders” rate derived from drop in 

Lequesne index scores as primary beneficial outcome 

§§ Combination glucosamine plus chondroitin study 

 
85 

Chondroitin. As shown in Table 38, two single-agent trials were judged as “good” quality; 

two were “fair,” and, 4 were “poor.” The failure to use allocation concealment and ITT analysis 

was a factor in all 4 poor-quality studies. 

Table 38. Quality ratings of randomized trials of chondroitin that meet protocol selection criteria 

Study 

Initial 

Assembly 

of Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance of 

Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Studies Included in Meta-Analyses 

Mazieres et 

al., 2001 Y Y Y Y Y Good 

Bourgeois et 

al., 1998 ?*

 Y Y Y Y Fair 

Bucsi and 

Poor, 1998 ?†

 Y Y Y N† Poor 

Conrozier, 

1998 ?c

 ? Y Y ? c Poor 

Uebelhart et 

al., 1998 ?†

 Y Y Y N† Poor 

L’Hirondel, 

1992 N‡

 ?‡ Y Y N‡ Poor 

Additional Studies

Michel et al., 

2005 Y N§

 Y Y Y Fair 

Uebelhart et 

al., 2004 Y Y Y Y Y Good 

*

Did not report allocation concealment, reported ITT analysis, but presented data on loss to percent due only to adverse events (8 

total across all 3 groups) with no mention of effect on composition of treatment groups 

†

Did not report allocation concealment or specify ITT analysis ‡

No demographic details shown, statistical measures of dispersion not provided, allocation concealment not specified, ITT analysis 

unclear 

§

Although 27% of pts dropped out, the completers did not differ statistically from the ITT in any parameter 

 Summary of Meta-Analyses. Information on the results of the MAs is summarized below. 

Study details are summarized in Appendix C*, Table IIA. 

 Bjordal, Klovning, Ljunggren, et al. (2006). Bjordal, Klovning, Ljunggren, et al. (2006) 

focused on placebo-controlled RCTs that reported on pain intensity (VAS global or walking 

pain, WOMAC pain subscale) within 4–12 weeks of treatment start. It was rated a 7 on the 

Oxman and Guyatt instrument (Table 27). 

Seven primary studies of glucosamine and 6 of chondroitin were pooled separately, as shown 

in Table 39. Because no evidence of heterogeneity was found, Bjordal, Klovning, Ljunggren, et 

al. (2006) used a fixed-effects model to pool WMDs and did not perform sensitivity analyses. 

The WMD for glucosamine ranged from 0.1 to 7.5 mm among individual studies, with a pooled 

WMD of -4.7 mm (95 percent CI: -0.3, -9.1). The WMD from 6 studies of chondroitin ranged 

from -0.4 (favoring placebo) to -6.5, with a pooled WMD of -3.7 mm (95 percent CI: -0.3, 

-7.0) at a best time point of 3.6 weeks. 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
86 

Table 39. Bjordal, Klovning, Ljunggren, et al. (2006) meta-analysis clinical outcomes 

Compound 

No. 

RCTs 

No. 

Treated 

Subjects 

Mean 

Study 

Quality* I

2 

(%) 

Pooling 

Metric 

(model) 

Pooled 

Result†

 

(mm) 

95% 

CI p value 

GH/GS 7 401 3.6 0 WMD 

(FE) 

-4.7 -0.3, -9.1 NR 

CS 6 362 3.5 0 WMD 

(FE) 

-3.7 -0.3, -7.0 NR 

*

Study quality rated according to 5-point Jadad scale 

†

100 mm VAS, negative pooled result indicates improvement 

CI: confidence interval; CS: chondroitin sulfate; FE: fixed effects; GH: glucosamine hydrochloride; GS: glucosamine sulfate; NR: 

not reported; WMD: weighted mean difference; 

 The investigators assessed the methodologic quality of the trials using the Jadad method, 

with scores that ranged from 3 to 5. Studies were flawed by failure in concealment of allocation, 

handling of withdrawals and use of intention-to-treat analyses (Tables 37 and 38). Four of the 

chondroitin trials were funded by pharmaceutical companies (Bourgeois, Chales, Dehais, et al., 

1998; Bucsi and Poor, 1998; Uebelhart, Thonar, Delmas, et al., 1998; Morreale, Manopulo, 

Galati, et al., 1996). Bjordal, Klovning, Ljunggren, et al. (2006) did not test for publication bias. 

 This MA included two studies that do not fit selection criteria for this Report. In one trial, 38 

percent of patients had hip OA (Mazieres, Loyau, Menkes, et al., 1992); in the second, an active 

NSAID control (diclofenac) was used (Morreale, Manopulo, Galati, et al., 1996). The Mazieres 

trial yielded a negative WMD, whereas the Morreale trial produced a positive WMD. Thus, we 

performed a sensitivity analysis, which confirmed that exclusion of both trials would not 

significantly affect the overall result or direction of this MA.*

 Bjordal, Klovning, Ljunggren, et 

al. (2006) excluded five studies that meet our study selection criteria, but the effect is unknown.† 

Comment. Bjordal and colleagues (2006) reported the results of separate meta-analyses of 

glucosamine or chondroitin on pain due to knee OA. Overall, in terms of the treatment 

parameters, disease, patient characteristics, and outcomes, their focus was compatible with the 

aims of this Evidence Report. 

 The Oxman and Guyatt quality rating for this MA (7) suggests it was not biased by design or 

analytic methods. However, Bjordal did not perform subgroup or sensitivity analyses of 

individual study quality parameters, such as the adequacy of allocation concealment or use of 

ITT analysis. Subgroup and sensitivity analyses are necessary in a MA to formally explore the 

influence of bias secondary to poor study quality, even in the documented absence of significant 

heterogeneity. 

 In contrast to the other MAs in which results were unitless SMDs, or effect sizes, Bjordal and 

colleagues (2006) used a WMD based on a 100-mm VAS for pain. Because a WMD uses the 

same scale as the original outcome data, the results have direct clinical meaning. The authors 

further interpreted their MAs in the context of a clinically meaningful benefit, defined as a 

minimal perceptible improvement threshold of 10 mm and a minimal clinically important 

improvement threshold of 20 mm. Thus, even though the pooled results were statistically 

significant, the WMDs and 95 percent CIs were below either clinically meaningful threshold. It 

may be concluded that treatment with glucosamine or chondroitin does not reach a level of 

 

*

 WMD = -3.94 (95 % CI = -0.03, -7.8) p=.048 

†

 Pavelka, Gatterova, Olejarova, et al., 2002; Reginster, Deroisy, Rovati, et al., 2001; Rovati, 1997; Conrozier, 1998; L’Hirondel, 

1992 
87 

clinical importance in relieving pain associated with mild-to-moderate knee OA over the 4- to 

12-week treatment period studied. 

 Towheed, Maxwell, Anastassiades, et al. (2006). This is the largest MA available on 

glucosamine as sole therapy for OA of the knee. A total of 20 double-blinded, placebo- or 

active-controlled RCTs were included that reported on glucosamine sulfate or glucosamine 

hydrochloride administered orally or parenterally to patients with primary or secondary OA at 

any site except temporomandibular joint (TMJ). We rated it a 7 on the Oxman and Guyatt scale, 

the highest quality level. 

Table 40 shows SMDs for glucosamine versus placebo. The mean Jadad quality scores 

ranged from 3.9 to 4.8. A random effects model was used for two comparisons (pain, LI) 

because significant interstudy heterogeneity was detected, and a fixed effects model was used for 

Table 40. Towheed, Maxwell, Anastassiades, et al. (2006) meta-analysis outcomes 

Outcome Measure 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality* I

2

(%) 

Pooling 

Metric 

(model) 

Pooled 

Result†

 95%CI p value 

Pain‡ 15 1,481 3.9 88.5 SMD 

(RE) 

-0.61 -0.95, -0.28 .0003 

Lequesne index 4 741 4.8 89.4 SMD 

(RE) 

-0.51 -0.96, -0.05 .03 

WOMAC pain 7 955 4.4 0.0 SMD 

(FE) 

-0.04 -0.17, 0.09 .5 

WOMAC stiffness 5 538 4.4 14.3 SMD 

(FE) 

-0.07 -0.21, 0.08 .4 

WOMAC function 6 750 4.3 0.0 SMD 

(FE) 

-0.07 -0.21, 0.08 .4 

WOMAC total 5 672 4.4 0.0 SMD 

(FE) 

-0.15 -0.30, 0.00 .06 

Adverse events (AEs) 14 1,685 3.9 0.0 RR 

(FE) 

0.97 0.88, 1.08 .6 

Withdrawals due to AEs 17 1,908 4.0 0.0 RR 

(FE) 

0.82 0.56, 1.21 .3 

*

Study quality rated according to 5-point Jadad scale 

†

negative pooled result indicates improvement 

‡

Composite including WOMAC pain (n=6 trials), scalar pain otherwise not defined (n=6), VAS pain (n=3) 

CI: confidence interval; FE: fixed effects; RE: random effects; RR: relative risk; SMD: standardized mean difference; 

the other comparisons. Statistically significant results were reported for two analyses, a 

composite measurement of pain (SMD: -0.61; 95 percent CI: -0.95, -0.28), and Lequesne Index 

(SMD: -0.51; 95 percent CI: -0.96, -0.05). None of the pooled results for other outcomes were 

statistically significant, including the relative risk for adverse events and for study withdrawals 

due to adverse events. 

 Subgroup analysis showed statistically favorable results for the composite pain outcome in 

placebo-controlled trials that used Rotta glucosamine sulfate or were otherwise associated with 

Rotta Research Laboratorium (SMD: -1.31; 95 percent CI: -1.99, -0.64). A second subgroup 

analysis of non-Rotta related studies was not significant (SMD: -0.15; 95 percent CI: -0.35, 

0.05). Sensitivity analysis of pooled results from studies that reported adequate allocation 

concealment (Table 41) suggested no difference between glucosamine and placebo in relieving 

pain (SMD: -0.19; 95 percent CI: -0.50, 0.11). 
88 

Table 41. Towheed, Maxwell, Anastassiades, et al. (2006) sensitivity and subgroup analyses for pooled 

composite pain measurement

Variable 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality* 

I

2 

(%) 

Pooling 

Metric 

Pooled 

Result† 95% CI p value 

Rotta product 7 730 3.8 93.3 SMD 

(RE) 

-1.31 -1.99, -

0.64 

.0001 

Non-Rotta product 8 751 4.0 43.6 SMD 

(RE) 

-0.15 -0.35, 0.05 .1 

Adequate allocation 

concealment 

8 1,111 4.5 83.4 SMD 

(RE) 

-0.19 -0.50, 0.11 .2 

*

Study quality rated according to 5-point Jadad scale 

†

negative pooled result indicates improvement 

CI: confidence interval;

 FE: fixed effects; SMD: standardized mean difference; RE: random effects; 

 None of the analyses that used other outcome measures (WOMAC subscales or Lequesne 

Index) showed statistically significant results in sensitivity analyses. 

 Comment. The analysis by Towheed, Maxwell, Anastassiades, et al. (2006) consists of 38 

separate meta-analyses based on different groupings of 20 RCTs. In the key analysis of pain, the 

pooled SMD from 15 RCTs was equated with a difference in the change from baseline of 28 

percent, suggesting a moderate effect. However, the authors did not test for publication bias, 

which could skew results. Broader study inclusion and substantial interstudy heterogeneity 

associated with the SMDs for pain (I2

 = 88.5 percent) and Lequesne Index (I2 = 89.4 percent) 

reflect differences in disease site, route of administration, study duration, and the use of 

reference and placebo controls. 

 In a subgroup analysis of the potential effect of Rotta glucosamine sulfate, or indirectly Rotta 

sponsorship, Towheed and colleagues pooled studies that involved parenteral routes of 

administration, disease sites other than the knee, and had wide variation in size and duration. 

Substantial heterogeneity (I2

 = 93.3 percent) and lower mean study quality score causes 

uncertainty in the results of this analysis. The authors explored a few potential sources of 

heterogeneity, but did not specifically assess the impact of ITT analysis and whether trials were 

industry-funded. A second sensitivity analysis showed a nonsignificant effect of glucosamine on 

pain in studies with adequate allocation concealment, suggesting bias secondary to study quality. 

However, interpretation of these results also is influenced by substantial interstudy heterogeneity 

(I2

 = 83.4 percent). 

 The authors conclude that there is a statistically significant effect in favor of glucosamine 

versus placebo in patients with OA. We believe this conclusion is compromised by interstudy 

heterogeneity and variability with respect to disease site, route of administration, study duration, 

and the use of active controls and placebo controls. The pooled results were reported as SMDs, 

which can be difficult to interpret. Finally, concern exists over the thoroughness of exploration 

of heterogeneity in this meta-analysis, particularly the influence of ITT analysis and industryfunding. While this meta-analysis had some strong methodologic characteristics, concerns noted 

here call its conclusions into question. 

 Poolsup, Suthisisang, Channark, et al. (2005). The main efficacy outcome of this 

glucosamine MA was joint space narrowing (JSN) in the signal joint, reported in terms of 

relative risk of disease progression, and defined as the proportion of patients with JSN >0.5 mm. 

Its Oxman and Guyatt score of 3 (major flaws) was primarily due to limitations in study selection 

criteria (Table 27). 

As shown in the Table 42, pooled SMDs for WOMAC pain (- 0.41, 95 percent CI: -0.21, 

-0.60) and function (0.46, 95 percent CI: -0.27, -0.66) were statistically significant versus 
89 

placebo at 3 years (p<.0001). No significant differences were noted (RR = 1.02; 95 percent CI: 

0.93, 1.11) in the risk of adverse events including abdominal pain, dyspepsia, diarrhea, increased 

blood pressure, fatigue, and rash. Mean Jadad study quality scores of 4.5 were reported. 

Table 42. Poolsup, Suthisisang, Channark, et al. (2005) meta-analysis clinical outcomes 

Outcome Measure 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality* I

2 

(%) 

Pooling 

Metric 

(model) 

Pooled 

Result †

95% 

CI p value c

WOMAC pain 2 414 4.5 0 SMD 

(RE) 

-0.41 -0.21, -0.60 <.0001 

WOMAC function 2 414 4.5 0 SMD 

(RE) 

-0.46 -0.27, -0.66 <.0001 

Adverse events 

(AEs) 

2 414 4.5 0 RR 

(RE) 

-1.02 -0.93, -1.11 NSD 

*

Study quality rated according to 5-point Jadad scale 

†

negative pooled result indicates improvement 

CI: confidence interval; NSD: no significant difference; RR: relative risk; RE: random effects; SMD: standardized mean difference; 

 Comment. Poolsup, Suthisisang, Channark, et al., (2005) focused on long-term structural 

progression of knee OA, rather than symptomatic outcomes that are the focus of this Evidence 

Report. They reported statistically significant pooled SMDs for two secondary outcomes, 

WOMAC pain and function, based on data from two RCTs (Pavelka, Gatterova, Olejarova, et al., 

2002; Reginster, Deroisy, Rovati, et al., 2001). Fourteen studies were excluded because they did 

not report structural outcome data.* While this MA was rated low in quality, the 2 trials included 

were fair quality, with no interstudy heterogeneity reported. Both were sponsored by Rotta.

 The conclusion that glucosamine sulfate possesses moderate efficacy in improving symptoms 

of OA of the knee is limited by the small number of trials and subjects included. Given the 

structural focus of this MA and narrow inclusion criteria, we conclude that it does not provide 

relevant information to address the Key Questions of this Evidence Report. 

 Richy, Bruyere, Ethgen, et al. (2003). This MA included a total of 15 double-blind, placebocontrolled RCTs of glucosamine or chondroitin that lasted at least 4 weeks. It is unique in that 

the authors pooled studies of glucosamine with those of chondroitin, which was justified on 

absence of efficacy differences (Table 27). Despite this design limitation, the fundamental 

methodological characteristics were sound (Table 28), with an Oxman and Guyatt score of 5. 

 As shown in Table 43, twelve studies for the main outcome of VAS pain showed a pooled 

SMD (random effects model) of -0.45 (95 percent CI: -0.33, -0.57), with a range among 

individual studies between -0.06 and -1.02. Pooled data from 2 to 11 trials yielded statistically 

significant results that favored glucosamine and chondroitin treatment for the WOMAC total 

score, Lequesne Index, mobility, joint space narrowing, and being a responder. The absolute risk 

difference for being a responder was 20 percent (95 percent CI: 15 percent to 26 percent), which 

translates to a NNT of about 5. There was no significant difference in adverse events. 

 The investigators used the Jadad method to determine mean scores of the pooled RCTs that 

ranged from 3.8 to 4.5. In the presence of interstudy heterogeneity (I2

 not reported), a random 

effects model was used to pool data. Tests for publication bias with funnel plots and Egger’s 

 

*

 Cohen, Wolfe, and Mai, 2003; Das and Hammad, 2000; Houpt, McMillan, Wein, et al., 1999; Hughes and Carr, 2002; Leffler, 

Philippi, Leffler, et al., 1999; Muller-Fassbender, Bach, Haase, et al., 1994; Noack, Fischer, Forster, et al., 1994; Pujalte, Llavore, 

Ylescupidez 1980; Qiu, Gao, Giacovelli, et al., 1998; Reichelt, Forster, Fischer, et al., 1994; Rindone, Hiller, Collacott, et al., 

2000; Vajanetra, 1984; Vajaradul, 1981; Lopes Vaz, 1982 
90 

linear regression test revealed a light asymmetry to the right side, suggesting that more studies of 

small sample size were associated with high effect sizes than with small effects. 

 Table 43. Richy, Bruyere, Ethgen, et al. (2003) meta-analysis clinical outcomes 

Outcome 

Measure 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality* I

2

(%) 

Pooling 

Metric 

(model) 

Pooled 

Result †

95% 

CI p value 

VAS pain 12 1267 3.8 NR 

SMD 

(RE) -0.45 -0.33, -0.57 <.001 

WOMAC 

pain 2 414 4.5 NR

SMD 

(FE) -0.30 -0.11, -0.49 <.001 

Lequesne 

index 10 1582 3.8 NR

SMD 

(FE) -0.43 -0.32, -0.54 <.001 

Mobility (not 

defined) 3 150 4.0 NR

SMD 

(FE) -0.59 -0.25, -0.92 <.001 

Responder 9 1159 3.9 NR

RR 

(FE) -1.59 -1.39, -1.83 <.001 

Adverse 

events 11 1770 4.1 NR

RR 

(RE) -0.80 -0.59, -1.08 .15 *

Study quality rated according to 5-point Jadad scale 

†

negative pooled result indicates improvement 

CI: confidence interval; FE: fixed effects; NR: not reported; RE: random effects; RR: relative risk; SMD: standardized 

mean difference; 

 Comment. Richy, Bruyere, Ethgen, et al. (2003) pooled glucosamine and chondroitin studies. 

They assert that the robustness of their findings, the conservative approach used to pool data, and 

the use of unpublished data constitute definitive evidence that glucosamine and chondroitin are 

beneficial. However, the pooled results from this MA are not useful for our purposes as they do 

not individually report the efficacy of these agents as sole therapy. 

 Leeb, Schweitzer, Montag, et al. (2000). Leeb, Schweitzer, Montag, et al. (2000) included 7 

double-blind, placebo-controlled RCTs of oral chondroitin that lasted 120 days or more. Their 

selection criteria specified that trials contain data on at least half of the efficacy variables 

proposed by EULAR (Lequesne Index, investigator’s global assessment, VAS for pain, patient’s 

global assessment) or SADOA guidelines (VAS for pain, functional index, Doyle index, loss of 

mobility, NSAID or analgesic consumption, number of flares over time, investigator’s global 

assessment, quality of life scale, walking or stair climbing time) in patients with knee or hip OA. 

Its low Oxman and Guyatt score (3) was primarily due to limited details on language restrictions 

and failure to seek unpublished data (Table 27). The methodologic aspects were poorly reported 

(Table 28). 

 Pooled results from all 7 included studies (Table 44) yielded a statistically significant SMD 

that favored chondroitin for VAS pain (mean SMD -0.9, 42 percent of baseline). Data pooled 

from 6 studies showed a statistically significant reduction in the Lequesne index amounting to 51 

percent of baseline at 180 days. Because neither SMD was accompanied by an explicit 95 

percent CI, those were estimated from the Forest plots shown in the MA. Adverse effects were 

mild and infrequent in all studies, with no significant difference between chondroitin and placebo 

groups. 

 
91 

Table 44. Leeb, Schweitzer, Montag, et al. (2000) meta-analysis clinical outcomes

Outcome Measure 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality 

I

2

(%) 

Pooling 

Metric 

(model) 

Pooled 

Result* 95% 

CI† p value 

VAS pain 7 699 NR NR 

SMD 

(NR) -0.90 -0.80, -1.0 <.05 

Lequesne index 6 653 NR NR

SMD 

(NR) -0.74 -0.62, -0.80 <.01 *

negative pooled result indicates improvement 

†

estimated from figures in report 

CI: confidence interval; NR: not reported; SMD: standardized mean difference; 

 Based on qualitative review of the RCTs, Leeb and co-workers (2000) asserted that there was 

little interstudy heterogeneity. Furthermore, the authors did not use a validated method such as 

the Jadad score to formally assess study quality. One primary RCT reported on patients with OA 

of the hip (Conrozier and Vignon, 1992), one included patients with OA of the hip and knee 

(Mazieres, Loyau, Menkes, et al., 1992), and one study used a reference intervention (diclofenac) 

in the control group (Morreale, Manopulo, Galati, et al., 1996). All three of these RCTs would 

be excluded by the selection criteria we defined to address the Key Questions of this Report. 

 Comment. Leeb and colleagues (2000) conclude that their results provide evidence for 

significant efficacy of chondroitin sulfate on pain and function in treatment of OA compared to 

placebo in patients followed for 4 months or more. However, these results have little utility for 

our purposes. Most notably, they did not assess the effect of heterogeneity, study quality, 

industry-funding or publication bias on the pooled results. The statistical techniques used to pool 

and analyze extracted data were poorly described. Finally, the selection criteria we defined to 

address the Key Questions in this Report would exclude three of 7 trials included in their MA. 

Given the significant methodological shortcomings, we believe this MA does not support a 

conclusion that chondroitin sulfate is more effective than placebo in therapy of knee OA. 

 McAlindon, LaValley, Gulin, et al. (2000). McAlindon and colleagues (2000) included 15 

double-blind, placebo-controlled RCTs of at least 4 weeks’ duration that compared the efficacy 

of glucosamine or chondroitin in patients with symptomatic OA. Its Oxman and Guyatt quality 

score was 4 (major flaws), due to limitations in the scope of the literature search and possible 

study selection bias (Table 27). The methodologic characteristics are summarized in Table 28. 

The authors used a random effects model to calculate pooled effect sizes based on a 

hierarchy of data for different outcome scales, including VAS pain, WOMAC pain, Lequesne 

Index, mobility, and NSAID use. Table 45 shows pooled data generally for pain outcomes 

extracted from six RCTs of glucosamine, yielding a SMD of -0.44 (95 percent CI: -0.24, -0.64), 

based on individual SMDs that ranged from -0.23 to -1.28. Data from nine individual 

chondroitin sulfate trials yielded a pooled SMD for pain of -0.96 (95 percent CI: -0.63, -1.3), 

with individual SMDs that ranged between -0.53 and -4.56. The authors did not report the 

statistical significance of any SMD. 
92 

Table 45. McAlindon, LaValley, Gulin, et al. (2000) meta-analysis clinical outcomes

Compound 

No. 

RCTs 

No. 

Subjects 

Mean 

Study 

Quality* 

(range) 

Heterogeneity 

(p value)

Pooling 

Metric†

Pooled 

Result‡

95% 

CI p value 

GH/GS 6 911 38 

(12–52) 

NSD SMD -0.44 -0.24, -0.64 NR 

CS 9 799 34 

(14–55) 

<.001 SMD -0.96 -0.63, -1.3 NR 

*

Study quality score based on reported compliance with 14 aspects of clinical trial conduct, ranging from 0 to 68 for negative and 

from 0 to 65 for positive studies, expressed as a percentage of the maximum possible score for each trial †

All results were pooled using a random-effects model; 

‡

negative pooled result indicates improvement 

CI: confidence interval; NR: not reported; NSD: no significant difference; SMD: standardized mean difference; 

 Tests for publication bias (funnel plots) showed statistical evidence of significant bias that 

reflected an absence of trials with both small numbers of participants and small or null treatment 

effects. Assessment of primary study quality showed allocation concealment was frequently 

inadequate and intention-to-treat analysis was rarely performed. 

 Several sensitivity analyses were performed, as shown in Table 46. Pooled effect sizes for 

both compounds were substantially higher with lower-quality trials compared with higher-quality 

trials. Trial size did not significantly influence the SMD calculated for glucosamine, whereas 

this parameter had a substantial influence on the effect size for chondroitin. Adverse events were 

not reported. 

Table 46. McAlindon, LaValley, Gulin, et al. (2000) sensitivity analyses for pooled composite pain 

measurement

Variable 

No. 

RCTs 

No. 

Subjects 

Study 

Quality*

Heterogeneity 

(p value) 

Pooling 

Metric†

Pooled 

Result‡

95% 

CI p value 

Low-quality 

GS/GH trials 

3 403 < 40 NR SMD -0.7 -0.4, -1.0 NR 

High-quality 

GS/GH trials 

3 508 ≥ 40 NR SMD -0.3 0.1, -0.5 NR 

Low-quality 

CS trials 

4 324 < 35 NR SMD -1.7 -0.7, -2.7 NR 

High-quality 

CS trials 

5 475 ≥ 35 NR SMD -0.8 -0.6, -1.0 NR 

Small GS/GH 

trials 

3 175 39 NR SMD -0.5 -0.1, -0.9 NR 

Large GS/GH 

trials 

3 736 36 NR SMD -0.4 -0.1, -0.7 NR 

Small CS 

trials 

4 183 34 NR SMD -1.7 -0.5, -2.8 NR 

Large CS 

trials 

5 616 34 NR SMD -0.8 -0.6, -1.0 NR 

*

Study quality score based on reported compliance with 14 aspects of clinical trial conduct, ranging from 0 to 68 for negative 

and from 0 to 65 for positive studies, expressed as a percentage of the maximum possible score for each trial †

All results were pooled using a random effects model; 

‡

negative pooled result indicates improvement 

CI: confidence interval; NR: not reported; SMD: standardized mean difference; 

One of six glucosamine RCTs involved parenteral administration (Vajaradul, 1981). Two 

chondroitin trials used intramuscular injection (Rovetta, 1991; Kerzberg, Roldan, Castelli, et al., 

1987) and one combined patients with OA of the knee or hip (Mazieres, Loyau, Menkes, et al., 
93 

1992). None of the primary studies reported receiving independent funding from a governmental 

or not-for-profit source. Thirteen of 15 RCTs reported some connection with the drug 

manufacturer. A number of studies relevant to our Report have been subsequently published for 

glucosamine sulfate/glucosamine hydrochloride (Houpt, McMillan, Wein, et al., 1999; Rindone, 

Hiller, Collacott, et al., 2000; Reginster, Deroisy, Rovati, et al., 2001; Pavelka, Gatterova, 

Olejarova, et al., 2002; Hughes and Carr, 2002; Usha and Naidu, 2004; and McAlindon, 

Formica, LaValley, et al., 2004). For chondroitin sulfate, one study was published later 

(Mazieres, Combe, Phan Van, et al., 2001). 

 Comment. The focus of the MA by McAlindon, LaValley, Gulin, et al. (2000) was generally 

comparable to that of our Evidence Report. However, it is limited for our purposes in several 

respects. First, the Oxman and Guyatt score (4) reflects major flaws in its design and conduct, 

primarily ascribed to study selection bias. McAlindon and colleagues included several trials that 

do not meet our selection criteria with respect to the route of drug administration and disease 

site. Second, sensitivity analyses suggested that heterogeneity due to differences in the quality 

and size of the primary studies differentially and substantially influenced the size of pooled 

SMDs depending on the intervention. Third, the presence of statistical evidence of bias in a 

funnel plot suggests caution is warranted in interpreting the results of this MA. The genesis of 

bias in this MA is unclear but could be a function of selective publication of positive trials, post 

hoc selection of study outcome measures, and premature trial termination once a positive 

outcome is achieved. Finally, the use of SMDs complicates interpretation and direct clinical 

application of the results. 

 The MA authors conclude that glucosamine and chondroitin may have efficacy in treating 

OA symptoms and are safe, although they conceded the necessity for additional high-quality, 

independent studies to determine the actual clinical effectiveness of these preparations as therapy 

for symptomatic OA. Given the uncertainties outlined, we conclude that this MA does not 

provide sufficient evidence to show a clinical benefit for glucosamine or chondroitin treatment of 

OA. 

 Summary of Additional Randomized Studies. We identified 5 placebo-controlled RCTs 

that were not pooled in the published MAs (Clegg, Reda, Harris, et al., 2006; Michel, Stucki, 

Frey, et al., 2005; Uebelhart, Malaise, Marcolongo, et al., 2004; Das and Hammad, 2000; 

Herrero-Beaumont, Roman, Trabado, et al., 2007). It should be noted that one of these studies 

(Das and Hammad, 2000) was excluded from the MA published by Poolsup and colleagues 

(2005). Descriptors of these studies can be found in Tables 31–33 (outcome measures), 34–36 

(baseline characteristics), and 37 and 38 (study quality). Study details are summarized in 

Appendix C*

, Tables IIB and IIC. 

 Clegg, Reda, Harris, et al. (2006; GAIT). The “Glucosamine/chondroitin Arthritis 

Intervention Trial” or “GAIT” (Clegg, Reda, Harris, et al., 2006) was a double-dummy, doubleblinded, placebo- and active-controlled NIH-funded RCT designed to evaluate the efficacy and 

safety of glucosamine, chondroitin, and the combination of the two versus placebo and 

celecoxib. Its design characteristics are detailed in Appendix C*, Table IIB, Part 1. Patients had 

primary OA of the knee ranging from mild to severe as per the Kellgren-Lawrence radiological 

scale and American Rheumatism Association (ARA) criteria. Our quality criteria suggest it was 

of “good” quality (Table 37). An absolute increase in the response rate of 15 percent, as 

compared with the rate in the placebo group, was considered indicative of a clinically 

meaningful treatment effect. Pair-wise comparisons between study arms used the Bonferroni 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
94 

convention to correct for multiple comparisons. Statistical significance was defined as an α value 

of 0.017 for each comparison with placebo, based on an overall α value of 0.05 using a two-sided 

chi-square test. The authors also performed a stratified subgroup comparison between treatment 

and control arms of patients with moderate-to-severe WOMAC pain. These results are 

considered in Key Question 3 in this Report. 

 Treatments included glucosamine hydrochloride 1,500 mg/day, chondroitin sulfate 1,200 

mg/day, both agents together at same doses, or a single daily dose of celecoxib 200 mg. The 

celecoxib arm serves to internally validate the results. The study was conducted under an 

Investigational New Drug (IND) application, subject to pharmaceutical regulation by the U.S. 

FDA. Patient enrollment and disposition are summarized in Appendix C*

, Table IIB, Part 2, and 

outcomes measures are summarized in Appendix C*, Table IIB, Part 3. 

A shown in Table 47, when considering all randomized patients, the rate of response to 

glucosamine and chondroitin, either alone or in combination, was not significantly higher than 

the rate of response to placebo for the primary outcome. A statistically significant effect 

(p=.008) on the primary outcome was observed in the celecoxib control group compared to 

placebo. The OMERACT-OARSI response rates exhibited a similar pattern, with differences 

between the placebo group and the three intervention groups not reaching statistical significance. 

The rate of response to celecoxib did reach statistical significance (p=.007) compared with 

placebo for the OMERACT-OARSI response rate. 

Table 47. Key health outcomes of all randomized patients in GAIT 

Primary Outcome Secondary Outcomes 

Intervention 20% decrease in 

WOMAC pain 

score, % (n) 

p value OMERACT-OARSI 

response, % 

(n) 

p value 50% decrease 

in WOMAC 

pain score, % 

(n) 

p value 

Placebo 60.1% (188/313) 56.9% (178/313) 42.2% 

(132/313) 

Glucosamine 64% (203/317) p=.30 60.6% (192/317) p=.35 46.4% 

(147/317) 

p=.29 

Chondroitin 65.4% (208/318) p=.17 63.5% (202/318) p=.09 42.1% 

(134/318) 

p=.99 

Glucosamine 

plus 

Chondroitin 

66.6% (211/317) p=.09 65.6% (208/317) p=.02*

 46.4% 

(147/317) 

p=.29 

Celecoxib 70.1% (223/318) p=.008†

 67.3% (214/318) p=0.007† 50% (159/318) p=0.05*

*p <0.05 for the comparison with placebo 

†p <0.017 for the comparison with placebo 

OMERACT-OARSI: Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society; WOMAC: 

Western Ontario and McMaster Universities; 

 As shown in Table 48, analysis of the primary outcome in the patients with mild pain (78% 

of the total patient sample) showed smaller treatment effects, none of which were of a clinically 

beneficial magnitude or statistically significant. 

 

*

 Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
95 

Table 48. GAIT patients with mild pain (WOMAC pain score 125–300) 

Primary Outcome Secondary Outcomes 

Intervention 20% decrease in 

WOMAC pain 

score, % (n) 

p value OMERACTOARSI 

response, % 

(n) 

p value 50% decrease 

in WOMAC 

pain score, % 

(n) 

p value 

Placebo 61.7% (150/243) 59.3% 

(144/243) 

 44.9% (109/243) 

Glucosamine 63.6% (157/247) p=.67 59.1% 

(146/247) 

p=.97 47.8% (118/247) p=.52 

Chondroitin 66.5% (165/248) p=.27 64.9% 

(161/248) 

p=.20 44.5% (109/248) p=.84 

Glucosamine 

plus Chondroitin 

62.9% (154/245) p=.80 62.9% 

(154/245) 

p=.42 44.5% (109/245) p=.94 

Celecoxib 70.3% (173/246) p=.04*

 67.5% 

(166/246) 

p=.06 51.2% (126/246) p=.16 

*p<.05 for the comparison with placebo 

OMERACT-OARSI: Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society; WOMAC: 

Western Ontario and McMaster Universities; 

 Comment. This is the largest (n=1,583) independently funded RCT of glucosamine and 

chondroitin that has been reported. It is a good-quality study, with a well-defined, clinically 

relevant subject sample. The 24-week treatment period is adequate to assess long-term benefit 

from the supplements. The lack of a significant response to either supplement alone, or the 

combination, in the context of the significant effect in the celecoxib-treated group, provides 

compelling evidence that neither glucosamine nor chondroitin provide clinically meaningful pain 

relief compared to placebo in patients with OA of the knee. A similar pattern of response to 

glucosamine plus chondroitin was observed for secondary outcomes, in particular the 

OMERACT-OARSI response rate and the 50 percent decrease in WOMAC pain among all 

randomized patients. None of the interventions had a significant effect among patients with mild 

pain. 

 It has been suggested that failure to demonstrate a statistically significant improvement in the 

main outcome in GAIT is related to use of glucosamine hydrochloride rather than glucosamine 

sulfate manufactured by Rotta Research Laboratorium (Hochberg, 2006). It also has been 

speculated that the positive result with combined therapy in GAIT could be related to co-delivery 

of sulfate from chondroitin sulfate and glucosamine, but it is unclear if the doses used would be 

clinically meaningful (Altman, Abramson, Bruyere, et al., 2006). GAIT provides no evidence to 

address either of those hypotheses. 

 Michel, Stucki, Frey, et al. (2005). This was a 24-month, independently funded, doubleblind, placebo-controlled RCT of chondroitin 4/6 sulfate. Patients ranged in age from 40 to 85 

years, with clinically symptomatic, primary knee OA of Kellgren-Lawrence grades 1–3 

diagnosed according to the ACR clinical and radiographic criteria. Patients with KellgrenLawrence grade 4 OA were excluded. Among 341 patients screened, 300 entered the study (150 

given chondroitin sulfate (Condrosulf, IBSA, Lugano, Switzerland) and 150 given placebo) and 

were included in the ITT analysis. A total of 27 percent of the patients dropped out, which was 

reported to have no significant impact on the composition of the groups. The clinical outcomes 

scored in this trial are shown in Table 32, its baseline characteristics are shown in Table 35, and 

its quality rating (fair) is outlined in Table 38. 

 As shown in Table 49, over the 2-year study period, there were no significant differences 

from baseline between the components of the WOMAC score or the total WOMAC score in the 
96 

treatment and placebo groups. No statistically significant differences were observed between the 

groups in the frequency of adverse events, such as abdominal pain, nausea, or headache. 

Table 49. Outcomes from Michel, Stucki, Frey, et al. (2005) 

Change from Baseline (%)* Outcome 

Placebo Group Treatment Group 

WOMAC pain -6.2 -11.0 

WOMAC stiffness -4.6 -7.8 

WOMAC function 5.9 -0.8 

WOMAC total 2.1 -3.9 

Adverse events 67 total, none serious 58 total, none serious 

* No significant differences between groups for any score 

 

 Comment. This RCT showed no significant difference in WOMAC pain, stiffness, function, 

or total scores with chondroitin therapy for 24 months versus placebo. It was of adequate design 

and execution to address the clinical efficacy of the intervention. Patients were generally 

representative of a typical OAK population. However, the relatively low mean pain score of 

patients at entry may have limited the ability to detect meaningful improvements. 

 Uebelhart, Malaise, Marcolongo, et al. (2004). This multicenter, double-blind placebocontrolled randomized trial involved two 3-month intermittent treatment periods with 

chondroitin sulfate (Condrosulf, IBSA, Lugano, Switzerland) to test the symptomatic efficacy of 

the study drug versus placebo. The clinical outcomes scored in this trial are shown in Table 32, 

its baseline characteristics are shown in Table 35, and its quality rating (good) is outlined in 

Table 38. 

 A total of 120 patients age 40 or over with clinically symptomatic, idiopathic OA of the knee 

according to ACR criteria were enrolled. Patients with Kellgren-Lawrence grade 1-3 disease and 

a minimum 25 percent remaining medial femoro-tibial joint space at entry were eligible. 

Treatment was administered for two periods, the first from entry to month 3 and the second 

between months 6 and 9; no treatment of any kind was given between months 3-6 and 9-12. 

 A total of 110 patients (54 chondroitin, 56 placebo) were included in the ITT analysis. Ten 

patients who did not take any dose of drug or report any data were lost to followup and excluded 

from the ITT analysis. A total of 43 in the chondroitin and 41 in the placebo group completed 

the study. 

