PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of bmjclinevidLink to Publisher's site
 
BMJ Clin Evid. 2007; 2007: 1121.
Published online 2007 September 1.
PMCID: PMC2943785

Osteoarthritis of the knee

Abstract

Introduction

Osteoarthritis of the knee affects about 10% of adults aged over 60 years, with risk increased in those with obesity, and joint damage or abnormalities. Progression of disease on x rays is commonplace, but x ray changes don’t correlate well with clinical symptoms.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-surgical treatments for osteoarthritis of the knee? What are the effects of surgical treatments for osteoarthritis of the knee? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, capsaicin, chondroitin, education to aid self-management, exercise and physiotherapy, glucosamine, insoles, intra-articular corticosteroids, intra-articular hyaluronan, joint bracing, knee replacement, non-steroidal anti-inflammatory drugs (including topical non-steroidal anti-inflammatory drugs), opioid analgesics, osteotomy, simple analgesics, and taping.

Key Points

Osteoarthritis of the knee affects about 10% of adults aged over 60 years, with risk increased in those with obesity, and joint damage or abnormalities.

  • Progression of disease on x rays is commonplace, but x ray changes don't correlate well with clinical symptoms.
  • We don't know the long-term effectiveness of any non-surgical treatment in reducing pain and improving function.

Exercise and physiotherapy and joint bracing or taping reduce pain and disability in people with knee osteoarthritis, but we don't know whether patient education or insoles are beneficial.

Oral and topical NSAIDs reduce pain in the short term compared with placebo, but can cause gastrointestinal, renal and cardiac adverse effects.

  • Paracetamol reduces pain in the short term compared with placebo, but may be less effective than NSAIDs.
  • Opioid analgesics reduce pain in knee osteoarthritis but they are associated with serious adverse effects so are not rcommended for first-line treatment.

Intra-articular corticosteroids and intra-articular hyaluronan may improve pain, although most studies are of poor quality.

Consensus is that total knee replacement is the most clinically effective treatment for severe osteoarthritis of the knee.

  • Unicompartmental knee replacement may be more effective than tricompartmental knee replacement in the long term.
  • Tibial osteotomy may be as effective as unicompartmental knee replacement in reducing symptoms of medial compartment knee osteoarthritis.

About this condition

Definition

Osteoarthritis is a heterogeneous condition for which the prevalence, risk factors, clinical manifestations, and prognosis vary according to the joints affected. It most commonly affects knees, hips, hands, and spinal apophyseal joints. It is characterised by focal areas of damage to the cartilage surfaces of synovial joints, and is associated with remodelling of the underlying bone, and mild synovitis. It is variously defined by a number of clinical and/or radiological features. Clinical features include pain, bony tenderness, and crepitus. When severe, there is often characteristic joint space narrowing and osteophyte formation, with visible subchondral bone changes on radiography. Osteoarthritis of the knee is common, causes considerable pain and frequent instability, and, consequently, often results in physical disability. x Ray changes are not strongly associated with disability.

Incidence/ Prevalence

Osteoarthritis is a common and important cause of pain and disability in older adults. Radiographical features are practically universal in at least some joints in people aged over 60 years, but significant clinical disease probably affects 10-20% of people. Knee disease is about twice as prevalent as hip disease in people aged over 60 years (about 10% knee v 5% hip). In a general practice setting. 1% of people aged over 45 years have a currently-recorded clinical diagnosis of knee osteoarthritis; 5% will have had the clinical diagnosis made at some point. A community-based cohort study showed that radiological features of knee osteoarthritis were very common: 13% of women aged 45-65 years developed new knee osteophytes — an incidence of 3% per year.

Aetiology/ Risk factors

Risk factors for osteoarthritis include abnormalities in joint shape, injury, and previous joint inflammation. Obesity is a major risk factor for osteoarthritis of the knee. Genetic factors modulate obesity and other risks.

Prognosis

The natural history of osteoarthritis of the knee is poorly understood. Radiological progression is commonplace, with 25% of osteoarthritic knees with initially normal joint space showing major damage after 10 years, although x ray progression is not related to clinical features. People with peripheral joint osteoarthritis of sufficient severity to lead to hospital referral have generally bad outcomes, with high levels of physical disability, anxiety, and depression; they also have high levels of healthcare resources utilisation, including joint replacement, drugs, and walking aids.

Aims of intervention

To reduce pain, stiffness, and disability; limit the risk of progressive joint damage; and improve quality of life, with minimal adverse effects.

Outcomes

Primary outcomes: Frequency and severity of joint pain (particularly activity-related pain and night pain); stiffness; functional impairment and disability; quality of life; perioperative complications (infection, bleeding, venous thromboembolism, and death); prosthesis survival and the need for revision surgery; reduced need for oral analgesics or NSAIDs. Outcome measures: A global knee rating scale that includes measures of pain, function, and range of movement; rating scales for pain, movement, depression; the Western Ontario and McMaster osteoarthritis (WOMAC) scale; the Lequesne Index; the Arthritis Self-Efficacy (ASE); the British Orthopaedic Association (BOA) score; Bristol Knee Score; Likert scale; Hamilton Depression Rating Scale; SF-36; Knee injury and Osteoarthritis Outcome Score (KOOS). Adverse events: Gastrointestinal (upper and lower), cardiovascular, liver toxicity, renal toxicity.

Methods

BMJ Clinical Evidence search and appraisal October 2006. The following databases were used to identify studies for this review: Medline 1966 to October 2006, Embase 1980 to October 2006, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this reviewwere: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviewas required. RCTs were excluded if they were in mixed osteoarthritis populations and did not provide separate data on people with osteoarthritis of the knee. Reviews which included mostly RCTs in people with knee osteoarthritis and a minority of RCTs in people with mixed site osteoarthritis were included if no recent reviews purely in knee osteoarthritis were available. In such cases we have stated how many RCTs and participants had mixed site osteoarthritis. Studies were also excluded if they had fewer than 20 people, except for oral NSAIDs compared with placebo, where the minimum number of people in each study was 200. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for osteoarthritis of the knee