 As shown in Table 50, the mean decrease in the primary outcome, Lequesne’s algofunctional 

index, was statistically significant after 12 months of chondroitin compared to placebo. This 

represented a 36 percent decline from baseline for treatment compared with 23 percent for 

placebo. A secondary outcome, Huskisson’s VAS for pain, fell 42 percent in the chondroitin 

group versus 25 percent in the placebo group, representing statistically significant differences 

from baseline and between groups (p<.05). Minor adverse events occurred, with a frequency of 

4 in the chondroitin group and 6 in the placebo recipients. The global assessment of tolerance 

expressed by patients and physicians was very similar, with no difference observed between the 

two groups. 
97 

Table 50. Outcomes from Uebelhart, Malaise, Marcolongo, et al. (2004)

Mean (± SD) Outcome 

Baseline 3 mos 6 mos 9 mos 12 mos 

Outcome 

Pl CS Pl CS Pl CS Pl CS Pl CS 

Lequesne 

Index 

9.1 ± 

3.2 

9.0 ± 

2.8 

7.4 ± 

4.2 

6.8 ± 

3.6 

7.5 ± 

4.0 

6.7 ± 

3.5 

7.0 ± 

3.9 

6.0 ± 

3.8 * 7.0 ± 

3.9 

5.8 ± 

3.6**

VAS (mm) 61.1 ± 

19.0 

58.8 ±

15.5 

49.1 ±

24.5 

42.9 ± 

23.2 

47.6 ± 

26.9 

40.5 ± 

23.9 

46.1 ± 

27.2 

34.0 ± 

26.4 * 45.8 ± 

27.6 

34.3 ± 

27.4*

*

 p<.05 vs. placebo; ** p<.01 (ANOVA between groups) 

 

 Comment. These results suggest 9 to 12 months of therapy with chondroitin may reduce pain 

and improve function in symptomatic OA of the knee. Chondroitin treatment was associated 

with few minor adverse events and an overall tolerable global assessment. The results are 

suggestive, but the small size of this trial limits its conclusions and generalizability. 

 Das and Hammad (2000). Patients in this 6-month, industry-funded (Nutramax Laboratories, 

Inc., Baltimore, MD), double-blind, placebo-controlled RCT of glucosamine hydrochloride and 

chondroitin sulfate were recruited from the principal investigator’s orthopedic practice through 

newspaper advertisement. The clinical outcomes scored in this trial are shown in Table 33, its 

baseline characteristics are shown in Table 36, and its quality rating (good) is outlined in Table 

37. 

 Ninety-three patients (46 G/C, 47 placebo) age 45 to 75 years were enrolled. All had primary 

OA of the knee with a minimal Lequesne Index score of 7, Kellgren-Lawrence radiographic 

grade 2 or more, and symptoms of more than 6 months duration. Randomization was stratified 

by disease severity according to the Kellgren-Lawrence grade. Analysis was planned a priori to 

be stratified by the Kellgren-Lawrence radiographic grade of OA, with the mild/moderate (2-3) 

group as the primary study population. Thus, of the 46 patients randomized to the intervention, 

33 had Kellgren-Lawrence grade 2-3 OA and 13 had Kellgren-Lawrence grade 4 OA. The 

placebo group had 39 patients with Kellgren-Lawrence grade 2-3 OA and 8 with KellgrenLawrence grade 4 OA. The primary outcome measure was defined as a 25 percent improvement 

in the Lequesne Index, with the total WOMAC score as a secondary outcome. The patient’s 

global assessment of improvement also was recorded. 

 As shown in Table 51, 52 percent of patients with mild/moderate OA of the knee achieved 

the primary outcome versus 28 percent in the placebo recipients (p=.04). There was no 

significant difference among those with severe OA of the knee in this outcome. No statistically 

significant differences were observed between the total WOMAC scores reported for the 

intervention and placebo groups. 

 Seventy percent of treatment recipients with mild-to-moderate OA of the knee reported more 

than 25 percent improvement in their global assessment compared with 46 percent of those given 

placebo (p=.04). In those with severe OA of the knee, the intervention had no impact on the 

global assessment response rate compared to placebo (31 percent versus 38 percent). There was 

a 17 percent incidence of adverse events in treatment recipients, primarily attributed to the GI 

tract, compared with 19 percent in the placebo group (NSD). Four patients dropped out, but all 

who had a baseline visit and received their medications were included in the ITT analysis. 
98 

Table 51. Outcomes from Das and Hammad (2000)

Mild/moderate cases 

Mn (± SEM) 

Severe cases 

Mn (± SEM) 

Outcome Time 

(mos) 

Pl (n=39) GH/CS (n=33) Pl (n=8) GH/CS (n=13) 

Lequesne Index Baseline 

2 

4 

6 

≥ 25% improvement 

10.4 (0.4) 

9.6 (0.5) 

9.2 (0.6) 

9.0 (0.6) 

11 (28%) 

10.2 (0.4) 

8.9 (0.5) 

7.2 (0.6) *

7.4 (0.6)†

15 (52%)†

10.7 (1.2) 

10.1 (1.4) 

9.6 (1.5) 

9.9 (1.6) 

2 (25) 

11.1 (0.80 

10.2 (0.8) 

9.4 (0.9) 

9.6 (1.0) 

3 (23) 

WOMAC total Baseline 

2 

4 

6 

≥ 25% improvement 

944 (55) 

831 (64) 

774 (79) 

724 (87) 

16 (41%) 

908 (71) 

768 (71) 

655 (72) 

626 (77) 

19 (58%) 

1089 (158) 

984 (166) 

900 (174) 

882 (183) 

2 (25%) 

1187 (119) 

1134 (121) 

1041 (126) 

1033 (126) 

4 (31%) *

p=.003;†p=.04 vs. placebo 

 

 Comment. This study was generally well-designed and -conducted. However, its 

conclusions are limited by the small number of patients. The study sample may be self-selected 

due to recruitment through newspaper advertisements, and perhaps not typical of a generalized 

OA of the knee population. The small numbers involved in patients with severe knee OA are 

insufficient to conclude that glucosamine and chondroitin treatment has a differential response in 

mild-to-moderate versus severe disease. 

 Herrero-Beaumont, Roman, Trabado, et al., 2007 (GUIDE). The “Glucosamine Unum in 

Die Efficacy” (GUIDE) trial is a multicenter, placebo-controlled RCT performed in Europe 

using Rotta glucosamine sulfate. A total of 318 patients (88 percent female) with OA of the knee 

(ACR criteria) were randomly allocated to glucosamine 1,500 mg daily, acetaminophen 1000 mg 

three times daily, or a placebo using a double-dummy design. Rescue medication consisted of 

ibuprofen as needed. The primary efficacy measure was the 6-month change in the Lequesne 

Index in the ITT population, using the “last observation carried forward” approach for patients 

who did not complete the study (34 on placebo, 28 each in the glucosamine sulfate and 

acetaminophen groups). Secondary measures included the total WOMAC score and OARSI-A 

responder criteria. 

The groups were comparable at baseline. Statistically significant results were observed in the 

glucosamine group versus placebo in all outcome measures (Table 52). Although the OARSI-A 

response was higher with acetaminophen than placebo, it did not reach the level of statistical 

significance for the other two outcomes. More patients in the placebo group used rescue 

medication than in the other two groups (p=.027 and .045 versus glucosamine sulfate and 

acetaminophen, respectively). No differences in adverse effects were observed. There was a 

substantial withdrawal rate on the order of 25% to 33% among the groups, a factor in the “fair” 

quality rating given this study. 
99 

Table 52. Outcomes from Herrero-Beaumont, Roman, Trabado, et al. (2007; GUIDE) 

Placebo 

(n=104) 

Acetaminophen 

(n=108) 

GS 

(n=106) 

Outcome 

Baseline 6 mos Baseline 6 mos Baseline 6 mos 

Lequesne Index 

(points)* 10.8 

(2.6) 

-1.9 

(-2.6, -1.2) 

11.1 

(2.7) 

-2.7 

(-3.3, -2.1) 

11.0 

(3.1) 

-3.1†

(-3.8, -2.3) 

WOMAC 

(points)* 37.9 

(14.3) 

-8.2 

(-11.3, -5.1) 

40.4 

(14.8) 

-12.3 

(-14.9, -9.7) 

38.3 

(15.2) 

-12.9‡

(-15.6, -10.1) 

OARSI-A responders (%) 21.2 33.3§ 39.6** *

Mean absolute (SD) at baseline and change (95% CI) at 6 mos 

†

p=.032 vs. placebo [difference = -1.2 (-2.3, -0.8); ‡p=.039 vs. placebo [difference = -4.7 (-9.1, -0.2); §p=.047 vs. placebo; **p=.007 

vs. placebo

 Comment. This RCT suggests glucosamine is efficacious in relieving mild-to-moderate pain 

of knee OA. However, it is not directly comparable to GAIT for several reasons. First, it uses a 

more sensitive, less rigorous primary outcome measures (OARSI-A) than the 20 percent 

reduction in WOMAC pain used in GAIT. Second, NSAIDs are considered modestly superior to 

acetaminophen for general or rest pain. For pain on motion and overall assessment of clinical 

response, NSAIDs also appear modestly superior, though differences are not always statistically 

significant. Only comparisons to placebo are reported, with no comparisons between the active 

arm and glucosamine. Finally, the use of glucosamine sulfate available only in Europe, and 

sponsorship by the manufacturer (Rotta) limit generalizability. Thus, while GUIDE provides 

evidence for glucosamine efficacy, its results are insufficient to establish this or to override the 

results of GAIT. It does provide a rationale for further independent study of glucosamine 

sulfate. 

 Rotta Glucosamine Sulfate. A subgroup analysis in the Towheed, Maxwell, Anastassiades, 

et al. (2006) meta-analysis, and results of GUIDE (Herrero-Beaumont, Roman, Trabado, et al., 

2007) suggest that glucosamine sulfate produced by Rotta Research Laboratorium has clinical 

efficacy in OA of the knee whereas glucosamine hydrochloride does not. We further assessed 

the RCTs included by the Towheed analysis, as well as GUIDE. As shown in Table 53, 5 of 8 

RCTs with Rotta involvement compared oral glucosamine sulfate to placebo. Three RCTs were 

excluded because they used parenteral glucosamine or did not specifically evaluate OA of the 

knee (D’Ambrosio, Casa, Bompani, et al., 1981; Crolle and D’Este, 1980: Drovanti, Bignamini, 

and Rovati, 1980). Substantial differences exist among theses RCTs in duration, primary 

outcomes, and data analysis and presentation. The data as a whole do not support or refute 

differential efficacy of glucosamine sulfate. However, the results are consistent in direction of 

change favoring glucosamine over placebo, justifying independent evaluation of Rotta 

glucosamine sulfate. 

 Adverse Events. Publications of RCTs of glucosamine and chondroitin provide information 

relating to the safety of these compounds. Tables 54 and 55 provide information on adverse 

events reported in primary studies. A low incidence of adverse events referable to the GI tract, 

musculoskeletal system, CNS, and other sites was reported, with no significant differences 

between treatment and placebo groups in any trial. Particular emphasis can be given to two 

RCTs (total N=414) of 3 years’ duration that compared glucosamine 1,500 mg daily to placebo, 

showing no significant differences in adverse events (Pavelka, Gatterova, Olejarova, et al., 2002; 

Reginster, Deroisy, Rovati, et al., 2001). No severe adverse events were reported in any study, 

and it is difficult to correlate adverse effects with either supplement. 
100 

 Glucose Metabolism. There has been speculation that because glucosamine is taken up by 

cells and metabolized through the same pathways as glucose, it could have an effect on glycemic 

control in humans (Hathcock and Shao, 2006; Matheson and Perry, 2003). Data from 11 in vitro 

studies showed that increasing concentrations of glucosamine altered glucose transport, glycogen 

synthesis, and insulin response to glucose (Institute of Medicine and National Research Council, 

2004; Anderson, Nicolosi, Borzelleca, et al., 2005). However, the clinical relevance these 

findings is unclear because they were obtained in isolated and cultured cell models using 

glucosamine concentrations 200 to 500 times the serum concentration expected with normal oral 

doses in humans. 

Glucosamine increases flux through the hexosamine pathway, which leads to deterioration of 

pancreatic beta cell function, thus possibly enhancing the risk of diabetes (Kaneto, Xu, Song, et 

al., 2001; Yoshikawa, Tajiri, Sako, et al., 2002). However, in two acute metabolic ward studies, 

large amounts of glucosamine (7.2 g or 9.7 g of free base) were infused over 5 hours with no 

change in insulin activity or glucose metabolism (Monauni, Zenti, Cretti, et al., 2000; Pouwels, 

Jacobs, Span, et al., 2001). 

 Specific effects of glucosamine on glycemic control have been studied. One double-blind, 

randomized, placebo-controlled trial compared the effect of oral glucosamine sulfate 1,500 mg 

daily with placebo (dextrose) for 12 weeks on serum insulin levels and glucose tolerance in 

healthy adults (Tannis, Barban, and Conquer, 2004). No baseline differences were observed in 

fasted levels of serum insulin or blood glucose in glucosamine sulfate recipients compared with 

those given placebo. Three-hour oral glucose tolerance tests showed glucosamine did not alter 

those parameters, with no significant differences within or between treatments, ages, or gender. 

Negative results in this study were limited by the small number of subjects (n=19), short 

duration, and large variability in the data. Moreover, blood levels of insulin and glucose 

represent surrogate markers for insulin sensitivity, not a gold standard for measuring it. 

 A second randomized, double-blind, placebo-controlled trial (n=38) examined the effect of 

daily administration of glucosamine 1,500 mg plus chondroitin sulfate 1,200 mg for 90 days on 

glycemic control in patients with well-controlled, type 2 diabetes mellitus (Scroggie, Albright, 

Harris, et al., 2003). As reflected by hemoglobin A1c concentrations, glycemic control was 

equivalent in the intervention and placebo arms, with no difference from baseline in either group. 

These results suggest glucosamine has no effect on glycemic control in patients with type 2 

diabetes. Because the trial lasted only 90 days, it is not possible to extrapolate its results beyond 

that time or to less well-controlled patients. 

 A third double-blind, placebo-controlled trial examined the effect of oral glucosamine 500 

mg thrice daily on insulin sensitivity or endothelial dysfunction in lean (n=20) and obese (n=20) 

subjects aged 22 to 65 years (Muniyappa, Karne, Hall, et al., 2006). Glucosamine or placebo 

treatment for 6 weeks was followed by a 1-week washout and crossover to the other study arm. 

The subjects in this study had expected clinical and biochemical characteristics. The lean 

subjects had normal metabolic and hemodynamic parameters while obese subjects exhibited 

typical insulin resistance and impaired insulin-stimulated brachial artery blood flow. Neither 

glucosamine nor placebo caused insulin resistance in healthy lean subjects or worsened this 

parameter in obese subjects. No significant changes were observed in either lean or obese 

subjects in any other measured parameters related to insulin sensitivity including lipid profiles, 

blood pressure, or hemoglobin A1c levels. Neither glucosamine nor placebo had an effect on 

endothelial dysfunction in either subject group. Thus, 6 weeks of oral glucosamine treatment at 

usual dose appears to have no deleterious effect on glucose metabolism or vascular function. 
101 

Table 53. Results of Rotta-related studies meeting protocol selection criteria 

Study N 

Tx/Pl 

Duration 

(wks) 

Outcome Baseline 

Tx/Pl** 

(rng or 

95% CI) 

End 

Tx/Pl** 

(rng or 

95%CI) 

∆ Mean 

(95% CI, 

p value) 

% 

Responders 

Tx/Pl 

(p value) 

USPSTF 

Quality 

Comment 

HerreroBeaumont 

et al., 

2007 

(GUIDE) 

106/104 24 Lequesne 

Index 

WOMAC 

index 

11.0 ± 3.1 

10.8 ± 2.6 

38.3 ± 15.2 

37.9 ± 14.3 

7.9 (calc) 

8.9 (calc) 

25.4 (calc) 

29.7 (calc) 

-1.2 (calc) 

(.032) 

-4.7 

(-9.1, -0.2) 

(0.39) 

39.6 vs. 21.2 

OARSI-A 

(.007) 

Fair Used 

acetaminophen 

as active 

control, NSD 

between active 

and GS group 

Pavelka 

et al., 

2002 

101/101 156 Lequesne 

Index 

WOMAC 

pain 

8.9 ± 2.3 

8.9 ± 2.3 

6.6 ± 3.4 

6.3 ± 3.1

7.2 (NR) 

8.1 (NR) 

NR 

-0.91 

(-0.34, 1.5) 

(.002) 

-0.7 

(-0.06, -

1.3) 

(.03) 

NR 

NR 

Good Primarily 

examined 

structural 

changes in 

mild-tomoderate 

OAK; WOMAC 

pain change 

-10.6% 

Reginster 

et al., 

2001 

106/106 156 WOMAC 

pain 

194 ± 102 

172 ± 104 

156 (NR) 

164 (NR) 

-30 

(estimated) 

NR Good Structural 

changes in 

mild-tomoderate 

OAK. 

WOMAC pain 

change 

-19.5% in GS 

pts, -5% in 

placebo (net -

15%) 

Rovati et 

al., 1997 

329 

total 

12 Lequesne 

Index 

10.5 

(estimated) 

10.1 

5.6 

(estimated) 

8.8 

(estimated) 

-3.6 

(estimated) 

NR Unrated 

(abstract) 

Patients with 

mild-tomoderate OAK 

showed 

 -35% change 

in LI 

Noack et 

al., 1994 

126/126 4 Lequesne 

Index 

10.6 ± 0.4 

(4-22) 

10.6 ± 0.4 

(4-20) 

7.4 ± 0.5 

(0-21) 

8.4 ± 0.4 

(0-24) 

-1.0 

(.05) 

52/37 

(.016) 

Fair Moderate-tosevere OAK*

; 

net difference 

about -9% with 

treatment 

Pujalte et 

al., 1980 

10/10 8 Composite 

measure of 

pain, 

tenderness, 

swelling, 

stiffness on 

1-4 point 

scale in 

order of 

increasing 

severity 

2.3 ± 0.15 

2.6 ± 0.31 

1.2 ± 0.08 

2.3 ± 0.25 

-0.81 80 vs. 20 

(pain) 

(.0004) 

Poor Patients with 

mild-tomoderate OA 

of the knee; 

used 

unvalidated 

composite 

measure of 

efficacy 

* ITT analysis, based on minimum 3-pt drop in Lequesne Index in the presence of an overall judgment of efficacy by the investigator rated 

“good” or “moderate” 

** Mn ± SD or SEM; 

NSD: non-significant difference; USPSTF: U.S. Preventive Services Task Force 
Table 54. Adverse events associated with glucosamine treatment in placebo-controlled RCTs that meet protocol selection crite

Study Summary 

Tx/Pl 

(p-value) 

CV 

No. 

Tx/Pl 

Local 

Skin 

No. 

Tx/Pl 

Headache 

No. 

Tx/Pl 

MS 

No. 

Tx/Pl 

GI Tract 

No. 

Tx/Pl 

Nervous 

System 

No. 

Tx/Pl 

Respiratory 

Tract 

No. 

Tx/Pl 

Urinary 

Tract 

No. 

Tx/Pl 

HerreroBeaumont et al., 2007 

Number of adverse events in each group were similar: 89 with Pl, 96 with acetaminophen, 95 with GS, most of minor clinical significance 

0/1 NR 2/4 10/5 11/16 3/5 9/9 NR 

Clegg et al., 2006 

77 total in 66 pts none serious, not separated by agent, described as generally mild (NSD) 

NR NR NR NR NR NR NR NR 

McAlindon et al., 2004 

18/14 (NSD) NR NR NR 7/2 4/6 2/2 NR NR 

Usha and Naidu, 2004 

Totals NR, none serious enough to discontinue therapy, described as well tolerated (NSD) 

NR NR NR NR > 5% pts 

reported 

diarrhea, grp 

not specified 

NR NR NR 

Hughes and Carr, 2004 

No serious events reported (NSD) NR 0/1 4/6 9/9 4/4 1/0 NR 1/0 

Pavelka et al., 2002 

138/123 total in 202 pts, 8/10 withdrew (NSD) 

23/20 10/15 NR 30/22 25/28 NR 17/7 12/11 

Reginster et al., 2001 

83/101 total in 212 pts, 21/18 withdrew (NSD) 

21/30 4/7 6/4 NR 27/37 11/20 NR NR 

Das and Hammad, 2000 

9/8 pts reported at least one adverse event, none judged serious (NSD) 

NR NR NR 0/1 7/10 NR NR NR 

Rindone et al., 2000 

No serious adverse events reported, 17/11 pts reported at least one event, 2/4 pts withdrew (NSD) 

X 

(no. 

NR) 

X 

(no. 

NR) 

X 

(no. NR) 

NR X 

(no. NR) 

X 

(no. NR) 

NR NR 

Houpt et al., 1999 

12% of pts in both grps reported mild adverse events (NSD) 

NR NR NR NR X (no. NR) NR NR NR 

Rovati, 1997 14.8%/23.7% of pts reported an 

adverse event (NSD) 

NR NR NR NR NR NR NR NR 

Noack et al., 1994 

No serious adverse events reported, 8/13 pts reported at least one event, 10/16 pts withdrew (NSD) 

0/2 1/3 2/2 NR 5/6 NR NR NR 

Pujalte et al., 1980 

No serious adverse events reported, none withdrew, described as well tolerated 

NR NR NR NR NR 0/1 NR NR 

CV = cardiovascular; MS = musculoskeletal; NSD = no significant difference; NR = not reported; Pl = placebo; Tx = treatment; 

102
Table 55. Adverse events associated with chondroitin treatment in placebo-controlled RCTs that meet protocol selection criter

Study Summary 

Tx/Pl 

(p value) 

CV 

No. 

Tx/Pl 

Local 

Skin 

No. 

Tx/Pl 

Headache 

No. 

Tx/Pl 

MS 

No. 

Tx/Pl 

GI 

Tract 

No. 

Tx/Pl 

Nervous 

System 

No. 

Tx/Pl 

Respiratory 

Tract 

No. 

Tx/Pl 

Clegg et al., 2006 

77 total in 66 pts none serious, not separated by agent, described as generally mild (NSD) 

NR NR NR NR NR NR NR 

Michel et al., 2005 

87/101 pts reported an adverse event, 9/9 withdrew, but only 2 events judged related to Tx (NSD) 

9/8 9/9 11/14 NR 6/17 NR 44/46 

Uebelhart et al., 2004 

Minor adverse events only, 1/1 withdrew (NSD) NR NR NR NR 4/6 NR NR 

Mazieres et al., 2001 

28/21 pts reported at least one adverse event, 4/3 withdrew, none were judged related to Tx (NSD) 

NR NR NR NR Tx > Pl 

(p=.04) 

NR Tx > Pl 

(p=.05) 

Das and Hammad, 2000 

9/8 pts reported at least one adverse event, none judged serious (NSD) 

NR NR NR 0/1 7/10 NR NR 

Bourgeois et al., 1998 

16/12 adverse events reported, none serious, 3/3 withdrew, Tx described as well tolerated (NSD) 

1/0 2/2 NR NR 11/10 NR NR 

Bucsi and Poor, 1998 

No serious adverse events reported, tolerance of Tx reported as excellent (NSD) 

NR NR NR NR 0/1 NR NR 

Conrozier, 1998 Tolerance reported as excellent in 90% of Tx 

pts, 2 (not specified) withdrew (NSD) 

NR NR NR NR NR NR NR 

Uebelhart et al., 1998 

Tolerance reported as good in both grps (NSD) NR NR NR NR NR NR NR 

L’Hirondel, 1992 No serious adverse events reported (NSD) NR NR NR NR 7/13 NR NR CV = cardiovascular; MS = musculoskeletal; NSD = no significant difference; NR = not reported; Pl = placebo; Tx = treatment; 

103
104 

 Two long-term placebo-controlled RCTs of glucosamine sulfate 1,500 mg daily for 3 years in 

OA of the knee reported findings on glucose metabolism. During one trial (total n=202) in 

which diabetic patients were excluded, four developed diabetes mellitus, 3 in the placebo group 

and one in the glucosamine group (Pavelka, Gatterova, Olejarova, et al., 2002). Although no 

quantitative data were provided, the authors reported routine safety laboratory test results did not 

show significant differences between groups. The second RCT (n =212) excluded individuals 

with substantial abnormalities in hematological, hepatic, renal, or metabolic functions, which 

could include diabetes (Reginster, Deroisy, Rovati, et al., 2001). No change was reported in 

glycemic homeostasis, with fasting plasma glucose concentrations slightly lower in the 

glucosamine group compared to placebo. Taken together, these results show long-term ingestion 

of glucosamine sulfate at a dose commonly used in OA of the knee has no impact on glucose 

metabolism in healthy patients. They do not, however, provide information relevant to diabetic 

patients. 

 A systematic review of 16 clinical studies, including 854 patients treated with glucosamine 

for a weighted average of 37 weeks (range 3–156 weeks), found no evidence that glucosamine 

ingestion is associated with significant changes in blood glucose levels (Anderson, Nicolosi, 

Borzelleca, et al., 2005). A second systematic review including virtually the same studies came 

to the same conclusion (Stumpf and Lin, 2006). The authors of that review suggest that because 

data on glucosamine use in patients with diabetes mellitus are limited, such patients should be 

closely monitored for possible changes in glucose control. 

 In sum, available laboratory studies are short-term, whereas longer (3 years) OA efficacy 

trials excluded patients with metabolic disorders. Many OA RCTs presented incomplete 

information about adverse events, and most did not evaluate blood chemistries systematically. 

Therefore, no conclusions concerning metabolic effects of chronic glucosamine use in the 

general population can be drawn. 

Results, Part II: Key Question 3 (Subgroup Analyses) 

 Our systematic review identified two RCTs that stratified patients according to OA severity 

(Clegg, Reda, Harris, et al., 2006; Das and Hammad, 2000). Given the small number of cases 

(n=8 treatment, 13 placebo) in the severe disease category presented by Das and Hammad, we do 

not consider their results further. We did not identify any studies that performed subgroup 

analyses by age, sex, race, weight, OA diagnosis, or symptom duration. 

Table 56 shows subgroup results from GAIT that stratified patients according to severity of 

baseline WOMAC pain. GAIT used ITT analysis and the last observation carried forward 

method to impute missing data as needed, and defined primary outcomes as threshold response 

rates using the WOMAC and OMERACT-OARSI scales (Clegg, Reda, Harris, et al., 2006). An 

absolute increase in the response rate of 15 percent, as compared with the rate in the placebo 

group, was considered indicative of a clinically meaningful treatment effect. Statistical 

significance was defined as an α value of 0.017 for each comparison with placebo, based on an 

overall α value of 0.05 using a two-sided chi-square test. 

 A clinically meaningful, statistically significant effect was observed in the primary outcome 

and one secondary measure (OMERACT-OARSI response rate) in patients who received 

glucosamine plus chondroitin compared to placebo. In the celecoxib arm the response rate for the 

primary outcome was not statistically different from that in the placebo arm. It did show a 

clinically meaningful treatment effect, defined by the investigators as an absolute increase in the 
105 

response rate of 15 percent. A similar pattern occurred using the OMERACT-OARSI outcome 

criteria. No statistically significant differences were seen when outcomes were assessed as a 50 

percent decrease in WOMAC pain. 

Comment. The benefit of combined treatment in patients with moderate-to-severe OA of the 

knee requires reconciling effect magnitudes and their consistency with statistical results in the 

glucosamine chondroitin and celecoxib arms. Results reported for combined therapy were 

consistent in direction, and of sufficient magnitude to reach statistical significance, based on the 

primary outcome (20 percent decrease in WOMAC pain score) or the secondary outcome 

(OMERACT-OARSI response rate). The direction and magnitude of effect in the celecoxib 

controls are consistent with clinical benefit, whether scored according to the primary outcome or 

the OMERACT-OARSI response criteria. The failure of the primary outcome to reach statistical 

significance in this arm may be explained by insufficient study power due to the relatively small 

numbers of patients. Overall, the GAIT subgroup data suggest, but do not prove, combination 

glucosamine chondroitin therapy provides clinically meaningful improvement in patients with 

moderate-to-severe pain of OA of the knee. 

Table 56. GAIT Patients with moderate-to-severe pain (WOMAC pain score 301–400) 

Primary Outcome Secondary Outcomes 

Intervention 20% decrease in 

WOMAC pain 

score, % (n) 

p value OMERACT-OARSI 

response, % (n) 

p value 50% decrease in 

WOMAC pain 

score, % (n) 

p value 

Placebo 54.3% (38/70) 48.6% (34/70) 32.9% (23/70) 

Glucosamine 65.7% (46/70) p=.17 65.7% (46/70) p=.04 41.4% (29/70) p=.29 

Chondroitin 61.4% (43/70) p=.39 58.6% (41/70) p=.24 35.7% (25/70) p=.72 

Glucosamine plus 

Chondroitin 

79.2% (57/72) p=.002** 75% (54/72) p=.001† 52.8% (38/72) p=.02*

Celecoxib 69.4% (50/72) p=.06 66.7% (48/72) p=.03* 45.8% (33/72) p=.11 

*p<.05 for the comparison with placebo 

†p<.017 for the comparison with placebo 

WOMAC = Western Ontario and McMaster Universities; OMERACT-OARSI = Outcomes Measures in Rheumatology Clinical TrialsOsteoarthritis Research Society 

 

 In summary, we sought prospective subgroup analyses from RCTs. No analyses, other than 

described above, were found.

Results, Part II: Key Question 4 (Comparative Outcomes) 

 In our systematic review, we did not find any direct comparative studies in which 

glucosamine, chondroitin, or glucosamine plus chondroitin were compared with arthroscopy or 

viscosupplementation to treat OA of the knee. Therefore, no conclusions can be drawn 

concerning comparative efficacy.
106 

Conclusions: Part II 

1. What are the Clinical Effectiveness and Harms of Enteral Glucosamine and 

Chondroitin Given Alone or in Combination, in Patients With Primary OA of the Knee? 

• The best available evidence found that glucosamine hydrochloride, chondroitin sulfate, 

or their combination provide no clinical benefit in patients with primary OA of the 

knee. 

The best evidence comes from the Glucosamine/Chondroitin Arthritis Intervention Trial 

(GAIT; Clegg, Reda, Harris, et al., 2006), a large (n=1,583), good quality, NIH-funded, 

multicenter RCT. GAIT compared glucosamine hydrochloride, chondroitin sulfate, or the 

combination of these agents, with placebo or celecoxib in patients with primary osteoarthritis of 

the knee. After 24 weeks of treatment, ITT analysis showed no significant difference in 

symptomatic relief between glucosamine hydrochloride, chondroitin sulfate, or glucosamine 

hydrochloride plus chondroitin sulfate compared to placebo. Substantiating this result was that 

celecoxib, the active control, was effective. 

• Five of six MAs concluded that glucosamine or chondroitin were superior to placebo. 

However, the MA results do not outweigh the GAIT results due to lower quality of the 

primary literature and small differences reported. 

 

 Six study-level MAs assessed glucosamine or chondroitin in OA of the knee. All but one of 

the MAs reported statistically significant differences between treatment and placebo. However, 

these MAs had limitations in the quality of the primary studies that were pooled. Limitations of 

the primary literature included small study size, inclusion of studies that assessed joints other 

than knee, and failure to report intent to treat analysis. In general, the MAs did not perform 

adequate quality appraisal of the primary studies. 

• Glucosamine sulfate has been reported to be more effective than glucosamine 

hydrochloride, but the evidence is insufficient to draw conclusions. 

 

 A subgroup analysis in the largest MA (Towheed, Maxwell, Anastassiades, et al., 2006) 

showed a statistically significant pooled effect from 7 RCTs favoring glucosamine sulfate in 

studies that involved Rotta Research Laboratorium, in contrast to no effect for 8 non-Rotta 

RCTs. Because the pooled estimate for the Rotta studies was accompanied by substantial 

heterogeneity secondary to elements of study design and analysis, patient samples, and routes of 

administration, there is a considerable degree of uncertainty in that result. The results of GUIDE 

(Herrero-Beaumont, Roman, Trabado, et al., 2007), a European placebo-controlled RCT 

(n=318), also sponsored by Rotta, seemingly support the effectiveness of glucosamine sulfate. 

To date, no independent studies of the Rotta glucosamine sulfate formulation have been 

conducted. While the overall results of GAIT show no benefit, in the subgroup of knee OA 

patients with moderate-to-severe pain at baseline, the combination of glucosamine hydrochloride 

and chondroitin sulfate significantly improved pain. Together, this evidence suggests an 

independent trial of glucosamine sulfate would be useful to definitively establish whether there is 

benefit. 
107 

• In general, adverse events with glucosamine or chondroitin treatment were no greater 

than placebo. No conclusions concerning metabolic effects of chronic glucosamine use 

in the general population can be drawn. 

 

 Adverse events reported in the literature included nausea, diarrhea, headache, 

musculoskeletal complaints, and others. There were no significant differences between placebo 

and treatment. There has been some concern from in vitro and preclinical studies that 

glucosamine supplementation could have a deleterious effect on glucose metabolism and 

glycemic control. However, available clinical studies are short-term, or if longer (3 years) 

excluded patients with metabolic disorders. 

2. What are the Clinical Effectiveness and Harms of the Interventions of Interest in 

Patients With Secondary OA of the Knee? 

 We identified no studies that enrolled patients with only secondary OA of the knee, or that 

reported separately on secondary OA of the knee. Therefore, no conclusions can be drawn about 

treatment outcomes in patients with secondary OA of the knee. 

3. How do the Short-Term and Long-Term Outcomes of the Interventions of Interest 

Differ by the Following Subpopulations: Age, Race/Ethnicity, Gender, Primary or 

Secondary OA, Disease Severity and Duration, Weight (Body Mass Index), and Prior 

Treatments? 

 GAIT found that glucosamine plus chondroitin produced a statistically and clinically 

significant improvement of pain in patients with moderate-to-severe pain from OA of the knee at 

baseline. Although the effect of celecoxib treatment in a similar group of patients was not 

statistically significant, the magnitude and direction of the response were consistent with clinical 

benefit. The nonsignificant statistical result in the celecoxib arm may be a function of 

insufficient power due to the small number of patients. Although this subgroup analysis was not 

explicitly prespecified in the GAIT protocol, the stratified randomization by disease severity 

yields statistically valid comparisons. A trial of glucosamine sulfate would be useful to 

definitively establish whether there is benefit 

4. How do the Short-Term and Long-Term Outcomes of the Interventions of Interest 

Compare for the Treatment of Primary OA of the Knee; and Secondary OA of the Knee? 

 

 We did not find any direct comparative studies in which glucosamine, chondroitin, or 

glucosamine plus chondroitin were compared with arthroscopy or viscosupplementation to treat 

OA of the knee. Therefore, no conclusions can be drawn concerning comparative efficacy. 
108 

Part III: Arthroscopy Effectiveness and Harms 

Literature Overview 

The effectiveness of arthroscopic lavage and debridement can be evaluated using several 

study designs. Placebo-controlled randomized, controlled trials (RCTs) could address whether 

arthroscopic lavage and debridement achieve results surpassing placebo. Placebo-controlled 

RCTs for surgical procedures can be especially difficult to execute because investigators may 

have ethical concerns about sham procedures and patients may be reluctant to participate. RCTs 

comparing an intervention with an active control treatment may receive greater acceptance by 

clinicians and patients. The key strength of RCTs generally concerns control for confounding 

and several sources of bias. Well-conducted subgroup analyses from RCTs can reveal whether 

the effects of an intervention differ according to particular patient characteristics. Quasiexperimental designs are controlled studies that do not assign patients randomly and are more 

susceptible to confounding. 

Uncontrolled studies, such as administrative database analyses and case series provide 

weaker evidence. Administrative databases can give a broader view of outcomes of 

interventions in everyday practice, compared to the tightly controlled conditions of an RCT. 

However, administrative database analyses can be flawed by poor data quality and unmeasured 

variables. Case series are a weak design for evaluating effectiveness due to lack of comparison 

groups and failure to control for placebo effects. Despite weaknesses, evidence from 

uncontrolled studies can support inferences about effectiveness, particularly when studies use 

high quality methods and the effects are large enough to exceed potential biases and nonspecific 

effects. Studies of different designs were sought to examine whether outcomes differed by 

subgroups, particularly primary versus secondary osteoarthritis (OA) of the knee and those with 

mechanical versus loading symptoms. This review of arthroscopic lavage and debridement will 

address evidence from different study designs in turn. 

Results, Part III: Key Questions 1 and 2 

 Placebo-Controlled RCT Evidence. Study Characteristics. The key study in this review is 

the blinded placebo-controlled randomized trial (Tables 57–62) conducted by Moseley, 

O’Malley, Petersen, et al. (2002). This trial randomized 180 patients to three groups (Table 57): 

(1) placebo (P, n=61), or sham arthroscopy; (2) arthroscopic lavage (L, n=59); and (3) 

arthroscopic debridement (D, n=60). It should be noted that debridement was accompanied by 

lavage, so the intervention groups consisted of lavage with or without debridement. All 

procedures were conducted by a single highly experienced surgeon at the Houston Veterans 

Affairs Medical Center (Table 58). Randomization was stratified within three OA disease 

severity groups: mild, moderate, and severe. The primary hypothesis was that patients in the 

intervention groups would report the same amount of knee pain at 2 years as patients in the 

placebo group. 

Patients appear comparable at baseline on age, sex, race, preoperative disease severity, pain, 

function, Knee Society Clinical Rating Scale symptoms and function; psychological attributes 

and type of analgesic use (Table 59). The sample seems somewhat younger (means in the three 
109 

groups between 51 and 54 years) and more male (93 percent) than the overall population of OA 

patients. 