Glossary

Ahlback's classification
A system for grading osteoarthritis of the knee (primarily focusing on reduction of the joint space as an indirect sign of cartilage loss) on a scale of I to V, with grade I indicating joint space narrowing (joint space < 3 mm) and grade V indicating severe bone erosion (> 10 mm).
Altman Grades
A system for classifying osteoarthritis of the knee based on clinical, radiographical, and laboratory criteria.
Arthritis Self-Efficacy (ASE)
The Arthritis Self-Efficacy consists of two subscales, one for pain (5 items) and one for other symptoms (6 items). Within each subscale, each item is scored from 0 (very uncertain) to 10 (very certain). Scores are summed across the items for each subscale, producing scores of 5–50 for ASE: pain and 6–60 for ASE: other symptoms.
Bristol Knee Score
The Bristol Knee Score consists of three subscores: pain, knee, and function.
British Orthopaedic Association (BOA) score
This is used as clinical evaluation and has a maximum score of 39 points.
Concentric isokinetic resistance training
A series of concentric extension, concentric flexion movements in a continuous mode.
Concentric–eccentric isokinetic resistance training
A series of concentric extension, eccentric extension movements, followed by concentric flexion, eccentric flexion movements using a spectrum of angular velocities ranging from 30°/second to 180°/second at 30°/second intervals.
Hamilton Depression Rating Scale
A scale that provides a measure of depressive symptoms.
Health Assessment Questionnaire (HAQ)
A self report functional status (disability) measure of outcome in people with a wide variety of rheumatic diseases. The modified version contains 20 items covering eight categories of disability which combine to derive a single disability index ranging from 0 to 3.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect
Kellgren and Lawrence criteria
A system for grading osteoarthritis of the knee (focusing on osteophytes or joint space narrowing, or both) on a scale of 0 to 4, with grade 0 indicating a normal knee joint and grade 4 indicating severe osteoarthritis.
Knee Society Clinical Rating System
The Knee Society Score is reported as two scores, Knee Score and Function Score. The Knee Score consists of points given for pain, range of motion, and stability. The Function Score consists of points given for the ability to walk on level surfaces, and the ability to ascend and descend stairs. The maximum 100 points is obtained by a well aligned knee with no pain (knee score) and by a person who can walk an unlimited distance and go up and down stairs (function score).
Knee injury and Osteoarthritis Outcome Score (KOOS)
The KOOS was developed as an extension of the WOMAC Osteoarthritis Index with the purpose of evaluating short and long term symptoms and function in people with knee injury, osteoarthritis, or both, particularly younger and more physically active people. The self administered KOOS holds five separate subscales: pain, other symptoms, function in daily living (ADL), function in sport and recreation (sport/rec), and knee-related quality of life (QOL). The effect size is generally largest for the QOL subscale followed by the pain subscale. See www.koos.nu for further details.
Lequesne Index
This includes the measurement of pain (5 questions), walking distance (1 question), and activities of daily living (4 questions), with versions available for the hip and knee. Scores for each question are added together to provide a combined disease severity score. Scores of 1–4 are classified as mild osteoarthritis, 5–7 moderate, 8–10 severe, 11–13 very severe, and 14 as extremely severe osteoarthritis.
Likert scale
A method of measuring attitudes that asks respondents to indicate their degree of agreement or disagreement with statements, according to a scoring system (usually 5 points). For example, subjects may be asked to rate their pain on a scale where none = 0, mild = 1, moderate = 2, severe = 3, and extreme = 4.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
SF-36
A scale that assesses health related quality of life across eight domains: limitations in physical activities (physical component); limitations in social activities; limitations in usual role activities owing to physical problems; pain; psychological distress and wellbeing (mental health component); limitations in usual role activities because of emotional problems; energy and fatigue; and general health perceptions.
Very low-quality evidence
Any estimate of effect is very uncertain.
Western Ontario and McMaster osteoarthritis (WOMAC) scale
This is a validated instrument for assessing lower limb (hip and knee) osteoarthritis and is sensitive to change. It is a self assessment questionnaire and includes questions on pain, stiffness, and physical function (such as walking ability). WOMAC is disease specific but not intervention specific; it can be used to assess any intervention in osteoarthritis. Question A1 looks at pain while walking on a flat surface.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Prof David Scott, Department of Rheumatology, King's College Medical School, London, UK.

Anna Kowalczyk, Department of Academic Rheumatology, King's College, London, UK.