Table 57. Arthroscopy placebo-controlled RCT, sample selection 

Study Inclusion Exclusion n, Enrolled n, Withdrawn 

n, Outcome 

Evaluated 

Moseley et 

al., 2002 

Hypothesis: 

pts in the L 

and D 

groups 

would have 

same 

amount of 

knee pain 

at 2 yrs as 

P pts 

10/95 – 9/98; pts recruited 

from Houston VAMC; < 75 

yo; OA of knee by ACR 

definition; at least 

moderate pain (VAS > 4) 

despite maximal medical 

treatment for > 6 mo; no 

arthroscopy in previous 2 

yrs; study knee was that 

with greatest pain-induced 

limitation of function; 

randomization to 1 of 3 

groups (debridement-D, 

lavage-L, placebo-P) 

stratified by 3 levels of 

severity of OA; used 

sealed, sequentially 

numbered envelopes 

handed to surgeon in 

operating suite, treatment 

assignment not revealed 

to patient; randomization 

stratified within 3 OA 

severity grades (1-3, 4-6, 

7-8) 

Severity 

grade >9/12; 

severe 

deformity; 

serious 

medical 

problems 

Of 324 consecutive 

pts who met 

inclusion criteria, 

144 (44%) declined 

to participate 

(participants were 

significantly 

younger, more 

likely to be white 

and had more 

severe OA). 

n=180 

L: 61 

D: 59 

P: 60 

Trial designed to 

have 90% power to 

detect 0.55 effect 

size between P and 

L+D on SF-36-P at 

2 yrs, n=180 and <

16 pts lost to F/U 

2 yrs: 

L: 6 

D: 6 

P: 5 

2 yrs: 

L: 55 

D: 53 

P: 55 

Table 58. Arthroscopy placebo-controlled RCT, interventions 

Study Intervention Prior Treatments 

Concurrent 

Treatments 

Moseley et al., 

2002 

One surgeon performed all procedures; D and L pts 

received general anesthesia; P pts received IV 

tranquilizer and opioid and spontaneously breathed 

oxygen-enriched air; L pts were irrigated with 10 L of 

fluid, anything that could be flushed through cannulas 

was removed, debridement among L pts only 

performed to resect portion of mechanically important 

unstable tears of the meniscus; D pts received 

lavage, rough articular cartilage was shaved, loose 

debris removed, all torn or degenerated meniscal 

fragments trimmed, remaining meniscus smoothed to 

a firm and stable rim, no abrasion arthroplasty or 

microfracture, bone spurs typically not removed 

except spurs from tibial spine area; P pts received 3 

1-cm incisions in the skin, surgeon asked for all 

instruments and manipulated the knee as if 

arthroscopy was being performed; saline was 

splashed to simulate sound of lavage, no instruments 

entered portals, P pts kept in operating room for 

amount of time required for debridement, P pts spent 

night in hospital cared for by nurses unaware of 

group assignment 

Maximal medical 

treatment for >6 mo 

Postop all pts 

received the same 

walking aids, 

graduated exercise 

program, and 

analgesics 
110 

Table 59. Arthroscopy placebo-controlled RCT, patient characteristics 

Study Age 

Percent 

Female Race (%) 

Preoperative 

Disease 

Severity (%) Pain Function 

Other 

Characteristics 

Moseley 

et al., 

2002 

L: mn 51.2, 

sd 10.5 

D: mn 53.6, 

sd 12.2 

P: mn 52.0, 

sd 11.1 

L: 12 

D: 3 

P: 7 

W/B/O 

L: 59/31/10 

D: 61/22/17 

P: 60/32/8 

Mild/mod/sev 

L: 28/46/26 

D: 31/46/24 

P: 28/47/25 

Mn 

KSPS 

pain 

L: 50.2 

D: 51.4 

P: 49.4 

Mn KSPS 

function 

L: 62.4 

D: 57.6 

P: 62.2 

Analgesic use 

(OTC/Rx) 

L: 67/21 

D: 64/15 

P: 70/22 

KSPS: Knee-Specific Pain Scale; mn: mean; OTC: over the counter; sd: standard deviation 

The report provides no information on the proportions of primary versus secondary OA in this 

sample. Blinding of patients to treatment was effective (similar percentages in placebo and 

intervention groups guessed they received placebo). Outcome was assessed by study personnel 

unaware of group assignment; the operating surgeon did not participate in any way. 

The primary outcome (Table 60) was 24-month Knee-Specific Pain Scale (KSPS), created 

for the study (0–100), and subsequently validated (O’Malley, Suarez-Almazor, Aniol et al., 

2003). Secondary outcomes included the pain subscale of the Arthritis Impact Measurement 

Scales (AIMS2-P); the pain subscale of SF-36(-P); the walking-bending subscale of AIMS2-P 

(-WB); the physical subscale of SF-36(-PF); and an investigator-devised Physical Functioning 

Scale (PFS, time to walk 30 m and ascend and descend a flight of stairs). All measures were 

scored on or transformed to a 0-100 scale, with higher scores being worse. Followup points were 

2 weeks, 6 weeks, 3 months, 6 months, 12 months, 18 months and 24 months. 

Table 60. Arthroscopy placebo-controlled RCT, outcome assessment 

Study Outcomes Assessed Response Criteria Observer F/U 

Moseley 

et al., 

2002 

Primary: 24 mo Knee-Specific Pain Scale 

(KSPS) created for the study (0-100); 

Secondary: pain subscale of Arthritis Impact 

Measurement Scales (AIMS2-P); pain subscale 

of SF-36(-P); walking-bending subscale of 

AIMS2-P(-WB); physical subscale of SF-36(-

PF); investigator-devised Physical Functioning 

Scale (PFS, time to walk 30 m and climb up and 

down flight of stairs as quickly as possible); all 

measures transformed to 0-100 scale; guess 

which procedure was performed 

Results viewed with respect to 

minimal important difference 

(MID) using stratified central 

tendency approach against 

change rating external criterion 

level described as somewhat 

better (or worse) and much 

better (or worse), and standard 

error of measurement-based 

method. 

Study 

personnel 

unaware of 

group 

assignment, 

operating 

surgeon did 

not participate 

in any way 

2 wk, 

6 wk, 

3 mo, 

6 mo, 

12 mo, 

24 mo 

The primary statistical analyses were based on followup scores although change scores were 

also analyzed and the results did not differ. Two-sided p values were used, which were not 

adjusted for multiple comparisons. If evidence of superiority of interventions over placebo was 

lacking, equivalence analyses were to be performed using the minimal important difference, 

calculated by both the standard error of measurement and the mean change score among patients 

rated as somewhat or much better or worse on an external criterion global change scale. 

On the U.S. Preventive Services Task Force quality rating system (Table 61), the Moseley, 

O’Malley, Petersen, et al. (2002) study rated favorably on the all of the following dimensions: 

initial assembly of comparable groups; low loss to followup (about 12 percent at 1 year and 2 

years), maintenance of comparable groups; measurements reliable, valid, equal; interventions 

comparable/clearly defined; and appropriate analysis of results. 
111 

Table 61. Arthroscopy placebo-controlled RCT, study quality assessment 

Study 

Initial 

Assembly of 

Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance 

of Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal* 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Moseley et al., 2002 Y Y Y Y Y Good 

 Results. On superiority analyses conducted by Moseley and co-workers (Table 62), at no 

followup time did either the lavage or debridement groups achieve significantly better mean 

outcomes than placebo on any of the 6 efficacy outcomes. Only 1 comparison after 2 weeks 

achieved statistical significance: at 1 year, the placebo group had significantly better time to 

walk 30 meters and scale a flight of stairs than the debridement group. The mean number of 

seconds on the 1 year Physical Function Scale (± standard deviation [SD]) was 45.6 (± 10.2) in 

the placebo group and 52.5 (± 20.3) in the debridement group (p=0.04). Of the 84 comparisons 

for equivalence, the minimal important difference was excluded from confidence intervals in 72. 

Moseley and colleagues (2002) presented limited adverse events data, stating that there were 

only two minor complications: incisional erythema in one patient and in another, calf swelling 

with venography negative for thrombosis. 

The authors of this RCT concluded it “provides strong evidence that arthroscopic lavage with or 

without debridement is not better than and appears to be equivalent to a placebo procedure in 

improving knee pain and self-reported function.” 

 Comment. The RCT by Moseley, O’Malley, Petersen, et al. (2002) provides the most 

important evidence on the outcomes of arthroscopic lavage and debridement for OA of the knee. 

The trial was rated as being good in quality, but was limited by uncertainty about generalizability 

due to inclusion of a single surgeon and a single clinical center. However, placebo-controlled, 

well-designed and well-conducted RCTs of surgical procedures are rarities that offer valuable 

information. These authors found no differences between placebo and arthroscopic interventions 

past 2 weeks of followup. Absent other placebo-controlled RCTs, evidence is lacking to show 

that arthroscopic lavage with or without debridement have effects above those of placebo.

Numerous critiques of the Moseley trial have been published (Laskin and Ohnsorge, 2005; 

Blacher, 2002; Chambers and Schulzer, 2002; Chambers, Schulzer, Sobolev et al., 2002; Ewing 

and Ewing, 2002; Felson and Buckwalter, 2002; Johnson, 2002; Lubowitz, 2002; Poehling, 

2002). The trial authors responded to some of these comments (Wray, Moseley, O’Malley, 

2002). Critical comments fall into three main areas: insufficient description of the patient 

sample; a patient sample that is unrepresentative of the population with OA of the knee; and 

problems with outcome assessment and data analysis. 

Several authors noted that the RCT patient sample was not well characterized. Information 

was lacking on the following variables: proportions of primary and secondary OA; knee range of 

motion; body weight; effusion; disability and worker’s compensation status; presence of 

mechanical symptoms; classification of preoperative radiographs and arthroscopic OA stage and 

pathologic details. Chambers, Schulzer, and Sobolev (2002) stated that inclusion and exclusion 

criteria were not well defined. 

Regarding the representativeness of the patient sample, the subjects in the RCT were clearly all 

veterans, fairly young, and a higher proportion of males compared to the general population with 

OA of the knee. The low participation rate (56 percent) led Lubowitz (2002) to speculate that 
Table 62. Arthroscopy placebo-controlled RCT, results 

Study 

Outcome F/U Group n mn (sd) p value (vs. 

placebo) 

Outcome F/U Group n mn (sd) 

Moseley et al., 2002 

KSPS-Pain 6 mo L 59 53.2 (22.6) 0.17 

 D 56 50.0 (21.0) 0.55  P 57 47.6 (20.7)  1 yr L 57 54.8 (19.8) 0.14  D 50 51.7 (22.4) 0.51  P 53 48.9 (21.9)  18 mo L 56 51.1 (22.7) 0.78  D 51 50.7 (25.3) 0.73  P 52 52.4 (22.4)  2 yr L 55 53.7 (23.7) 0.64  D 53 51.4 (23.2) 0.96  P 55 51.6 (23.7) AIMS2-WB 6 mo L 59 48.7 (31.6) 0.94  D 55 52.5 (28.7) 0.51  P 57 49.1 (25.8)  1 yr L 57 49.6 (29.1) 0.98  D 51 56.4 (28.4) 0.19  P 54 49.4 (25.5)  18 mo L 57 50.5 (28.5) 0.34  D 51 53.1 (29.3) 0.66  P 52 55.6 (26.6)  2 yr L 56 51.1 (28.3) 0.61  D 53 56.4 (29.4) 0.64  P 55 53.8 (27.5) AIMS2-P 6 mo L 59 54.8 (21.6) 0.23  D 55 52.2 (20.8) 0.60  P 57 50.0 (20.7)  1 yr L 57 57.8 (23.5) 0.34  D 51 53.3 (25.4) 0.95  P 54 53.6 (22.1)  18 mo L 57 55.4 (24.6) 0.95  D 51 50.7 (24.4) 0.30  P 52 55.6 (23.6)  2 yr L 56 56.7 (24.1) 0.37  D 53 54.0 (23.3) 0.75  P 55 52.5 (25.1) 

PFS 6 mo L 52 49.4 (20.4)  D 54 49.8 (17.4)  P 54 47.0 (13.0)  1 yr L 54 50.4 (17.6)  D 47 52.5 (20.3)  P 49 45.6 (10.2)  18 mo L 49 51.2 (18.8)  D 44 52.8 (20.9)  P 46 48.5 (12.4)  2 yr L 50 53.2 (21.6)  D 44 52.6 (16.4)  P 44 47.7 (12.0) SF-36-P 6 mo L 59 46.0 (22.0)  D 55 45.1 (20.6)  P 57 46.3 (26.4)  1 yr L 57 42.8 (21.2)  D 51 44.5 (24.3)  P 54 43.6 (24.8)  18 mo L 57 44.4 (24.9)  D 51 46.8 (22.8)  P 52 40.8 (24.9)  2 yr L 57 44.4 (22.4)  D 52 45.0 (23.0)  P 55 42.3 (24.2) SF-36-PF 6 mo L 59 53.4 (27.6)  D 55 51.0 (25.9)  P 57 48.4 (25.9)  1 yr L 57 50.0 (28.0)  D 50 47.3 (27.1)  P 54 49.3 (24.5)  18 mo L 57 47.0 (28.8)  D 51 50.9 (26.1)  P 52 49.1 (25.0)  2 yr L 57 50.9 (27.3)  D 52 47.9 (26.6)  P 54 49.0 (27.2) 

AIMS2-P: pain subscale of the Arthritis Impact Measurement Scales; AIMS2-WB: walking-bending subscale of AIMS2 scale; KSPS: KnePFS: Physical Functioning Scale (time to walk 30 m and ascend and descend a flight of stairs; SF-36-P: pain subscale of the SF-36 hea

scale; SF-36-PF: physical function subscale of the SF-36 health-related quality of life scale 

112
113 

Moseley’s patients may have had a different prognosis than the general population with OA of 

the knee and they may have been more susceptible to the placebo effect. Ewing and Ewing 

(2002) mentioned that patient selection should have been based on plain-film radiography during 

posterior-anterior flexion in a position of weight bearing. Johnson (2002) noted that the Moseley 

RCT included patients who were contraindicated for arthroscopy, including patients presenting 

only because of pain, as well as those with nonreactive joint, multiple compartment involvement, 

angulatory deformity, and noncompliance with non-weight-bearing for at least 1 month.

Several comments focused on outcome assessment and data analysis. It was noted that the 

primary outcome, the Knee Specific Pain Scale, had not been validated. However, a 

subsequently published study demonstrated that it has good psychometric qualities (O’Malley, 

Suarez-Almazor, Aniol et al., 2003). Estimation of sample size was based on the SF-36 pain 

subscale at 90 percent power to detect a moderate effect size, but that was not the primary 

outcome, so the trial does not have the stated level of power for the primary outcome. 

Chambers, Schulzer, and Sobolev (2002) observed that the trial was designed to test the 

superiority of interventions over placebo, but it was converted to an equivalence trial and that 

equivalence trials tend to require larger samples to achieve comparable power. They calculated 

power levels across outcomes and comparisons, finding that it ranged from 14 percent to 70 

percent. They also argued that the minimal important difference should have been determined a 

priori and not based on trial data. 

The trialists responded to critics by clarifying that 172 of 180 patients had one or more 

mechanical symptoms and that alignment was assessed preoperatively with plain-film 

radiography during posterior-anterior flexion in a position of weight bearing. The authors 

performed subgroup analyses on OA stage, alignment and mechanical symptoms, finding no 

differences in results by subgroup. Regarding the preponderance of men in the sample, the 

trialists cite the comment by Felson and Buckwalter (2002) that there is no basis in data to 

suspect that the effect of intervention depends on sex. The trialists argued that the selected 

patients were highly representative of those receiving arthroscopy. In response to speculation 

that subgroups may benefit from arthroscopic intervention, they challenge investigators to collect 

evidence from placebo-controlled trials among specific subpopulations. 

With regard to equivalence comparisons, Moseley and colleagues found that the minimal 

important difference was excluded from confidence intervals in nearly all instances, suggesting 

equivalence between arthroscopy and placebo in this trial. In response to whether they provided 

an unbiased estimate of the minimal important difference, the trialists noted the lack of sufficient 

previously published studies quantifying it, and that the quantity used in equivalence analyses 

was the midpoint of literature-based and trial data-based estimates. Complaints about low power 

to find equivalence are misplaced because the Moseley trial found equivalence in the vast 

majority of comparisons. Moreover, findings of equivalence have more than statistical 

relevance, they suggest that arthroscopic lavage and debridement are no better than a placebo 

intervention involving merely incisions. Evidence of superiority over placebo should be the 

standard to judge arthroscopy. 

 Non-Placebo RCT Evidence. Study Characteristics. Appendix C*

, Table IIIA shows 8 

RCTs that included either arthroscopic lavage or debridement among interventions being 

compared, but they made comparisons that are not of interest to this Evidence Report. Three 

RCTs make relevant comparisons. Merchan and Galindo (1993) compared groups treated with 

arthroscopic debridement plus physical therapy and nonoperative conservative treatment, 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
114 

consisting of NSAIDs along with a decrease in the intensity of activities of daily living (ADLs) 

plus physical therapy. Chang, Falconer, Stulberg, et al. (1993) compared arthroscopic lavage 

and debridement with closed needle lavage. This study used closed needle lavage as a control 

intervention to offset placebo effects and to control for the lavage component of arthroscopic 

treatment. Forster and Straw (2003) randomized patients to arthroscopic lavage and debridement 

or intra-articular Hyalgan®. It should be noted that the Forster and Straw trial is the only study 

meeting selection criteria for this Evidence Report’s Key Question 4, concerning the 

comparative short-term and long-term outcomes of viscosupplements, glucosamine and 

chondroitin, or arthroscopic lavage and debridement. The trial by Forster and Straw will be 

discussed separately, following discussion of Key Questions 1–3. Summary information is 

presented for Merchan and Galindo (1993) and Chang, Falconer, Stulberg et al. (1993) below on 

sample selection (Table 63), patient characteristics (Table 64), interventions (Table 65) and study 

quality (Table 66). 

Table 63. Arthroscopy non-placebo RCTs, sample selection 

Study Inclusion Exclusion n, Enrolled 

n, 

Withdrawn 

n, Outcome 

Evaluated 

Merchan and 

Galindo, 1993 

AD+PT 

vs. 

Conservative 

treatment (Cons): 

NSAID+↓ADLs+PT 

Sedentary patients 

>50 yrs of age with 

painful limited 

degenerative OA of the 

femorotibial (FT) joint, 

as assessed by 

preoperative 

radiographs showing 

minimal joint space 

narrowing 

Duration of pain >6 

mos, weight >85 kg 

in men and >70 kg in 

women, history of 

previous knee 

surgery, appreciable 

joint instability or 

angular deformity 

(varus/valgus) >15 

degrees, 

femoropatellar joint 

involvement 

AD+PT:40 

Cons: 40 

AD+PT: 5 

(died) 

Cons: 2 

(died) 

AD+PT:35 

Cons: 38 

Chang et al., 1993 

ALD vs. needle 

lavage (NL) 

Persistent knee pain 

>3 mo, despite 

conservative medical/ 

rehabilitation management, unacceptable 

restrictions in work/ 

athletic/self-care 

activities; `KellgrenLawrence grade 1-3; 

age >20 yrs; will to 

attend 3 mo/12 mo 

followup 

Knee surgery <6 mo; 

total knee 

replacement; 

concurrent illness 

that would influence 

functional 

assessment of knee/ 

preclude 

arthroscopic surgery; 

Kellgren-Lawrence 

grade 4 

ALD: 19 

NL: 15 

ALD: 1 

NL: 1 

(both intercurrent 

medical 

problems) 

ALD: 18 

NL: 15 

Table 64. Arthroscopy non-placebo RCTs, patient characteristics 

Study Age 

% 

Female 

OA Duration 

(months) 

Preoperative 

OA Severity Pain Function 

Merchan 

and 

Galindo, 

1993 

AD+PT 

vs.Cons 

AD+PT: mn 

57.1 

Cons: mn 

56.9 

AD+PT: 80 

Cons: 66 

 HSS Knee Rating 

Score 

AD+PT: mn 26.85 

Cons: mn 29.86 

Chang et 

al., 1993 

ALD vs. NL 

ALD: mn 61, 

sd 11 

NL: mn 65, 

sd 13 

ALD: 72 

NL: 71 

ALD: mn 51, 

sd 51 

NL: mn 53, sd 

57 

KellgrenLawrence 

%I/II/III 

ALD: 22/28/50 

NL: 14/36/50 

AIMS (0-1) 

ALD: mn 

6.5, sd 2.0 

NL: mn 6.1, 

sd 2.1 

AIMS Physical 

Function (0-10) 

ALD: mn 2.3, sd 1.6 

NL: mn 1.7, sd 1.0 
115 

Table 65. Arthroscopy non-placebo RCTs, interventions 

Study Interventions Prior 

Treatments 

Concurrent Treatments 

Merchan and 

Galindo, 1993 

AD+PT vs. Cons 

AD+PT: debridement of synovial tissue, partial 

meniscectomy, osteophytectomy, removal of loose 

bodies, limited chondroplasty, no abrasion; 

physical therapy (PT) 4 wks postop 

Cons: conservative (nonoperative) treatment with 

NSAIDs, ↓ in ADLs, PT as in AD+PT group 

 AD+PT: compression 

bandage, early exercises, 

motion, weight bearing as 

tolerated 

Chang et al., 1993 

ALD vs. NL 

ALD: general anesthesia, continuous saline 

lavage, debridement of torn meniscus, removal of 

meniscal, anterior cruciate ligament fragments, 

removal of proliferative synovium, excision of loose 

articular cartilage fragments, no drilling 

NL: closed needle tidal lavage, 1 liter saline, local 

anesthesia 

Conservative 

medical and 

rehabilitation 

management 

Non-narcotic analgesics, 

physical therapy 

Table 66. Arthroscopy non-placebo RCTs, study quality 

Study 

Initial 

Assembly of 

Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance 

of Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal* 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Merchan and Galindo, 

1993 

AD+PT vs. Cons 

? Y N Y Y Poor 

Chang et al., 1993 

ALD vs. NL ? Y Y Y Y Fair 

Merchan and Galindo (1993) randomized 40 patients each to arthroscopic debridement plus 

physical therapy and nonoperative conservative therapy. Seven patients died and were excluded 

from data analysis, five in the arthroscopy group and two in the conservative treatment group. 

Arthroscopic debridement included excision of synovial tissue, partial meniscectomy, 

osteophytectomy, removal of loose bodies, limited chondroplasty and no abrasion. Patients over 

50 years of age were included for painful limited OA and minimal joint space narrowing on 

preoperative radiography. Groups were comparable at baseline on age, percent female and 

Hospital for Special Surgery (HSS) knee score; however, information is lacking on duration of 

disease, and body weight. Mean followup was 25 months in the arthroscopy group and 23 

months in the conservative treatment group. Outcome measures were the followup HSS score, 

change in HSS and patient global change assessment. This trial was rated as poor in quality due 

to incomplete information about comparability of groups at baseline, use of an outcome of 

uncertain validity and lack of a blinded outcome assessor. 

Chang, Falconer, Stulberg et al. (1993) randomized 34 patients to either arthroscopic lavage 

and debridement or closed needle lavage. One patient in each group dropped out for intercurrent 

medical problems so the analysis was based on 32 patients. Arthroscopic procedures entailed 

removal of loose tissue fragments, partial meniscectomy, synovectomy, excision of loose 

articular cartilage and no drilling. Closed-needle lavage employed one liter of saline injected 

into the knee and aspirated. Patients were selected for persistent knee pain of more than three 

months despite conservative medical and rehabilitation management. All patients had KellgrenLawrence grade 1–3 osteoarthritis. Groups were well-balanced at baseline on age, percent 

female, duration of knee pain, osteoarthritis grade and several pain and function scales. 

Outcome scales measured at 3 months and 12 months included the AIMS subscales, 50-foot 
116 

walk time, patient global assessment and physician percent improvement. Patients were not 

blinded to group assignment but outcome assessors were. The quality of the trial was rated as 

fair because of uncertainty about whether allocation to groups at randomization was concealed. 

 Results. Table 67 summarizes results from Merchan and Galindo (1993) and Chang, 

Falconer, Stulberg, et al. (1993). In the former trial, the group receiving arthroscopic 

debridement plus physical therapy had significantly better results than the conservative treatment 

group on followup HSS score (p=.022), change in HSS (p=.001) and patient global change 

assessment (p<.001). The latter trial reported no significant differences at either 3 month or 12 

month followup between arthroscopic lavage and debridement and closed needle lavage on 5 

AIMS subscales, 50-foot walk time, patient global assessment and physician percent improved. 

However, this small trial lacks sufficient statistical power to detect small or modest treatment 

effects. 

Table 67. Arthroscopy non-placebo RCTs, results 

Study Outcomes 

Merchan 

and 

Galindo, 

1993 

AD+PT vs. 

Cons 

 F/U (mo) 

Group n mn (rng) Outcome mn p value 

AD+PT 35 25 (12-36) F/U HSS 37.00 0.022 

Cons 38 23 (12-36) (higher=better) 32.76 

AD+PT ∆ HSS 10.14 0.001 

Cons (higher=better) 2.89 

 F/U % Improved % Unchanged % Worse p value 

AD+PT last 75 14 11 <0.001 

Cons 16 13 53 

Chang et 

al., 1993 

ALD vs. 

NL 

 3 mo 12 mo 

 ALD NL ALD NL 

Outcome mn mn Difference (95% CI) mn mn Difference (95% CI)

AIMS Pain Scale 5.0 5.4 -0.4 (-1.6, 0.9) 5.3 5.0 0.3 (-1.1, 1.8) 

AIMS Physical Activity 5.0 6.3 -1.3 (-3.0, 0.4) 4.8 6.2 -1.4 (-3.3, 0.4) 

AIMS Physical Function 1.5 2.0 -0.5 (-1.2, 0.3) 1.7 2.0 -0.3 (-1.1, 0.5) 

AIMS Social Activity 4.3 4.7 -0.4 (-1.4, 0.7) 4.6 4.3 0.3 (-1.1, 1.5) 

AIMS Depression 2.7 2.5 0.2 (-0.8, 1.1) 1.8 2.6 -0.8 (-1.6, 0.1) 

AIMS Anxiety 3.8 3.9 -0.1 (-1.3, 1.0) 3.2 3.5 -0.3 (-1.3, 0.6) 

50-ft walk time, secs 14.2 15.0 -0.8 (-2.8, 1.2) 13.9 14.1 -0.2 (-2.8, 2.3) 

Patient global assessment 3.4 3.6 -0.2 (-10.6, 13.8) 4.1 3.3 0.8 (-5.3, 21.2) 

Physician global % improved 47 46 1 (-34, 36) 41 23 18 (-15, 51) 

 Comment. The small, poor-quality, unblinded RCT by Merchan and Galindo (1993) does not 

provide strong evidence of an advantage favoring arthroscopy over nonoperative therapy. These 

authors found significantly better results for arthroscopic debridement plus physical therapy 

relative to conservative treatment comprised of NSAIDs with a decrease in ADLs plus physical 

therapy. However, Merchan and Galindo did not report whether groups were comparable at 

baseline on duration of osteoarthritis or body weight, the outcome scale is of uncertain validity 

and a blinded outcome assessor was not used. The small trial by Chang, Falconer, Stulberg, et 

al. (1993) found no differences between arthroscopic lavage and debridement and closed needle 

lavage on pain, function and global assessment scales. This trial does not offer support for 

improved outcomes when arthroscopic debridement is added to lavage of the knee. 

The results of the good quality placebo-controlled Moseley, O’Malley, Petersen, et al. (2002) 

create uncertainty about whether arthroscopic lavage and debridement achieve results surpassing 

placebo. The results from Merchan and Galindo are insufficient to establish the superiority of 
117 

arthroscopic debridement over an active nonsurgical control therapy. The trial by Chang, 

Falconer, Stulberg et al. (1993) does not resolve uncertainty over the effects of arthroscopic 

intervention relative to placebo or active controls. Overall, the RCT evidence does not 

definitively show arthroscopy to be ineffective, nor does it establish effectiveness. 

 Quasi-Experimental Evidence. Study Characteristics. A single nonrandomized 

comparative (quasi-experimental) study met selection criteria for this Evidence Report (Tables 

68–72). It compared arthroscopic lavage plus physical therapy with physical therapy alone 

(Livesley, Doherty, Needoff, et al., 1991). Enrollment included 69 patients with OA of the knee 

and no obvious mechanical derangement of the joint. Patients were excluded if they had 

hematologic abnormalities, urate crystals in the joint aspirate, atypical radiologic signs and 

treatable lesions seen on arthroscopy (apparently referring to lesions treatable by arthroscopic 

debridement or partial meniscectomy). Patients were allocated to groups according to which of 

two surgeons they were initially referred; 41 were assigned to lavage plus physical therapy and 

28 to physical therapy alone. Four patients were withdrawn from the arthroscopy group (two 

were lost, two underwent meniscectomy) and four patients in the physical therapy alone group 

were lost to followup. Arthroscopic lavage was performed with a tourniquet, two standard 

portals and 2 liters of normal saline. No details were provided about physical therapy. 

Table 68. Arthroscopy quasi-experimental study, sample selection 

Study Inclusion Exclusion n, Enrolled 

n, 

Withdrawn 

n, Outcome 

Evaluated 

Livesley et al., 1991; 

AL+PT vs. PT 

pts allocated to groups 

according to which of 2 

surgeons they were 

initially referred 

OA of knee and 

pain with no 

obvious mechanical 

derangement of 

joint 

Hematologic 

abnormalities; urate 

crystals in the joint 

aspirate; atypical 

radiologic signs; 

treatable lesions seen 

on arthroscopy 

AL+PT: 41 

PT: 28 

AL+PT: 4 

(2 lost, 2 

meniscectomy) 

PT: 4 (lost) 

AL+PT: 37 

PT: 24 

Table 69. Arthroscopy quasi-experimental study, patient characteristics 

Study Age 

% 

Female Preoperative OA Severity 

Other 

Characteristics 

Livesley et al., 

1991; 

AL+PT vs. PT 

AL+PT: mn 61, sd 7.8 

PT: mn 60.7, sd 7.9 

AL+PT: 32 

PT: 46 

Thomas radiography score 

AL+PT: mn 5.3, sd 2.6 

PT: mn 5.29, sd 2.7 

Stress pain and morning 

stiffness worse in PT 

group; swelling and 

effusions more common in 

AL+PT group 

Table 70. Arthroscopy quasi-experimental study, interventions 

Study Interventions 

Prior 

Treatments 

Concurrent 

Treatments 

Livesley et al., 1991; 

AL+PT vs. PT 

AL: 2 standard portals; tourniquet; Key Med 

Olympus arthroscope and a hook; lavage with 2 

L normal saline at room temperature; 

PT: same regimen for both groups, no details on 

PT provided 

 
118 

Table 71. Arthroscopy quasi-experimental study, study quality 

Study 

Initial 

Assembly of 

Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance 

of Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal* 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Livesley et al., 1991; 

AL+PT vs. PT N N N N N Poor 

Table 72. Arthroscopy quasi-experimental study, results 

Study Outcomes 

Livesley et al., 

1991 

AL+PT vs. PT 

Investigator-devised outcome measures, 16 dimensions; -1 to +1, 3 point scale (patient global 

change assessment); 0-4 point scale (pain at rest, pain on activity, pain at night, joint tenderness, 

periarticular tenderness); 0-3 point scale (effusions); scale in minutes (duration of stiffness after 

rest, in the morning); scale in degrees (knee range of motion); dichotomous scale, present/absent 

(warmth, stress pain, wasting crepitus, sleep deprivation, swelling) 

F/U at 3, 6, 12 mo; 48 possible between-group comparisons of improvement in outcome 

(data provided for 32 comparisons) 

N=61 (37 AL+PT, 24 PT) 

Significant differences in degree of improvement, AL+PT vs. PT 

Outcome F/U p value 

pain on activity 3 mo 0.003 

 6 mo 0.05 

pain at night 3 mo 0.01 

joint tenderness 6 mo 0.02 

swelling 3 mo 0.03 

Subgroup analyses provided on pain at rest and pain on activity for 3 preoperative radiographic 

OA classes (slight, moderate, severe): significant between-group difference favoring AL+PT at 3 

mo for moderate subgroup. 

Patients were assessed on a large number of knee measures at baseline and followup. Pain 

was of primary interest and it was rated at rest, on activity and at night. The authors assessed 

nine signs of inflammation, including joint tenderness, peri-articular tenderness, duration of 

stiffness at rest and in the morning, effusions, warmth, stress pain, sleep disturbance and 

swelling. Other measures included knee range of motion, the presence of wasting and crepitus 

and patient global change assessment at followup. Patients were comparable at baseline on age, 

percent female and preoperative radiographic OA severity. Information was lacking on baseline 

duration of osteoarthritis and body weight. There were differences between groups in baseline 

stress pain, morning stiffness, swelling and effusions. Using the U.S. Preventive Services Task 

Force rating system, the Livesley, Doherty, Needoff et al. (1991) trial was rated unfavorably on 

all 6 dimensions. 

 Results. Followup was conducted at 3, 6 and 12 months. Of the 48 possible between-group 

comparisons, the article provides data for 32. Five comparisons revealed statistically significant 

results favoring arthroscopic lavage plus physical therapy: pain on activity at 3 and 6 months, 

pain at night at 3 months, joint tenderness at 6 months, and swelling at 3 months. Subgroup 

analyses were provided on pain at rest and pain on activity for three classes of preoperative 

radiographic OA severity (slight, moderate, and severe). The article reports a significant 

advantage at 3 months among moderate class patients in the lavage plus physical therapy group. 

In addition, presence or absence of effusion was not found to be correlated with results. 
119 

 Comment. Livesley, Doherty, Needoff et al. (1991) conclude that their results confirm the 

effectiveness of arthroscopic lavage as a treatment for symptomatic OA of the knee. However, 

critical review of this study contradicts this view. This small study reported no significant 

advantage for lavage in 43 of 48 comparisons. Furthermore, it was flawed by lack of blinding, 

lack of data on some baseline characteristics, imbalances on baseline characteristics without 

corresponding adjustment in the analysis, and absence of details about physical therapy. In 

addition, the study does not address the possible contribution of placebo effects to the observed 

results. This poor-quality quasi-experimental study does not support conclusions about the 

relative effectiveness of arthroscopic lavage plus physical therapy and physical therapy alone. 

 Administrative Database Evidence. Study Characteristics. The largest single source of 

evidence came from an administrative database, with 14,391 patients (Wai, Kreder, and 

Williams, 2002). This analysis was conducted within the Ontario Health Insurance Plan 

physician claims system between 1992 and 1996. The focus of the study was to evaluate 

outcome (further surgery, adverse events) and patterns of utilization across 16 intraprovincial 

geographic units. Claims were linked with discharge abstracts to collect outcome data. The 

maximum followup was 3 years. An algorithm was created to capture patients with a primary 

diagnosis of OA of the knee. Patients were excluded for having a primary diagnosis of 

rheumatoid arthritis and those with bilateral knee procedures on the same day. Data were 

analyzed with a Cox proportional hazards regression model. The Charlton-Deyo comorbidity 

index was used for adjustment purposes. Minimum age for inclusion was 50 years, the mean 

was 62.4 and the oldest age was 92. The proportion of females was 49.9 percent. No other 

patient baseline characteristics were mentioned. Details were unavailable about the arthroscopic 

debridement procedure. With the exception of the lack of more details describing the patients, 

the intervention and whether data quality was audited, this study was generally well-reported and 

well-conducted. No funds were received to support the study and the authors received no 

benefits from commercial parties. 

 Results. Table 73 shows that the probability of repeat arthroscopy was 2.8 percent within 1 

year and 7.7 percent within 3 years. Wai and co-workers also found that total knee arthroplasty 

was performed in 9.2 percent within 1 year and 18.4 percent within 3 years. High tibial 

osteotomy was performed in 1.2 percent within 1 year and 2.9 percent within 3 years. Wai, 

Kreder, and Williams (2002) found that all 3 types of further surgery increased significantly in 

frequency with age. The risk of all complications (Table 74) was 1.9 percent. Surgical 

complications were noted in 0.5 percent. The risk of stroke or myocardial infarction was 0.3 

percent. Infections occurred in 0.5 percent and deep vein thrombosis was found in 0.6 percent. 

The probability of death within 3 months was 0.1 percent. 

Regarding utilization, on average there were 1.4 arthroscopic debridements per 1000 

individuals in Ontario between 1992 and 1996. Across this time period, there were significant 

increases in the age and sex-adjusted population rates, at an average rate of 10.1 percent per year. 

Across intraprovincial geographic units, population rates ranged between 0.7 to 2.3 persons per 

1,000. Geographic units with higher rates of arthroscopic debridement were associated with 

higher rates of total knee arthroplasty within 1 year for patients aged 60 or older. 
120 

Table 73. Arthroscopy administrative database, further surgery results 

Study 

 % % % 

 Repeat Total High Tibial 

Group n F/U Arthroscopy Arthroplasty Osteotomy 

Wai et al., 2002; AD All pts 14391 < 1 yr 2.8 9.2 1.2 

 6212 < 3 yr 7.7 18.4 2.9 

50-59 yo 6487 < 1 yr 3.3 4.0 1.6 

 2918 < 3 yr 8.9 9.7 4.2 

60-69 yo 5435 < 1 yr 2.4 11.1 1.0 

 2354 < 3 yr 6.8 23.7 2.0 

70-79 yo 2223 < 1 yr 2.2 19.0 0.4 

 854 < 3 yr 6.2 32.7 0.8 

> 80 yo 246 < 1 yr 1.6 17.5 0.0 

 86 < 3 yr 8.1 31.4 0.0 

Rate of total knee arthroplasties increased with age at 1 yr and 3 yrs 

(p=.0001); Cox's proportional hazards model adjusted analysis – age still 

associated (p=.02). No other significant relationships in unadjusted or 

adjusted analyses. 

Table 74. Arthroscopy administrative database, adverse event results 

Study 

% % % % 

All/Any Surgical Stroke/ Deep % 

Adverse Compli- Myocardial % Vein Death 

Events cations Infarction Infections Thrombosis <3 mo 

Wai et al., 2002; 

AD 

(n=14,391)

1.9 0.5 0.3 0.5 0.6 0.1 

 Comment. The study by Wai, Kreder, and Williams (2002) provides estimates of the 

probabilities of further surgery and adverse events for the most populous Canadian province 

from 1992 to 1996. These data may be representative of outcomes in everyday practice, but 

administrative databases are also susceptible to biases of underreporting and problems in the 

quality of available data. Thus, it is unclear how accurately this study reflects the frequency of 

adverse events after arthroscopic surgery. Furthermore, this study did not report on pain or 

function outcomes. The report only presented significant differences in further surgery with 

increasing age. It included no comparison with placebo or other interventions. This 

administrative database analysis offers evidence of limited value to this evidence report. While 

it shows different rates of further surgery across age subgroups, it leaves unanswered the 

question of whether there are different effects in terms of other outcomes of arthroscopy versus 

placebo or other treatments. 

 Case Series Evidence. Study Characteristics. The literature search revealed 17 case series 

(Tables 75–86; Appendix C*

, Tables IIIB–IIIH) with samples of 50 or more patients, reporting 

outcomes after arthroscopic lavage and debridement for OA of the knee. These studies 

collectively included a total of 2,398 patients, with individual sample sizes ranging between 54 

and 441. 

Patients were selected in various ways (Table 75). Only two studies mentioned using the 

ACR diagnostic criteria or similar case definition criteria (Aaron, Skolnick, Reinert et al., 2006; 

Jackson and Dieterichs, 2003). Four studies selected patients based on intraoperative findings of 

arthroscopy (Bernard, Lemon, and Patterson, 2004; Linschoten and Johnson, 1997; McLaren, 

 

* Appendixes cited in this report are available electronically at http://www.ahrq.gov/clinic/tp/oakneetp.htm
121 

Blokker, Fowler, et al., 1991; Sprague, 1981). Failed response to conservative management was 

noted in nine studies (Aaron, Skolnick, Reinert et al., 2006; Bernard, Lemon, and Patterson, 

2004; Dervin, Stiell, Rody, et al., 2003; Shannon, Devitt, Poynton, et al., 2001; Harwin, 1999; 

Yang and Nisonson, 1995; McLaren, Blokker, Fowler, et al., 1991; Ogilvie-Harris and Fitsialos, 

1991; Bert and Maschka, 1989). 

Beyond age and proportion of female patients, these patient samples were not well described 

(Table 76). One study reported that the mean age was 49 (Aichroth, Patel, and Moyes, 1991), 

while average age was in the 50s and 60s for all other studies. The proportion of women in study 

samples ranged from 19 percent to 67 percent; it was 50 percent or higher in six of 17 studies. 

 Only four studies gave data on baseline body weight (Aaron, Skolnick, Reinert et al., 2006; 

Dervin, Stiell, Rody, et al., 2003; Shannon, Devitt, Poynton, et al., 2001; Bert and Maschka, 

1989). Two studies specified whether patients had primary versus secondary OA, with both 

studies selecting more than 80 percent primary OA (Krystallis, Kirkos, Papavasiliou, et al., 2004; 

McLaren, Blokker, Fowler, et al., 1991). Four articles provided information about disease 

duration (Shannon, Devitt, Poynton, et al., 2001; Yang and Nisonson, 1995; Ogilvie-Harris and 

Fitsialos, 1991; Timoney, Kneisl, Barrack, et al., 1990). Three studies mentioned preoperative 

disease severity classification (Jackson and Dieterichs, 2003; Yang and Nisonson, 1995; 

Timoney, Kneisl, Barrack, et al., 1990), 3 studies described only arthroscopic disease severity 

ratings (Dervin, Stiell, Rody, et al., 2003; McGinley, Cushner, and Scott, 1999; Ogilvie-Harris 

and Fitsialos, 1991), and four studies provided both pre- and intra-operative information (Aaron, 

Skolnick, Reinert et al., 2006; Krystallis, Kirkos, Papavasiliou, et al., 2004; Bohnsack, Lipka, 

Ruhmann, et al., 2002; Bert and Maschka, 1989). Four articles stated that some patients had 

mechanical symptoms (Aaron, Skolnick, Reinert et al., 2006; Krystallis, Kirkos, Papavasiliou, et 

al., 2004; Dervin, Stiell, Rody, et al., 2003; Aichroth, Patel, and Moyes, 1991). 

Details about arthroscopic treatment are shown in Table 77. Of the 17 studies, 13 stated that 

lavage with debridement were performed. Four studies described debridement procedures, but 

failed to mention whether lavage was also performed, although debridement without lavage is 

unlikely. Sixteen studies noted that trimming or shaving of loose articular cartilage 

(chondroplasty) was part of the treatment. Partial or total meniscectomy was performed in 

subsets of patient samples in all 17 studies. Partial synovectomy was an element of treatment in 

11 studies and osteophytes were removed in five studies. Three studies included abrasion 

arthroplasty and drilling of bone occurred in two. 

We applied the case series quality assessment tool developed by Carey and Boden (2003; see 

Methods chapter) to this group of studies (Table 78). It comprises the following 8 items: These 

items are relevant to external validity: a well-described study population and a well-described 

intervention. A well-described study population, particularly details on numbers of individuals 

included, excluded and lost could also reflect on bias. Other items related to bias include use of 

validated outcome measures (independently assessed), appropriate statistical analysis and welldescribed results. 
Table 75. Arthroscopy case series, sample selection 

Study Inclusion Exclusion n

Aaron et al., 2006, ALD Consecutive pts; met ACR OA of tibiofemoral joint; failed oral 

anti-inflammatory treatment; age 18-70 yo; Kellgren-Lawrence grade >2 

Previous infection; OA of patellofemoral joint; other/confounding diagnoses; 

1

Bernard et al., 2004; ALD 01/91 – 12/93; consecutive pts; knee OA (Outerbridge 3 or 4); 

pain uncontrolled by non-operative treatment; radiographic OA changes 

 1

Krystallis et al., 2004; ALD 02/97 – 06/01; OA of the knee; standard conservative nonoperative treatment had failed; local (L), general (G) or peridual 

anesthesia (P) 

 2

Dervin et al., 2003; AD 03/95 – 11/97; OA of knee; 40-75 yo; remained symptomatic 

despite supervised PT and comprehensive medical management 

Inflammatory/traumatic forms of OA; 

 

Jackson and Dieterichs, 2003; ALD 

01/95 – 06/97; ACR criteria diagnosis of OA of knee; Jackson and Dieterichs stage III/IV; consecutive series 

Stage I and IV; marrow stimulation techniques, laser or radio-frequency chondroplasty 

 

Bohnsack et al., 2002; AD 05/89 – 11/96; history of knee pain, swelling, radiological signs of 

severe OA (grade I-IV) 

 

Shannon et al., 2001; ALD Retrospective consecutive series; mild-moderate OA over 4-yr 

period; symptoms not severe enough for joint replacement; conservative treatment alone had failed or non-specific mechanical symptoms out of proportion to clinical and radiologic findings 

Preop clinical/radiologic diagnosis of meniscal tear or loose body 

5

Harwin, 1999; ALD 1980 -1993; areas of fibrillated articular cartilage with exposed 

bone; unresponsive to all modalities of nonoperative treatment 

 2

McGinley et al., 1999; AD 1981-87; pts > 55 yo OA symptoms including pain limiting 

function and Albach radiographic JSN grade 2-3; > 10 yr F/U 

 9

Linschoten and Johnson, 1997; ALD 

07/85 – 01/88; age > 40 yo; arthroscopically confirmed 

degenerative changes in > 2 of 3 compartments or single compartment Outerbridge III/IV 

Arthroscopies for diagnosis or treatment of acute injuries, preliminary diagnosis of degenerative joint disease not confirmed intraoperatively 

5

Yang and Nisonson, 1995; ALD 

07/89 – 07/93; did not respond to conservative nonoperative treatment; persistent evidence of internal derangement of knee; 

did not show severe signs and symptoms to merit total knee 

arthroplasty 

History of rheumatoid arthritis; gout; ochronosis; ankylosing spondylitis; hemophilia; osteonecrosis; posttraumatic or postinfectious osteoarthritis 

1

Aichroth et al., 1991; ALD 1977 – 1988; degenerative knee joint 2McLaren et al., 1991; ALD 07/82 – 07/86; OA confirmed at arthroscopy; nonoperative 

treatments either did not control symptoms sufficiently to allow normal daily activities or control rest pain 

Inflammatory joint disease, malunited fractures and ligamentous instability 

 

122
Table 75. Arthroscopy case series, sample selection (continued) 

Study Inclusion Exclusion n

Ogilvie-Harris and Fitsialos, 1991; ALD 

1979 – 1987; degenerative arthritis of the knee; persistent 

symptoms despite adequate medical management 

 

Timoney et al., 1990; ALD 07/81 – 02/86; age > 40 yo; intraoperative diagnosis of OA rheumatoid arthritis, acute 

infection arthritis, acute injury 

1

Bert and Maschka, 1989; AD 

09/81 – 12/82; conservative methods of treatment had failed; available for 5 yr followup 

 

Sprague, 1981; ALD 08/78 – 11/79; pre- and postop moderate to extreme 

degenerative arthritis of 2-3 compartments; initial conservative treatment 

 6

123
Table 76. Arthroscopy case series, patient characteristics 

Study Age 

% 

Female Obesity (%) 

Disease 

Category 

(%) 

Disease 

Duration 

Preoperative 

Disease 

Severity (%) 

Arthros

Disea

Severity 

Aaron et al., 2006; ALD 

Mn 61.7 67 Mn BMI: 

31.8 

 KellgrenLawrence (2/3/4) 

53/29/18 

Noyes-Stamn total 2

Bernard et al., 2004; ALD 

Mn 55, sd 13 39 

Krystallis et al., 2004; ALD 

L: mn 60.8, rng 31-71 G: mn 59.9, rng 30-67 P: mn 62.2, rng 35-75 

49 1o: 94 

2o: 6 

 Fairbank 

(0/I/II/III) 12/36/40/12 

Outerbridg(I-II/III/IV) 12/28/60 

Dervin et al., 2003; AD 

Mn 61.7, sd 8.6 53 BMI > 27: 67 

BMI > 33: 25 

 Dougados 

Medial III/Lateral III/

Jackson and Dieterichs, 2003; ALD 

I: mn 35.5, rng 22-60 II: mn 54, rng 26-85 III: mn 56, rng 24-78 IV: mn 64, rng 41-83 

 Jackson and 

Dieterichs (I/II/III/IV) 7/26/32/35 

Bohnsack et al., 2002; AD 

Mn 60, rng 50-83 52 Jaeger and Wirth 

III/IV 

OuterbridgIII/IV: 50-8

Shannon et al., 2001; ALD 

Mn 60.9, rng 48-83 56 Mn wt: 76.6 

kg, rng 54-100 

 # mo: % 

< 3: 20 3-12: 43 > 12: 39 

Harwin, 1999; ALD Mn 62.1, rng 32-88 57 McGinley et al., 1999; AD 

Mn 62.6, rng 55-82 Outerbridg

100 

Linschoten and Johnson, 1997; ALD 

Mn 62.5, rng 41-79 51 

Yang and Nisonson, 1995; ALD 

Mn 64.2, sd 4.3 19 # mo: % 

< 1: 17 1-12: 62 > 12: 15 

Fairbank (0/I/II/III) 15/50/24/7 

Aichroth et al., 1991; ALD 

Mn 49, rng 28-82 28 

McLaren et al., 1991; ALD 

Mn 54, rng 23-82 30 1o: 81 

2o: 19 

Ogilvie-Harris and Fitsialos, 1991; ALD 

Mn 58, rng 28-92 > 2 yrs in 

most pts 

 Outerbridg

I-II/III/IV) 32/36/32 

124
Table 76. Arthroscopy case series, patient characteristics (continued) 

Study Age 

% 

Female Obesity (%) 

Disease 

Category 

(%) 

Disease 

Duration 

Preoperative 

Disease 

Severity (%) 

Arthros

Disea

Severity 

Timoney et al., 1990; ALD 

Mn 58.1, rng 40-81 31 mn 48.9 mo, 

rng 2-144 

0-III scale 

Bert and Maschka, 1989; AD 

DA mn 66, rng 46-84 D mn 61, rng 39-82 

DA 46 D 42 

% obese: DA 26 D 22 

 Ahlback 

II-100 

OuterbridgIV: 100 

Sprague, 1981; ALD Mn 56, rng 24-78 38 

125
Table 77. Arthroscopy case series, treatments 

Study 

Lavage + 

Debridement Lavage Debridement Chondroplasty 

Partial/Total 

Meniscectomy 

Partial 

Synovectomy Osteophyt- ectomy 

Aaron et al., 2006 X X X X X Bernard et al., 2004 X X X Krystallis et al., 2004 X X X Dervin et al., 2003 AD X X X X Jackson and Dieterichs 2003 X X X Bohnsack et al., 2002 X X X X Shannon et al., 2001 X X Harwin, 1999 ALD X X X X McGinley et al., 1999 X X X Linschoten and Johnson, 1997 X X X X Yang and Nisonson, 1995 X X X X Aichroth et al., 1991 X X X X X McLaren et al., 1991 X X X X Ogilvie-Harris and Fitsialos, 1991 X X X Timoney et al., 1990 X X X X X Bert and Maschka, 1989 X X X X X Sprague, 1981 ALD X X X X X 

126
Table 78. Arthroscopy case series, study quality 

Study 

Clearly Defined Question 

WellDescribed Study Population 

WellDescribed Intervention 

Use of Validated Outcome Measures (Independently Assessed) 

Appropriate Statistical Analysis 

WellDescribed Results 

DiscussConcluSupporData 

Aaron et al., 2006 + - + + (+) + - + Bernard et al., 2004 ALD + - - + (?) + - + Krystallis et al., 2004 ALD - - + ? (?) + - - Dervin et al., 2003 AD + - - + (?) + - + Jackson and Dieterichs, 2003 ALD + - - - (?) - - + Bohnsack et al., 2002 AD - - - + (?) + - - Shannon et al., 2001 ALD + - + +(?) - - + Harwin, 1999 ALD + - + + (?) - + - McGinley et al.,1999 AD - - - -(?) - - - Linschoten and Johnson, 1997 ALD - - + - (?) - - - Yang and Nisonson, 1995 ALD + - + - (?) - - - Aichroth et al., 1991 ALD - - + - (?) - - - McLaren et al., 1991 ALD + - + +(?) - - - Ogilvie-Harris and Fitsialos, 1991 ALD - - - - (?) - - - Timoney et al., 1990 ALD + - - ? (?) + - - Bert and Maschka, 1989 AD - - + ? (?) - - - Sprague, 1981 ALD - - + - (?) - - - 

127
128 

1. Clearly Defined Question: Of the 17 studies, nine put forward a clearly defined question. 

The remainder either did not state a clear question or stated one that was beyond the reach of 

the case series as a study design. 

2. Well-Described Study Population: None of the case series were satisfactory on this 

element. None clearly stated the preoperative case definition criteria for OA of the knee, 

although Aaron, Skolnick, Reinert et al. (2006) and Jackson and Dieterichs (2003) cited the 

ACR diagnostic criteria. Only two studies (Yang and Nisonson, 1995; Timoney, Kneisl, 

Barrack, et al., 1990) reported on all items of the minimal set of baseline patient 

characteristics: age, sex, preoperative disease severity and duration of disease. This element 

primarily influences external validity in that it is easier to generalize from a well-described 

study population than a poorly described population. It also reflects on internal validity to 

the extent that investigators provide complete accounting of participants included, excluded 

and lost to followup. Only six of 17 studies provided a full accounting of participant flow. 

3. Well-Described Intervention: Ten studies gave sufficient descriptions of interventions. 

Other reports either failed to note cointerventions or did not mention whether lavage 

accompanied debridement. 

4. Use of Validated Outcome Measures (Independently Assessed): Only one study 

mentioned using an independent outcome assessor (Aaron, Skolnick, Reinert et al., 2006). 

Thus, outcome measures could be influenced by bias due to participants and investigators. 

Only seven studies used validated outcome measures, including the Knee Society pain 

domain scale (Aaron, Skolnick, Reinert et al., 2006), Lysholm and Gillquist rating scale 

(Bohnsack, Lipka, Ruhmann, et al., 2002); the WOMAC and SF-36 scales (Dervin, Stiell, 

Rody, et al., 2003). Bernard, Lemon, and Patterson (2004) assessed Kaplan-Meier time to 

further major surgery. Three studies measured global patient change assessment, for which 

no external criterion validation is necessary (Shannon, Devitt, Poynton, et al., 2001; Harwin, 

1999; McLaren, Blokker, Fowler, et al., 1991). It is unclear whether several scales have been 

validated, including the Duke Arthroscopy score (Shannon, Devitt, Poynton, et al., 2001), the 

Baumgaetner scale (Krystallis, Kirkos, Papavasiliou, et al., 2004) and the Hospital for 

Special Surgery rating score (Timoney, Kneisl, Barrack, et al., 1990). All other rating 

instruments appear to be scales devised by the study investigators having uncertain 

pyschometric properties. Average followup ranged from about 1 year to 13.2 years. 

5. Appropriate Statistical Analysis: Six studies used appropriate statistical analyses, for 

example, performing prepost tests on paired data. The remaining 11 studies either reported 

no statistical test results or inappropriate ones. Absent statistical tests or inappropriate 

analyses could give a biased view of study outcomes. 

6. Well-Described Results: Only one of the 17 studies (Harwin, 1999) gave well-described 

results, consisting of validated measures, with adequate accounting of followup; and 

inclusion of both potentially beneficial outcomes and adverse events. Incomplete reporting 

of results could lead to a biased representation of a study’s findings. 
129 

7. Discussion/Conclusions Supported by Data: Five articles stated conclusions that were 

supported by data. The other 12 articles either failed to note limitations of the data or stated 

conclusions that went beyond the data and design of the study. 

8. Funding/Sponsorship Source Acknowledged: Only four articles mentioned whether the 

study was funded or if the authors had financial relationships with manufacturers. 

Overall, this body of case series evidence is of poor quality. The best-rated studies (Aaron, 

Skolnick, Reinert et al., 2006; Dervin, Stiell, Rody, et al., 2003) were favorable on 6 of 8 items. 

Only three studies (Bernard, Lemon, and Patterson, 2004; Shannon, Devitt, Poynton, et al., 2001; 

Harwin, 1999) were rated favorably on four out of the eight items in the Carey and Boden scale. 

Two studies (Yang and Nisonson, 1995; McLaren, Blokker, Fowler, et al., 1991) rated well on 

three of eight items. Ten other case series were rated favorably on two or fewer items. Bias is a 

particular concern in that only six studies give a full accounting of participant flow, no study 

used an independent outcome assessor, and only one study presented well-described results. 

Lack of an independent assessor, in all but one study, is perhaps the most important factor given 

that the outcomes generally assessed, pain, function and global result, are subjective and 

susceptible to bias and placebo effects. 

 Results. Only two studies used validated multidimensional outcome scales (Table 79). 

Bohnsack, Lipka, Ruhmann, et al. (2002) used the Lysholm and Gillquist scale in 104 patients, 

finding significant improvement in scores after an average of 5.4 years. Dervin, Stiell, Rody, et 

al. (2003) reported that 44 percent of 126 patients achieved a minimal clinically important 

improvement on the WOMAC scale at 2 years. It is unclear whether the Hospital for Special 

Surgery rating scale has been validated (Table 80), but Timoney, Kneisl, Barrack, et al. (1990) 

found significant improvement on it among 108 patients after an average of 50.6 months. 

Table 79. Arthroscopy case series, validated outcome scales 

Study Outcomes 

Aaron et al., 

2006 ALD 

N=110, 12 lost to F/U; mn F/U 34 mo (24-74 mo) 

Knee Society pain Pre F/U p 

Mn 11.9 30.8 <0.001 

Success=Knee Society pain > 30 in 72 (65%), failure in 38 (35%) 

Significant predictors of percent success: Kellgren-Lawrence grade, 

abnormal limb alignment, medial/lateral joint space width; 

intraoperative lesion severity; mechanical symptoms did not predict 

success, 

Bohnsack et al., 

2002 

AD 

N=104; mn F/U 5.4 r 

Lysholm & Gillquist Pre F/U p 

Mn 40 69 <0.01 

Higher gain in Lysholm & Gillquist score in pts < 60 yo, monolateral 

OA; no influence of meniscectomy. 

Dervin et al., 

2003 

AD 

N=126; mn F/U 2 yr 

MCII WOMAC pain: 44% 

MCII predicted by tenderness at medial joint line, positive Steinman, 

unstable meniscal tear (logistic regression) 

Table 80. Arthroscopy case series, Hospital for Special Surgery rating 

Study Outcomes 

Timoney et al., 

1990 

ALD 

N=108; mn F/U 50.6 mo 

 Pre F/U p 

Mn HSS score (sd) 24.7 (9.2) 36.1 (16.3) <0.001 
130 

A validated pain scale, the Knee Society pain domain was assessed in the study by Aaron, 

Skolnick, Reinert et al. (2006). Mean scores improved from 11.9 to 30.8 at an average of 34 

months’ followup (p<0.001). The authors selected a gain of 30 points on as successful outcome, 

finding that 65 percent met this definition, while 35 percent were failures. 

Three studies reported on a patient global change scale, sorting patients into three outcome 

classes: better/improved, the same/unchanged or worse (Table 81). Shannon, Devitt, Poynton, et 

al. (2001, n=54, mean followup 29.6 months) found that 67 percent were improved and 33 

percent were unchanged. Harwin (1999, n=190, mean followup 7.4 years) observed that 63 

percent were better, 21 percent were unchanged and 16 percent were worse. McLaren, Blokker, 

Fowler, et al. (1991, n=170, mean followup 25 months) reported that 65 percent were improved, 

28 percent were the same and 7 percent were worse. 

Table 81. Arthroscopy case series, patient global change assessment 

Study 

 % % 

 Mean Better/ Same/ % 

Group n F/U Improved Unchanged Worse 

Shannon et al., 

2001 

ALD 

All pts 54 29.6 mo 67 33 0 

Mn duration of symptom relief 25.5 mo, rng 1-51 

No influence on results of sex, age, weight, preop Duke score, duration of symptoms 

Harwin, 1999 

ALD 

All pts 190 7.4 yr 63 21 16 

Normal alignment 57 84 12 4 

Mod malalignment 102 68 24 9 

Sev malalignment 45 27 27 47 

McLaren et al., 

1991 

ALD 

All pts 170 25 mo 65 28 7 

Nine studies used a patient global result scale, using classes such as excellent, good, fair and 

poor (Table 82). These studies collectively included 1,472 patients. Among three studies that 

provided specific data on the percentage with excellent results, Krystallis, Kirkos, Papavasiliou, 

et al. (2004, n=201, mean followup 32 months) observed that 43 percent of all patients achieved 

this. Yang and Nisonson (1995, n=103, mean followup 11.7 months) reported excellent results 

in 20 percent and good results in 45 percent. Aichroth, Patel, and Moyes (1991, n=254, mean 

followup 44 months) found excellent results in 18 percent and good results in 57 percent. 

Jackson and Dieterichs (n=121) had at least 4 years of followup, reporting excellent or good 

results in 50 percent. Excellent or good results were achieved in 51 percent of 59 patients who 

underwent debridement plus abrasion and 66 percent of 67 patients receiving debridement alone 

in the series by Bert and Maschka (1989, 5 year followup). 

Ogilive-Harris and Fitsialos (1991, n=441, minimum 2 year followup) reported good results 

in 68 percent and Sprague (1981, n=63, mean followup 13.6 months) found good results in 74 

percent. Linschoten and Johnson (1997, n=55, mean followup 49 months) found good results in 

68 percent. Timoney, Kneisl, Barrack, et al. (1990, n=108, mean followup 50.6 months) found 

good results in 50 percent and significantly worse results for those with symptoms over 48 

months and those with severe chondromalacia on arthroscopy. 
131 

Table 82. Arthroscopy case series, patient global result assessment 

Study 

 % 

 Mean % Excel/ % % % 

Group n F/U Excel Good Good Fair Poor 

Krystallis et al., 2004 

ALD 

All pts 201 32 mo 43 

Mechanical sx 67 66 

Loading sx 134 31 

No difference between local, general and peridural anesthesia groups (ANOVA, 

p=0.71) 

Jackson and Dieterichs, 

2003 

ALD 

All pts 121 > 4 yr 50 27 22 

Stage I 8 100 0 0 

Stage II 32 91 0 9 

Stage III 39 49 28 23 

Stage IV 42 12 52 36 

Linschoten and Johnson, 

1997 

ALD 

All pts 55 49 mo 68 32 

 6 mo 82 18 

 12 mo 77 23 

 24 mo 70 30 

 36 mo 68 32 

 48 mo 68 32 

Significantly poorer results for Outerbridge class IV on arthroscopy in both medial 

and lateral compartments 

Yang and Nisonson, 1995 

ALD 

All pts 103` 11.7 mo 20 45 32 3 

Sx < 1 mo 78 

Sx > 12 mo 52 

Mechanical sx 96 

No mechanical 42 

Fairbank 0/I 69 

Fairbank II/III 36 

Mild degeneration 74 

Severe degeneration 39 

Outcome significantly better for mechanical symptoms, mild degeneration. Outcome 

not correlated with age, sex, side or duration of followup 

Aichroth et al., 1991 

ALD 

All pts 254 44 mo 18 57 15 10 

All pts 75 

< 60 yo 78 

> 60 yo 55 

Satisfactory result correlated with age (p<0.008), Ahlback preop radiographic 

severity (p<0.001) and with Outerbridge operative severity (p<0.001); no correlation 

with type or location of meniscal tear or performance of previous surgery 

Ogilvie-Harris and 

Fitsialos, 1991 

ALD 

All pts 441 > 2 yr 68 

1 compartment 103 82 

2 compartments 135 58 

Abrasion 32 56 

Meniscectomy 149 68 

Lavage only 4 25 

Timoney et al., 1990 

ALD 

All pts 108 50.6 mo 5049 20 41 

Subjective results deteriorated over time. 

Subjective results significantly worse for those with symptoms > 48 mo, those with 

severe chondromalacia; not correlated with meniscal pathology, condition of ACL, 

those undergoing limited lavage and debridement 

Bert and Maschka, 1989 

AD 

Debridement 

Abrasion 59 5 yr 51 16 33 

Debridement 67 66 13 21 

Sprague, 1981 

ALD 

All pts 63 13.6 mo 74 10 16 
132 

Table 83 shows results from 2 studies that report whether pain and/or function improved on 

unvalidated outcome scales. McLaren, Blokker, Fowler, et al. (n=170, mean followup 25 

months) provided pre- and post-treatment proportions with various classes of disability, but 

provided no statistical test results. Ogilive-Harris and Fitsialos (1991, n=441, about 4 years 

mean followup) reported on pain, activity, analgesic use and satisfaction, without appropriate 

statistical comparisons of baseline and followup status. 

Table 83. Arthroscopy case series, symptom/function improvement 

Study Outcomes 

McLaren et al., 

1991 

ALD 

n=170; mean followup 25 mo 

Disability (%) Pre Post 

No restriction 10 32 

Limited recreation & sports 48 45 

Unable to work 25 12 

Restricted daily activities 17 11 

Ogilvie-Harris 

and Fitsialos, 

1991 

ALD 

n=441; mean followup ~4 yr 

Domain % 

Pain, no/occasional 53 

Pain improved 86 

Activity limitation, no/occasional 59 

Activity improved 83 

Analgesic, no/occasional 79 

Analgesic, improved 32 

Satisfaction 90 

Results related to disease severity 

Data on further surgery after arthroscopy were given in 14 case series (Table 84). Bernard, 

Lemon, and Patterson (2004, n=100) reported that the 5-year probability of freedom from major 

surgery was about 84 percent. Across three studies, the probability of further surgery was 

between 13 percent and 20 percent (Bohnsack, Lipka, Ruhmann, et al., 2002, n=104; Linschoten 

and Johnson, 1997, n=55; Aichroth, Patel, and Moyes, 1991, n=254). In eight studies, the 

proportion undergoing repeat arthroscopy ranged between 2 percent and 13 percent at varying 

lengths of followup. Eleven studies report that the percentage of patients who underwent total 

knee arthroplasty ranged from 2 percent to 33 percent. In 3 case series, high tibial osteotomy 

was done between 2 percent and 4 percent. 

Seven studies report on adverse events (Table 85). Two studies reported proportions of 

prolonged drainage of 1.2 percent and 13 percent (McLaren, Blokker, Fowler, et al., 1991, 

n=170; Linschoten and Johnson, 1997, n=55). Hemarthrosis occurred in 2 percent in the series 

by Harwin (1999, n=190) and 24.9 percent by Krystallis, Kirkos, Papavasiliou, et al. (2004, 

n=197). Effusions were noted in 6.5 percent by Timoney, Kneisl, Barrack, et al. (1990, n=108) 

and 1.9 percent by Linschoten and Johnson (1997). Timoney, Kneisl, Barrack, et al. (1990) 

found infections in 0 percent. Among 4 studies, deep vein thromboses occurred between 0.6 

percent and 1 percent. 

 Comment. Authors of case series commonly conclude from their results that arthroscopic 

lavage and debridement are effective, paying inadequate attention to their studies’ limitations. 

The case series is a weak design that can demonstrate effectiveness under certain circumstances. 

The methodologic quality of case series must be high, with use of validated outcome scales 

assessed independently, full accounting of selected and excluded patients and appropriate 

analysis of both beneficial outcomes and adverse events. In addition, the observed effect in case 

series must be large enough to exceed potential biases and nonspecific effects. This set of 

studies is of particularly low quality. Only one study clearly used an independent outcome 
Table 84. Arthroscopy case series, further surgery 

Study 

 % % %  % % Repeat Unicondylar TotaGroup n F/U Any Major Arthroscopy Arthroplasty Arth

Aaron et al., 2006; ALD All pts 110 34 mo 15 

Total knee arthroplasty was related to baseline Kellgren-Lawrence grade. 

Bernard et al., 2004; ALD All pts 100 18 3 11 

5-yr major surgery-free survival: all: ~85%; < 60 yo: 89%; > 60 yo: 68% (X2, p=0.02); prior menisc

outcome 

Jackson and Dieterichs, 2003; ALD All pts 121 > 4 yr 10 12 

Stage I 8 0 0 Stage II 32 9 0 Stage III 39 15 8 Stage IV 42 7 29 

Bohnsack et al., 2002; AD All pts 104 33.1 mo 20 4 4 8 

unspecified procedure (4%) 

Shannon et al., 2001; ALD All pts 54 29.6 mo 7 19 Harwin, 1999; ALD All pts 190 7.4 yr 15 13 McGinley et al., 1999; AD All pts 77 13.2 yr 33 Linschoten and Johnson, 1997; ALD All pts 55 13 

Further surgery was significantly associated with presence of Outerbridge class IV on arthroscopy chondromalacia in lateral compartment. 

Yang and Nisonson, 1995; ALD All pts 103 11.7 mo 3 2 Aichroth et al., 1991; ALD All pts 254 46 mo 14 McLaren et al., 1991; ALD All pts 170 25 mo 5 4 Timoney et al., 1990; ALD All pts 108 50.6 mo 6 21 Bert and Maschka, 1989; AD All pts 126 5 yr 20 Sprague, 1981; ALD All pts 63 13.6 mo 3 2 

133
Table 85. Arthroscopy case series, adverse events 

Study 

 % %  Mean All/ Prolonged % % % % % Group n F/U Any Drainage Hemarthrosis Effusion Infections DVTs Ot

Krystallis et al., 2004; ALD 

All pts 197 32 mo 24.9 mi

Shannon et al., 2001; ALD 

All pts 54 29.6 mo 0 

Harwin, 1999; ALD 

All pts 190 7.4 yr 2 0.5 

Linschoten and Johnson, 1997; ALD 

All pts 55 49 mo 13 1.9 sp po

Yang and Nisonson, 1995; ALD 

All pts 103 11.7 mo 1 su

McLaren et al., 1991; ALD 

All pts 170 25 mo 1.2 0.6 

Timoney et al., 1990; ALD 

134

All pts 108 50.6 mo 6.5 0 0.9 
135 

assessor and most used outcome scales that are unvalidated or of uncertain validity. Patient 

samples were poorly described, appropriate statistical analyses were rare and only one of these 

articles gave well-described results. This low-quality body of case series evidence contrasts with 

the high-quality placebo-controlled RCT evidence from Moseley, O’Malley, Petersen, et al. 

(2002), which did not find that arthoscopic lavage and debridement are superior to placebo. 

Thus, the case series evidence reviewed here is inadequate to resolve uncertainty raised by the 

Moseley trial. 

Results, Part III: Key Question 3 (Subgroup Analyses) 

On the question of whether arthroscopy outcomes differ across subgroups, it is fundamental 

to first establish whether the effects of arthroscopic exceed those of placebo. If a placebocontrolled RCT shows that treatment effects of arthroscopy are significantly greater in certain 

subgroups, this would be strong evidence to support use of arthroscopic in particular patient 

subsets. However, lacking this type of evidence, subgroup analyses from other types of studies 

would be of very limited value. 

 Placebo-Controlled RCT Evidence. The publication by Moseley, O’Malley, Petersen, et al. 

(2002) describing the only placebo-controlled RCT did not present any subgroup analyses. In 

response to letters to the editor about subgroups, the authors replied (Wray, Moseley, O’Malley, 

2002) that they performed subgroup analyses on OA stage, alignment and mechanical symptoms, 

finding no differences in results by subgroup. Thus, it has not been established that arthroscopic 

lavage and debridement produce better results than placebo for any specific group of patients. 

 Quasi-Experimental Evidence. Livesley, Doherty, Needoff, et al. (1991, n=61, followup 

<12 months) compared arthroscopic debridement plus physical therapy with physical therapy 

alone. Subgroup analyses were provided on pain at rest and pain on activity for 3 classes of 

preoperative radiographic OA severity (slight, moderate and severe). The article reports a 

significant advantage at 3 months among moderate class patients in the lavage plus physical 

therapy group. In addition, presence or absence of effusion was not found to be correlated with 

results. This poor quality study was flawed by lack of blinding, imbalances on baseline 

characteristics without corresponding adjustment in the analysis, and absence of details about 

physical therapy. The suggestion of better outcomes in the moderate OA subgroup should not be 

interpreted as evidence that arthroscopic debridement achieves better results than placebo for this 

subgroup. 

 Administrative Database Evidence. In the article by Wai, Kreder, and Williams (2002), 

data from the 14,391 patients who underwent arthroscopic debridement for OA of the knee 

within the Ontario Health Insurance Plan physician claims system were analyzed with a 

multivariable Cox proportional hazards regression model. The authors estimated the risks of 

further surgery and adverse events from 1992 to 1996. Subgroup analyses apparently focused on 

sex, Charlton-Deyo comorbidity and age. The report only presented significant differences in 

further surgery with increasing age (Table 73). It included no comparison with placebo or other 

interventions. This administrative database analysis offers evidence of limited value to this 

evidence report. While it shows different rates of further surgery across age subgroups, it leaves 

unanswered the question of whether there are different effects in terms of other outcomes of 

arthroscopy versus placebo based on age or any other variable. 

 Case Series Evidence. Among case series using validated multidimensional outcome scales 

(Table 75), Aaron, Skolnick, Reinert et al. (2006, n=110, mean followup 34 months) reported on 
136 

the Knee Society pain domain, finding that successful outcome was predicted by preoperative 

OA grade, abnormal limb alignment, medial and lateral joint space width, and intraoperative 

lesion severity. Presence of mechanical symptoms did not predict outcome in this study. 

Bohnsack, Lipka, Ruhmann, et al. (2002, n=104, mean followup 5.4 years) used the Lysholm 

and Gillquist scale finding significant improvement among all patients and there was 

significantly greater improvement in patients under 60 and in those with unilateral OA. Dervin, 

Stiell, Rody, et al. (2003; n=126, 2-year followup) used multivariable logistic regression analysis 

to try to find variables predicting a minimal clinically important improvement on the WOMAC 

scale. The only significant independent predictors were tenderness at the medial joint line, a 

positive Steinman test sign and unstable meniscal tear. 

On a patient global change scale (Table 81), Harwin (1999, n=190, mean followup 7.4 years) 

found that patients with more severe preoperative malalignment appeared to have worse results. 

Using a similar scale, Shannon, Devitt, Poynton, et al. (2001, n=54, mean followup 29.6 months) 

found no influence on results of sex, age, weight, preoperative Duke score and duration of 

symptoms. 

On a patient global result scale, using classes such as excellent, good, fair and poor (Table 

82), Krystallis, Kirkos, Papavasiliou, et al. (2004, n=201, mean followup 32 months) observed 

that the rate was 66 percent for those with mechanical symptoms and 31 percent for those with 

loading symptoms (no statistical test was done). Yang and Nisonson (1995, n=103, mean 

followup 11.7 months) reported that results were significantly better for patients with mechanical 

symptoms (96 percent good) versus no mechanical symptoms (42 percent) as well as those with 

mild rather than severe degeneration seen on arthroscopy. Aichroth, Patel, and Moyes (1991, 

n=254, mean followup 44 months) found that poorer results were significantly correlated with 

age over 60, greater preoperative radiographic OA rating and worse arthroscopic OA stage. 

Jackson and Dieterichs (n=121) had at least 4 years of followup, reported that excellent or good 

results appeared to be related to clinical and arthroscopic OA stage, the authors did not provide 

statistical test results. Linschoten and Johnson (1997, n=55, mean followup 49 months) 

observed that worse results were significantly more likely in patients with the most severe 

arthroscopic OA status in both the medial and lateral compartments. Timoney, Kneisl, Barrack, 

et al. (1990, n=108, mean followup 50.6 months) reported significantly worse results for those 

with symptoms over 48 months and those with severe chondromalacia on arthroscopy. 

Data on further surgery after arthroscopy were given in 14 case series (Table 84). Aaron, 

Skolnick, Reinert et al. (2006, n=110) found that the probability of total knee arthroplasty was 

significantly related to preoperative OA grade. Bernard, Lemon, and Patterson (2004, n=100) 

reported that the 5-year probability of freedom from major surgery was significantly worse for 

those aged 60 or older. Linschoten and Johnson reported that further surgery was significantly 

associated with presence of Outerbridge class IV on arthroscopy and presence of chondromalacia 

in the lateral compartment. In the Jackson and Dieterichs series (2003, n=121), the risk of total 

knee arthroplasty appears higher in those with the most severe clinical and arthroscopic stage of 

OA, but not statistical test results were reported. 

To summarize case series evidence, three patient factors were represented by at least two 

studies showing different outcomes for patient subgroups. Three studies found better outcomes 

among patients younger than 60 years of age (Bernard, Lemon, and Patterson, 2004; Bohnsack, 

Lipka, Ruhmann, et al., 2002; Yang and Nisonson, 1995). Two studies found that patients with 

mechanical symptoms had better results than those without them (Krystallis, Kirkos, 

Papavasiliou, et al., 2004; Yang and Nisonson, 1995) and one study found no relationship 
137 

(Aaron, Skolnick, Reinert et al., 2006). Six studies found that increased OA severity was 

correlated with worse results (Aaron, Skolnick, Reinert et al., 2006; Jackson and Dieterichs, 

2003; Linschoten and Johnson, 1997; Yang and Nisonson, 1995; Aichroth, Patel, and Moyes, 

1991; Timoney, Kneisl, Barrack, et al., 1990). Among these, OA severity was rated only with 

arthroscopy in three studies, with arthroscopy combined with preoperative information in one; 

and with radiography and arthroscopy separately in two. A useful function of case series is to 

suggest patient populations that may be worthwhile to include in controlled trials. While the 

Moseley trial found no differences in treatment effect by patient characteristics, case series 

evidence of different outcomes by age, presence of mechanical symptoms and OA severity 

should be noted by investigators analyzing future RCTs, but it cannot be viewed as showing that 

arthroscopy is particularly effective in particular subgroups. 