References

1. Fitzgerald GK, Piva SR, Irrgang JJ. Reports of joint instability in knee osteoarthritis: its prevalence and relationship to physical function. Arthritis Rheum 2004;51:941–946. [PubMed]
2. Barker K, Lamb SE, Toye F, et al. Association between radiographic joint space narrowing, function, pain and muscle power in severe osteoarthritis of the knee. Clin Rehabil 2004;18:793–800. [PubMed]
3. Petersson IF. Occurrence of osteoarthritis of the peripheral joints in European populations. Ann Rheum Dis 1996;55:659–661. [PMC free article] [PubMed]
4. Felson DT. Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 1988;10:1–28. [PubMed]
5. Gaffney KL. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Ann Rheum Dis 1995;54:379–381. [PMC free article] [PubMed]
6. Pavelka JKS. Glycosaminoglycan polysulfuric acid (GAGPS) in osteoarthritis of the knee. Osteoarthritis Cartilage 1995;3:15–23. [PubMed]
7. Bedson J, Jordan K, Croft P. The prevalence and history of knee osteoarthritis in general practice: a case-control study. Fam Pract 2005;22:103–108. [PubMed]
8. Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study. Arthritis Rheum 1999;42:17–24. [PubMed]
9. Manek NJ, Hart D, Spector TD. The association of body mass index and osteoarthritis of the knee joint: an examination of genetic and environmental influences. Arthritis Rheum 2003;48:1024–1029. [PubMed]
10. Wolfe F, Lane NE. The long term outcome of osteoarthritis: rates and predictors of joint space narrowing in symptomatic patients with knee osteoarthritis. J Rheumatol 2002;29:139–146. [PubMed]
11. Dieppe PA, Cushnaghan J, Shepstone L. The Bristol ‘OA500' study: progression of osteoarthritis (OA) over 3 years and the relationship between clinical and radiographic changes at the knee joint. Osteoarthritis Cartilage 1997;5:87–97. [PubMed]
12. Dieppe P, Cushnaghan J, Tucker M. The Bristol ‘OA500 study': progression and impact of the disease after 8 years. Osteoarthritis Cartilage 2000;8:63–68. [PubMed]
13. Fransen M, McConnell S, Bell M. Exercise for osteoarthritis of the hip or knee. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Cochrane Controlled Trials Register, Cochrane Musculoskeletal Group Trials Register, Medline, Cinahl, and Pedro.
14. Brosseau L, MacLeay L, Robinson V, et al. Intensity of exercise for the treatment of osteoarthritis. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Medline, Embase, Pedro, Current Contents, Sports Discus, Cinahl, Cochrane Field of Rehabilitation and Related Therapies, and Cochrane Musculoskeletal Review Group.
15. Roddy E, Zhang W, Doherty M. Aerobic walking or strengthening exercise for osteoarthritis of the knee? A systematic review. Ann Rheum Dis 2005;64:544–548. Search date 2003; primary sources Medline, Pubmed, Embase, Cinahl, Pedro, Cochrane controlled trials register, and hand searches of reference lists. [PMC free article] [PubMed]
16. vos-Comby L, Cronan T, Roesch SC. Do exercise and self-management interventions benefit patients with osteoarthritis of the knee? A metaanalytic review. J Rheumatol 2006;33:744–756. [PubMed]
17. Dias RC, Dias JM, Ramos LR. Impact of an exercise and walking protocol on quality of life for elderly people with OA of the knee. Physiother Res Int 2003;8:121–130. [PubMed]
18. Huang MH, Lin YS, Yang RC, et al. A comparison of various therapeutic exercises on the functional status of patients with knee osteoarthritis. Semin Arthritis Rheum 2003;32:398–406. [PubMed]
19. Thorstensson CA, Roos EM, Petersson IF, et al. Six-week high-intensity exercise program for middle-aged patients with knee osteoarthritis: a randomized controlled trial. BMC Musculoskelet Disord 2005;6:27. [PMC free article] [PubMed]
20. Thomas KS, Miller P, Doherty M, et al. Cost effectiveness of a two-year home exercise program for the treatment of knee pain. Arthritis rheum 2005;53:388–394. [PubMed]
21. Huang MH, Yang RC, Lee CL, et al. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis Rheum 2005/12/15;53:812–820. [PubMed]
22. Focht BC, Rejeski WJ, Ambrosius WT, et al. Exercise, self-efficacy, and mobility performance in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum 200515;53:659–665. [PubMed]
23. Rejeski WJ, Focht BC, Messier SP, et al. Obese, older adults with knee osteoarthritis: weight loss, exercise, and quality of life. Health Psychol 2002;21:419–426. [PubMed]
24. Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 2004;50:1501–1510. [PubMed]
25. Gür H, Çakín N, Akova B, et al. Concentric versus combined concentric-eccentric isokinetic training: effects on functional capacity and symptoms in patients with osteoarthrosis of the knee. Arch Phys Med Rehabil 2002;83:308–316. [PubMed]
26. Bjordal JM, Ljunggren AE, Klovning A, et al. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ 2004;329:1317. [PMC free article] [PubMed]
27. Golden HE, Moskowitz RW, Minic M. Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee. Am J Ther 2004;11:85–94. [PubMed]
28. Lehmann R, Brzosko M, Kopsa P, et al. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib. Curr Med Res Opin 2005;21:517–526. [PubMed]
29. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology. Semin Arthritis Rheum 1997;26:755–770. Search date 1994; primary source Medline. [PubMed]
30. Garner SE, Fidan DD, Frankish R, et al. Rofecoxib for osteoarthritis. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004; primary sources Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database, hand searches of reference lists, and contact with experts.
31. Huskisson EC, Berry H, Gishen P, et al. Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. J Rheumatol 1995;22;1941–1946. [PubMed]
32. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312:1563–1566. [PMC free article] [PubMed]
33. Langman MJ. Non-steroidal anti-inflammatory drugs and peptic ulcer. Hepatogastroenterology 1992;39(suppl 1):37–39. [PubMed]
34. Garcia Rodriguez LA, Williams R, Derby LE, et al. Acute liver injury associated with non-steroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med 1994;154:311–316. [PubMed]
35. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366–1369. [PMC free article] [PubMed]
36. Galli G, Panzetta G. Do non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors have different renal effects? J Nephrol 2002;15:480–488. [PubMed]
37. Brandt KD. Nonsurgical management of osteoarthritis, with an emphasis on nonpharmacologic measures. Arch Fam Med 1995;4:1057–1064. [PubMed]
38. Wollheim FA. Current pharmacological treatment of osteoarthritis. Drugs 1996;52(suppl 3):27–38. [PubMed]
39. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum 2001;44:819–825. Search date 1999; primary sources Embase, Psychlit, Mantis, Science Citation Index, Campain, Cochrane Controlled Trials Registry, and Cochrane Collaboration Complementary Medicine Field Trials Registry. [PubMed]
40. Markow MJ, Secor ER. Acupuncture for the pain management of osteoarthritis of the knee. Techniques in Orthopaedics 2003;18:33–36. Search date 2003; primary sources Cinahl, Medline, Alt. Med, and Cochrane database.
41. Berman BM, Lao L, Langenberg P, et al. Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med 2004;141:901–910. [PubMed]
42. Vas J, Mendez C, Perea-Milla E, et al. Acupuncture as a complementary therapy to the pharmacological treatment of osteoarthritis of the knee: randomised controlled trial. BMJ 2004;329:1216. [PMC free article] [PubMed]
43. Witt C, Brinkhaus B, Jena S, et al. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet 2005;366:136–143. [PubMed]
44. Scharf HP, Mansmann U, Streitberger K, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial.[summary for patients in Ann Intern Med. 2006 Jul 4;145(1):I17; PMID: 16818921]. Ann Intern Med 2006;145:12–20. [PubMed]
45. McAlindon TE, LaValley MP, Gulin JP, et al. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469–1475. Search date 1999; primary sources Medline and Cochrane Controlled Trials Register. [PubMed]
46. Richy F, Bruyere O, Ethgen O, et al. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003;163:1514–1522. Search date 2002; primary sources Medline, Premedline, Embase, Cochrane Database of Systematic Reviews, Current Contents, Biosis Previews, Healthstar, EBM Reviews, manual review of the literature and congressional abstracts, and contact with authors and manufacturers of glucosamine and chondroitin. [PubMed]
47. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage 2004;12:269–276. [PubMed]
48. Michel BA, Stucki G, Frey D, et al. Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis Rheum 2005;52:779–786. [PubMed]
49. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795–808. [PubMed]
50. Bellamy N, Campbell J, Robinson V, et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2006; primary sources Medline, Embase, Cochrane Controlled Trials Register, and hand searches of reference lists of retrieved articles.
51. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2006; primary sources Medline, Embase, Cochrane Controlled Trials Register, and hand searches of reference lists of retrieved articles.
52. Modawal A, Ferrer M, Choi HK, et al. Hyaluronic acid injections relieve knee pain. J Fam Pract 2005;54:758–767. [PubMed]
53. Raynauld JP, Goldsmith CH, Bellamy N, et al. Effectiveness and safety of repeat courses of hylan G-F 20 in patients with knee osteoarthritis. Osteoarthritis Cartilage / OARS., Osteoarthritis Research Society 2005;13:111–119. [PubMed]
54. Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol 2006;33:951–956. [PubMed]
55. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells. Viscosupplementation for the treatment of osteoarthritis of the knee. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003; primary sources Medline, Embase, Premedline, Current Contents, Cochrane Central Register of Controlled Trials, and hand searches of specialised journals and reference lists.
56. Brouwer RW, Jakma TS, Verhagen AP, et al. Braces and orthoses for treating osteoarthritis of the knee. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Cochrane Central Register of Controlled Trials, Medline, Embase, Current contents, Health Star, and hand searches of reference lists.
57. Brouwer RW, van Raaij TM, Verhaar JAN, et al. Brace treatment for osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis Cartilage 2006;14:777–783. [PubMed]
58. Hinman RS, Crossley KM, McConnell J, Bennell KL. Efficacy of knee tape in the management of osteoarthritis of the knee: blinded randomised controlled trial. BMJ 2003;327:135. [PMC free article] [PubMed]
59. Reilly KA, Barker KL, Shamley D. A systematic review of lateral wedge orthotics-how useful are they in the management of medial compartment osteoarthritis?. Knee 2006;. 13:- [PubMed]
60. Toda Y, Tsukimura N, Kato A. The effects of different elevations of laterally wedged insoles with subtalar strapping on medial compartment osteoarthritis of the knee. Arch Phys Med Rehabil 2004;85:673–677. [PubMed]
61. Toda Y, Tsukimura N. A comparative study on the effect of the insole materials with subtalar strapping in patients with medial compartment osteoarthritis of the knee. Mod Rheumatol 2004;14:459–465. [PubMed]
62. Toda Y, Tsukimura N, Segal N. An optimal duration of daily wear for an insole with subtalar strapping in patients with varus deformity osteoarthritis of the knee. Osteoarthritis Cartilage 2005;13:353–360. [PubMed]
63. Pham T, Maillefert JF, Hudry C, et al. Laterally elevated wedged insoles in the treatment of medial knee osteoarthritis. A two-year prospective randomized controlled study. Osteoarthritis Cartilage 2004;12:46–55. [PubMed]
64. Towheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. In: The Cochrane Library Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005; primary sources Medline, Embase, Cochrane Central Register of Controlled Trials, ACP Journal Club, DARE, Cochrane Database of Systematic Reviews, and hand searches of specialised journals and reference lists.
65. Wegman A, Van Der Windt D, Van Tulder M, et al. Nonsteroidal antiinflammatory drugs or acetaminophen for osteoarthritis of the hip or knee? A systematic review of evidence and guidelines. J Rheumatol 2004;31:344–354. Search date 2001; primary sources Medline, Embase, and Cochrane Database. [PubMed]
66. Towheed TE, Judd MJ, Hochberg MC, et al. Acetaminophen for osteoarthritis. In: Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002; primary sources Cochrane Controlled Trials Register, Medline, and Current Contents.
67. Lin J, Zhang W, Jones A, et al. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ 2004;329:324–326. [PMC free article] [PubMed]
68. Towheed TE. Pennsaid therapy for osteoarthritis of the knee: a systematic review and metaanalysis of randomized controlled trials. J Rheumatol 2006;33:567–573. [PubMed]
69. Trnavsky K, Fischer M, Vogtle Junkert U, et al. Efficacy and safety of 5% ibuprofen cream treatment in knee osteoarthritis. Results of a randomized, double-blind, placebo-controlled study. J Rheumatol 2004;31:565–572. [PubMed]
70. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteoarthritis of the knee with a topical diclofenac solution: A randomised controlled, 6-week trial. BMC Musculoskelet Disord 2005;6:44. [PMC free article] [PubMed]
71. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol 2005/12;32:2384–2392. [PubMed]
72. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol 2004;31:2002–2012. [PubMed]
73. Dickson DJ. A double-blind evaluation of topical piroxicam gel with oral ibuprofen in osteoarthritis of the knee. Curr Ther Res Clin Exp 1991;49:199–207.
74. Sandelin J, Harilainen A, Crone H, et al. Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee. A double blind study comparing eltenac with oral diclofenac and placebo gel. Scand J Rheumatol 1997;26:287–292. [PubMed]
75. Bookman AA, Williams KS, Shainhouse JZ. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ 2004;171:333–338. [PMC free article] [PubMed]
76. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 2004;164:2017–2023. [PubMed]
77. Victor CR, Triggs E, Ross F, et al. Lack of benefit of a primary care-based nurse-led education programme for people with osteoarthritis of the knee. Clin Rheumatol 2005;24:358–364. [PubMed]
78. Mazzuca SA, Brandt KD, Katz BP, et al. Can a nurse-directed intervention reduce the exposure of patients with knee osteoarthritis to nonsteroidal antiinflammatory drugs? J Clin Rheumatol 2004;10:315–322. [PubMed]
79. Nunez M, Nunez E, Segur JM, et al. The effect of an educational program to improve health-related quality of life in patients with osteoarthritis on waiting list for total knee replacement: a randomized study. Osteoarthritis Cartilage 2006;14:279–285. [PubMed]
80. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with non-steroidal anti-inflammatory drug treatment. Arthritis Care Res 1996;9:292–301. Search date 1993; primary source Medline. [PubMed]
81. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2005; primary sources Medline, Premedline, Embase, Amed, ACP Journal Club, Dare, CDSR, CCTR, letters to experts, and hand searches of reference lists.
82. Poolsup N, Suthisisang C, Channark P, et al. Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother. 2005;39:1080–1087. [PubMed]
83. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. In: The Cochrane Library Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005; primary sources Medline, Embase, Lilacs database.
84. Langford R, McKenna F, Ratcliffe S, et al. Transdermal fentanyl for improvement of pain and functioning in osteoarthritis: a randomized, placebo-controlled trial. Arthritis Rheum 2006;54:1829–1837. [PubMed]
85. Joint Formulary Committee. British national formulary 51st ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 2006.
86. Australian Safety and Efficacy Register of New Interventional Procedures –Surgical. Unicompartmental knee arthroplasty for unicompartmental osteoarthritis: a systematic review. ASERNIP-S 2005 (report no 44):93. Search date 2004; primary sources Medline, Embase, Cochrane Library, Current Contents, US Clinical Trials database, NHS Centre for Reviews and Dissemination database, NHS Health Technology Assessment database, UK National Research Register, Current Controlled Trials, and hand searches of reference lists.
87. Weidenhielm L, Olsson E, Brostrom LA, et al. Improvement in gait one year after surgery for knee osteoarthrosis: a comparison between high tibial osteotomy and prosthetic replacement in a prospective randomized study. Scand J Rehabil Med 1993;25:25–31. [PubMed]
88. Broughton NS, Newman JH, Baily RAJ. Unicompartmental replacement and high tibial osteotomy for osteoarthritis of the knee. A comparative study after 5–10 years' follow up. J Bone Joint Surg Br 1986;68:447–452. [PubMed]
89. Newman JH, Ackroyd CE, Shah NA. Unicompartmental or total knee replacement? Five-year results of a prospective, randomised trial of 102 osteoarthritic knees with unicompartmental arthritis. J Bone Joint Surg Br 1998;80:862–865. [PubMed]
90. Callahan CM, Drake BG, Heck DA, et al. Patient outcomes following tricompartmental total knee replacement: a meta-analysis. JAMA 1994;271:1349–1357. Search date 1992; primary sources Medical Literature Analysis and Retrieval System (Medlars) and hand searches of references. [PubMed]
91. Callahan CM, Drake BG, Heck DA, et al. Patient outcomes following unicompartmental or bicompartmental knee arthroplasty: a meta-analysis. J Arthroplasty 1995;10:141–150. Search date 1992; primary sources Medical Literature Analysis and Retrieval System (Medlars) and hand searches of references. [PubMed]
92. Jacobs WC, Clement DJ, Wymenga AB. Retention versus removal of the posterior cruciate ligament in total knee replacement: a systematic literature review within the Cochrane framework. Acta Orthop 2005;76:757–768. [PubMed]
93. Jacobs WC, Clement DJ, Wymenga AB. Retention versus sacrifice of the posterior cruciate ligament in total knee replacement for treatment of osteoarthritis and rheumatoid arthritis. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2004; primary sources Medline, Embase, Cochrane Controlled Trials Register, and hand searches of reference lists of retrieved articles.
94. Gildone A, Manfredini M, Biscione R, et al. Patella resurfacing in posterior stabilised total knee arthroplasty: a follow-up study in 56 patients. Acta Orthop Belg. 2005;71:445–451. [PubMed]
95. Myles CM, Rowe PJ, Nutton RW, et al. The effect of patella resurfacing in total knee arthroplasty on functional range of movement measured by flexible electrogoniometry. Clin Biomech. 2006;21:733–739. [PubMed]
96. Freund DA. Assessing and improving outcomes: total knee replacement: patient outcomes research team (PORT): final report. Maryland: Agency for Health Care Policy and Research, 1997.
97. Böhm P, Holy T, Pietsch-Breitfeld B, et al. Mortality after total knee arthroplasty in patients with osteoarthrosis and rheumatoid arthritis. Arch Orthop Trauma Surg 2000;120:75–78. [PubMed]
98. Kim YH. The incidence of deep vein thrombosis after cementless and cemented knee replacement. J Bone Joint Surg Br 1990;72:779–783. [PubMed]
99. Faunø P, Suomalainen O, Rehnberg V, et al. Prophylaxis for the prevention of venous thromboembolism after total knee arthroplasty. A comparison between unfractionated and low-molecular-weight heparin. J Bone Joint Surg Am 1994;76:1814–1818. [PubMed]
100. Robinson AH, Palmer CR, Villar RN. Is revision as good as primary hip replacement? A comparison of quality of life. J Bone Joint Surg Br 1999;81:42–45. [PubMed]
101. Knutson K, Lewold S, Robertsson O, et al. The Swedish knee arthroplasty register. A nation-wide study of 30 003 knees. Acta Orthop Scand 1994;65:375–386. [PubMed]
102. Robertsson O, Borgquist L, Knutson K, et al. Use of unicompartmental instead of tricompartmental prostheses for unicompartmental arthrosis of the knee is a cost-effective alternative. 15 437 primary tricompartmental prostheses were compared with 10 624 primary medical or lateral unicompartmental prostheses. Acta Orthop Scand 1999;70:170–175. [PubMed]
103. Norton EC, Garfinkel SA, McQuay LJ, et al. The effect of hospital volume on the in-hospital complication rate in knee replacement patients. Health Serv Res 1998;33:1191–1210. [PMC free article] [PubMed]
104. De Leeuw JM, Villar RN. Obesity and quality of life after primary total knee replacement. Knee 1998;5:119–123.
105. Lubitz R, Dittus R, Robinson R, et al. Effects of severe obesity on health status 2 years after knee replacement. J Gen Intern Med 1996;11:145.
106. Winiarsky R, Barth P, Lotke P. Total knee arthroplasty in morbidly obese patients. J Bone Joint Surg Am 1998;80:1770–1774. [PubMed]
107. Donnell ST, Neyret P, Dejour H, et al. The effect of age on the quality of life after knee replacement. Knee 1998;5:125–112.
108. Laskin RS. Total knee replacement in patients older than 85 years. Clin Orthop 1999;367:43–49. [PubMed]
109. Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to anti-rheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833–1840. [PubMed]
110. Dougados M, Devogelaer JP, Annefeldt M, et al. Recommendations for the registration of drugs used in the treatment of osteoarthritis. Ann Rheum Dis 1996;55:552–557. [PMC free article] [PubMed]
111. Altman R, Brandt K, Hochberg M, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996;4:217–243. [PubMed]
112. Lequesne M, Mery C, Samson M, et al. Indexes of severity for osteoarthritis of the hip and knee. Indexes of severity for osteoarthritis of the hip and knee. Validation — value in comparison with other assessment tests. Scand J Rheumatol Suppl 1987;65:85–89. [PubMed]
113. Roos EM, Roos HP, Lohmander LS. WOMAC osteoarthritis index – additional dimensions for use in subjects with post-traumatic osteoarthritis of the knee. Osteoarthritis Cartilage 1999;7:216–221. [PubMed]
114. Thorstensson CA, Roos EM, Petersson IF, et al. Six-week high-intensity exercise program for middle-aged patients with knee osteoarthritis: a randomized controlled trial [ISRCTN20244858]. BMC Musculoskelet.Disord. 2005;6:27- [PMC free article] [PubMed]
115. Cubukcu D, Ardic F, Karabulut N, et al. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clin Rheumatol 2005;24:336–341. [PubMed]
2007; 2007: 1121.
Published online 2007 September 1.