Results, Part III: Key Question 4 (Comparative Outcomes) 

 RCT Evidence. The single study comparing the interventions of interest to this Evidence 

Report was conducted by Forster and Straw (2003). Study methods are summarized in Tables 

86–90. Investigators randomized 38 patients with “symptomatic” knee osteoarthritis 

accompanying radiographic evidence of joint space remaining on weight bearing. Individuals 

with mechanical symptoms, intra-articular injection in the prior 6 months, or previous 

arthroscopic surgery were excluded. Participants were allocated (19 per arm) to five weekly 20 

mg Hyalgan® injections or arthroscopic lavage (at least 2 liters normal saline) and indicated 

debridement with excision of large chondral flaps or meniscal tears). Followup took place 

through 1 year. Four participants were lost to followup (two per group) and two randomized to 

arthroscopy declined treatment. Outcome measures included 10 cm VAS pain, function score 

from the Knee Society rating system (0 to 100), and Lequesne index (0 to 24). This trial was 

rated as poor in quality due to imbalance on Knee Society scores at baseline, lack of blinding and 

lack of adjustment in data analysis. 

Table 86. Arthroscopy non-placebo RCTs, sample selection 

Study Inclusion Exclusion n, Enrolled 

n, 

Withdrawn 

n, Outcome 

Evaluated 

Forster and Straw, 

2003 

ALD vs. IA 

Hyalgan 

On waiting list for 

arthroscopic washout; 

symptomatic knee OA; 

radiographic evidence of 

some remaining joint 

space on weight bearing 

films; fit for regional or 

general anesthesia 

Mechanical 

symptoms; IA 

injection < 6 mo; 

hypersensitivity to 

avian proteins 

ALD: 19 

Hyalgan: 19 

ALD: 4 (2 

lost, 2 

refused) 

Hyalgan: 2 

(lost) 

ALD: 15 

Hyalgan: 17 

Table 87. Arthroscopy non-placebo RCTs, patient characteristics 

Study Age 

% 

Female Pain Function 

Forster and Straw, 

2003 

ALD vs. IA Hyalgan 

ALD: mn 63 

Hyalgan: mn 60 

 VAS 

ALD: mn 7.5 

Hyalgan: mn 7.6 

Knee Society: 

ALD: mn 45 

Hyalgan: mn 65 (p<0.05) 

LI: 

ALD: mn 13 

Hyalgan: mn 10.5 
138 

Table 88. Arthroscopy non-placebo RCTs, interventions 

Study Interventions 

Prior 

Treatments 

Concurrent 

Treatments 

Forster and Straw, 

2003 

ALD vs. IA Hyalgan 

ALD: general or spinal anesthesia; saline lavage; 

debridement of articular surface or menisci as considered 

necessary at surgeon’s discretion; large chondral or 

meniscal flaps excised but stable, degenerative menisci 

left intact 

IA Hyalgan: any effusion aspirated; 5 injections of 20 mg 

Hyalgan in affected knee at 1-wk intervals 

 

Table 89. Arthroscopy non-placebo RCTs, study quality 

Study 

Initial 

Assembly of 

Comparable 

Groups 

Low Loss to 

Followup, 

Maintenance 

of Comparable 

Groups 

Measurements 

Reliable, Valid, 

Equal* 

Interventions 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Overall 

Rating 

Forster and Straw, 

2003 

ALD vs. IA Hyalgan 

? Y N Y N Poor 

These investigators found that at 1 year, seven participants in the Hyalgan® arm underwent 

further intervention including arthroscopy and total knee replacement; one in the arthroscopy and 

debridement arm underwent total knee replacement, and a replacement was planned for two 

additional participants. Of the remainder not undergoing further intervention eight in each group 

reported improvement. There were no significant differences between groups on VAS pain and 

the Lequesne Index across 4 followup points (Table 90). While the Hyalgan® arm had greater 

improvement on the Knee Society function measure, none of the between-arm differences were 

significant at any followup times. 

The Forster and Straw trial found no differences between Hyalgan® and arthroscopic lavage 

and debridement over a 1-year followup. However, the trial was clearly underpowered and had 

significant baseline differences between arms with no adjustment for such in the data analysis. 

Forster and Straw represent the only study making direct comparisons among viscosupplements 

and arthroscopic treatment; no studies compared glucosamine or chondroitin with the former 

treatments. This trial provides an inadequate evidence base to form conclusions about the 

comparative effects of viscosupplements and arthroscopy. 

Table 90. Arthroscopy non-placebo RCTs, results 

Study Outcomes 

Forster and 

Straw, 2003 

ALD vs. IA 

Hyalgan 

Group n Outcome 6 wk mn 3 mo mn 6 mo mn 1 yr mn p values 

ALD 15 VAS 5.4 6.0 6.2 5.7 all NS 

Hyalgan 17 (higher=worse) 6.6 6.0 5.4 5.7 

ALD Knee Society 55 45 45 55 all NS 

Hyalgan (higher=better) 70 65 80 90 

ALD LI 10 13 12 10.5 all NS 

Hyalgan (higher=worse) 11 11 9 8 

Further surgery: arthroscopy (ALD 29%, Hyalgan® 0%); total knee arthroplasty (ALD 12%, 

Hyalgan® 7%); total knee arthroplasty waiting list (ALD 18%, Hyalgan® 13%) 
139 

Conclusions: Part III 

1. What are the Clinical Effectiveness and Harms of Arthroscopic Lavage and 

Debridement in Patients With Primary OA of the Knee? 

• The best available evidence, a single placebo-controlled RCT, found arthroscopic lavage 

with or without debridement was not superior to placebo. The evidence base does not 

definitively show that arthroscopy is no more effective than placebo. But additional RCTs of 

high quality and with favorable would be necessary to refute the existing trial, which 

suggests equivalence between placebo and arthroscopy. 

– Neither the placebo-controlled RCT, published by Moseley, O’Malley, Petersen, et al., in 

2002, nor other studies distinguished between primary and secondary OA. However, due 

to the age of patients, it is likely most patients had primary OA. 

– No other study besides Moseley, O’Malley, Petersen, et al. (2002) addressed the potential 

contribution of placebo effects to apparent improvement in outcome after arthroscopy. 

– The primary limitations of the Moseley, O’Malley, Petersen, et al. (2002) trial are lack of 

details describing the patient sample, the use of a single surgeon and enrollment of 

patients at a single Veterans Affairs Medical Center. These concerns call into question 

the generalizability of this trial’s findings. 

– Since OA of the knee affects a large population, uncertainty about arthroscopy’s 

effectiveness should be resolved with further well-conducted and well-reported RCTs. 

– Major methodologic shortcomings in non-placebo RCTs, an administrative database 

analysis and case series preclude resolution of uncertainties raised by the trial of 

Moseley, O’Malley, Petersen, et al. (2002). 

• Evidence on the harms after arthroscopic lavage and debridement comes primarily from an 

administrative database analysis and case series reports. Potential harms include infection, 

prolonged drainage from arthroscopic portals, effusion, hemarthrosis, and deep vein 

thrombosis. To determine whether the risk of such harms is acceptable, it is important to 

establish whether the effectiveness of arthroscopic lavage and debridement surpasses 

placebo. 

2. What are the Clinical Effectiveness and Harms of Arthroscopic Lavage and 

Debridement in Patients With Secondary OA of the Knee? 

• We identified no studies that enrolled patients with only secondary OA of the knee, or that 

reported separately on secondary OA of the knee. Therefore, no conclusions can be drawn 

about treatment outcomes in patients with secondary OA of the knee. 

3. How do the Short-Term and Long-Term Outcomes of Arthroscopic Lavage and 

Debridement Differ by the Following Subpopulations: Age, Race/Ethnicity, Sex, Primary 

or Secondary OA, Disease Severity and Duration, Weight (Body Mass Index), and Prior 

Treatments? 
140 

• Subgroup analyses for mechanical symptoms, alignment and OA stage were performed in the 

placebo-controlled RCT by Moseley and colleagues. No differences in results were observed 

within subgroups. Thus, it cannot be concluded that arthroscopic lavage with or without 

debridement has effects greater than placebo for specific subgroups. 

• Subgroup analyses were also performed in a quasi-experimental study, an administrative 

database and several case series. In these studies, different outcomes were observed 

according to age, presence of mechanical symptoms and severity of OA. However, since 

these studies had substantial methodologic flaws so it cannot be concluded that arthroscopy 

has greater effectiveness in specific patient subgroups. 

4. How do the Short-Term and Long-Term Outcomes of Arthroscopic Lavage and 

Debridement, Viscosupplements and Glucosamine/Chondroitin Compare for the 

Treatment of: Primary OA of the Knee; and Secondary OA of the Knee? 

 

• A single RCT compared use of arthroscopic lavage and debridement with intra-articular 

Hyalgan®. This poor quality study analyzed data from only 32 patients, finding no 

significant differences between groups on 3 scales concerned with pain and function. 

• This trial provides an inadequate evidence base to form conclusions about the comparative 

effects of viscosupplements and arthroscopy.

• No other comparative study, randomized or nonrandomized, addressed the relative effects of 

arthroscopic lavage and debridement, viscosupplements, and glucosamine/chondroitin.
141 

Chapter 4. Discussion and Future Research 

Osteoarthritis (OA) of the knee is a common condition and the three interventions reviewed 

in this report are widely used in the treatment of OA of the knee. Yet the best available evidence 

reports that glucosamine/chondroitin and arthroscopic surgery are no more effective than 

placebo. The Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (n=1,583) found that 

neither glucosamine hydrochloride, chondroitin sulfate, nor the combination was superior to 

placebo and that all were inferior to celecoxib. The double-blind, randomized, controlled trial by 

Moseley, O’Malley, Petersen, et al. (2002, n=180) found that arthroscopic lavage with or without 

debridement was not superior to sham arthroscopy. Results from 42 randomized controlled trials 

(RCTs), all but one of which were synthesized in various combinations in six meta-analyses, 

generally show positive effects of viscosupplementation on pain and function scores compared to 

placebo. However, the evidence on viscosupplementation is accompanied by considerable 

uncertainty due to variable trial quality, potential publication bias, and unclear clinical 

significance of the changes reported. 

Are we to conclude, then, that all three interventions are ineffective? It is erroneous to 

conclude that “no evidence of effect” is the same as “evidence of no effect.” The distinction 

between no evidence and no effect applies somewhat differently to each intervention. 

• While the overall results of GAIT show no benefit, in the subgroup of knee OA patients with 

moderate-to-severe pain at baseline, the combination of glucosamine hydrochloride and 

chondroitin sulfate significantly improved pain. Although this subgroup analysis was not 

explicitly prespecified in the GAIT protocol, the stratified randomization by disease severity 

yields statistically valid comparisons. The nonsignificant statistical result in the celecoxib 

arm in the same patient subgroup may be a function of insufficient power. Given the small 

number of patients in the moderate-to-severe subgroup, and the large number of such patients 

in the general population, a further trial can be justified. These subgroup results, although 

suggestive, do not override the overall results of GAIT, which must stand unless equally 

compelling evidence of benefit to a selected subgroup is produced. 

• The existing evidence does not definitively show that arthroscopic lavage with or without 

debridement is only as effective as placebo. However, additional placebo-controlled RCTs 

showing clinically significant advantage for arthroscopy would be necessary to refute the 

Mosley results, which show equivalence between placebo and arthroscopy. The recently 

published (Weinstein, Tosteson, Lurie, et al., 2006) Spine Patient Outcomes Research Trial 

(SPORT) offers an alternative study design that could be informative, a rigorous RCT 

comparing surgery to conservative management, rather than sham. 

• The existing evidence leaves uncertainty whether viscosupplementation achieves minimal 

clinically important improvement compared to placebo. Higher-quality trials are in the 

minority and show smaller effects; there are numerous patients lost to follow-up, and a 

substantial portion of studies (25 percent of total patients) have not been published as fulltext articles. The clinical significance of reported changes in pain and function scores is 

uncertain, as almost all studies compare only mean difference between arms. Although the 

overall pooled estimate suggests that hylan G-F 20 may have a larger effect than other 
142 

hyaluronans, whether this represents a meaningful clinical effect or limitations in the quality 

and completeness of study reporting is unknown. A rigorous RCT that showed strong 

evidence of improvement in pain and function would be necessary to conclude that 

viscosupplementation is beneficial. 

Overall, our recommendations for future research reach beyond the specific treatments 

addressed in this report, and are intended broadly to improve the quality of research and 

reporting on interventions for osteoarthritis of the knee. 

Minimal Clinically Important Improvement in Pain and 

Function Should be the Measure of Success for all Trials 

 Clinically meaningful results require outcome measures establishing that patients experience 

improvement that is important to them—meaningful clinically important improvement. The 

range of magnitude of improvement clinically important to patients has been estimated for VAS 

pain and WOMAC measures, while to a lesser degree for the Lequesne Index (see Methods). 

Few RCTs reported results in terms of response: the proportion achieving a meaningful clinically 

important improvement in pain and function. The vast majority of trials compared only mean 

change between groups. Follow up duration and intervals for measurement, appropriate to each 

intervention, should be established by expert consensus. 

Common measures and intervals will produce a more robust body of cumulative evidence 

and improve the ability to compare and pool results among trials. As a result of the variety of 

measures and intervals used in primary studies, meta-analyses available for this type of evidence 

often report pooled outcomes as the standardized mean difference, a statistical construct that 

lacks meaning to clinicians and patients. 

Unpublished Studies Should be Made Available 

as Full-Text Publications 

 Among RCTs of viscosupplementation, those that have not been published in full-text 

comprise approximately 25 percent of the total patient population. Several meta-analyses of 

glucosamine report that trials of the Rotta product, glucosamine sulfate, show outcomes superior 

to trials of glucosamine hydrochloride. Yet key studies that provide some of the data supporting 

superior efficacy have not been published as full-text studies. Existing studies should be 

published in full. Finally, all trials should be registered at inception at ClinicalTrials.gov along 

with anticipated date for full release of results. 

 The Pitfalls of Meta-Analysis Should be More Widely 

Recognized and Acknowledged 

 Our evidence report draws heavily on six study level meta-analyses of 

glucosamine/chondroitin and five of viscosupplementation. While we used a validated 

instrument to appraise the quality of the systematic reviews, the instrument does not address the 
143 

question of when meta-analysis is appropriate to a systematic review. Meta-analysis is a 

technique with underlying assumptions that may or may not hold when a particular collection of 

results are pooled. Furthermore, meta-analyses may fail to convey the real uncertainty and 

potential bias accompanying pooled estimates. 

In many respects, the focus on meta-analysis in the systematic reviews available for this 

evidence report, served to obscure the overall weakness of the primary literature. For example, 

the Oxman and Guyatt meta-analysis quality assessment tool asked if conclusions made by 

authors were supported by the data. However, the tool does not adequately address whether 

quality concerns of the underlying literature were incorporated into conclusions, which was a 

frequent flaw in the meta-analyses reviewed here. Building on the Oxman and Guyatt tool, Shea, 

Grimshaw, Wells et al. 2007 have developed a new scale which more clearly assesses whether 

conclusions took appropriate account of the quality of included studies and the potential for 

publication bias. 

For RCTs of both glucosamine/chondroitin and viscosupplementation, potential sources of 

bias included lack of reporting intention-to-treat results, high drop-out or loss to follow-up rates, 

poor quality, and lack of a priori sample size calculations. A number of these characteristics 

were noted by meta-analysts to influence results. 

Uncertainty in the magnitude of effects pooled is influenced by factors intrinsic to the 

underlying trials. Among these are variable patient characteristics, trial characteristics, and the 

indication that a few trial results were outliers and influential on pooled estimates. The metaanalyses frequently reported high inter-trial heterogeneity. Random effects models were used in 

the face of high heterogeneity, but a consequence is to increase the influence of smaller trials on 

the pooled results. The meta-analyses did not address a threshold question, one that has not been 

clearly resolved by practitioners of meta-analysis: when is heterogeneity too high to justify 

pooling trial results. A related concern is the practice of reporting on multiple outcome measures 

and time intervals, which may be represented by a small portion of studies, thus potentially 

introducing bias. 

 

Specific Research Recommendations 

Table 91 summarizes recommendations for future research on interventions addressed in this 

report, using the “Evidence, Population, Intervention, Comparison, Outcome, Timestamp,” or 

“EPICOT” framework (Brown, Brunnhuber, Chalkidou, et al., 2006). Note that all the 

recommendations in Table 91 delineate the evidence that is needed to establish that each of these 

interventions achieve a clinically meaningful improvement in OA of the knee. However, our 

population is aging, there is increasing prevalence of obesity, and increasing burden of knee 

osteoarthritis, together with inconsistent evidence regarding disease treatments. Given the public 

health impact, research on new approaches to prevention and treatment should be given high 

priority. 
144 

Table 91. Future Research Recommendations for Osteoarthritis of the Knee --- EPICOT Framework 

 Viscosupplementation Glucosamine/Chondroitin Arthroscopy 

Evidence (What is the 

current state of the 

evidence?) 

Current evidence 

consists largely of trials 

with high loss to followup and lack rigorous 

measurement to test 

whether intra-articular 

hyaluronans achieve 

meaningful clinically 

important improvement 

in pain and function. 

The evidence does not 

clearly demonstrate that 

intra-articular 

hyaluronans achieve 

clinically significant 

improvement in pain 

and function compared 

to placebo. 

A rigorous multi-center 

RCT, preferably with 

independent 

sponsorship, is needed 

to either establish or 

refute whether hylan GF 20 is beneficial. 

Adverse events, 

reportedly uncommon, 

have not been 

systematically studied. 

Based on GAIT, neither 

glucosamine, chondroitin or 

their combination provide 

meaningful clinically 

important improvement in 

pain or function. 

A subgroup analysis found 

that the combination of 

glucosamine hydrochloride 

and chondroitin sulfate 

significantly improved pain 

in patients with moderateto-severe OA of the knee. 

Given the small number of 

patients in the moderate to 

severe subgroup, and the 

large number of such 

patients in the general 

population, confirmation in 

a large, rigorous multicenter RCT, preferably with 

independent sponsorship, is 

desirable. 

No conclusions concerning 

metabolic effects of chronic 

glucosamine use in the 

general population can be 

drawn. 

 

A single placebocontrolled RCT found 

arthroscopic lavage 

with or without 

debridement to be 

equivalent to placebo. 

Adverse events have 

not been 

systematically 

studied. 

Population (What is 

the population of 

interest?) 

Individuals with OA of 

the knee of varying 

severity. Future trials 

should be accompanied 

by stratified 

randomization 

according to disease 

severity and duration. 

Individuals with moderateto-severe OA of the knee. 

Inclusion of diabetic 

individuals with metabolic 

testing and long-term 

observational follow-up. 

The target population 

consists of patients 

with clinically 

diagnosed OA of the 

knee and who have 

tried conservative 

treatments with 

transient or 

unsatisfactory results. 

Intervention (What 

are the interventions of 

interest?) 

Pooled estimate 

suggests effect obtained 

with hylan G-F 20 may 

be larger than with other 

hyaluronans, whether 

this represents a 

meaningful clinical 

effect or study 

limitations is unknown. 

1. glucosamine 

hydrochloride and 

chondroitin sulfate 

2. glucosamine 

sulfate, preferably 

the Rotta product 

Arthroscopic lavage, 

with or without 

debridement, 
145 

Table 91. Future Research Recommendations for Osteoarthritis of the Knee --- EPICOT 

Framework (continued) 

 Viscosupplementation Glucosamine/Chondroitin Arthroscopy 

Comparison (What 

are the comparisons of 

interest?) 

Placebo intra-articular 

injection is required to 

establish efficacy. 

Comparison paralleling 

GAIT: intervention(s), 

placebo, and a reference 

NSAID 

Comparison with 

sham arthroscopy (as 

in Moseley). And/or 

comparison to 

conservative 

treatment as in Spine 

Patient Outcomes 

Research Trial 

(SPORT) 

Outcome (What are 

the outcomes of 

interest?) 

Response criteria 

anchored to a 

meaningful clinically 

important improvement 

in pain and function. 

The magnitude of 

improvement clinically 

important to patients 

has been reasonably 

estimated for VAS pain, 

WOMAC measures, and 

Lequesne Index. 

Outcomes measured in 

the likely window for 

clinical improvement (5-

13 weeks). 

Same as 

viscosupplementation. 

Sufficient duration (24 

weeks or more) to observe 

effect. 

Same as 

viscosupplementation 

Time Stamp (Date of 

recommendation) 

April 2007 April 2007 April 2007 

147 

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List of Acronyms/Abbreviations 

? unknown; unclear 

1° primary 

2° secondary 

A arthroscopy 

Acet acetaminophen 

ACR American College of Rheumatology 

ADL Activities of Daily Living 

ADL arthroscopy, lavage, and debridement 

AE(s) adverse events 

AL arthroscopy and lavage 

ARA American Rheumatism Association 

BMI body mass index 

CI confidence interval 

D debridement 

dis disease 

FE fixed effects 

GH glucosamine hydrochloride 

GS glucosamine sulfate 

HSS Hospital for Special Surgery 

IA intra-articular 

ITT intention-to-treat 

JSN joint space narrowing 

K-L Kellgren-Lawrence 

L lavage 

LI Lequesne Index 

MA(s) meta-analysis(es) 

mn mean 

mo(s) month(s) 

N number 

n number 

N no 

NR not reported 

NS nonsignificant 

NSAID(s) nonsteroidal anti-inflammatory drug(s) 

NSD no significant difference 

OA osteoarthritis 

OAK osteoarthritis of the knee 

OMERACT-OARSI Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society 

Pl placebo 

PT physical therapy 

pts patients 

RCT(s) randomized, controlled trial(s) 

RE random effects 

rng range 

RR relative risk 

sd standard deviation 

SEM standard error of the mean 

SMD standardized mean difference 

Tx treatment 

USPSTF U.S. Preventive Services Task Force 

VAS visual analog scale 

WMD weighted mean difference 

WOMAC Western Ontario and McMaster Universities Osteoarthritis Index 

Y yes 

yr(s) year(s) 
APPENDIXES 
A-1

Appendix A. Exact Search Strings 

• MEDLINE® (through March 29, 2007) 

• EMBASE (through March 16, 2006) 

• Cochrane Controlled Trials Register (through November 27, 2006) 

EMBASE was updated with abbreviated searches through November 27, 2006.

Database Search Strategies: 

• "osteoarthritis, knee"[MeSH] OR 

• "osteoarthritis"[MeSH] AND (knee(tw) OR knees(tw)) OR 

• osteoarthritis*(tw) AND (knee(tw) OR knees(tw)) OR 

• "osteoarthritis"[MeSH] AND patellofemoral (tw) 

AND 

• human (limit/tag) 

Results of the above search were limited to citations also identified by the Cochrane Handbook 

search strategy for controlled trials (Alderson et al. 2004): 

• randomized controlled trial [pt] OR 

• controlled clinical trial [pt] OR 

• randomized controlled trials [mh] OR 

• random allocation [mh] OR 

• double-blind method [mh] OR 

• single-blind method [mh] OR 

• clinical trial [pt] OR 

• clinical trials [mh] OR 

• "clinical trial" [tw] OR 

• ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR 

blind* [tw])) OR 

• placebos [mh] OR 

• placebo* [tw] OR 

• random* [tw] OR 

• research design [mh:noexp] OR 

• comparative study [mh] OR 

• evaluation studies [mh] OR 

• follow-up studies [mh] OR 

• prospective studies [mh] OR 

• control* [tw] OR 

• prospectiv* [tw] OR 

• volunteer* [tw]) 
A-2

For glucosamine and chondroitin, the results of the above search were combined with the results 

of a search using: 

• "Glucosamine"[MeSH] OR "Chondroitin"[MeSH] OR 

• glucosamine(tw) OR 

• acetylglucosamine(tw) OR 

• "n-acetylglucosamine"(tw) OR 

• "n-acetyl-d-glucosamine"(tw) OR 

• chondroitin(tw) 

For hyaluronic acid, the results of the first search above were combined with the results of a 

search using: 

• "Hyaluronic Acid"[MeSH] OR 

• "sodium hyaluronate"(tw) OR 

• hyaluronan(tw) OR 

• hyaluronic(tw) OR 

• hylan(tw) OR 

• hyalgan(tw) OR 

• synvisc(tw) OR 

• orthovisc(tw) OR 

• euflexxa(tw) OR 

• supartz(tw) OR 

• nuflexxa(tw) OR 

• viscosupplement* 

For arthroscopy, the results of the first search above were combined with the results of a search 

using: 

• "Arthroscopy"[MeSH] OR 

• arthroscopy(tw) OR 

• arthroscopic(tw) OR 

• arthroscope(tw)) OR 

• lavage(tw) OR 

• debridement(tw) 
B-1

Appendix B. Listing of Excluded Studies 

Exclusion Codes 

AO arthroscopic procedure other than lavage and debridement 

CS case series 

FEW too few subjects (< 50 for arthroscopy case series) 

FLA foreign language article 

FNA foreign language, no abstract 

NDE not correct study design 

NPD no primary data 

NRA narrative review article 

NRD non-relevant disease 

NRQ non-relevant study question 

RCT randomized controlled trial 

Intervention Codes

ARTH arthroscopy 

GC glucosamine/chondroitin 

VS viscosupplementation 

 1. Arthroscopic lavage for osteoarthritis of the knee. Evid.-Based Healthc. Public Health 2005; 9(3):192-6. 

Notes: ARTH NRA 

 2. Arthroscopy no benefit for osteoarthritis. OR Manager 2002; 18(9):32. 

Notes: ARTH NPD 

 3. Further evidence supports use of glucosamine for knee pain. Pharm. J. 2003; 270 (7234):142. 

Notes: GC NPD 

 4. Glucosamine/chondroitin: No clear benefit in knee pain. Pharm. J. 2005; 275 (7377):657. 

Notes: GC NPD 

 5. Glucosamine delays progression of osteoarthritis in the knee joint. Pharm. J. 2002; 269(7221):594. 

Notes: GC NRQ RCT 

 6. Hyaluronan or hylans for knee osteoarthritis? Drug Ther Bull 1999; 37(9):71-2. 

Notes: VS NRA 

 7. Hyaluronic acid minimally effective for knee degenerative joint disease. Cleve Clin J Med 2004; 71(4):272. 

Notes: VS NPD 

 8. Adams ME. An analysis of clinical studies of the use of crosslinked hyaluronan, hylan, in the treatment of 

osteoarthritis. J Rheumatol Suppl 1993; 39:16-8. 

Notes: VS NRA 
B-2

 9. Adams ME, Atkinson MH, Lussier AJ 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(4):213-25. 

Notes: VS NRQ RCT 

 10. Adams ME, Li DK, McConkey JP et al. Evaluation of cartilage lesions by magnetic resonance imaging at 

0.15 T: comparison with anatomy and concordance with arthroscopy. J Rheumatol 1991; 

18(10):1573-80. 

Notes: ARTH AO 

 11. Aderinto J, Cobb AG. Lateral release for patellofemoral arthritis. Arthroscopy 2002; 18(4):399-403. 

Notes: ARTH AO 

 12. Aggarwal A, Sempowski IP. Hyaluronic acid injections for knee osteoarthritis. Systematic review of the 

literature. Can Fam Physician 2004; 50:249-56. 

Notes: VS NRQ 

 13. Aglietti P, Pisaneschi A, Buzzi R, Gaudenzi A, Allegra M. Arthroscopic lateral release for patellar pain or 

instability. Arthroscopy 1989; 5(3):176-83. 

Notes: ARTH AO 

 14. Aichroth P. Knee surgery--great strides. Trans Med Soc Lond 1990-1991; 107:61-73. 

Notes: ARTH NRA 

 15. Akermark C, Berg P, Bjorkman A, Malm P. Non-animal stabilised hyaluronic acid in the treatment of 

osteoarthritis of the knee: A tolerability study. Clin. Drug Invest. 2002; 22(3):157-66. 

Notes: VS NDE 

 16. Akizuki S, Yasukawa Y, Takizawa T. Does arthroscopic abrasion arthroplasty promote cartilage regeneration 

in osteoarthritic knees with eburnation? A prospective study of high tibial osteotomy with abrasion 

arthroplasty versus high tibial osteotomy alone. Arthroscopy 1997; 13(1):9-17. 

Notes: ARTH NA 

 17. Alekseeva LI, Arkhangel'skaia GS, Davydova AF et al. [Long-term effects of structum administration 

(according to data from multicenter trial)]. Ter Arkh 2003; 75(9):82-6. 

Notes: GC NRQ RCT 

 18. Alekseeva LI, Benevolenskaia LI, Nasonov EL, Chichasova NV, Kariakin AN. [Structum (chondroitin 

sulfate)--a new agent for the treatment of osteoarthrosis]. Ter Arkh 1999; 71(5):51-3. 

Notes: GC NRQ RCT 

 19. Alekseeva LI, Chichasova NV, Benevolenskaia LI, Nasonov EL, Mendel' OI. [Combined medication 

ARTRA in the treatment of osteoarthrosis]. Ter Arkh 2005; 77(11):69-75. 

Notes: GC NRQ RCT 

 20. Alekseeva LI, Mednikov BL, Piiavskii SA, Nasonova VA, Soldatov DG. [Pharmacoeconomic aspects of use 

of structum in osteoarthrosis]. Ter Arkh 2001; 73(11):90-2. 

Notes: GC NRQ RCT 

 21. Allhoff P, Graf von der Schulenburg JM. [Cost-effectiveness of conservative therapy of knee joint 

osteoarthritis]. Z Orthop Ihre Grenzgeb 1998; 136(4):288-92. 

Notes: VS NRQ 
B-3

 22. Alonge TO, Oni OO. An investigation of the frequency of co-existence of osteophytes and circumscribed full 

thickness articular surface defects in the knee joint. Afr J Med Med Sci 2000; 29(2):151-3. 

Notes: ARTH NRD 

 23. Altman RD, Abramson S, Bruyere O et al. Commentary: osteoarthritis of the knee and glucosamine. 

Osteoarthritis Cartilage 2006; Epub. 

Notes: GC NPD 

 24. Altman RD, Moskowitz R. A randomized clinical trial of intra-articular sodium hyaluronate in patients with 

osteoarthritis of the knee: a summary. Am J Orthop 1999; 28(11 Suppl):3-4. 

Notes: VS NPD 

 25. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: A review of effects on glucose 

metabolism, side effects, safety considerations and efficacy. Food Chem. Toxicol. 2005; 43(2):187-

201. 

Notes: GC NRA 

 26. Andersson-Molina H, Karlsson H, Rockborn P. Arthroscopic partial and total meniscectomy: A long-term 

follow-up study with matched controls. Arthroscopy 2002; 18(2):183-9. 

Notes: ARTH AO 

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6. 

Notes: VS NRQ RCT 

 275. Pietrogrande V , Melanotte PL , D'Agnolo B et al. Hyaluronic acid versus methylprednisolone intraarticularly injected for treatment of osteoarthritis of the knee. Curr Ther Res Clin Exp 1991; 

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Notes: VS NRQ RCT 

 276. Poehling GG. Degenerative arthritis arthroscopy and research. Arthroscopy 2002; 18(7):683. 

Notes: ARTH NPD 

 277. Puddu G, Cipolla M, Cerullo G, Scala A. Arthroscopic treatment of the flexed arthritic knee in active middleaged patients. Knee Surg Sports Traumatol Arthrosc 1994; 2(2):73-5. 

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 278. Puhl W, Scharf P. Intra-articular hyaluronan treatment for osteoarthritis. Ann Rheum Dis 1997; 56(7): 441. 

Notes: VS NRQ 
B-23

 279. Puttick MP , Wade JP , Chalmers A , Connell DG , Rangno KK. Acute local reactions after intraarticular 

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Notes: VS NDE 

 280. Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I. Efficacy and safety of glucosamine sulfate versus 

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Notes: GC NRQ RCT 

 281. Qiu G-X, Weng X-S, Zhang K et al. A multi-central randomized, controlled clinical trial of glucosamine 

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Notes: GC NRQ RCT 

 282. Rand JA. Role of arthroscopy in osteoarthritis of the knee. Arthroscopy 1991; 7(4):358-63. 

Notes: ARTH AO 

 283. Rangger C, Klestil T, Gloetzer W, Kemmler G, Benedetto KP. Osteoarthritis after arthroscopic partial 

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Notes: ARTH AO 

 284. Ravaud P, Moulinier L, Giraudeau B et al. Effects of joint lavage and steroid injection in patients with 

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Notes: ARTH NRQ RCT 

 285. Raynauld JP, Goldsmith CH, Bellamy N et al. Effectiveness and safety of repeat courses of hylan G-F 20 in 

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Notes: VS NRQ RCT 

 286. Raynauld JP, Torrance GW, Band PA et al. A prospective, randomized, pragmatic, health outcomes trial 

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Notes: VS NRQ RCT 

 287. Reichelt A, Forster KK, Fischer M, Rovati LC, Setnikar I. Efficacy and safety of intramuscular glucosamine 

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Notes: GC NRQ RCT 

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Notes: GC NRA 

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 290. Richards RJ, Lonergan RP. Arthroscopic surgery for relief of pain in the osteoarthritis knee. Orthopedics 

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Notes: ARTH AO 
B-24

 291. Rodrigo JJ, Steadman JR, Silliman JF, Fulstone HA. Improvement of full-thickness chondral defect healing 

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Notes: ARTH AO 

 292. Roman JA , Chismol J , Morales M , Donderis JL. Intra-articular treatment with hyaluronic acid. Comparative 

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Notes: VS NRQ RCT 

 293. Roos EM, Ostenberg A, Roos H, Ekdahl C, Lohmander LS. Long-term outcome of meniscectomy: 

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Notes: ARTH AO 

 294. Roos EM, Roos HP, Ryd L, Lohmander LS . Substantial disability 3 months after arthroscopic partial 

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 295. Roos H, Adalberth T, Dahlberg L, Lohmander LS. Osteoarthritis of the knee after injury to the anterior 

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Notes: ARTH AO 

 296. Roposch A, Brunner G, Schatz KD, Kotz R, Wurnig C. [Arthroscopic menisectomy in older patients: 

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Notes: ARTH FLA CS 

 297. Rovetta G. Galactosaminoglycuronoglycan sulfate (matrix) in therapy of tibiofibular osteoarthritis of the 

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 299. Ruffin MT 4th, Hunter RE. Arthroscopy in the geriatric patient. Acute injuries and chronic joint diseases. J 

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 301. Rupp S, Seil R, Jochum P, Kohn D. Popliteal cysts in adults. Prevalence, associated intraarticular lesions, and 

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 302. Salisbury RB, Nottage WM, Gardner V. The effect of alignment on results in arthroscopic debridement of the 

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Notes: ARTH CS FEW 
B-25

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 311. Singh S, Lee CC, Tay BK. Results of arthroscopic abrasion arthroplasty in osteoarthritis of the knee joint. 

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 312. Smith MD, Wetherall M, Darby T et al. A randomized placebo-controlled trial of arthroscopic lavage versus 

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 313. Soballe K, Hansen AJ. Late results after meniscectomy in children. Injury 1987; 18(3):182-4. 

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 315. Spahn G, Wittig R. Short-term effects of different arthroscopic techniques in the treatment of chondral 

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 316. Stuart MJ. Arthroscopic management for degenerative arthritis of the knee. Instr Course Lect 1999; 48:135-

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Notes: ARTH NRA 
B-26

 317. Su JY, Chang JK, Lu YM, Lin SY. Arthroscopic debridement for osteoarthritis of the knee: a seven years 

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 318. Szachnowski P, Wei N, Arnold WJ, Cohen LM. Complications of office based arthroscopy of the knee. J 

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Notes: VS NRQ RCT 

 321. Thomas RH, Resnick D, Alazraki NP, Daniel D, Greenfield R. Compartmental evaluation of osteoarthritis of 

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 322. Thompson JI , Huang YW , Zaibel R. Safety and efcacy of fermentation-derived high molecular weight 

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 323. Tibrewal SB. The pneumatic tourniquet in arthroscopic surgery of the knee. Int Orthop 2001; 24(6):347-9. 

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 324. Toda Y. [A comparison of the efficacy of conservative therapies for obese patients with osteoarthritis of the 

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Notes: GC NDE 

 325. Torrance GW, Raynauld JP, Walker V et al. A prospective, randomized, pragmatic, health outcomes trial 

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Notes: VS NRQ 

 327. Travers V, Norotte G, Roger B, Apoil A. [Treatment of acute pyogenic arthritis of large joints of the limbs. 

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Notes: ARTH NRD 

 328. Tsai L, Wredmark T. Arthroscopic surgery of the knee in local anaesthesia. An analysis of age-related 

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Notes: ARTH AO 

 329. Tsukamoto Y , Yamamoto M , Motegi M et al. A double-blind trial of intra-articular higher molecular 

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Notes: VS NRQ RCT 
B-27

 330. Tsumura H, Ikeda S, Torisu T. Debridement and continuous irrigation for the treatment of pyogenic arthritis 

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Notes: ARTH CS FEW 

 331. Vad VB, Bhat AL, Sculco TP, Wickiewicz TL. Management of knee osteoarthritis: knee lavage combined 

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Notes: ARTH AO 

 332. Vajaradul Y. Double-blind clinical evaluation of intra-articular glucosamine in outpatients with gonarthrosis. 

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Notes: GC NRQ RCT 

 333. Vajranetra P. Clinical trial of glucosamine compounds for osteoarthrosis of knee joints. J Med Assoc Thai 

1984; 67(7):409-18. 

Notes: GC NDE 

 334. Van Der Linden AJ. Debridement in case of gonarthrosis. Acta Orthop Belg 1976; 42(4):367-72. 

Notes: ARTH NA 

 335. Vaz AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in 

the management of osteoarthrosis of the knee in out-patients. Current Medical Research and 

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Notes: GC NRQ RCT 

 336. Villani P, Bouvenot G. [Assessment of the placebo effect of symptomatic slow-acting anti-arthritics]. Presse 

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Notes: GC NRA 

 337. Vojtassak J, Seliga J. High tibial osteotomy and debridement of the knee joint in treatment of varotic 

gonarthrosis. Bratisl Lek Listy 2001; 102(10):470-2. 

Notes: ARTH NA 

 338. Wada M, Baba H, Imura S, Morita A, Kusaka Y. Relationship between radiographic classification and 

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Notes: ARTH AO 

 339. Waddell D, Rein A, Panarites C, Coleman PM, Weiss C. Cost implications of introducing an alternative 

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Notes: VS NDE 

 340. Waddell DD. The tolerability of viscosupplementation: Low incidence and clinical management of local 

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Notes: VS NPD 

 341. Waddell DD, Bricker DC. Clinical experience with the effectiveness and tolerability of hylan G-F 20 in 1047 

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Notes: VS NDE 

 342. Waddell DD, Bricker DC. Hylan G-F 20 tolerability with repeat treatment in a large orthopedic practice: a 

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Notes: VS NDE 
B-28

 343. Waddell DD, Cefalu CA, Bricker DC. An open-label study of a second course of hylan G-F 20 for the 

treatment of pain associated with knee osteoarthritis. Curr Med Res Opin 2003; 19(6):499-507. 