Exercise and physiotherapy

Summary

PAIN Compared with control: Exercise and physiotherapy may reduce pain in people with knee osteoarthritis ( low-quality evidence ). DISABILITY Compared with control: Exercise and physiotherapy may reduce disability in people with knee osteoarthritis ( low-quality evidence ).

Benefits

We found four systematic reviews, , six subsequent RCTs, , and two additional RCTs (reported in three publications).

The first systematic review (search date 2002, 17 RCTs, 2562 people with osteoarthritis of the knee) compared land-based therapeutic exercise versus a non-exercise group. The exercise programmes included aerobic, resistance, stretching, strengthening, and range-of-motion exercises, among others. The programmes were delivered individually, in a group format, or undertaken by the person at home. The review found a beneficial effect for therapeutic exercise compared with control (home visits, education, waiting list, telephone call, relaxation, no intervention) for self-reported pain (SMD 0.39, 95% CI 0.30 to 0.47) and for self-reported physical function (SMD 0.31, 95% CI 0.23 to 0.39). Group format programmes seemed to be as beneficial as one-to-one programmes. The second systematic review (search date 2002, 1 RCT, 39 people with osteoarthritis of the knee) compared high- versus low-intensity aerobic exercise. It found no significant difference between high- and low-intensity aerobic exercise for pain (measured on arthritis impact measurement scale 2 [AIMS2]; WMD –0.11, 95% CI –1.32 to +1.10) and functional status (timed chair rise: WMD +0.30 seconds, 95% CI –4.09 seconds to +4.69 seconds; 6 minute walk test: WMD +13.68 minutes, 95% CI –60.12 minutes to +87.48 minutes). The third systematic review (search date 2003, 13 RCTs, 2304 people with osteoarthritis of the knee; including 11 RCTs identified in the first review) compared aerobic walking or home-based quadriceps-strengthening exercise versus a non-exercise control group. There was considerable variation in the content (e.g. strengthening exercise combined with lifestyle advice, patellar taping, and NSAIDs), and duration of the exercise programmes (8 weeks to 2 years). It found that both types of exercise significantly reduced pain (aerobic walking, 4 RCTs, effect size 0.52, 95% CI 0.34 to 0.70; strengthening exercise, 10 RCTs, effect size 0.32, 95% CI 0.23 to 0.42) and disability (aerobic walking, 2 RCTs, effect size 0.46, 95% CI 0.25 to 0.67; and strengthening exercise, 11 RCTs, effect size 0.32, 95% CI 0.23 to 0.41).The fourth systematic review (search date 2005, 16 RCTs, 2154 people with osteoarthritis of the knee) compared various exercise interventions (strength training of the knee muscles, light physical activity like walking, and flexibility exercises), self-management interventions (education about osteoarthritis and pain coping skills) and controls (no treatment and standard care). The review found that exercise regimens significantly improved physical health and the clinical impact of osteoarthritis compared with control conditions (self-report and direct measures used; 13 RCTs evaluating exercise, effect size 0.2, 95% CI 0.13 to 0.27). Perceived psychological health was unchanged by the exercise. There was considerable heterogeneity in the study design and in the interventions themselves.

The first subsequent RCT (50 people, aged 65 years or over, with osteoarthritis of the knee) compared physiotherapist-provided exercise versus no exercise. It found that exercise significantly improved the Lequesne Index, the Health Assessment Questionnaire, and the SF-36 (except the emotional domain) at 3 and 6 months compared with no exercise (P < 0.01 for all outcomes). The second subsequent RCT (132 people with moderate bilateral osteoarthritis of the knee, Altman Grade II) compared four interventions: isokinetic muscle strengthening exercise, isotonic muscle strengthening exercise, isometric muscle strengthening exercise, and control (no exercise). It found a significant improvement in pain reduction, disability reduction, and walking speed after 8 weeks' treatment and the 1 year follow-up compared with baseline for all treatment groups (P < 0.05). The third subsequent RCT compared exercise (twice-weekly 1-hour supervised intensive exercise sessions involving weight-bearing exercises) versus no exercise over 6 weeks. It found no significant difference between exercise and no exercise in Knee injury and Osteoarthritis Outcome Score (KOOS) at both 6 weeks and 6 months (61 people with osteoarthritis of the knee, grade 3 osteoarthritis as judged by Kellgren and Lawrence criteria, aged 36–65 years; at 6 weeks: P = 0.49; at 6 months: P = 0.32). It found the exercise group significantly improved KOOS quality of life scores compared with no exercise at 6 weeks (mean change: +4.0 with exercise v –0.7 with no intervention; P = 0.05) and at 6 months (+5.1 with exercise v –2.3 with no intervention; P = 0.02).The fourth subsequent RCT (316 overweight people with symptomatic knee osteoarthritis) compared exercise alone, dietary weight loss alone, the combination of both, and healthy lifestyle control over 18 months. The RCT found that exercise plus dietary weight loss significantly improved stair-climb performance and 6-minute-walk performance compared with healthy lifestyle control (mean change in stair climb: –1.53 seconds with exercise plus diet v +0.41 with control, P = 0.025; mean change in 6-minute-walk performance: +163 feet with exercise plus diet v –11 feet with control, P = 0.0003) The fifth subsequent RCT (140 people with bilateral knee osteoarthritis) compared isokinetic exercises alone, isokinetic exercises plus pulse ultrasound, isokinetic exercises plus pulse ultrasound plus intra-articular hyaluronan, and a control group (warm-up exercises only). It found that, when added to other treatments, exercise produced a significantly greater improvement in the Lequesne Index than control over 8 weeks (mean change: –1.5 with exercise v –0.5 with controls; P < 0.05).The sixth subsequent RCT (759 people over 45 years with current knee pain) compared exercise therapy (quadriceps strengthening and aerobic exercise), monthly telephone contact, both together, and no intervention. It found that exercise therapy significantly improved WOMAC pain scores compared with control treatment (no exercise) over 2 years (mean change: –0.74; 95% CI –1.22 to –0.25; P = 0.003). Telephone contact had no impact.

The first additional RCT (316 people, aged 60 years or more, body mass index of at last 28 kg/m2 with osteoarthritis of the knee) compared four groups: exercise alone; dietary weight loss alone; exercise plus dietary weight loss; and a healthy-lifestyle control group (which included group presentations and talks on topics concerning osteoarthritis, obesity, and exercise) over 18 months. The RCT found no significant difference among groups in a composite mental health score of the SF-36 after 18 months. It found that exercise plus dietary weight loss significantly improved composite physical health score of the SF-36 compared with the healthy lifestyle control (P < 0.01). The exercise-plus-dietary-weight-loss and exercise-alone groups significantly improved people's satisfaction with physical function compared with the healthy lifestyle control (either treatment v healthy lifestyle; P < 0.01). However, only the exercise-plus-dietary-weight-loss group significantly improved WOMAC function scores compared with the healthy-lifestyle control (results displayed graphically; P < 0.05). The second additional RCT (23 people with bilateral complaints of osteoarthritis of the knee, grade 2 or 3 osteoarthritis as judged by Kellgren and Lawrence criteria, aged 41–75 years) compared three groups: concentric isokinetic resistance training; combined concentric–eccentric isokinetic resistance training, and control (no training). The RCT found that both training groups significantly increased functional capacity after 8 weeks compared with control (either training group v control; P < 0.01), and significantly decreased pain (either training group v control; P < 0.01). Functional capacity measurement included walking, standing, rising from a chair, stair climbing, and descending stairs.

Harms

The systematic reviews[13][14][15] and RCTs[16][17][18][19][20][21] did not report on adverse effects.

Comment

Clinical guide:

There is a large body of evidence to suggest that exercise and physiotherapy relieve symptoms of osteoarthritis of the knee. However, people with osteoarthritis of the knee may need education on the benefits of exercise, as it often seems counter-intuitive to exercise a damaged joint, and people may require continued encouragement to maintain exercise or physiotherapy regimens.

Substantive changes

Exercise and physiotherapy) One systematic review and three subsequent RCTs added. Categorisation unchanged (Beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

NSAIDs (oral)

Summary

PAIN Compared with placebo: NSAIDs may reduce pain at 2–13 weeks compared with placebo in people with osteoarthritis of the knee, but we don't know whether they are effective in the long term ( very low-quality evidence ). Compared with other NSAIDs: We don't know whether any one NSAID is better than the others at reducing pain in people with osteoarthritis of the knee (very low-quality evidence). Compared with topical NSAIDs: Oral NSAIDs may be as effective as topical NSAIDs at reducing pain in people with osteoarthritis of the knee (very low-quality evidence). Compared with simple analgesics: Oral NSAIDs may be more effective than paracetamol at reducing pain in people with osteoarthritis of the knee (very low-quality evidence). Compared with glucosamine: Oral NSAIDs are less effective than glucosamine at reducing pain in people with osteoarthritis of the knee ( moderate-quality evidence ). ADVERSE EFFECTS Compared with oral NSAIDs: Topical NSAIDs may be less likely to cause gastrointestinal adverse effects compared with oral NSAIDs at 4–12 weeks ( very low-quality evidence ). Current use of rofecoxib, diclofenac, and ibuprofen has been associated with an increased risk of myocardial infarction. Rofecoxib was withdrawn from the market in 2004 because of the increased risk of myocardial infarction. NSAIDs increase the risk of renal or gastrointestinal damage, including haemorrhage, particularly in the elderly and in people with intercurrent disease. NOTE We found no clinically important results about the effects of oral NSAIDs compared with opioids.

Benefits

Oral NSAIDs versus placebo:

We found one systematic review comparing oral NSAIDs versus placebo, and three subsequent RCTs. The review (search date 2004, 23 trials, 10,845 people with osteoarthritis of the knee) found that NSAIDs significantly reduced short-term pain (2–13 weeks) compared with placebo (23 RCTs, effect size 0.32, 95% CI 0.24 to 0.39; P < 0.001; WMD on 100 mm visual analogue scale 10.1, 95% CI, 7.4 to 12.8). Only one trial reported long-term results for pain, and it found no significant difference in pain at 1–4 years (actual figures not reported). Two subsequent RCTs were of identical design, and only pooled analyses of their data were reported. They compared naproxen (660 mg/day or 440 mg/day for people aged > 65 years), paracetamol (4000 mg/day), and placebo over 7 days. Pooled analysis found that naproxen significantly reduced pain during the day (P < 0.0001), at night (P < 0.02), on passive motion (P < 0.05), on weight bearing (P < 0.01), and at rest (P < 0.05; pain measured on a 5-point scale, all results displayed graphically).The third subsequent RCT compared lumiracoxib (100 mg/day), celecoxib (200 mg/day), and placebo over 13 weeks. It found that both lumiracoxib at either dose and celecoxib significantly reduced pain intensity in the target knee compared with placebo (mean reduction in OA pain intensity: 26.8 mm for lumiracoxib 100 mg daily v 26.2 mm with lumiracoxib 100 mg daily plus loading dose v 26.6 mm with celecoxib v 21.4 mm with placebo, P < 0.01; patient's global assessment of disease activity: 25.1 mm with lumiracoxib 100 mg daily v 21.9 mm with lumiracoxib 100 mg daily plus loading dose v 22.9 mm with celecoxib v 18.9 mm with placebo, P < 0.05; WOMAC total score: 15.2 with lumiracoxib 100 mg daily v 14.8 with lumiracoxib 100 mg daily plus loading dose v 14.7 with celecoxib v 11.3 with placebo, P < 0.01).