Notes: VS NDE 

 344. Waddell DD, Cefalu CA, Bricker DC. A second course of hylan G-F 20 for the treatment of osteoarthritic 

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Notes: VS NDE 

 345. Waddell JP. Arthroscopic debridement of the knee. Can J Surg 1991; 34(6):532. 

Notes: ARTH NPD 

 346. Wallace DA, Carr AJ, Loach AB, Wilson-MacDonald J. Day case arthroscopy under local anaesthesia. Ann R 

Coll Surg Engl 1994; 76(5):330-1. 

Notes: ARTH NRD 

 347. Wallny T, Brackmann HH, Semper H et al. Intra-articular hyaluronic acid in the treatment of haemophilic 

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Notes: VS NRD 

 348. Wang DW, Cai X, Liu YJ, Wang ZG, Gao L. [Meniscus injury in osteoarthritis of knee joints: under 

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Notes: ARTH FLA CS 

 349. Wei N, Delauter SK, Erlichman MS. The holmium YAG laser in office based arthroscopy of the knee: 

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24(9):1806-8. 

Notes: ARTH AO 

 350. Wein CR, Houpt JB, McMillan R, Russell AHK. Open trial of Glucosamine Hydrochloride (Arthroid) in the 

Treatment of Pain of Osteoarthritis of the Knee

. Unpublished 1998. 

Notes: GC NDE 

 351. Weiss C , Tillero W , Balazs L. The treatment of osteoarthritis of the knee with hylan G-F20 in orthopedic 

practice. Proceedings of the 4th Congress of the OsteoArthritis Research Society International 

(OARSI), September 16-19, 1999, Vienna, Austria 1999. 

Notes: VS NDE 

 352. Wouters E, Bassett FH 3rd, Hardaker WT Jr, Garrett WE Jr. An algorithm for arthroscopy in the over-50 age 

group. Am J Sports Med 1992; 20(2):141-5. 

Notes: ARTH NRD 

 353. Wray NP, Moseley JB, O'Malley K. Arthroscopic treatment of osteoarthritis of the knee. J Bone Joint Surg 

Am 2003; 85-A(2):381. 

Notes: ARTH NPD 

 354. Wray NR, Moseley JB, O'Malley K. Arthroscopic treatment of osteoarthritis of the knee [1]. J. Bone Jt. Surg. 

Ser. A 2003; 85(2):381. 

Notes: ARTH NPD 

 355. Zenk JL, Helmer TR, Kuskowski MA. The effects of milk protein concentrate on the symptoms of 

osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial. Current 

Therapeutic Research 2002; 63(7):430-42. 

Notes: GC NRD 
C-1 

Appendix C. Evidence Tables 
C-2 

Part I: Viscosupplementation Appendix Table IA. Baseline Characteristics of Placebo-Controlled Randomized Trials of Intraarticular Viscosupplements Injection

No. Pts 

Randomized 

OA Diagnosis 

(criteria) 

Me

Movement 

(VAS mm) 

Study HA 

Derivative 

(Trade Name) 

Tx Plac 

Overall 

Mean Age 

(years) 

Female Pts (%) 

1° 2° 1° 

2° 

? 

OA 

Stage 

(%) 

Mean 

Disease 

Duration 

(years) 

Tx Pl 

Altman and 

Moskowitz 

(1998) 

Sodium 

hyaluronate 

(Hyalgan) 

164 168 64 58 x1 KL 2-3 > 1 yr 54 55 

Altman et al 

(2004) 

Non-animal 

stabilized 

hyaluronic 

acid 

(Durolane) 

173 174 62.9 (Tx) 63.3(Plac) 55 x1

KL 

2 (23) 3 (54) 4 (24) 

5.0 (0-45.5) 

(Tx) 

6.5 (0-50.5) 

(Plac) 

NR NR 

Bragantini et al 

(1987) 

Sodium 

hyaluronate 

(Hyalgan) 

39 

joints 

55 pts 

total 

18 

joints 57 75 x KL 2-4 

<1 (16%) 

1-5 (44%) 

5-10 (16%) 

>10 (19%) 

NR (5%) 

NR NR 

Brandt et al 

(2001) 

Sodium 

hyaluronate 

(Orthovisc) 

114 112 66 63 x1 KL 2-3 NR NR NR 

Bunyaratavej 

et al 

(2001) 

Sodium 

hyaluronate 

(Hyalgan) 

24 25 60 78 x1

KL 

1-2 

(62) 

3-4 

(38) 

HA 2.5 (3.1) 

Plac 3 (3.4) 70 70 

Carrabba et al 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

60 40 60 63 x1 NR 

Plac≈2.4 (1.3) 

1inj 2.2 (1.3) 3inj 2.3 (1.8) 5inj 2.9 (1.3) 

62(1inj) 

64 (3inj) 63 (5inj) 

64 

Cohen et al 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

19 20 NR NR x NR NR NR NR 

Corrado et al 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

21 19 61 78 x2 NR ≥ 0.5 69 62 

Creamer et al 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

12 

knees 

12 

knee

s 

72 100 x KL 2-44 22 52 (Figure) 54 (Figur e) 

Cubukcu et al 

(2004) 

Hylan G-F 20 

(Synvisc) 20 10 55 80 x1 Mean KL 1.9, 1.8 HA 2.7 (.81) Plac 1.8 (.63) 71 67 
C-3 

Appendix Table IA. Baseline Characteristics of Placebo-Controlled Randomized Trials of Intraarticular Viscosupplements Injection

No. Pts 

Randomized 

OA Diagnosis 

(criteria) 

Me

Movement 

(VAS mm) 

Study HA 

Derivative 

(Trade Name) 

Tx Plac 

Overall 

Mean Age 

(years) 

Female Pts (%) 

1° 2° 1° 

2° 

? 

OA 

Stage 

(%) 

Mean 

Disease 

Duration 

(years) 

Tx Pl 

Dahlberg et al 

(1994) 

Sodium 

hyaluronate 

(Supartz) 

28 24 45 NR x35 NR NR NR NR 

Day et al 

(2004) 

Sodium 

hyaluronate 

(Artz) 

116 124 62 56 x NR >5 (49%) NR NR 

Dickson and 

Hosie 

(1998/2001) 

Hylan G-F 20 

(Synvisc) 53 57 63 53 x NR NR NR NR 

Dixon et al 

(1988) 

Sodium 

hyaluronate 

(Hyalgan) 

30 33 69 54 x NR NR NR NR 

Dougados et al 

(1993) 

Sodium 

hyaluronate 

(Hyalgan) 

55 55 68 71 x

1

 NR HA 5 Plac 6.4 68 62 

Formiguera 

and Estevel 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

20 

knees 

20 

knee

s 

62 73 x NR NR NR NR 

France (1995) 

Sodium 

hyaluronate 

(Supartz) 

87 (3 

inj) 

87 (5 

inj) 

80 

63.9 (3 inj) 64.7 (5 inj) 

65.2 (Plac) 

73.6 (3) 60.9 (5) 

68.8 

(Plac) 

 x 

NR NR 

57.9 

(3 inj) 

56.9 

(5 inj) 

59.8 

(pl) 

Grecomoro et 

al 

(1987) 

Sodium 

hyaluronate 

(Hyalgan) 

20 

knees 

20 

knee

s 

65 56 x NR NR 

48 

Sponta

neous 

43 

Spont

aneou

s 

Guler et al. 

(1996) 

Sodium 

hyaluronate 

(Orthovisc) 

15 15 NR NR x NR NR NR NR 

Henderson et 

al. 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

45 46 65 (approx) 69 x KL 1-4 NR 

44 

(mild 

OA) 

49 

(mod 

OA) 

53 

(mild 

OA) 

49 

(mod 

OA) 

Hizmetli 

(1999) 

Sodium 

hyaluronate 

(Orthovisc) 

25 25 56 68 x KL 1-2 NR NR 

Huskisson and 

Donnelly 

(1999) 

Sodium 

hyaluronate 

(Hyalgan) 

50 50 65 67 x

2 KL 

2-3 NR 66 62 
C-4 

Appendix Table IA. Baseline Characteristics of Placebo-Controlled Randomized Trials of Intraarticular Viscosupplements Injection

No. Pts 

Randomized 

OA Diagnosis 

(criteria) 

Me

Movement 

(VAS mm) 

Study HA 

Derivative 

(Trade Name) 

Tx Plac 

Overall 

Mean Age 

(years) 

Female Pts (%) 

1° 2° 1° 

2° 

? 

OA 

Stage 

(%) 

Mean 

Disease 

Duration 

(years) 

Tx Pl 

Jubb et al 

(2003) 

Sodium 

hyaluronate 

(Hyalgan) 

208 200 64 68 x1 KL 2-3 8 57 56 

Karlsson et al 

(2002) 

Sodium 

hyaluronan 

(Artzal) or 

Hylan G-F 20 

(Synvisc) 

92 

(Artzal) 

88 

(Synvis

c) 

66 71 65 x Ahl 1-2 NR 

64 

(Artzal) 

63 

(Synvis

c) 

65 

Kotevoglu et al 

(2006) 

Sodium 

hyaluronate 

(Orthovisc) 

Hylan G-F 20 

(Synvisc) 

26 26 26 

58.6 (Orth) 

59.7 (Syn) 

60.1(Plac) 

85 

(Orth) 

90 

(Syn) 

89 

(Plac) 

x1 KL 

2-4 

3.9 (4.6) 

(Ortho) 

4.3 (5.2) (Syn) 

3.7 (4.0) (Plac) 

NR NR 

Lohmander et 

al 

(1996) 

Sodium 

hyaluronate 

(Artzal/Supart

z) 

120 120 58 56 x1 Ahl 1-2 NR 44 42 

Moreland et al 

(1993) 

Hylan G-F 20 

(Synvisc) 46 48 NR 67 x KL 2-4 NR 79 (Walkin g) 80 (Walki ng) 

Neustadt et al 

(2005) 

Sodium 

hyaluronate 

(Orthovisc) 

128 4 

inj 

120 3 

inj 

124 

58.4 (8.9) 

4inj 

58.9 (8.9) 

3inj 

59.1(8.3) 

Plac 

48 x1

KL 

1 (13) 2 (50) 3 (38) 

NR NR NR 

Petrella et al 

(2002) 

Sodium 

hyaluronate 

(Suplasyn) 

25 28 66 46 x2 Altman 1-3 NR NR NR 

Pham et al 

(2004) 

Sodium 

hyaluronate 

(NRD 101) 

131 85 65 67 x1

KL 

0 (1) 1 (3) 

2 (23) 3 (69) 

4 (3) 

NR 62 59 

Puhl et al 

(1993) 

Sodium 

hyaluronate 

(Artz) 

102 107 62 64 x4 NR 1-5 (50% of pts) 54 51 
C-5 

Appendix Table IA. Baseline Characteristics of Placebo-Controlled Randomized Trials of Intraarticular Viscosupplements Injectio

No. Pts 

Randomized 

OA Diagnosis 

(criteria) 

Me

Movement 

(VAS mm) 

Study HA 

Derivative 

(Trade Name) 

Tx Plac 

Overall 

Mean Age 

(years) 

Female Pts (%) 

1° 2° 1° 

2° 

? 

OA 

Stage 

(%) 

Mean 

Disease 

Duration 

(years) 

Tx Pl 

Rolf et al. 

(2005) 

Hylan G-F 20 

(Synvisc) 

Sodium 

hyaluronate 

(Artz) 

90 Syn 

91 Artz 

91 

Plac 

54.5 (9.2) 

Syn 

53.9 (9.0) 

Artz 

53.1 (10) 

Plac 

44 Syn 

38 Artz 

38 Plac 40.4 All 

 x3 ? 

Ahl 0-3 

7.2 (5.9) Syn 

8.3 (7.6) Artz 

7.8 (5.9) 

Plac 

NR NR 

Russell et al 

(1992) 

Sodium 

hyaluronate 

(unspecified) 

71 71 62 56 x NR NR NR NR 

Scale et al 

(1994) 

Hylan G-F 20 

(Synvisc) 

25 (2inj) 15 (3inj) 40 59 51 x5

Larsen 

2 (44) 3 (48) 

4 (9) 

4-6 

62 (2inj) 

67(3inj) 70 

Sezgin et al. 

(2005) 

Sodium 

hyaluronate 

(Orthovisc) 22 19 59.7 75.6 x1 KL 2-3 41.7 HA 31.0 Plac NR NR 

Shichikawa 

(1983a) 

Sodium 

hyaluronate 

(Artz) 

114 114 NR NR x KL 1-4 NR NR NR 

Shichikawa 

(1983b) 

Sodium 

hyaluronate 

(Artz) 

52 55 62 83 x NR NR NR NR 

Tamir et al 

(2001) 

Sodium 

hyaluronate 

(BioHy/Nuflex

xa) 

25 24 71 73 x1

KL 

2 (22)) 

3 (55) 4 (20) 

NR NR NR 

Tsai et al 

(2003) 

Sodium 

hyaluronate 

(Hyalgan) 

100 100 65 76 x1 KL 2-3 1.2 48 46 

UK 

(1996) 

Sodium 

hyaluronate 

(Orthovisc) 

116 115 60.8 (HA) 61.6(Plac) 

60.3(H

A) 

53.9(Pl

ac) 

 x NR NR NR NR 
C-6 

Appendix Table IA. Baseline Characteristics of Placebo-Controlled Randomized Trials of Intraarticular Viscosupplements Injectio

No. Pts 

Randomized 

OA Diagnosis 

(criteria) 

Me

Movement 

(VAS mm) 

Study HA 

Derivative 

(Trade Name) 

Tx Plac 

Overall 

Mean Age 

(years) 

Female Pts (%) 

1° 2° 1° 

2° 

? 

OA 

Stage 

(%) 

Mean 

Disease 

Duration 

(years) 

Tx Pl 

Wobig et al 

(1998) 

Hylan G-F 20 

(Synvisc) 

 52 54  4 pts both

62 65 x5

Larsen 

1 (11) 2 (46) 3 (36) 

4 (7) 

6 71 75 

Wu et al 

(1997) 

Sodium 

hyaluronate 

(Artz) 

90 total; 116 knees Pts per group not reported 

69 28 x NR 1.6 NR NR 

KL – Kellgren and Lawrence criteria; Ahl -- Ahlbäck; Plac – Placebo; HA – hyaluronan; Syn – Synvisc or hylan G-F 20; Ortho — Orthovisc; 1 ACR criteria; 2 Altman criteria; 3 Outerbridge criteria; 4 Lequesne; 5 Larsen; 4 Presumed Kellgren-Lawrence; 5 65% had prior injury; 6 Ahlbäck 
C-7 

Appendix Table IB. RCTs of Intra-articular Hyaluronan Injections for OAK: Treatments, Trial Duration, Number Randomized (Hyalu

Blinding (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published). 

Treatment 

Arms Injections 

Trial 

Duration 

(weeks) 

Number 

Randomized 

Altman & Moskowitz 1998 HA 20mg 

(HA, placebo arms) Placebo 5 26 332 

HA (NASHA) 60mg Altman et al. 2004 

Placebo 1 26 347 

 HA 40mg 

Bragantini et al. 1987 HA 20mg 

Placebo 

3 8.6 55 

HA 30mg Brandt et al. 2001 Placebo 3 27 226 HA 20mg Bunyaratavej et al. 2001 Placebo 4 26 49 

HA 20mg x 5 HA 20mg x 3 HA 20mg x 1 

Arthrocentesis 

Carrabba et al . 1995 

Arthrocentesis/ Placebo 

5 

(placebo for HA 

after 3 or 1 

injections) 

26 100 

HA 20mg Cohen et al. 1994 Placebo 3 8 39 HA 20mg Corrado et al. 1995 Placebo 5 8 40 HA 20mg Creamer et al. 1994 

Placebo 

5 9 knees from 12 subjects 

GF 20 Cubukcu et al. 2004 Placebo 3 8 30 subjects 40 knees U

HA 25mg Dahlberg et al. 1994 Placebo 5 52 52 HA 25mg Day et al. 2004 Placebo 5 18 240 
C-8 

Appendix Table IB. RCTs of Intra-articular Hyaluronan Injections for OAK: Treatments, Trial Duration, Number Randomized (Hyalu

Blinding (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published) (continued) 

Treatment 

Arms Injections 

Trial 

Duration 

(weeks) 

Number 

Randomized 

GF 20 Dickson et al. 2001 Placebo* 3 12 110 

HA 20mg Dixon et al. 1988 Placebo up to 11 48 63 HA 20mg Dougados et al. 1993 Placebo 4 52 110 HA 20mg Formiguera & Esteve 1995 Placebo 5 13 36 

HA 25mg 5 inj 

France 1995 HA 25mg 3 inj 

Placebo 

3 or 5 13 254 

HA 20mg Grecomoro et al. 1987 

Placebo 

3 8.6 34 pts 40 knees 

HA 30mg Guler et al. 1996 

Placebo 

3 10.0 30 

HA 20mg KL 1 

Placebo KL 1 

HA 20mg KL 3,4 Henderson et al. 1994 

Placebo KL 3,4 

5 

Main 5 wks

Partial to 5 

months 

91 

HA 20mg Hizmetli et al. 1999 

Placebo 

3and at 6 mo 52 50 

HA 20mg Huskisson & Donnelly 1999 Placebo 5 24 100 HA 20mg Jubb et al. 2003 

Placebo 

3 every 4 

months 52 408 

HA 25mg 

Karlsson et al. 2002 GF 20 

Placebo 

3 52 246 

HA 20mg 

Kotevoglu et al. 2006 GF 20 

Placebo 

3 26 78 
C-9 

Appendix Table IB. RCTs of Intra-articular Hyaluronan Injections for OAK: Treatments, Trial Duration, Number Randomized (Hyalu

Blinding (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published) (continued) 

Treatment 

Arms Injections 

Trial 

Duration 

(weeks) 

Number 

Randomized 

HA 25mg Lohmander et al. 1996 

Placebo 

5 20 240 

GF 20 Moreland et al, 1993 Placebo 3 26 104 

HA 30mg 4 

Neustadt et. al. 2005 HA 30mg 3, 1 placebo 

Placebo 4 

28 372 

HA 20mg/Oral Placebo Petrella et al. 2002 4 arm trial with NSAID 

Placebo/Oral Placebo 

3 12 53 

Pham et al. 2004 HA NRD 101 

 3-arm trial; here report only HA, Placebo Placebo 3 52 216 

HA 25 mg Puhl et al. 1993 

Placebo 

5 14 209 

GF 20 

Rolf et al. 2005 HA 25mg 

Placebo 

3 52 272 

HA 20mg Russell et al. 1992 

Placebo 3 14 210 

GF 20 3 GF 20 2 

Placebo 3 Scale et al. 1994 Placebo 2 

12 80 

HA 30mg Sezgin et al. 2005 Placebo 3 4 41 

HA 25mg/Oral Plac Shichikawa et al. 1983a 

HA 0.25mg/Oral Plac 

5 5 228 

HA 25 mg/Oral Plac Shichikawa et al. 1983b 

HA 0.5mg/Oral Plac 

5 5 107 

HA 20mg Tamir et al. 2001 

Placebo 5 20 49 
C-10 

Appendix Table IB. RCTs of Intra-articular Hyaluronan Injections for OAK: Treatments, Trial Duration, Number Randomized (Hyalu

Blinding (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published) (continued) 

Treatment 

Arms Injections 

Trial 

Duration 

(weeks) 

Number 

Randomized 

HA 20mg Tsai et al. 2003 

Placebo 

5 25 200 

HA 25mg UK 1996 

Placebo 

5 25 231 

GF 20 Wobig et al. 1998 Placebo 3 26 110 pts 117 knees 

HA 25mg Wu et al. 1997 

Placebo 

5 26 90 pts 116 knees 

Abbreviations: KL—Kellgren-Lawrence radiographic grade HA—Hyaluronan GF—Hylan G-F 20 * Also included a NSAID/arthrocentesis arm; because NSAID given in that arm, the HA and placebo/arthrocentesis arms were given placebo 
C-11 

Appendix Table IC. Treatment of Missing Data, Per Patient of Per Knee Analyses, and Multiple Comparison Adjustment in RCTs of Injections for OA of the Knee (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published

Analyses 

Intention to Treat (ITT) /Per Protocol (PP) Intention to Treat Analyse

Trial ITT 

Analyses 

PP 

Analyses

*

Number Randomized 

Number 

PP 

Analyses 

Primary Analyses 

(e.g., reported in 

abstract) 

Performed 

and 

Reported 

Performe

but not 

Detaile

Altman & Moskowitz 1998 Yes Yes 332 220 No Yes 

Altman et al. 2004 Yes Yes 347 232 Yes Yes 

Bragantini et al. 1987 No Yes 55 52 No No 

Brandt et al. 2001 Yes Yes 226 135 No No† 

Bunyaratavej et al. 2001 Yes — 49 — Yes 

Carrabba et al. 1995 Yes† — 100 — Yes§ Yes 

Cohen et al. 1994 No Yes 39 37 No No 

Corrado et al. 1995 No Yes 40 35 No No 

Creamer et al. 1994 Yes† — 24 knees; 12 subjects — Yes† Yes 

Cubukcu et al. 2004 Yes† — 40 knees; 30 subjects — Yes† Yes 

Dahlberg et al. 1994 Yes — 52 — Yes Yes 

Day et al. 2004 No Yes 240 223 No No 

Dickson et al. 2001 Yes Yes 110 92 Yes Yes 

Dixon et al. 1988 Unclear Probable 63 53 Unclear Unclear 

Dougados et al. 1993 Yes Yes 110 95 No No Yes 

Formiguera & Esteve 1995 Yes — 40 knees; 36 subjects 40 knees Yes Yes 

France 1995 Yes?†† — 254 — NA NA 

Grecomoro et al. 1987 Yes — 40 knees; 34 subjects 40 knees Yes Yes 

Guler et al. 1996 Yes — 30 — Yes Yes 

Henderson et al. 1994 Yes — 91 — Yes Yes 

*

— indicates no distinction made and considered intention to treat. 

† Only reported ITT "differences between treatment groups did not reach statistical significance". ‡ NR is not reported § Not specified as ITT, but no lower losses to follow-up when primary efficacy outcome was assessed.** No losses to follow-up at 2 months when primary efficacy outcome assessed; by 6 months 10% loss to follow-up †† Results reported in Supartz® package insert “ITT” population. 
C-12 

Appendix Table IC. Treatment of Missing Data, Per Patient of Per Knee Analyses, and Multiple Comparison Adjustment in RCTs of Injections for OA of the Knee (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published

Analyses 

Intention to Treat (ITT) /Per Protocol (PP) Intention to Treat Analys

Trial ITT 

Analyses 

PP 

Analyses

*

Number Randomized 

Number 

PP 

Analyses 

Primary Analyses 

(e.g., reported in 

abstract) 

Performed 

and 

Reported 

Perform

but no

Detaile

Hizmetli et al. 1999 No Yes† 50 40 NA NA 

Huskisson & Donnelly 1999 Yes Yes 100 80/81 Yes Yes 

Jubb et al. 2003 Yes‡ Yes 408 273 No Yes 

Karlsson et al. 2002 No Yes 246 210 No No Yes 

Kotevoglu et al. 2006 No Yes 78 59 No No 

Lohmander et al. 1996 Yes Yes 240 189 No Partial Partia

Moreland et al, 1993 Unclear Probable 104 94? Unclear 

Neustadt et. al. 2005 No Yes 372 336 No No 

Petrella et al. 2002 Yes No 120 — Yes 

Pham et al. 2004 Yes Yes 216 202 Yes Yes 

Puhl et al. 1993 Yes Yes 209 195 No No Yes 

Rolf et al. 2005 Yes Yes 272 268 Yes Yes 

Russell et al. 1992 NR 142 NR 

Scale et al. 1994 No

**

 80 Unclear 

Sezgin et al. 2005 Yes — 41 Yes 

Shichikawa et al. 1983a No Yes 228 219 No Shichikawa et al. 1983b No Yes 107 98 No 

Tamir et al. 2001 Unclear — 49 — No No No 

Tsai et al. 2003 Yes Yes 200 Yes 

UK 1996 Unknown 131 NR 

Wobig et al. 1998 Yes No 117 knees; 110 subjects Yes Yes 

Wu et al. 1997 No Yes 116 knees; 90 subjects 58 knees‡‡‡ No No No 

*

— indicates no distinction made and considered intention to treat. 

† As reported by Bellamy et al. (2006) ‡ Reported PP values in paper.§ Through 26 weeks** Combined 2 control groups post-hoc so not an intention to treat analysis (see also text).†† At 26 weeks 
C-13 

Appendix Table ID. Trial Quality for Hyaluronan-Products (bolded studies are unpublished trials in any form; highlighted abstracts published) 

Trial 

Quality 

Initial 

Assembly 

Comparable 

Groups 

< 80% loss to 

follow up, 

Maintain 

Comparable 

Groups 

Measurements 

Reliable, 

Valid, Equal 

Intervention 

Comparable/ 

Clearly 

Defined 

Appropriate 

Analysis of 

Results 

Allocation 

concealment 

Altman & Moskowitz 1998 Fair Y N Y Y Y B 

Altman et al. 2004 Good Y Y Y Y Y A 

Bragantini et al. 1987 Poor N Y Y Y N B 

Brandt et al. 2001 Poor Y N Y Y N A 

Bunyaratavej et al. 2001 Fair Y Unclear Y Y Y B 

Carrabba et al . 1995 Good Y Y Y Y Y B 

Cohen et al. 1994 Poor Y Y Y Y N B 

Corrado et al. 1995 Fair Y Y Y Y N B 

Creamer et al. 1994 Fair Y Y N Y Y B 

Cubukcu et al. 2004 Fair Y Y Y Y N B 

Dahlberg et al. 1994 Good Y Y Y Y Y B 

Day et al. 2004 Good Y Y Y Y Unclear B 

Dickson et al.† 2001 Fair Y Y Y Y No B 

Dixon et al. 1988 Poor N Y Y N Unclear B 

Dougados et al. 1993 Poor N Y Y Y Unclear B 

Formiguera & Esteve 1995 Poor Unclear Y Unclear Y Unclear B 

France 1995 NA NA NA NA NA NA NA 

Grecomoro et al. 1987 Poor NR Y Y Y No B 

Guler et al. 1996 NA NA NA NA NA NA B

Henderson et al. 1994 Good Y Y Y Y Y B 

Hizmetli et al. 1999 NA NA NA NA NA NA NA 

Huskisson & Donnelly 1999 Good Y Y Y Y Y B 

Jubb et al. 2003 Fair Y N Y Y Y B 

Karlsson et al. 2002 Fair Y N Y Y N B 

Kotevoglu et al. 2006 Poor Y N Y Y N B 

Lohmander et al. 1996 Poor Y N Y Y N B 

Moreland et al, 1993 Poor NR NR NR Y NR B 

Neustadt et. al. 2005 Fair Y Y Y Y N A 
C-14 

Appendix Table ID. Trial Quality for Hyaluronan-Products (bolded studies are unpublished trials in any form; highlighted abstracts published) (continued) 

Petrella et al. 2002 Good Y Y Y Y Y A 

Pham et al. 2004 Good Y Y Y Y Y A 

Puhl et al. 1993 Fair N Y Y Y N A 

Rolf et al. 2005 Good Y Y Y Y Y B 

Russell et al. 1992 NA 

Scale et al. 1994 Poor Y NR Y Y N A 

Sezgin et al. 2005 Fair Y Y Y Y Unclear B 

Shichikawa et al. 1983a Fair Y Y Y Y N A Shichikawa et al. 1983b Fair Y Y Y Y N A 

Tamir et al. 2001 Fair Y Unclear Y Y Y B 

Tsai et al. 2003 Fair U U Y Y U B 

UK 1996 NA 

Wobig et al. 1998 Poor N Y Y Y N A 

Wu et al. 1997 Fair Y N Y Y N B 
C-15 

Appendix Table IE. Sample Size Calculations Described in RCTs of Hyaluronan-based Products (bolded studies are unpublished t

highlighted abstracts not subsequently published) 

Sample Size Calculation 

Trial 

Performed 

Type I

Error Power Difference Powered to Detect 

Altman & Moskowitz 1998 (HA placebo arms) Yes 0.05 0.80 8mm VAS pain 50 foot walk for 50mm baseline 

Altman et al. 2004 Yes 0.05 0.80 35% HA vs. 20% Placebo 

Bragantini et al. 1987 No 

Brandt et al. 2001 Yes 0.05 0.80 0.5 unit WOMAC pain 1 to 5 (12.5%) 

Bunyaratavej et al. 2001 No 

Carrabba et al . 1995 No 

Cohen et al. 1994 No 

Corrado et al. 1995 No 

Creamer et al. 1994 No 

Cubukcu et al. 2004 No 

Dahlberg et al. 1994 Yes 0.05 0.80 18 mm VAS improvement HA; 9 mm placebo; baseline 4

Day et al. 2004 Yes 0.05 0.90 10% reduction in WOMAC pain score 

Dickson et al. 2001 Yes 0.05 0.80 25% difference in proportion of patients with 25% decrea

Dixon et al. 1988 No 

Dougados et al. 1993 Yes 0.05 0.80 Disappearance of knee effusion at week 7; 20% placebo

Formiguera & Esteve 1995 No 

France 1995 Unknown 

Grecomoro et al. 1987 No 

Guler et al. 1996 Unknown 

Henderson et al. 1994 Yes 0.05 0.90 13.1 mm difference on VAS pain 

Hizmetli et al. 1999 Unknown 

Huskisson & Donnelly 1999 Yes 0.05 0.90 15.4 mm difference on VAS pain 

Jubb et al. 2003 Yes NR NR Standardized difference in JSN of 0.32 with dropout rate 

Karlsson et al. 2002 Yes 0.05 0.80 Detect a 15mm difference in VAS pain decrease 

Kotevoglu et al. 2006 Yes 0.05 0.80 No outcome difference specified 

Lohmander et al. 1996 Yes 0.05 0.90 VAS pain treatment difference of 12 mm 

Moreland et al. 1993 Unknown 

Neustadt et. al. 2005 Yes 0.05 0.80 55% placebo and 60% saline response 

Petrella et al. 2002 Yes NR 0.80 “20% pain reduction among groups” 
C-16 

Appendix Table IE. Sample Size Calculations Described in RCTs of Hyaluronan-based Products (bolded studies are unpublished t

highlighted abstracts not subsequently published) (continued) 

Sample Size Calculation 

Trial 

Performed 

Type I

Error Power Difference Powered to Detect 

Pham et al. 2004 Yes 0.05 0.90 Difference between baseline and year of 15 mm VAS pa

Puhl et al. 1993 Yes 0.05 0.90 SMD in Lequesne of 0.5 between hyaluronan and placeb

Rolf et al. 2005 Yes 0.05 0.80 40% Synvisc; 20% Artzal would be symptom free; placeb

Russell et al. 1992 Unknown 

Scale et al. 1994 No 

Sezgin et al. 2005 No 

Shichikawa et al. 1983a No Shichikawa et al. 1983b No 

Tamir et al. 2001 No 

Tsai et al. 2003 Unknown 

UK 1996 (not all information available) Unknown 

Wobig et al. 1998 Yes 0.05 0.80 15 mm on VAS with SD of 25 

Wu et al. 1997 No 
C-17 

Appendix Table IF. Industry Involvement in RCTs of Intra-articular Hyaluronan Injections for OAK (bolded 

studies are unpublished trials in any form; highlighted abstracts not subsequently published). 

Industry Involvement 

Trial 

Funding Analyses Author 

Altman & Moskowitz 1998 Fidia Fidia 

Altman et al. 2004 Q-Med 

Bragantini et al. 1987 NR Yes 

Brandt et al. 2001 Anika 

Bunyaratavej et al. 2001 NR 

Carrabba et al. 1995 NR Fidia 

Cohen et al. 1994 Bioniche 

Corrado et al. 1995 NR 

Creamer et al. 1994 Fidia 

Cubukcu et al. 2004 NR 

Dahlberg et al. 1994 KaroBio 

Day et al. 2004 Seikagaku 

Dickson et al. 2001 Syntex/Roche 

Dixon et al. 1988 Fidia 

Dougados et al. 1993 NR Fidia 

Formiguera & Esteve 1995 NR 

France 1995 Seikagaku Seikagaku Unpublished 

Grecomoro 1987 NR 

Guler et al. 1996 NR 

Henderson et al. 1994 Fidia/Product 

Hizmetli et al. 1999 Anika Anika Anika 

Huskisson & Donnelly 1999 NR 

Jubb et al. 2003 Fidia Fidia Fidia 

Karlsson et al. 2002 Astra Lakemedel Author 

Kotevoglu et al. 2006 NR 

Lohmander et al. 1996 Multiple inc Industry 

Moreland et al, 1993 Biomatrix 

Neustadt et. al. 2005 Anika Therapeutics 

Petrella et al. 2002 Bioniche ?Bioniche Bioniche 

Pham et al. 2004 NR Author 

Puhl et al. 1993 Luitpold Pharma Luitpold 

Rolf et al. 2005 Biomatrix/Roche/Genxyme 2 Authors 

Russell et al. 1992 NR 

Scale et al. 1994 Biomatrix ?* 

Sezgin et al. 2005 NR 

Shichikawa et al. 1983a Seikagaku ? 

Shichikawa et al. 1983b Seikagaku (drug) 

Tamir et al. 2001 NR Affiliation 

Tsai et al. 2003 Medpharma Fidia 

UK 1996 NR 

Wobig et al. 1998 Biomatrix 

Wu et al. 1997 NR 

* Address for correspondence Arnold Goldman, PhD at Biomatrix who was not listed as author. 
C-18 

Appendix Table IG. Treatment of Missing Data, Per Patient of Per Knee Analyses, and Multiple Comparison Adjustment in RCTs oInjections for OAK (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published). 

Analyses 

 Per Patient or Per Knee 

Analysis Missing Data Multiple Comparison Adjustment 

Altman & Moskowitz 1998 Patient LOCF No 

Altman et al. 2004 Patient LOCF No 

Bragantini et al. 1987 Knee NR No 

Brandt et al. 2001 Patient NR No 

Bunyaratavej et al. 2001 Patient NR No 

Carrabba et al . 1995 Patient NR Yes 

Cohen et al. 1994 Patient NR NR 

Corrado et al. 1995 Patient NR Yes 

Creamer et al. 1994 Knee NR No 

Cubukcu et al. 2004 Knee NR Yes 

Dahlberg et al. 1994 Patient NR No 

Day et al. 2004 Patient LOCF Repeated Measures ANCOVA 

Dickson et al. 2001 Patient NR Repeated Measures ANOVA 

Dixon et al. 1988 Patient NR No 

Dougados et al. 1993 Patient NR No 

Formiguera & Esteve 1995 Knee NR MANOVA 

France 1995 Patient NR Repeated Measures ANCOVA 

Grecomoro et al. 1987 Knee NR ANOVA to day 21 

Guler et al. 1996 NR NR NR 

Henderson et al. 1994 Patient Complete case No 

Hizmetli et al. 1999 Patient Unknown Unknown 

Huskisson & Donnelly 1999 Patient LOCF No 

Jubb et al. 2003 Patient LOCF No 

Karlsson et al. 2002 Patient LOCF No 

Kotevoglu et al. 2006 Patient NR Yes/Tukey 

Lohmander et al. 1996 Patient LOCF No 

Moreland et al, 1993 Knee NR NR 

Neustadt et. al. 2005 Patient GEE (MCAR) Yes/Hochberg 

Petrella et al. 2002 Patient NR Repeated Measures ANCOVA 

Pham et al. 2004 Patient LOCF NR 

Puhl et al. 1993 Patient ?LOCF/MANOVA Bonferroni-Holm 
C-19 

Appendix Table IG. Treatment of Missing Data, Per Patient of Per Knee Analyses, and Multiple Comparison Adjustment in RCTs oInjections for OAK (bolded studies are unpublished trials in any form; highlighted abstracts not subsequently published). (continu

Analyses 

 Per Patient or Per Knee 

Analysis Missing Data Multiple Comparison Adjustment 

Rolf et al. 2005 Patient NR No 

Russell et al. 1992 NR NR NR 

Scale et al. 1994 Patient NR NR 

Sezgin et al. 2005 Patient None LSD; Rep meas ANOVA 

Shichikawa et al. 1983a Patient NR NA Shichikawa et al. 1983b Patient NR NA 

Tamir et al. 2001 Patient NR NR 

Tsai et al. 2003 Patient LOCF NR 

UK 1996 NR Unknown Unknown 

Wobig et al. 1998 Knee Complete Case NR 

Wu et al. 1997 Knee NR NR 

Abbreviations LOCF—Last Observation Carried Forward NR—Not reported NA—Not available GEE—Generalized Estimating Equation regression MCAR—Missing Completely At Random assumption for missing data ANOVA—Analysis of Variance ANCOVA—Analysis of Covariance 
C-20 

Appendix Table IH. Adverse Events Associated with Hyaluronan Injections for Knee OA in Placebo-Controlled RCTs. 

Injection Site 

Pain/Infection 

n (%) 

Local Joint 

Pain/Swelling 

n (%) 

Local Skin 

n (%) 

Headache 

n (%) 

GI Tract 

n (%) 

Nervous 

System 

n (%) 

R

Study 

(year) 

HA Derivative 

(Trade Name) 

Tx PL Tx PL Tx PL Tx PL Tx PL Tx PL T

Altman and 

Moskowitz 

(1998) 

Sodium 

hyaluronate 

(Hyalgan) 

38 

(23) 

22 

(13) 

21 

(13) 

22 

(13) 

35 

(21) 

33 

(14) 

30 

(18) 

29 

(17) 

48 

(29) 

59 

(36) NR NR N

Altman et al 

(2004) 

Non animal 

stabilized 

hyaluronic acid 

(Durolane) 

NR NR 11 (6) 5 (3) NR NR NR NR NR NR NR NR N

Bragantini et al 

(1987) 

Sodium 

hyaluronate 

(Hyalgan) 

4 

(10) NR 4 (10) NR NR NR NR NR NR NR NR NR N

Brandt et al 

(2001) 

Sodium 

hyaluronate 

(Orthovisc) 

1.2% 1.5% 34 (30) 30 (27) 5 (4) 6 (5) NR NR 11 (10) 16 (14) 15 (13) 16 (14) 2

(2

Bunyaratavej et al 

(2001) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Carrabba et al . 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 3 (5) 1 (3) NR NR NR NR NR NR NR NR N

Cohen et al. 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 3 (16) 6 (30) NR NR NR NR NR NR NR NR N

Corrado et al 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Creamer et al. 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 3 (25) 1 (8) NR NR NR NR NR NR NR NR N

Cubukcu et al. 