Oral NSAIDs versus each other:

We found one systematic review, which identified many RCTs comparing NSAIDs with other NSAIDs for the treatment of osteoarthritis of the knee. Most of these trials found benefit from using NSAIDs to treat osteoarthritis; however, only 5/32 (16%) of RCTs found one NSAID to be significantly better than another.

Oral NSAIDs versus topical NSAIDs:

See benefits of topical NSAIDs.

Oral NSAIDs versus simple analgesics:

See benefits of simple analgesics.

Oral NSAIDs versus opioid analgesics:

We found no RCTs.

Oral NSAIDs versus glucosamine:

See benefits of glucosamine.

Harms

The systematic review did not report on adverse events by treatment group. We found another systematic review, one RCT, one meta-analysis, one non-systematic review, and two case-control studies, assessing the adverse effects of NSAIDs. The additional systematic review (search date 2004) compared the cyclo-oxygenase-2 (COX-2) inhibitor rofecoxib versus placebo in people with osteoarthritis of various joints. It found that rofecoxib was associated with significantly more adverse events. Rofecoxib was withdrawn from the market at the end of September 2004 after it was shown that long term use (> 18 months) could increase the risk of myocardial infarction and stroke. See reveiw on NSAIDs for more description of harms. A large population-based nested case-control study (9218 cases and 86,349 controls) looked at the risk of myocardial infarction in people taking COX-2 inhibitors and non-selective NSAIDs. It found a significantly increased risk of myocardial infarction in people currently taking rofecoxib (adjusted OR 1.32, 95% CI 1.09 to 1.61), diclofenac (adjusted OR 1.55, 95% CI 1.39 to 1.72), or ibuprofen (adjusted OR 1.24, 95% CI 1.11 to 1.61) compared with people who had not used these NSAIDs in the previous 3 years. It found increased risks of myocardial infarction associated with current use of other selective NSAIDs, naproxen, and non-selective NSAIDs; these risks were significant at P < 0.05, but not at the pre-specified level of P < 0.01. One RCT (812 people with osteoarthritis of the knee) found that indometacin (indomethacin) may accelerate joint damage in osteoarthritis. A high withdrawal rate made the results difficult to interpret. Studies have found a risk with NSAIDs of gastrointestinal or renal damage in older people with osteoarthritis, particularly those with intercurrent disease. One non-systematic review of case control studies of several thousand people suggested that the odds ratio of gastrointestinal haemorrhage when taking any NSAID was about 4–5, the risk increasing with certain drugs and with increased doses. The second case-control study of over 625,000 people receiving more than 2 million prescriptions for one of 12 NSAIDs found only a small risk of acute liver injury (incidence per 100,000 users 3.7, 95% CI 2.5 to 5.5). A meta-analysis (search date 1994) ranked the risk of gastrointestinal complications from different drugs and found it to be dose dependent (see table 1 ). We found insufficient evidence comparing the gastrointestinal effects of COX-2 inhibitors versus traditional NSAIDs to calculate the comparative risk for more recently introduced NSAIDs (see differences between NSAIDs in the review on NSAIDs).

Table 1
Estimated relative risk of gastrointestinal adverse effects with the use of individual NSAIDs (pooled from 12 studies) (see text). Reproduced with permission from the BMJ Publishing Group.

Oral NSAIDs versus topical NSAIDs:

See harms of topical NSAIDs.

Oral NSAIDs versus simple analgesics:

See harms of simple analgesics.

Oral NSAIDs versus opioid analgesics:

We found no RCTs.

Oral NSAIDs versus glucosamine:

See harms of glucosamine.

Drug safety alert

MHRA issues drug safety alert on serious hepatoxicity leading to liver failure or death associated with lumiracoxib (24/08/07).

Since the last update of this review, a drug safety alert has been issued on serious hepatotoxic effects leading to liver failure or death associated with lumiracoxib ( www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=con2032270&RevisionSelectionMethod=Latest).

Comment

Despite the many studies of NSAID use in osteoarthritis, the evidence we found on efficacy remains poor and difficult to generalise. Most RCTs suffer from weak methods, including: short duration; exclusion of older people, those with intercurrent disease, or those at risk of gastrointestinal and other drug complications; variable outcome measures; comparison of one drug versus another rather than versus placebo; and funding bias. In the absence of clear evidence of the superiority of one type of treatment or product, other considerations, such as safety (particularly the risk of cardiovascular adverse events and gastrointestinal bleeding with NSAIDs) and cost, should determine the choice of drug (see review on NSAIDs).

Clinical guide:

Oral NSAIDs offer clinically effective pain relief for osteoarthritis of the knee in the short term. However, adverse effects can be considerable.

Substantive changes

NSAIDs (oral) One RCT added. Categorisation unchanged (Beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

Acupuncture

Summary

PAIN Compared with sham acupuncture or control: Acupuncture may be no more effective than sham acupuncture or control at reducing pain in people with osteoarthritis of the knee ( very low-quality evidence ). FUNCTION Compared with sham acupuncture or control: Acupuncture may be no more effective at improving function than sham acupuncture or control in people with osteoarthritis of the knee (very low-quality evidence).