(2005) 

Hylan G-F 20 

(Synvisc) NR NR 1 NR NR NR NR NR NR NR NR N

Dahlberg et al 

(1994) 

Sodium 

hyaluronate 

(Supartz) 

“a 

few” 

1 

(4) 

“a 

few” 

“a 

few” 

“a 

few” 

“a 

few” NR NR NR NR NR NR N

Day et al 

(2004) 

Sodium 

hyaluronate 

(Artz) 

16 

(14) 

13 

(10) NR NR NR NR NR NR NR NR NR NR N

Dickson and 

Hosie 

(1998) 

Hylan G-F 20 

(Synvisc) 

1.8% per 

injection 

rate 

0.6% per 

injection 

rate 

NR NR NR NR NR NR 5 (11) 4 (9) NR NR N

Dixon et al 

(1988) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 3 (10) NR NR NR NR NR NR NR NR NR N
C-21 

Appendix Table IH. Adverse Events Associated with Hyaluronan Injections for Knee OA in Placebo-Controlled RCTs (continued). 

Injection Site 

Pain/Infection 

n (%) 

Local Joint 

Pain/Swelling 

n (%) 

Local Skin 

n (%) 

Headache 

n (%) 

GI Tract 

n (%) 

Nervous 

System 

n (%) 

R

Study 

(year) 

HA Derivative 

(Trade Name) 

Tx PL Tx PL Tx PL Tx PL Tx PL Tx PL T

Dougados et al 

(1993) 

Sodium 

hyaluronate 

(Hyalgan) 

18 

(33) 

18 

(33) NR NR NR NR 1 (2) NR NR NR NR NR N

Formiguera Sala 

et al 

(1995) 

Sodium 

hyaluronate 

(Hyalgan) 

3 

(15) 

3 

(15) NR NR NR NR NR NR NR NR NR NR N

France 

(1995) 

Sodium 

hyaluronate 

(Supartz) 

Only reported 

for 3 injection 

arm (not 5 

injection) 

3 

(3.4) 

4 

(5.0) 

11 

(12.6) 

3 inj 

5 not 

reporte

d 

12 

(15) NR NR 3 (3.4) 4 (5.0) NR NR NR NR N

Grecomoro et al 

(1987) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Guler et al. 

(1996) 

Sodium 

hyaluronate 

(Orthovisc) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Henderson et al 

(1994) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 21 (47) 10 (22) NR NR NR NR NR NR NR NR N

Huskisson and 

Donnelly 

(1999) 

Sodium 

hyaluronate 

(Hyalgan) 

NR NR 7 (14) 7 (14) NR NR NR NR NR NR NR NR N

Jubb et al 

(2003) 

Sodium 

hyaluronate 

(Hyalgan) 

25 

(12) 

Infection 

22 

(10.6) 

20 

(10) 

Infection 

27 

(13.5) 

75 

(36) 

45 

(23) NR NR 26 (13) 15 (8) 11 (5) 10 (5) 13 (6) 8 (4) 1

(9

Karlsson et al 

(2002) 

Sodium 

hyaluronan 

(Artzal) or 

Hylan G-F 20 

(Synvisc) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Kotevoglu et al. 

2006

Sodium 

hyaluronate 

(Orthovisc) 

Hylan G-F 20 

(Synvisc) 

NR NR NR NR NR NR NR NR NR NR NR NR N
C-22 

Appendix Table IH. Adverse Events Associated with Hyaluronan Injections for Knee OA in Placebo-Controlled RCTs (continued). 

Injection Site 

Pain/Infection 

n (%) 

Local Joint 

Pain/Swelling 

n (%) 

Local Skin 

n (%) 

Headache 

n (%) 

GI Tract 

n (%) 

Nervous 

System 

n (%) 

R

Study 

(year) 

HA Derivative 

(Trade Name) 

Tx PL Tx PL Tx PL Tx PL Tx PL Tx PL T

Lohmander et al 

(1996) 

Sodium 

hyaluronan 

(Artzal) 

NR NR 

Significant 

difference in 

favor of PL in 

maximum 

severity of 

injection site 

swelling (p = 

0.041) 

NR NR NR NR NR NR NR NR N

Moreland et al 

(1993) 

Hylan G-F 20 

(Synvisc) NR NR 

1% of 

400 

injectio

ns 

NR NR NR NR NR NR NR NR NR N

Neustdat 

(2005) 

Sodium 

hyaluronate 

(Hyalgan) 

49 

(20) 

7 

(3) 

20 

(14) 

2 

(2) 

4 

(3) 

4 

(3) 

A “most frequent 

AE but not 

numbers not 

stated 

21 

(9) 

10 

(8) 

38 

(15) 

26 

(21) 

9 

(4

Petrella et al 

(2002) 

Sodium 

hyaluronate 

(Suplasyn) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Pham et al 

(2004) 

Sodium 

hyaluronate 

(NRD 101) 

NR NR 

24 

(18) 

(p = 

.0088 

vs PL) 

19 

(22) 9 

(7) 

1 

(1) 

Included in 

nervous system 

tally 

27 

(20) 

25 

(29) 

8 

(6) 

2 

(2) 

1

(1

Puhl et al 

(1993) 

Sodium 

hyaluronate 

(Supartz) 

3 

(3) 

1 

(1) NR NR NR NR NR NR NR NR NR NR N

Rolf et al. 

(2005) 

Hylan G-F 20 

(Synvisc) 

Sodium 

hyaluronate 

(Artz) 

3 

(2) 

0 

(0) NR NR NR NR 28 (15) 21 (23) 6 (3) 2 (2) 

30 

(17) 

inc 

HA 

21 

(23) 

inc 

HA 

9 

(5

Russell et al 

(1992) 

Sodium 

hyaluronate (not 

specified) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Scale et al 

(1994) 

Hylan G-F 20 

(Synvisc) 

1 (group 

not 

specified

) 

NR NR NR NR NR NR NR NR NR NR NR N
C-23 

Appendix Table IH. Adverse Events Associated with Hyaluronan Injections for Knee OA in Placebo-Controlled RCTs (continued). 

Injection Site 

Pain/Infection 

n (%) 

Local Joint 

Pain/Swelling 

n (%) 

Local Skin 

n (%) 

Headache 

n (%) 

GI Tract 

n (%) 

Nervous 

System 

n (%) 

R

Study 

(year) 

HA Derivative 

(Trade Name) 

Tx PL Tx PL Tx PL Tx PL Tx PL Tx PL T

Shichikawa 

(1983a) 

Sodium 

hyaluronate 

(Artz) 

NR NR 1 (1) 5 (4) NR NR NR NR NR NR NR NR N

Shichikawa 

(1983b) 

Sodium 

hyaluronate 

(Artz) 

NR NR 1 (2) 1 (2) NR NR NR NR NR NR NR NR N

Sezgin 

(2005) 

Sodium 

hyaluronate 

(Orthovisc) 

NR NR NR NR NR NR NR NR NR NR NR NR N

Tamir et al 

(2001) 

Sodium 

hyaluronate 

(BioHy) 

18 

(72) 

11 

(46) NR NR NR NR NR NR NR NR NR NR N

Wobig et al 

(1998) 

Hylan G-F 20 

(Synvisc) NR 2 (3) NR NR 1 (2) NR NR NR 1 (2) NR NR NR N

Wu et al 

(1997) 

Sodium 

hyaluronate 

(Artz) 

NR NR NR NR NR NR NR NR NR NR NR NR N

NR – Not Reported 
C-24 

Appendix Table IJ. Authors’ conclusions from the five study-level meta-analyses. Meta-Analysis Relevant conclusions Lo (2003) “Intra-articular hyaluronic acid has a small effect when compared with an intra-articular placebo. The pre

publication bias suggests even this effect may be overestimated. Compared with lower-molecular-weight 

the highest-molecular-weight hyaluronic acid may be more efficacious in treating knee OA, but heterogestudies limits definitive conclusions.” “[A]pproximately 80% of the treatment effect of intra-articular hyaluronic acid was accounted for by the p

intra-articular injection.” 

Wang (2004) “This meta-analysis confirmed the therapeutic efficacy and safety of intra-articular injection of hyaluronic 

treatment of osteoarthritis of the knee. Additional well-designed randomized controlled RCTs with high mare needed to resolve the continued uncertainty about the therapeutic effects of different types of hyaluro

on osteoarthritis of the knee in various clinical situations and patient populations.” 

Arrich (2005) “The methodologic quality of most RCTs was poor” 

“According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinica

may be associated with a greater risk of adverse events.” 

Modawal (2005) “Intra-articular viscosupplementation was moderately effective in relieving knee pain in patients with oste

and 8 to 10 weeks after the last injection but not at 15 to 22 weeks.” 

Bellamy (2006) “... viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, fun

global assessment; and at different post injection periods but especially at the 5 to 13 week post injection clinical effect for some products, against placebo, on some variables at some timepoints is in the moderasize range.... Overall, the analyses performed are positive for the HA class and particularly positive for s

respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks post injectio
C-25 

Part II: Glucosamine/Chondroitin Appendix Table IIA. General Comparison of Glucosamine and Chondroitin Meta-Analyses in Knee Osteoarthritis 

Key Question 

Addressed 

Author 

(year) 

1 2 3 4 

Literature Search Study Inclusion Criteria Search 

Results 

Overall Patient 

Demographics 

Interventio

Bjordal et al (2006) 

x x MEDLINE, EMBASE, 

PedRo, CCTR All databases searched from 1966 to November 2005 using a specified protocol to identify RCTs Manual search of reference lists of systematic reviews, conference abstracts, and discussions with clinical experts Papers in English, German, and Scandinavian languages were eligible for inclusion 

Blinded, randomized, placebocontrolled trials that lasted at least 4 weeks, included patients with knee OA verified by clinical examination according to ACR or X-ray criteria, with minimum symptom duration of 3 months, and primary outcome measure of pain intensity within 4 weeks of treatment start scored on WOMAC pain subscale or a 100 mm VAS 

Initial search: number of hits unclear 7 RCTs on GS and 6 on CS included in MA 

401 pts in GS trials 362 pts in CS trials Mn age 58.6 yrs in GS trials Mn age 63.0 yrs in CS trials Sex distribution not provided for individual interventions, overall 63% female 

Oral GS 1500 daily, duration specified Oral CS 800 mdaily, duration specified 
C-26 

Towheed et al (2006) 

x x MEDLINE, EMBASE, 

PREMEDLINE, Cochrane Controlled Trials Register (CCTR), Cochrane Database of Systematic Reviews (CDSR), American College of Physicians (ACP) Journal Club, Database of Abstracts of Reviews of Effectiveness (DARE), Allied and Complementary Medicine (AMED) All databases searched from inception to January 2005 using a validated protocol to identify RCTs Manual search of reference lists of primary and review articles No language or age restrictions used in initial searches 

Single- or double-blinded, placebo- or active-controlled randomized clinical trials (RCTs) that reported usable quantitative data on the efficacy and toxicity of glucosamine sulfate (GS) or glucosamine hydrochloride (GH) [Rotta in 13 trials, 6 used non-Rotta product] administered by any route on at least one of the outcomes of interest in patients age 18 years or older with primary or secondary OA at any site except temporomandibular joint (TMJ) 

Initial search: number of hits unclear 20 RCTs included in MA 

2,596 total pts Mn age 61.1 yrs 67% female 

17/20 (85%) Rcompared GS trials) or GH (to placebo 4 RCTs compGS to ibuproftrials) or piroxtrial) 16 RCTs useglucosamine mg/day as a sdose (4 trials) 500 mg thrice (12 trials) 3 RCTs used parenteral (IMIV) GS 400 mdaily (2 trials) twice weekly 16 RCTs evathe knee onlyRCTs evaluaat multiple sit(knee, hip, othRCTs did not the OA site 7 RCTs includprimary OA, 1RCTs did not clear distinctiobetween primsecondary OA 
C-27 

Poolsup et al (2005) 

x MEDLINE, EMBASE, 

BIOSIS, EBM review, Cochrane Library All databases searched from inception to August 2004 using MeSH search terms (osteoarthritis, glucosamine, knee, disease progression and clinical trial) followed by a key word search (degenerative joint disease, degenerative arthritis, osteoarthrosis, and gonarthrosis) Manual search of reference lists of primary and review articles Language restriction not noted 

Double-blind, randomized, controlled trials that lasted at least one year in patients with primary knee OA 

Initial search: number of hits unclear 2/17 RCTs included in MA 

414 total pts Mn age 64.1 yrs 77% female 

Oral GS 1500 once daily for versus oral pl
C-28 

Richy et al (2003) 

x MEDLINE, PREMEDLINE, 

EMBASE, BIOSIS Previews, HealthSTAR, EBM reviews, Cochrane Library, Current Contents All databases searched from January 1980 to March 2002 using a validated protocol to identify RCTs Manual search of reference lists of primary and review articles, abstracts of scientific meetings, contacts of authors for unpublished data No language or age restrictions 

Double-blind, randomized, placebocontrolled trials that lasted at least 4 weeks, with sufficient precision in design, methods and results, in patients with knee or hip OA 

Initial search:  > 500 hits 15/36 RCTs included in MA 

1,775 total pts (1,020 given GS, 755 chondroitin sulfate [CS]) Mn age 62.1 yrs Sex distribution not provided in MA, but no significant differences were noted in the report 

Oral GS 750 mg daily for 1mos Oral CS 200-mg daily for 3mos 

Leeb et al (2000) 

x x MEDLINE, EMBASE, 

personal searches Time period of search not provided, no keywords or protocol specified Language or age restrictions not noted 

Double-blind, randomized, placebocontrolled trials that contained data on at least half of the efficacy variables proposed by EULAR, in patients with knee or hip OA 

Initial search: 16 hits 7/16 RCTs included in MA 

703 total pts (372 given CS, 331 controls) Sex and age distributions not provided in MA, but no significant differences were noted in the report 

Oral CS 800-mg daily for 3mos 
C-29 

McAlindon et al (2000) 

x x MEDLINE, Cochrane 

Controlled Trials Register All databases searched from 1966 to June 1999 using a validated protocol to identify RCTs Manual search of reference lists of primary and review articles, abstracts of scientific meetings, contacts of authors for unpublished or incomplete data No language or age restrictions 

Double-blind, randomized, placebocontrolled trials that lasted at least 4 weeks and included at least one of the outcome measures recommended for OA clinical trials in patients with knee or hip OA 

Initial search: 37 hits 15/37 RCTs included in MA 

1,710 total pts (911 in glucosamine trials, 799 chondroitin) Sex and age distributions not provided in MA 

Oral or IA glucosamine, regimens not provided Oral or IM chondroitin, dregimens not provided 
C-30 

Appendix Table IIB, Part 1. Design Characteristics of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)

*

Purpose Design

**

 Patient Eligibility Criteria

***

 Patient Exclusion 

Criteria 

To evaluate rigorously the efficacy and safety of glucosamine, chondroitin sulfate, and the two in combination in the treatment of pain due to osteoarthritis of the knee 

Double-dummy, double-blind, 5-arm, randomized, placebo- and active-controlled clinical trial, using 

permuted-block randomization scheme with random block sizes stratified according to the 16 clinical centers and baseline WOMAC pain stratum (miled, defined as a score of 125 to 300, or moderate to severe, defined as a score of 301 to 400) Study conducted under an IND, with agents subjected to pharmaceutical regulation by FDA 

Age 40 years or more Knee pain for at least 6 months and on the majority of days during the preceding month Radiographic evidence of primary knee OA, as exemplified by the presence of tibiofemoral osteophytes of at least 1 mm, signifying Kellgren-Lawrence disease grade 2 or 3 Summed pain score of 125 to 400 on the index knee according to the WOMAC OA index ARA functional class I, II, or III 

Concurrent arthritic or medical conditions that could confound evaluation of the index knee Predominant patellofemoral disease History of clinically significant trauma or surgery to the index knee Coexisting disease that could preclude successful completion of the trial 

PlaceCapsnutriccapsuschedGluco500 mChon400 mGluco500 mplus 4Active 200 mPfize

*

 Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New Engl J Med. 20

**

 IND = investigational new drug; FDA = Food and Drug Administration; WOMAC = Western Ontario and McMaster Universities 

*** OA = osteoarthritis; ARA = American Rheumatism Association 
C-31 

Appendix Table IIB, Part 2. Enrollment and Disposition of Patients in the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)

*

No. of Patients Treatment Group (%) 

**

Placebo Glucosamine Chondroitin Glucosamine plus 

Chondroitin 

Assigned 313 317 318 317 Completed 248 (79.2) 242 (76.3) 248 (78.0) 254 (80.1) Withdrew 65 (20.8) 

11 adverse event 

22 lack of efficacy 

17 lost to follow-up 

15 other reasons 

75 (23.7) 

9 adverse event 

27 lack of efficacy 

20 lost to follow-up 

19 other reasons 

70 (22.0) 

20 adverse event 

25 lack of efficacy 

15 lost to follow-up 

10 other reasons 

63 (19.9) 

12 adverse event 

17 lack of efficacy 

16 lost to follow-up 

18 other reasons 

*

 Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New Engl J Med. 20

**

 3,238 screened, 1,655 (51%) excluded, 1,583 (49%) underwent randomization 
C-32 

Appendix Table IIB, Part 3. Outcome Measures and Analysis of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)

*

Outcome Measures Adverse Events Statistical Analysis Study Q

Primary Outcome: 20% decrease in the summed score for the WOMAC pain subscale from baseline to week 24 Secondary Outcomes: Scores for the stiffness and function subscale of WOMAC Patient’s global asssessment of disease status and response to therapy, using 100 mm VAS Investigator’s global asssessment of disease status and response to therapy, using 100 mm VAS Presence or absence of soft-tissue swelling, effusion, or both in the index knee Scores on the Medical Outcomes Study 36-item Short-Form General Health Survey Scores on the Health Assesment Questionnaire Acetaminophen use 

At each study visit, safety monitoring included: Complete blood counts Serum aspartate and alanine aminotransferase levels, glucose, glycosylated hemoglobin levels (diabetics only) creatinine, and partial thromboplastin time Urinalysis At week 24: Fecal occult blood (Hemoccult, Bedkman Coulter) 

Analysis of the primary outcome measure conducted according to the ITT All statistical tests were two-sided An absolute increase in the response rate of 15%, as compared with the rate in the placebo group, was considered to indicate a clinically meaningful treatment effect Pairwise comparisons of the GH, CS and combinedtreatment groups with the PL group were made using a two-sided chi-square test at alpha = 0.017 for each comparison (overall alpha = 0.05) Secondary outcomes analyzed according to pairwise comparison scheme outlined above Chi-square test used for categorical data T-test for independent groups used to compare changes between groups in quantitative data from baseline to end of study Used last-observation-carried forward method to analyze all outcomes among patients who made at least one follow-up visit but who did not complete follow-up 

Criteria: Initial assembly and mgroups: Yes Important differential high loss to follow-up: (average drop-out rate 23.7%, NS) Use of equal, reliableincluding masking of o(described as double-Clear definition of inte(active and PL regimeAll important outcome(primary and secondaAdjustment for potentanalysis: Yes (stipulated in text) Overall rating: Good (Unclear if subgroup aplanned or unplanned 

*

 Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New Engl J Med. 2

**

 OA = osteoarthritis; WOMAC = Western Ontario and McMaster Universities; VAS = visual analog scale; GH = glucosamine hydrochloride; CS = chondr

***

 U.S. Preventive Services Task Force approach 
C-33 

Appendix Table IIC, Part 1. Additional RCT Sample Selection Study Inclusion Exclusion No. Enrolled 

No. 

HerreroBeaumont et al (2007) 

May 2000-December 2002 Outpatients (age not specified); clinically symptomatic idiopathic OAK (ACR criteria), with a K-L grade 2-3 

Did not meet OARSI criteria

*

 for exclusion from 

OA clinical trial; enrollment of obese (BMI > 30 kg/m2) patients discouraged 

325 GS: 106 Acetaminophen: 108 Pl: 104 

6 moGS: AcetPl: 3

Michel et al (2005) 

March 1996-May 2001 Age 40-85 years; clinically symptomatic OAK (pain while standing, walking, and/or in motion for at least 25 of the 30 days prior to entry, with no required minimum level of pain); diagnosed according to ACR criteria of OAK; K-L grades 1,2, or 3 

Any causes of secondary OAK (calcium pyrophosphate deposition disease, traumatic knee lesions) severe comorbidity; previous joint surgery; intraarticular medications in the previous month; foreseeable major surgery during the 2-years study period 

300 CS: 150 Pl: 150 

24 mCS: Pl: 4

Uebelhart et al (2004) 

February 1996-June 1998 Age 40 years and over, clinically symptomatic idiopathic OAK (ACR criteria), with a K-L grade 1-3 and a minimum 25% remaining medial femoro-tibial joint space 

Other inflammatory joint diseases or systemic conditions affecting or involving the joints; primary or secondary neoplasias; bone metabolic diseases and/or other metabolic or systemic diseases; other treatments such as intraarticular corticosteroids, NSAIDs, symptom-modifying agents or bone-oriented therapies such as fluorides, bisphosphonates, calcitonin or patients under hormonal substitution within 3 mos before beginning the study 

120 CS: 54 Pl: 56 

3-12 CS: Pl: 1

Das and Hammad (2000) 

Pts not exhibiting any of the exclusion criteria who had an ISK of at least 7 points; K-L grade ≥ 2; both genders, age 45 – 75 years, 

ambulatory, willingness to comply with protocol, OA symptom duration ≥ 6 mos; allocated to study groups using randomized block design using computer-based pseudorandom number generator with code concealed to pts and investigators 

Pregnancy; severe activity-limiting chronic diseases; non-insulin-dependent diabetes; alcoholism; history of significant hematological disorder, hepatic or renal impairment; active peptic ulcer; associated musculoskeletal disease other than OAK; associated metabolic diseases; injury to or surgery on index knee within 6 mos; intraarticular corticosteroid injection within previous 2 mos; regular use (> 3 times weekly) of NSAID during previous 2 mos 

93 GH/CS: 46 Pl: 47 Trial designed to have 80% power to detect difference of 2 points or more between intervention and placebo in the primary outcome (ISK score) 

6 moGH/CPl: 3 

* Altman R, Brandt K, Hochberg M, Moskowitz R. Design and conduct of clinical trials of patients with osteoarthritis: recommendations from a task force 

Society. Osteoarthirtis Cartilage 1996;4:217-43. 
C-34 

Appendix Table IIC, Part 2. Additional RCT Baseline Patient Characteristicsa

Study (Year) 

Intervention 

(Dose) 

No. Pts 

Tx/Pl 

Mn 

Age 

(yrs) 

Tx/Pl 

Female 

Pts (%) 

Tx/Pl 

BMI 

(kg/m2) 

Tx/Pl 

OA 

Diagb

(%) 

OA 

Stage 

(%Tx/ 

%Pl)c

Mn Dis 

Duration 

(yrs) 

Tx/Pl 

Mn VAS 

Rest 

(mm) 

Tx/Pl 

Mn 

WOMAC 

Pain 

Tx/Pl 

Mn 

WOMAC 

Function 

Tx/Pl 

M

WOM

Stiff

Tx

HerreroBeaumont et al (2007) 

GS (1500 mg/day) 

106/108/104 GS: 

63.4 ± 6.9 Acet: 63.8 ± 6.9 Pl: 64.5 ± 7.2 

91/93/89 GS: 

27.7 ± 2.3 Acet: 27.9 ± 2.3 Pl: 27.6 ± 2.4 

1o 

(100) 

KL 2: 50/56/50 KL 3: 41/31/39 Kl 2/3: 9/12/11 

GS: 7.4 ± 6.0 Acet: 6.5 ± 5.3 Pl: 7.2 ± 5.8

 GS: 7.8 

± 3.0 Acet: 8.0 ± 2.9 Pl: 7.9 ± 3.0 

GS: 27.8 ± 11.4 Acet: 29.4 ± 11.0 Pl: 27.2 ± 10.9 

NR 

Michel et al (2005) 

CS 4&6 (800 mg/day) 

150/150 T: 62.5 

± 9.1 Pl: 63.1 ± 10.7 

51/52 Tx: 

27.7 ± 5.2 Pl: 28.1  ± 5.5 

1o 

(100) 

KL All: 1-3 (100) 

NR (0-10) 

2.5/2.7 

(0-10) 2.1/2.5 

(0-103.0/3

Uebelhart et al (2004) 

CS 4&6 (800 mg/day) 

54/56 Tx: 

63.2 ± 9.1 Pl: 63.7 ± 8.1 

80/82 NR 1o

(100) 

KL 1 (7/6) 2 (32/33) 3 (15/17) 

4.2/4.4 58.8/61.1 

Das and Hammad (2000) 

GH (1500 mg/day) plus CS (1600 mg/day) 

46/47 Tx:64.5 

± 9.8 Pl: 66.0 ± 1.5 

72/78 Tx: 

30.5 ± 1.0 Pl: 30.2 ± 0.9 (SEM) 

1o

Tx: 85 Pl: 87 

KL 2/3 (72/83) KL 4 (28/17) 

5.6/7.4 

a All values are mean ± SD unless otherwise noted; CS = chondroitin sulfate; OA = osteoarthritis b ACR = American College of Rheumatology c KL = Kellgren and Lawrence criteria

d Outcomes are generally those that are denoted in the paper as being the primary study outcomes; WOMAC = Western Ontario and McMaster Universit

visual analog scale
C-35 

Appendix Table IIC, Part 3. Additional RCT Treatments Study Intervention 

Dose 

(mg/day) Prior Treatments Concurrent Treatments 

Herrero-Beaumont et al (2007) 

GS 1500 None specified Rescue analgesia, ibuprofen 400 mg every 8 hr for maximum o

Michel et al (2005) 

CS 4&6 800 None specified Rescue analgesia, either acetaminophen maximum 3000 mg/d

or NSAID for up to maximum of 5 consecutive days; physical thlimited to application of warmth and strengthening exercises as 

Uebelhart et al (2004) 

CS 4&6 800 None specified Rescue analgesia, acetaminophen maximum 4000 mg/day 

Das and Hammad (2000) 

GH plus CS GH: 1500 CS: 1600 Occasional use of NSAID Rescue analgesia, either acetaminophen or NSAID for up to m

of 3 days per week; 

CS = chondroitin sulfate; GH = glucosamine hydrochloride; NSAID = non-steroidal antiinflammatory drug 
C-36 

Appendix Table IIC, Part 4. Additional RCT Outcome Assessment Study (Year) Outcomes Assessed Response Criteria HerreroBeaumont et al (2007) 

Primary outcome: Lequesne’s index (0-24); secondary outcomes 0-4 point Likert scale WOMAC; OARSI-A and –B; proportion of patients reporting at least minimal clinically important improvement (MCII) 

OARSI-A responder criteria that define high degree of improvement in pain 

as either 55% relative change on WOMAC pain subscale and absolute change of at least 30 on a 0-100 standardized scale or moderate improvement in 2 of 3 domains of pain, function and patients global assessment (35%, 15% and 15% relative changes, with 10, 20 and 15 standardized units of absolute change, respectively 

Stuunagroass

Michel et al (2005) 

WOMAC score (0-10), total (24 questions), pain (5 questions), function (17 questions), stiffness (2 questions); 50-ft walking time; numerical rating scales ranging from 1 to 10 were used; adverse events 

Improvement of WOMAC scores based on percentage change from baseline, 

separate analysis of individual WOMAC subscales, compared using repeatedmeasures ANOVA and comparison of the 2-year variations using Wilcoxon 

test 

Stuunagroass

Uebelhart et al (2004) 

Primary outcome: Lequesne’s algofunctional index at the end of the study; secondary outcomes: spontaneous joint pain assessed by Huskisson’s VAS (100 mm); 20-meter walking time on flat track; gobal assessment of efficacy by patient and physician; overall acetaminophen consumption; safety and tolerability 

Absolute and percentage change from baseline of mean LI scores, walking 

time, Huskisson VAS, and AEs compared using repeated-measures ANOVA with Bonferroni’s correction for multiple comparisons 

Stuunagroass

Das and Hammad (2000) 

Primary outcome: Lequesne’s index of severity of OAK; secondary outcomes: VAS version of WOMAC, patient’s global assessment, use of pain rescue medication; stratified at randomization by radiographic severity of OAK into mild-to-moderate and severe strata 

Positive response defined as improvement of 25% or more in any of the 

parameters (LI, WOMAC, global assessment) 

Stuunagroass
C-37 

Appendix Table IID, Part 1. Subgroup Analysis of RCTs of Glucosamine Meeting Protocol Study Selection Criteria Study (Year) 

Relevant Subgroup Results Reported 

Subgroup report using ITT sample or per protocol 

Method for imputing missing data if present (ie no missing or method

Herrero-Beaumont et al (2007) 

N NA NA 

Clegg et al (2006) 

Y ITT LOCF method 

Usha and Naidu (2004) 

N NA NA 

Hughes and Carr (2002) 

N NA NA 

Pavelka et al (2002) 

N NA NA 

Reginster et al (2001) 

N NA NA 

Ridone et al (2000) 

N NA NA 

Houpt et al (1999) 

N NA NA 

Rovati (1997) 

N NA NA 

Noack et al (1994) 

N NA NA 

Pujalte et al (1980) 

N NA NA 
C-38 

Appendix Table IID, Part 2. Subgroup Analysis of RCTs of Glucosamine Meeting Protocol Study Selection Criteria 

Reporting Description 

Subgroup Reported (Y/N) Subgroup Reported; Result; subgroup size; total randomized 

Study (Year) 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease 

Severity 

Previous 

Treatment 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease Severity 

HerreroBeaumont et al (2007) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Clegg et al (2006) 

N N N N N N Y N N N N N N N WOMAC 

severe (pn = 70-7125-300randomizfor any c

Usha and Naidu (2004) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Hughes and Carr (2002) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Pavelka et al (2002) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Reginster et al (2001) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Ridone et al (2000) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Houpt et al (1999) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 
C-39 

Appendix Table IID, Part 2. Subgroup Analysis of RCTs of Glucosamine Meeting Protocol Study Selection Criteria (cont’d) 

Reporting Description 

Subgroup Reported (Y/N) Subgroup Reported; Result; subgroup size; total randomized 

Study (Year) 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease 

Severity 

Previous 

Treatment 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease Severity 

Rovati (1997) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Noack et al (1994) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 

Pujalte et al (1980) 

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 
C-40 

Appendix Table IID, Part 3. Subgroup Analysis of RCTs of Glucosamine Meeting Protocol Study Selection Criteria Study Specific Subgroup Methods (Year) 

Interaction test performed prior to subgroup analyses Y/N 

Interaction reported as qualitative or quantitative qual/quan 

Stratified analysis (MantelHaenszel) or regression term for interaction 

Stratified randomization and prespecified subgoups (number planned) 

Prespecified subgroups w/o stratified randomization (number planned) 

Post hoc subgroups 

Adjustment for multiple testing (type I error) 

Probanumbstatistests cond

HerreroBeaumont et al (2007) 

NA NA NA NA NA NA NA NA 

Clegg et al (2006) 

Y quan N Y (3) N N Y 3 

Usha and Naidu (2004) 

NA NA NA NA NA NA NA NA 

Hughes and Carr (2002) 

NA NA NA NA NA NA NA NA 

Pavelka et al (2002) 

NA NA NA NA NA NA NA NA 

Reginster et al (2001) 

NA NA NA NA NA NA NA NA 

Ridone et al (2000) 

NA NA NA NA NA NA NA NA 

Houpt et al (1999) 

NA NA NA NA NA NA NA NA 

Rovati (1997) 

NA NA NA NA NA NA NA NA 

Noack et al (1994) 

NA NA NA NA NA NA NA NA 

Pujalte et al (1980) 

NA NA NA NA NA NA NA NA 
C-41 

Appendix Table IIE, Part 1. Subgroup Analysis of RCTs of Chondroitin Meeting Protocol 

Study Selection Criteria 

Study 

(Year) 

Relevant Subgroup 

Results Reported 

Subgroup report using ITT 

sample or per protocol 

Method for imputing missing 

data if present 

(ie no missing or method) 

Clegg et al 

(2006) 

Y ITT LOCF method 

Michel et al 

(2005) 

N NA NA 

Uebelhart et al 

(2004) 

N NA NA 

Mazieres et al 

(2001) 

N NA NA 

Bourgeois et al 

(1998) 

N NA NA 

Bucsi and Poor 

(1998) 

N NA NA 

Conrozier 

(1998) 

N NA NA 

Uebelhart et al 

(1998) 

N NA NA 

L’Hirondel 

(1992) 

N NA NA 
C-42 

Appendix Table IIE, Part 2. Subgroup Analysis of RCTs of Chondroitin Meeting Protocol Study Selection Criteria 

Reporting Description 

Subgroup Reported (Y/N) Subgroup Reported; Result; s

Study (Year) 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease 

Severity 

Previous 

Treatment 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Disease Severity 

Clegg et al (2006) 

N N N N N N Y N N N N N WOMAC pain: moderate-to-s

score 301-400) n = 70-72; mi125-300) n = 243-248; total ra1,583; NSD for any comparis

Michel et al (2005) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Uebelhart et al (2004) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Mazieres et al (2001) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Bourgeois et al (1998) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Bucsi and Poor (1998) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Conrozier (1998) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

Uebelhart et al (1998) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 

L’Hirondel (1992) 

NA NA NA NA NA NA NA NA NA NA NA NA NA 
C-43 

Appendix Table IIE, Part 3. Subgroup Analysis of RCTs of Chondroitin Meeting Protocol Study Selection Criteria Study Specific Subgroup Methods (Year) Interaction test 

performed prior to subgroup analyses Y/N 

Interaction reported as qualitative or quantitative qual/quan 

Stratified analysis (MantelHaenszel) or regression term for interaction 

Stratified randomization & prespecified ubgroups (number planned) 

Prespecified subgroups w/o stratified randomization (number planned) 

Post hoc subgroups 

Adjustment for multiple testing (type I error) 

Pronumstatcon

Clegg et al (2006) 

Y Quant N Y N N Y 3 

Michel et al (2005) 

NA NA NA NA NA NA NA NA 

Uebelhart et al (2004) 

NA NA NA NA NA NA NA NA 

Mazieres et al (2001) 

NA NA NA NA NA NA NA NA 

Bourgeois et al (1998) 

NA NA NA NA NA NA NA NA 

Bucsi and Poor (1998) 

NA NA NA NA NA NA NA NA 

Conrozier (1998) 

NA NA NA NA NA NA NA NA 

Uebelhart et al (1998) 

NA NA NA NA NA NA NA NA 

L’Hirondel (1992) 

NA NA NA NA NA NA NA NA 
C-44 

Appendix Table IIF, Part 1. Subgroup Analysis of RCTs of Glucosamine plus Chondroitin Meeting Protocol Study Selection 

Criteria 

Study 

(Year) 

Relevant Subgroup 

Results Reported 

Subgroup report using ITT 

sample or per protocol 

Method for imputing missing 

data if present (ie no missing or method) 

Clegg et al 

(2006) 

Y ITT LOCF method 

Das and Hammad 

(2000) 

Y ITT LOCF method 
C-45 

Appendix Table IIF, Part 2. Subgroup Analysis of RCTs of Glucosamine plus Chondroitin Meeting Protocol Study Selection Criteria 

Reporting Description 

Subgroup Reported (Y/N) Subgroup Reported; Result; subgroup size; total randomized 

Study  (Year) 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease 

Severity 

Previous 

Treatment 

Age 

Ethnicity/ 

Race 

Sex 

Primary/ 

Secondary 

OA 

Weight/ 

BMI 

Disease 

Duration 

Disease Severity 

Clegg et al (2006) 

N N N N N N Y N N N N N N N WOMAC 

severe (400) n = score 12248; tota1,583; P 20% redpain in mpain; NSpain 

Das and Hammad (2000) 

N N N N N N Y N N N N N N N LI: mild-m

33/Pl = 313/Pl = 8= 93; P = in mild-mvs Pl for 
C-46 

Appendix Table IIF, Part 3. Subgroup Analysis of RCTs of Glucosamine plus Chondroitin Meeting Protocol Study Selection Criteria 

Specific Subgroup Methods 

Study (Year) 

Interaction test performed prior to subgroup analyses Y/N 

Interaction reported as qualitative or quantitative qual/quan 

Stratified analysis (MantelHaenszel) or regression term for interaction 

Stratified randomization and prespecified subgroups (number planned) 

Prespecified subgroups w/o stratified randomization (number planned) 

Post hoc subgroups 

Adjustment for multiple testing (type I error) 

Pnustteco

Clegg et al (2006) 

Y Quant N Y (3) N N Y 3 

Das and Hammad (2000) 

N NR NR Y (2) N N N 1 
C-47 

Part III. Arthroscopy Tables. 

Appendix Table IIIA. Randomized Studies of Arthroscopic Lavage/Debridement (cont’d) 

Author 

(Year) 

Patient Inclusion/Exclusion Criteria Interventions 

Gibson et al 

(1992) 

Inclusion: 

Moderate unilateral osteoarthritis (OA) of 

the knee 

Exclusion: 

Age > 70 yrs, > 20 degree varus or valgus 

deformity measured on a weight-bearing 

radiograph 

Arthroscopic Lavage: 

N = 10, 6 M/4 F, mean age 53 ± 10 yrs 

Arthroscopic Debridement: 

N = 10, 8 M/2 F, mean age 57 ± 7 yrs 

Chang et al 

(1993) 

Inclusion: 

Persistent knee pain for > 3 mos, despite 

conservative medical and rehabilitation, 

which restricted activities, weight-bearing 

radiographs showing grade 1,2, or 3 

changes according to Kellgren and 

Lawrence (KL), age > 20 yrs, willingness 

to follow-up at 3 and 12 mos, and give 

informed consent 

Exclusion: 

Knee surgery within 6 mos of study entry, 

total knee replacement (TKR) concurrent 

illness that would influence functional 

assessment of the knee or preclude 

arthroscopic surgery, KL class 4 changes 

on radiographs 

Closed-Needle Joint Lavage: 

N = 14, 4 M/10 F, mean age 65 ± 13 yrs 

Arthroscopic Surgery

(debridement/excision of proliferative 

synovium or loose bodies): 

N = 18, 5 M/13 F, mean age 61 ± 11 yrs 

Edelson et al 

(1995) 

Inclusion: 

Symptomatic knee OA unresponsive to 

NSAID therapy, grade I –III radiographic 

OA according to Holden et al (1988) 

Exclusion: 

Clinical signs or symptoms of meniscal 

tears or obvious mechanical symptoms 

23 patients, 20 M/3 F, mean age 58 yrs 

(rng 39-79) 

29 knees were subjected to arthroscopic 

washout with hypertonic lactated 

Ringer’s solution 

Immediately following initial washout, 

patients were randomly allocated to:

Placebo Treatment: 

13 knees received a 3 mL intraarticular 

(IA) injection of placebo (lactated 

Ringer’s solution) 

IA Hyaluron Treatment: 

16 knees received a single 3 mL IA 

injection of hyaluronic acid (0.5-1.0 mD) 
C-48 

Appendix Table IIIA. Randomized Studies of Arthroscopic Lavage/Debridement (cont’d) 

Author 

(Year) 

Patient Inclusion/Exclusion Criteria Interventions 

Hubbard 

(1996) 

Inclusion: 

Symptoms of knee OA > 1 yr, no prior 

surgery to index knee, no laxity, no 

deformity, single medial femoral condyle 

degenerative lesion grade 3 or 4 

(Outerbridge), no other IA pathology, 

normal plain radiograph, modified 

Lysholm score < 38/70 

Exclusion: 

All knees that showed radiographic loss of 

joint space, previous operation, previous 

steroid injection for any reason 

Arthroscopic Lavage: 

N = 36, 20 M/16 F, mean age classified 

according to success (46 yrs) or failure 

(59 yrs) 

Arthroscopic Debridement: 

N = 40, 28 M/12 F, mean age classified 

according to success (51 yrs) or failure 

(45 yrs) 

Ravaud et al 

(1999) 

Inclusion: 

American College of Rheumatology 

(ACR) criteria for knee OA, pain scored 

by patient at 40 or greater on a 100-mm 

visual analog scale (VAS), radiographic 

evidence of at least KL grade II 

tibiofemoral OA (within last 6 mos) with 

osteophytes and minimal joint space 

narrowing 

Exclusion: 

Serious concomitant illness, secondary 

OA as defined by the Osteoarthritis 

Research Society, knee surgery scheduled 

within the following 12 mos, local or 

systemic contraindication to the use of IA 

corticosteroids or to joint lavage, any IA 

injection during the 3 mos prior to study 

entry, current treatment with systemic 

corticosteroids or any slow-acting anti-OA 

drugs 

Placebo Treatment: 

N = 28, 10 M/18 F, mean age 63 ± 11 yrs 

IA Corticosteroid Treatment: 

N = 25, 7 M/18 F, mean age 67 ± 12 yrs 

Arthroscopic Lavage plus Placebo 

Treatment: 

N = 21, 7 M/14F, mean age 65 ± 8 yrs 

Arthroscopic Lavage plus IA 

Corticosteroid Treatment: 

N = 24, 8 M/16F, mean age 67 ± 11 yrs 
C-49 

Appendix Table IIIA. Randomized Studies of Arthroscopic Lavage/Debridement (cont’d) 

Author 

(Year) 

Patient Inclusion/Exclusion Criteria Interventions 

Kalunian et 

al 

(2000) 

Inclusion: 

Age > 40 yrs, knee pain for 10 yrs or less, 

unsatisfactory pain relief despite 6 wks of 

supervised physical therapy and two or 

more different NSAIDs and/or analgesics 

given for 3 or more wks each, willingness 

to undergo follow-up and give informed 

consent, normal or minimally abnormal 

radiographs (KL grade 0-2), fulfill ACR 

criteria for classification of knee OA using 

either clinical and radiographic, traditional 

clinical or clinical and laboratory methods, 

or classification tree clinical or clinical 

and laboratory methods 

Exclusion: 

Back/hip or ankle/foot OA of significant 

severity to confuse the clinical assessment 

of knee OA, IA corticosteroid injection 

within 1 mo prior to study, significantly 

abnormal radiographs (KL grades 3-4), 

body mass index (BMI) > 35 kg/m2, 

sensitivity to amide anesthetic agents, 

serious medical illness that would place 

patient at risk in the event of surgery, 

recent history of substance abuse 

Control Group - Minimal Arthroscopic 

Lavage: 

N = 49, 23 M/26 F, mean age 58 yrs (rng 

40-85) 

Treatment Group – Large Volume 

Arthroscopic Lavage: 

N = 41, 19 M/22 F, mean age 61 yrs (rng 

41-88) 

Smith et al 

(2003) 

Inclusion: 

Symptomatic OA of the knee, fulfilling 

ACR criteria for knee OA, already 

receiving NSAID or other analgesic 

therapy 

Exclusion: 

Mechanical symptoms upon diagnostic 

arthroscopy, comorbidities preventing 

arthroscopy, unwillingness to comply with 

study demands or provide informed 

consent 

Arthroscopic Lavage plus Placebo 

Injection: 

N = 33, 18 M/15 F, mean age 66 ± 12 yrs 

Arthroscopic Lavage plus IA 

Corticosteroid Treatment: 

N = 38, 26 M/12F, mean age 67 ± 10 yrs 
C-50 

Appendix Table IIIA. Randomized Studies of Arthroscopic Lavage/Debridement (cont’d) 

Author 

(Year) 

Patient Inclusion/Exclusion Criteria Interventions 

Frias et al 

(2004) 

Inclusion: 

Symptomatic OA of the knee for > 3 mos 

despite conservative medical therapy, 

fulfilled ACR criteria for knee OA, KL 

OA radiological grades 2-3, no disability 

assessment at the time of enrollment, 

voluntary cooperation and informed 

consent, age > 18 yrs 

Exclusion: 

Ankylosis of the index joint, TKA of the 

index knee, potentially infected injury near 

puncture site, current anticoagulant 

therapy, history of coagulation problems, 

suspected deep venous thrombosis (DVT) 

or marked venous insufficiency, history of 

surface thrombosis or DVT 

Overall 299 knees belonging to 205 

patients (45 M/160 F), mean age 67 ± 8 

yrs were randomly allocated to: 

Arthroscopic Lavage: 

N = 62, sex and age not given 

Arthroscopic Lavage Plus IA 

Corticosteroid Injection: 

N = 237, sex and age not given 
C-51 

Appendix Table IIIB. Arthroscopy Case Series Sample Selection Study Inclusion Exclusion n, Enrolled 

n, Withdr

Aaron 2006, ALD 

Consecutive pts; met ACR OA of tibiofemoral joint; failed oral anti-inflammatory treatment; age 18-70 yo; KellgrenLawrence grade > 2 

Previous infection; OA of pattelo-femoral joint; other/confounding diabnoses; 

122 12 

Bernard 2004 ALD 

01/91 – 12/93; consecutive patients who underwent knee arthroscopy and washout for OA of the knee (Outerbridge grade 3 or 4); pain not controlled by non-operative treatments; radiographic OA changes; 

 100 knees, 99 

pts 

 

Krystallis 2004 ALD 

02/97 – 06/01; OA of the knee; standard conservative nonoperative treatment had failed; local anesthesia (L) in 67 pts (71 operations); general anesthesia (G) in 65 pts; peridual anesthesia (P) in 65 pts; local anesthesia contraindicated for emotionally labile, low tolerance for discomfort 

 201 knees, 

197 pts 

 

Dervin 2003 AD 

03/95 – 11/97; OA of knee; 40-75 yo; referred to orthopaedic outpatient clinic at Ottawa Hospital General Campus; remained symptomatic despite supervised physical therapy and comprehensive medical management 

Inflammatory/traumatic forms of OA; 

156 pts 30 pts 

Jackson and Dieterichs 2003 ALD 

01/95 – 06/97; ACR criteria diagnosis of OA of knee; 

Jackson and Dieterichs stage I-IV; consecutive series 

Stage I and IV not suited for arthroscopy; pts treated with marrow stimulation techniques, laser or radiofrequency chondroplasty 

121 pts 

Bohnsack 2002 AD 

05/89 – 11/96; history of knee pain, swelling, radiological 

signs of severe OA (grade III/IV) 

 104 pts 

Shannon 2001 ALD 

Retrospective consecutive series of all pts with mildmoderate OA who had arthroscopic lavage and/or 

debridement of knee over 4-yr period; symptoms not severe enough for joint replacement; conservative treatment alone had failed or non-specific mechanical symptoms out of proportion to clinical and radiologic findings 

Preop clinical/radiologic diagnosis of meniscal tear or loose body 

55 procedures, 54 pts 

 

Harwin 1999 ALD 

1980 -1993; of 2,730 knee arthroscopies by author, 248 knees in 220 pts had areas of fibrillated articular cartilage 

with exposed bone and underwent debridement; Group I - mechanical axis normal at 0o (n=57); Group II – < 5o of 

varus or valgus (n=102); Group III - > 5o varus or valgus 

(n=45); unresponsive to all modalities of nonoperative treatment, including lifestyle alterations, NSAIDs, PT, occasional IA steroid injection 

 248 knees, 

220 pts 

44 kneepts 

McGinley 1999 AD 

1981-87; of 191 pts > 55 yo who underwent arthroscopic debridement by 1 surgeon; pts with OA symptoms including pain limiting function and Albach radiographic JSN grade 2-3; > 10 yr F/U 

 91 knees, 77 

pts 

 
C-52 

Appendix Table IIIB. Arthroscopy Case Series Sample Selection (continued) Study Inclusion Exclusion n, Enrolled 

n, Withdr

Linschoten and Johnson 1997 ALD 

07/85 – 01/88; of 169 pts who had arthroscopy of knee; age > 40 yo; preop diagnosis of OA or RA with 

arthroscopically confirmed degenerative changes; degenerative changes in > 2 of 3 compartments or single 

compartment Outerbridge III/IV 

Arthroscopies for diagnosis or treatment of acute injuries, preliminary diagnosis of degenerative joint disease not confirmed intraoperatively 

68 knees, 67 pts 

12 kneepts 

Yang and Nisonson 1995 ALD 

07/89 – 07/93; did not respond to conservative nonoperative treatment and had persistent evidence of 

internal derangement of knee; did not show severe signs and symptoms to merit total knee arthroplasty 

History of rheumatoid arthritis; gout; ochronosis; ankylosing spondylitis; hemophilia; osteonecrosis; posttraumatic/postinfectious osteoarthritis 

105 procedures, 103 pts 

 

Aichroth 1991 ALD 

77 – 88; had arthroscopic debridement and irrigation of a degenerative knee joint; under care of single author 

 280 pts 26 pts 

McLaren 1991 ALD 

07/82 – 07/86; OA confirmed at arthroscopy; nonoperative 

treatments either did not control symptoms sufficiently to allow normal daily activities or control rest pain 

Inflammatory joint disease, malunited fractures and ligamentous instability 

171 pts 

Ogilvie-Harris and Fitsialos 1991 ALD 

1979 – 1987; arthroscopic surgery for degenerative arthritis of the knee; persistent symptoms despite adequate medical management 

 551 pts 110 pts 

Timoney 1990 ALD 

07/81 – 02/86; underwent knee arthroscopy at Naval Hospital, Oakland; age > 40 yo; intraoperative diagnosis of OA 

Inflammatory disease (rheumatoid arthritis, acute infection arthritis), acute injury 

125 pts 17 pts 

Bert and Maschka 1989 AD 

09/81 – 12/82; all pts offered arthroscopic debridement plus abrasion arthroplasty (DA) for unicompartmental gonarthrosis, those who refused it were offered arthroscopic debridement alone (D); conservative methods of treatment had failed; available for 5 yr follow-up 

 DA 59 pts; D 

67 pts 

 

Sprague 1981 ALD 

08/78 – 11/79; of 331 arthroscopies, 78 were pre- and postoperatively diagnosed as degenerative arthritis of the knee; moderate to extreme degeneration of the articular surfaces of 2-3 compartments; all pts had initially undergone a conservative treatment program with antiinflammatories, exercise program, physical modalities 

 78 knees, 72 

pts 

9 kneespts 
C-53 

Appendix Table IIIC. Arthroscopy Case Series Patient Characteristics Study Age 

Percent Female) 

Race (%) 

Obesity (%) 

Disease Category (%) 

Disease Duration 

Preop Disease Severity (%) 

Arthoscopic Disease Severity (%) Pain Functio

Aaron 2006 ALD 

Mn 61.7 67 Mn BMI: 

31.8 

 KellgrenLawrence 

(2/3/4) 53/29/18 

NoyesStabler mn total 21.6 

Knee Society mn 11.9 

 

Bernard 2004 ALD 

Mn 55, sd 13 

39 

Krystallis 2004 ALD 

L: mn 60.8, rng 31-71 G: mn 59.9, rng 30-67 P: mn 62.2, rng 35-75 

49 1o: 94 

2o: 6 

 Fairbank 

0: 12 I: 36 II: 40 III: 12 

Outerbridge: I/II: 12 III: 28 IV: 60 

 

Dervin 2003 AD 

Mn 61.7, sd 8.6 

53 BMI > 27: 

67 BMI > 33: 25 

 Dougados 

Medial III/IV: 62 Lateral III/IV: 13 

WOMAC M: mn 22, sd 11.2 F: mn 25.5, sd 9.9 

WOMAC M: mn 7sd 34.8 F: mn 87.2, sd 38.9 

Jackson and Dieterichs 2003 ALD 

I: mn 35.5, rng 22-60 II: mn 54, rng 26-85 III: mn 56, rng 24-78 IV: mn 64, rng 41-83 

 Jackson 

and Dieterichs I: 7 II: 26 III: 32 IV: 35 

Bohnsack 2002 AD 

Mn 60, rng 50-83 

52 Jaeger 

and Wirth III/IV in medial or lateral compartments 

Outerbridge: III/IV: 50-80% by surface 

 Lysholm 

and Gillquist Mn 40 
C-54 

Appendix Table IIIC. Arthroscopy Case Series Patient Characteristics (cont’d) Study Age 

Percent Female) 

Race (%) 

Obesity (%) 

Disease Category (%) 

Disease Duration 

Preop Disease Severity (%) 

Arthoscopic Disease Severity (%) Pain Functio

Shannon 2001 ALD 

Mn 60.9, rng 48-83 

56 Mn wt: 

76.6 kg, rng 54-100 

 # mo: % 

< 3: 20 3-12: 43 > 12: 39 

Harwin 1999 ALD 

Mn 62.1, rng 32-88 

57 
C-55 

Appendix Table IIIC. Arthroscopy Case Series Patient Characteristics (continued) Study Age 

Percent Female) 

Race (%) 

Obesity (%) 

Disease Category (%) 

Disease Duration 

Preop Disease Severity (%) 

Arthoscopic Disease Severity (%) Pain Functio

McGinley 1999 AD 

Mn 62.6, rng 55-82 

 Outerbridge: 

IV: 100 

Linschoten and Johnson 1997 ALD 

Mn 62.5, rng 41-79 

51 

Yang and Nisonson 1995 ALD 

Mn 64.2, sd 4.3 

19 # mo: % 

< 1: 17 1-12: 62 > 12: 15 

Fairbank 0: 15 I: 50 II: 24 III: 7 

Aichroth 1991 ALD 

Mn 49, rng 28-82 

28 

McLaren 1991 ALD 

Mn 54, rng 23-82 

30 1o: 81 

2o: 19 

OgilvieHarris and Fitsialos 1991 ALD 

Mn 58, rng 28-92 

 > 2 yrs in 

most pts 

 Outerbridge 

I/II: 32 III: 36 IV: 32 

Timoney 1990 ALD 

Mn 58.1, rng 40-81 

31 mn 48.9 

mo, rng 2-144 

0-III scale HSS 

Mn 24.7, sd 9.2, rng 8-44 

Bert and Maschka 1989 AD 

DA mn 66, rng 46-84 D mn 61, rng 39-82 

DA 46 D 42 

 % obese: 

DA 26 D 22 

 Ahlback 

II-100 

Outerbridge IV: 100 

 

Sprague 1981 ALD 

Mn 56, rng 24-78 

38 
C-56 

Appendix Table IIID. Arthroscopy Case Series Treatments Study Arthroscopic Procedure Prior Treatments 

Concurrent Treatments 

Aaron 2006 ALD 

One surgeon; 3 portals; Dyonics 4 mm arthroscope; limited surgical debridement of damaged cartilage with chromotome; loose flaps resected; crater edges smooted; loose bodies removed; torn meniscal cartilage, hypertrophic synovial tissue resected; no drilling/abrasion; joint irrigated and evacuated 

Mn 2 different NSAIDs; intra-articular corticosteroid injections in 20; physical therapy in 12 

Knee immobpartial weighbearing for 2days, then Rexercises/gatolerated 

Bernard 2004 ALD 

2 portal arthroscopy; 1 surgeon; meniscal tears resected (meniscectomy in 40); debridement of loose bodies, unstable chondral flaps; lavage; no synovectomy; punches, scissors and curettes; Outerbridge grading of all 3 compartments 

Krystallis 2004 ALD 

2 portal arthroscopy; no tourniquet; 4-mm 30o arthroscope; IM midazolam; local 

anesthesia with ropivacine, lidocaine, bupivacaine; sterile saline lavage with infusion pump; debris/fragments removed; meniscal lesions given conservative partial meniscectomy without repair; unstable peripheral cartilage flaps removed; mechanical shavers, basket forceps; no abrasion arthroplasty; isolated chondral defects > 1 cm micro-fractured; Outerbridge grading 

 Crutches, g

progress to weight bearafter 2-3 wk

Dervin 2003 AD 

2 portal arthroscopy; tourniquet optional; diagnosis first; resection of loose chondral flaps and unstable meniscal tears; synovectomy only when needed for visualization; standard hand and shaver instruments; no abrasion arthroplasty or drilling; 

25% had > 1 IA 

cortisone; 58% regular users of non-narcotic analgesics and/or NSAIDs 

Jackson and Dieterichs 2003 ALD 

Arthroscopic lavage and debridement; removal of loose bodies; trimming of meniscal fragments; conservative or minimal mechanical removal of any separating or desquamating articular cartilage fragments from the femoral condyles 

Bohnsack 2002 AD 

Partial, subtotal or total meniscectomy in 73%; one or more loose bodies removed in 11%; shaving of articular surface in 35%; plica mediopatellaris dissected in 1%; diagnostic-only arthroscopy only in 11% 

Pain-reducing drugs in 42.3% 

Shannon 2001 ALD 

General anesthesia; tourniquet; 4-mm 30o arthroscope; 2 portals; IA bupivacaine 

in 27 knees by surgeon’s preference; diagnostic arthroscopy and lavage; removal of loose bodies, debridement of degenerative meniscus and partial meniscectomy in 19 pts 

Unresponsive to conservative nonsurgical treatments (PT, NSAIDs, weight loss) 

Crutches; P

Harwin 1999 ALD 

Lavage and debridement; partial synovectomy; decompression of the anterior 

chamber by resection of impinging plicae and removal of hypertrophic adipose tissue; partial meniscectomies removed only loose unstable fragments; chondroplasties – removal of only loose, unstable or irregular flaps; osteophytes removed rarely if only directly impinging; general anesthesia in most cases, others had epidural/spinal or local 

 Dressing re

in 24-48 hrsencouraged bear as mucweight as tousing cane, crutches, waPT as soon possible; NS
C-57 

Appendix Table IIID. Arthroscopy Case Series Treatments (continued) Study Arthroscopic Procedure Prior Treatments 

Concurrent Treatments 

McGinley 1999 AD 

Debridement included meniscus tear resection and nonaggressive shaving of frayed articular cartilage; 5 pts also had drilling of the medial femoral condyle; 3 pts had removal of loose bodies; 1 pt had lateral release 

Linschoten and Johnson 1997 ALD 

Diagnostic first; individualized according to findings; meniscal tears excised by partial or total meniscectomy; loose bodies removed; synovium and fat interfering with visualization debrided; partial synovectomy when synovial impingement suspected; unstable articular cartilage flaps or fronds debrided; no drilling or abrasion chondroplasty; normal saline lavage 

 Robert Jone

dressing for hrs; weight-with cane/cras tolerated 

Yang and Nisonson 1995 ALD 

2-portal arthroscopy; general or regional anesthesia; tourniquet used for all pts; 4-mm 30o arthroscope; lavage; intraarticular debris and loose bodies were removed; meniscal disease addressed by partial meniscectomy preserving as much stable meniscal tissue as possible; mechanical shavers, basket forceps to remove unstable cartilage flaps at the periphery; osteochondral fragments or articular cartilage lestion that potentially could detach and become loose bodies 

were removed; some isolated chondral defects > 1.5 cm drilled with multiple holes; synovectomies using mechanical shavers for significant peripatellar hypertrophic reactive synovitis; meniscal lesions found in 96% 

5 pts had previous surgery: arthroscopy and drilling, arthroscopy and debridement, repair of quadriceps rupture, excision of patella bursa, Maquet procedure 

SC pubivaclight compredressing; paweightbearicrutches 4-7 progess to fweightbearicane 1-2 wk 

Aichroth 1991 ALD 

Degenerative meniscal tears excised and trimmed; degenerative articular cartilage shaved and loose bodies removed; small osteotome used to remove impinging osteophytes; overgrown synovium cut away; irrigation 

 Compressio

bandage usearly exericmotion and bearing as tolerated 

McLaren 1991 ALD 

4 surgeons using similar surgical techniques; normal saline medium; tourniquet used; outpatient setting unless otherwise indicated medially; partial anterior synovectomy often required to aid in visualization; lavage; chondrectomy performed with motorized shaver or curette; removed articular cartilage that was 

separated from subchondral bone or had gross softening, fibrillation, fissuring; full-thickness chondrectomy often followed by curettage of subchondral bone or abrasion using a burr (except for eburnated subchondral bone in end-stage compartments); meniscal tears were treated with partial meniscectomy; free bodies removed; 

Activity modification, anti-inflammatory agents; PT; 

Local anestcorticosteroinjected in spatients with stage tricommental disecrutches folby progressfull weight-bPT; anti-inflatory medicarequired 

Ogilvie-Harris and Fitsialos 1991 ALD 

General anesthetic in most case, some had spinal or epidural anesthesia, ~5% had local; lavage and debridement (removal of loose areas of articular cartilage from degenerative area, preserving as much surrounding articular surface as stable) with manual and power instruments for mild and moderate OA; abrasion when erosions involving up to half femoral condyle; minor meniscal degeneration left alone, substantial unstable meniscal flap tears resected, rim contoured; saline lavage alone for extensive degenerative changes without mechanical lesions 

NSAIDs in all, IA cortisone in ~25%; previous operation in 61% 
C-58 

Appendix Table IIID. Arthroscopy Case Series Treatments (continued) Study Arthroscopic Procedure Prior Treatments 

Concurrent Treatments 

Timoney 1990 ALD 

Lavage, debridement of degenerative meniscal tears and chondral lesions, partial synovectomy with osteophytecomy as indicated 

Bert and Maschka 1989 AD 

DA abrasion using Dyonics abrasion instrumentation system; only stage IV lesions abraded; subchondral intracortical bone abraded to depth of ~ 1-2 mm until bleeding bone noted; additional debridement and partial meniscectomy; loose bodies and other joint debris removed; loose or impinging osteophytes removed; D performed with partial meniscectomy by manual and electrocautery instrumentation as above; partial synovectomy if necessary 

 DA pts no w

bearing for 6 D pts weighbearing whetolerable 

Sprague 1981 ALD 

General anesthesia; many outpatient; hospitalization < 36 hrs; 1 surgeon; tourniquet applied, sometimes used; 4 arthroscopes from 4 mm to 6.5 mm; mechanized shaving instruments; 2-3 portals; meniscal tears excised back to intact, stable meniscal tissue; shaggy degenerative tissue of articular surfaces was shaved and debrided; loose bodies, fragments and debris removed; osteophytes trimmed; localized areas of hypertrophic synovium trimmed or excised; synovectomy in 4 pts; normal saline lavage 

 Bulky comp

dressing for encouraged ambulate folimited distaexercises; ainflammator
C-59 

Appendix Table IIIE. Arthroscopy Case Series Outcome Assessment Study Outcomes Assessed Response Criteria Observer F/U Aaron 2006 ALD 

Knee Society pain; need for total knee replacement 

Post-treatment Knee Society pain success: < 30 Independent 

assessor 

Mn 34 rng 24

Bernard 2004 ALD 

Time to further major surgery (Kaplan-Meier) 

Osteotomy, unicondylar arthroplasty, total knee 

replacement 

Krystallis 2004 ALD 

Baumgaertner (pain, function, patient enthusiasm, 0-9) Adverse events 

Excellent=9; Good=6-8; Fair=4-5; Failure=0-3 Mn 32 

rng 24

Dervin 2003 AD 

WOMAC pain; WOMAC stiffness; WOMAC function; SF-36 

MCIC per item (domain): WOMAC pain – 1.5 cm (7.5 cm); WOMAC stiffness – 1.75 cm (3.5 cm); WOMAC function – 2 cm (34 cm); success also defined as 20% improvement 

 2 yrs 

Jackson and Dieterichs 2003 ALD 

Patient global assessment Excellent, good, fair, poor > 4 yrs 

Bohnsack 2002 AD 

Lysholm and Gillquist score; use of pain-reducing drugs Further surgery 

 Mn 5.4 

rng 2-

Shannon 2001 ALD 

Duke arthroscopy score (NRS pain and function); subjective assessment of improvement; further surgery; adverse events 

No change=0; fair=1-20, good=21-40; excellent=41-60 Mn 29

rng 9-

Harwin 1999 ALD 

Patient global assessment Better, unchanged, worse Mn 7.4

rng 2-

McGinley 1999 AD 

Further surgery Mn 13

Linschoten and Johnson 1997 ALD 

Good/poor outcome; further surgery; adverse events 

Good=symptomatic improvement, activity better than preop, satisfaction, would do again for other knee 

 Mn 49 

rng 24

Yang and Nisonson 1995 ALD 

Investigator-designed pain, function, range of motion (ROM); adverse events, further surgery 

All 3 domains rated on 4-point scale, summed Excellent=11-12; good=9-10; fair=6-8; poor=3-5 

 Mn 11

sd 13.6-60 

Aichroth 1991 ALD 

Investigator-devised grade:symptoms, knee movement, ADLs, sports, analgesics; further surgery 

Satisfactory (excellent, good); unsatisfactory (fair, poor) Mn 44 

McLaren 1991 ALD 

Pain, function; satisfaction; further surgery; adverse events 

Pain=none, mild, moderate, severe Function=ADLs, sports, work 

 Mn 25 

rng 12

Ogilvie-Harris and Fitsialos 1991 ALD 

Pain; pain change; activity limitations activity change; analgesics; analgesics change; satisfaction 

All outcomes on 4-point scale except satisfaction (3-point) Good result=no or occasional pain and no or occasional limitations of activity 

 Mn ~ 4 

rng 2-

Timoney 1990 ALD 

Modified Hospital for Special Surgery rating score (HSS, pain and function); patient subjective assessment of surgical outcome; adverse events; further surgery 

HSS (8-52 points) Patient assessment: good, fair, poor 

 Mn 50

rng 24
C-60 

Appendix Table IIIE. Arthroscopy Case Series Outcome Assessment (continued) Study Outcomes Assessed Response Criteria Observer F/U Bert and Maschka 1989 AD 

Hospital for Special Surgery (HSS) system; further surgery 

HSS, Excellent= > 85; good=70-84; fair=60-69; poor= < 60 5 yr 

Sprague 1981 ALD 

Subjective assessment (4 levels, worse to markedly better); functional level (3 levels, reduced to increased); additional surgery performed or contemplated (Y/N) 

Good, fair, poor (article describes algorithm for combining subjective assessment, functional level and additional surgery) 

 Mn 13

rng 6-
C-61 

Appendix Table IIIF. Arthroscopy Case Series Results Study Outcomes Outcomes Aaron et al. 2006 ALD 

Knee Society pain Pre F/U p Mn 11.9 30.8 <0.001 Success=Knee Society pain > 30 in 72 (65%), failure in 38 (35%) 

Significant predictors of percent success: Kellgren-Lawrence grade, abnormal limb alignment, medial/lateral joint space width; intraoperative lesion severity; mechanical symptoms did not predict success, 

Further surgery: total knee replacement (15%) - Kellgren-Lawrence grade. 

Bernard 2004 ALD 

18 knees required further major surgery (osteotomy – 4; unicondylar arthroplasty – 3; total knee replacement – 11) 5-yr major surgery-free survival all: ~82% < 60 yo: 89% > 60 yo: 68% (X2, p=0.02) prior meniscectomy did not affect outcome 

Krystallis 2004 ALD 

Excellent results: All pts: 42.3% Mechanical sx: 65.7% Loading sx: 30.6% No difference between anesthesia groups (ANOVA, p=0.71) 

Adverse events (#): minor intraoperative complichemarthrosis (24.9%, 6.1% had to be drained) 

Dervin 2003 AD 

MCII WOMAC pain: 44% MCII predicted by tenderness at medial joint line, positive Steinman, unstable meniscal tear (logistic regression) 

Jackson and Dieterichs 2003 ALD 

Group Excellent/good Fair Poor (%) All 50 27 22 I 100 0 0 II 91 0 9 III 49 28 23 IV 12 52 36 

 Repeat Arthroscopy (%) Arthroplasty (%I 0 0 II 9 0 III 15 8 IV 7 29 

Bohnsack 2002 AD 

Lysholm & Gillquist Pre F/U p Mn 40 69 <0.01 Higher gain in Lysholm & Gillquist score in pts < 60 yo, monolateral OA; no influence of meniscectomy. 

 Pre F/U Use of pain-reducing drugs (%) 42 19 Between 5 and 98 mo (mn 33.1), 20% required fknee arthroplasty (8%), monocondylar knee arthtibial osteotomy (2%), repeat arthroscopy (4%), (4%) 

Shannon 2001 ALD 

Assessment (%) Improved Unchanged Worse All pts 67 33 0 Mn duration of symptom relief 25.5 mo, rng 1-51 No influence on results of sex, age, weight, preop Duke score, duration of symptoms 

Further surgery: arthroscopy (7.4%); total knee aAdverse events: none 
C-62 

Appendix Table IIIF. Arthroscopy Case Series Results (continued) Study Outcomes Outcomes Harwin 1999 ALD 

Assessment (%) Better Unchanged Worse All pts 63 21 16 Group I 84 12 4 Group II 68 24 9 Group III 27 27 47 

Further surgery: repeat arthroscopy (13.2%), me3.2 yr, rng 6 mo – 12 yrs; other surgery (15.3%)osteotomy 3.5 yrs, rng 2-6 yrs, mean time to joinrng 6 mo – 10 yrs Adverse events: hemarthroses (2%); deep vein 

McGinley 1999 AD 

Total knee replacement in 33% of knees 

Linschoten and Johnson 1997 ALD 

Assessment (%) Good Poor All pts, last F/U 68 32 6 mo F/U 82 18 12 mo F/U 77 23 24 mo F/U 70 30 36 mo F/U 68 32 48 mo F/U 68 32 

Further surgery (12.5%) Adverse events: prolonged drainage (7.3%); spieffusion requiring aspiration (1.9%); postop naus(1.95) 

Yang and Nisonson 1995 ALD 

Group Rating Excellent Good Fair Poor All pts % 20 45 32 3 Sx < 1 mo 78 Sx > 12 mo 52 Mechanical sx 96 No mechanical 42 Fairbank 0/I 69 Fairbank II/III 36 Mild degeneration 74 Severe degeneration 39 Outcome not correlated with age, gender, side or duration of follow-up

Adverse events: deep vein thrombosis (1%); suprepeat arthroscopy (3%); total knee replacemen

Aichroth 1991 ALD 

% Excellent Good Fair Poor All pts 18 57 15 10  Satisfactory Unsatisfactory All pts 75 25 < 60 yo 78 22 p<0.008 > 60 yo 55 45 Satisfactory result correlated with Ahlback preop radiographic severity (p<0.001) and with Outerbridge operative severity (p<0.001); no correlation with type or location of meniscal tear or performance of previous surgery 

Further surgery in 14% after mean 46 mo 
C-63 

Appendix Table IIIF. Arthroscopy Case Series Results (continued) Study Outcomes Outcomes McLaren 1991 ALD 

% Improved Same Worse Pain 78 19 2 Disability 22 68 10 Ambulation limitation 49 45 6 Overall assessment 65 28 7 Disability (%) Pre Post No restriction 10 32 Limited recreation & sports 48 45 Unable to work 25 12 Restricted daily activities 17 11 

Superficial portal drainage controlled by orally ad(1.2%); deep vein thrombosis (0.6%); further surarthroscopy (4.7%), high tibial arthroscopy (4.1%replacement (3.5%) 

Ogilvie-Harris and Fitsialos 1991 ALD 

 % Good mn % Procedure n > 2 yr F/U Good Debridement 1 compartment 103 82 4.3 66 Debridement 2 compartments 135 58 3.6 41 Abrasion 32 56 4.1 53 Meniscectomy 18 83 4.7 72 Meniscectomy+debridement 149 68 4.3 53 Lavage only 4 25 3.4 25 All pts 441 68 4.1 53 

Domain % Pain, no/occasional 53 Pain improved 86 Activity limitation, no/occasional 59 Activity improved 83 Analgesic, no/occasional 79 Analgesic, improved 32 Satisfaction 90 Results related to disease severity 

Timoney 1990 ALD 

 Pre F/U p Mn HSS score (sd) 24.7 (9.2) 36.1 (16.3) <0.001 Subjective Good Fair Poor % 49 20 41 Subjective results deteriorated over time. Subjective results significantly worse for those with symptoms > 48 mo, those with severe chondromalacia; not correlated with meniscal pathology, condition of ACL, those undergoing limited lavage and debridement 

Adverse events: postoperative effusions (6.5%); (0.9%); infections (0%) Further Surgery: repeat arthroscopy (5.6%); tota(21.3%) 

Bert and Maschka 1989 AD 

Group (%) Good-Excellent Fair Poor DA 51 16 33 D 66 13 21 

Further surgery: total knee replacement (DA 25%

Sprague 1981 ALD 

Assessment (%) Good Fair Poor All pts 74 10 16 

Further surgery: repeat arthroscopy (3.2%); tota(1.6%) 
D-1

Appendix D. Technical Expert Panel (TEP) and 

Reviewers 

Technical Expert Panel (TEP) 

In designing the study questions and methodology at the outset of this report, the EPC consulted 

several technical and content experts. Broad expertise and perspectives are sought. Divergent 

and conflicted opinions are common and perceived as health scientific discourse that results in a 

thoughtful, relevant systematic review. Therefore, in the end, study questions, design and/or 

methodologic approaches do not necessarily represent the views of individual technical and 

content experts. 

Mathias P.G. Bostrom, M.D. 

Hospital for Special Surgery 

New York, NY 

(Nominated by the American Academy of Orthopaedic Surgeons) 

Warren Reid Dunn, M.D., M.P.H. 

Assistant Professor, Orthopaedics and Rehabilitation 

Assistant Professor, Medicine & Public Health 

Vanderbilt University Medical Center 

Nashville, TN 

David T. Felson, M.D., M.P.H. 

Chief 

Boston University Clinical Epidemiology Research Training Unit 

Boston, MA 

Marc C. Hochberg, M.D., M.P.H. 

Professor of Medicine 

Head, Division of Rheumatology & Clinical Immunology 

Professor of Epidemiology and Preventive Medicine 

University of Maryland School of Medicine 

Baltimore, MD 

Nancy E. Lane, M.D. 

Director and Distinguished Professor 

Aging Center, Medicine and Rheumatology 

University of California at Davis Medical Center 

Sacramento, CA 
D-2

Technical Expert Panel (TEP) (continued) 

Capt. Ernestine (Tina) Murray, R.N., M.A.S. 

Senior Health Policy Analyst 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Rockville, MD 

Neil A. Segal, M.D. 

Assistant Professor and Staff Physiatrist 

Department of Orthopaedics & Rehabilitation 

University of Iowa 

Iowa City, IA 

Philip Sloane, M.D., M.P.H. 

Department of Family Medicine 

University of North Carolina at Chapel Hill 

Chapel Hill, NC 

Charles M. Turkelson, Ph.D. 

Director, Research and Scientific Affairs Department 

American Academy of Orthopedic Surgeons 

Rosemont, IL 

Peer Reviewers 

Peer reviewer comments on a preliminary draft of this report were considered by the EPC in 

preparation of this final report. Synthesis of the scientific literature presented here does not 

necessarily represent the views of individual reviewers. 

David Atkins, M.D., M.P.H. 

Chief Medical Officer 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Rockville, MD 

Rowland W. Chang, M.D., M.P.H. 

Professor of Preventive Medicine 

Medicine, and Physical Medicine and Rehabilitation 

Northwestern University 

Feinberg School of Medicine 

Chicago, IL 
D-3

Peer Reviewers (continued) 

Gregory J. Dennis, M.D. 

Director, Clinical Care and Training 

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 

National Institutes of Health 

Bethesda, MD 

(Nominated by the National Institute of Arthritis and Musculoskeletal and Skin Diseases)

Kay Dickersin, Ph.D. 

Professor 

Director, Center for Clinical Trials 

Department of Epidemiology 

Johns Hopkins 

Bloomberg School of Public Health 

Baltimore, MD 

Peter Juhn, M.D., M.P.H. 

Executive Medical Director 

Johnson & Johnson 

New Brunswick, NJ 

Jeffrey N. Katz, M.D., M.S. 

Associate Professor of Medicine and Orthopaedic Surgery 

Chief, Section of Clinical Sciences 

Division of Rheumatology, Immunology and Allergy 

Brigham and Women's Hospital 

Boston, MA 

John Kirwan, M.D. 

Professor of Rheumatic Diseases 

Bristol Royal Infirmary 

Bristol 

UK 

Kathleen Kolsun, M.D. 

Assistant Director, Medical Affairs Orthopedics Division 

Ferring Pharmaceuticals 

Suffern, NY 

Jeffrey L. Kraines, M.D. 

Senior Medical Director 

Genzyme Corporation 

Cambridge, MA 
D-4

Peer Reviewers (continued) 

Stephan Lohmander, M.D., Ph.D. 

Professor and Senior Consultant 

Department of Orthopaedics, Clinical Sciences Lund 

Lund University 

Lund University Hospital 

Lund, Sweden 

Jamal Mikdashi, M.D. 

Assistant Professor of Medicine (Rheumatology) 

University of Maryland Medical Center 

Baltimore, MD 

Roland W. Moskowitz, M.D. 

Co-director 

Arthritis Translational Research Program 

Beachwood, OH 

(Nominated by the Arthritis Foundation) 

Lee S. Simon, M.D., Ph.D. 

Associate Clinical Professor of Medicine 

Harvard Medical School and 

Beth Israel Deaconess Medical Center 

Cambridge, MA