Benefits

We found two systematic reviews. and four subsequent RCTs. The first systematic review (search date 1999, 7 RCTs, 393 people with osteoarthritis of the knee) compared acupuncture versus a control group (waiting list control, sham acupuncture, or physiotherapy). The review found limited evidence that acupuncture was more effective than waiting list control for pain and function. There was strong evidence that real acupuncture was more effective than sham acupuncture for pain; however, for function, the evidence was inconclusive. There was limited evidence that real acupuncture was more effective than physiotherapy for pain or function (numerical data not reported). The second systematic review (search date 2003, 5 RCTs [including 2 RCTs from the previous review], 205 people with osteoarthritis of the knee) compared real acupuncture versus sham acupuncture or no acupuncture. It found that real acupuncture reduced pain in people with osteoarthritis of the knee. The results were not presented in full but as part of an assessment looking at patient parameters (see comment below). The first subsequent RCT compared real acupuncture (23 sessions over 26 weeks), sham acupuncture (23 sessions over 26 weeks), and education (six 2-hour group sessions based on the Arthritis Self-Management Program). It found that real acupuncture significantly improved WOMAC function scores at 8 and 26 weeks compared with sham acupuncture (570 people aged > 50 years with osteoarthritis of the knee of grade 2 or greater [Kellgren and Lawrence criteria]; mean difference at 8 weeks: –2.9, 95% CI –5.0 to –0.8; mean difference at 26 weeks: –2.5, 95% CI –4.7 to –0.4). However, real acupuncture only significantly improved WOMAC pain scores compared with sham acupuncture at 26 weeks (mean difference at 8 weeks: –0.5, 95% CI –1.2 to +0.2; mean difference at 26 weeks: –0.87, 95% CI –1.58 to –0.16). This RCT had high withdrawal rates (at 26 weeks: 43% of people in the education group v 25% in each of the acupuncture groups). Pain at baseline was significantly higher in people who withdrew from the education (P = 0.05) and real acupuncture groups (P = 0.04) than in completers. The second subsequent RCT found that acupuncture plus diclofenac significantly improved visual analogue scale (VAS) pain scores (score range 0 to 100) and WOMAC total, pain, stiffness, and function scores compared with placebo acupuncture plus diclofenac over 12 weeks (97 people, aged > 45 years; mean difference in VAS pain score: –26.6, 95% CI –18.5 to –34.8; mean difference in WOMAC total scores: –23.9, 95% CI –15.0 to –32.8; WOMAC pain: –4.7, 95% CI –2.9 to –6.5; WOMAC stiffness: –1.7, 95% CI –0.8 to –2.5; WOMAC function: –17.5, 95% CI –11.0 to –24.0). The third subsequent RCT compared real acupuncture (12 sessions over 8 weeks), sham acupuncture (superficial insertion of fine needles at predefined non-acupuncture points), and a waiting list control. The RCT found that real acupuncture significantly improved WOMAC total score compared with sham acupuncture and waiting list control at 8 weeks (300 people, aged 50–75 years with osteoarthritis of the knee of grade 2 or greater by Kellgren and Lawrence criteria; mean difference between acupuncture and minimal acupuncture in WOMAC total score: –8.8, 95% CI –13.5 to –4.2; mean difference between acupuncture and waiting list: –22.7, 95% CI –27.5 to –17.9; P < 0.001). There was no significant difference in WOMAC total score between real acupuncture and sham acupuncture at 26 and 52 weeks (mean difference in WOMAC total score at 26 weeks: –5.8, 95% CI –12.0 to +0.3; mean difference at 52 weeks: –5.7, 95% CI –12.1 to +0.7). The fourth subsequent RCT (1007 people with chronic pain from knee osteoarthritis) compared traditional Chinese acupuncture, sham acupuncture (needling at defined non-acupuncture points) and conservative therapy (physiotherapy and as-needed antiinflammatory drugs) over 26 weeks. It found that both traditional Chinese acupuncture and sham acupuncture significantly improved pain compared with conservative therapy, but found no significant difference between traditional acupuncture and sham acupuncture (success rates measured by at least 36% improvement in WOMAC score at 26 weeks: 53% for traditional Chinese acupuncture v 51% for sham acupuncture v 29% for conservative therapy; P < 0.001 for both genuine and sham v control; P = 0.48 for genuine v sham acupuncture).

Harms

The first systematic review noted that adverse events were not reported in many studies, and it was not clear whether they did not occur, were not measured, or were not reported. The second systematic review found rare but mild adverse effects with acupuncture, including increased pain, nausea, and bruising. More serious effects included a large haematoma that disappeared in 14 days, and a vasovagal attack. The first subsequent RCT found no treatment-related adverse events in the real-acupuncture group. The second subsequent RCT reported that adverse events after acupuncture treatment were limited to three people who experienced bruising at one of the acupuncture points. The third subsequent RCT noted that adverse effects of acupuncture were of minor severity, but provided no further details. The fourth subsequent RCT reported that the number of adverse effects were comparable across the the three groups (acupuncture 179 events in 326 people; sham acupuncture 177 events in 365 people; conservative therapy 159 events in 316 people). Frequent adverse events reported included arthralgia, bone pain, and haematoma (arthralgia: 8.9% of all adverse events for acupuncture v 8.5% for sham v 8.2% for conservative therapy; bone pain: 5.6% for acupuncture v 5.6% for sham v 8.2% for conservative therapy; haematoma: 6.7% for acupuncture v 10.2% for sham v 0.6% for conservative therapy).

Comment

In the first systematic review, traditional Chinese medicine (TCM) acupuncture was used. Two studies compared acupuncture (manual and low-frequency electroacupuncture) with a waiting list control group; three studies compared acupuncture with sham acupuncture; and the other two studies compared acupuncture with physiotherapy. The number of treatments varied from 6 to 16 over a course of 3–8 weeks. The second review compared TCM acupuncture, or acupuncture to one or both knees, versus sham or no acupuncture. The second review stated that its objective was to “review research on acupuncture in the treatment of osteoarthritis of the knee, to document adverse events and identify patient parameters associated with outcomes”. The only table presented was a list of outcome measures used and details of treatments. The number of treatments varied from 6 to 9 over a course of 3–6 weeks for four of the five studies. The fifth study lasted for 49 weeks and the number of treatments was varied. In the subsequent RCTs, people were permitted to continue with their osteoarthritis medications during the trials.

Clinical guide:

There is a body of evidence that suggests that acupuncture relieves symptoms of osteoarthritis of the knee; however, the mechanism of action for this remains unclear, and this hampers its widespread acceptance. Additional research is also needed to determine the minimum effective dosage of acupuncture.

Substantive changes

Acupuncture One large RCT added suggesting that real acupuncture may be no more effective than sham acupuncture. Recategorised from Likely to be beneficial to Unknown effectiveness.

2007; 2007: 1121.
Published online 2007 September 1.

Chondroitin

Summary

PAIN Compared with placebo: We don't know whether chondroitin reduces pain at up to 2 years compared with placebo in people with osteoarthritis of the knee ( very low-quality evidence ). FUNCTION Compared with placebo: We don't know whether chondroitin reduces pain at up to 2 years compared with placebo in people with osteoarthritis of the knee (very low-quality evidence).

Benefits

Chondroitin versus placebo:

We found two systematic reviews, and three subsequent RCTs. The first systematic review (search date 1999, 8 RCTs, 679 people with osteoarthritis of the knee, and 1 RCT, 120 people with osteoarthritis of the knee and hip) found that chondroitin (oral or intramuscular) significantly reduced pain and improved function compared with placebo (effect size 0.78, 95% CI 0.60 to 0.95; meta-analysis included 1 RCT of osteoarthritis of the knee and hip, and excluded an outlying RCT to remove heterogeneity). The second systematic review (search date 2002, 7 RCTs, 741 people with osteoarthritis of the knee) performed a combined meta-analysis on RCTs of chondroitin and glucosamine. The review included six RCTs from the first systematic review, but did not include two RCTs from the first review that studied intramuscular chondroitin. Six of the RCTs found that chondroitin significantly reduced pain compared with placebo (pain measured on a visual analogue scale; P < 0.05); one of the RCTs found no significant difference between chondroitin and placebo (P = 0.12). Six of the RCTs reported Lequesne Index scores; five RCTs found that chondroitin significantly reduced Lequesne Index scores compared with placebo (P < 0.05); one RCT found no significant difference between chondroitin and placebo (P = 0.06). The first subsequent RCT found that chondroitin (800 mg/day for 3 months from baseline and then from months 6 to 9) significantly improved Lequesne Index scores compared with placebo at 9 and 12 months, but not at 6 months (120 people aged > 40 years randomised, see comment below; mean Lequesne Index scores at 6 months: 6.7 with chondroitin v 7.5 with placebo; reported as not significant, P value not reported; at 9 months: 6.0 with chondroitin v 7.0 with placebo; P < 0.05; at 12 months: 5.6 with chondroitin v 7.0 with placebo; P < 0.01). The second subsequent RCT (300 people with knee osteoarthritis) compared chondroitin (800 mg/day) with placebo over 2 years. It found no significant improvement in mean joint space narrowing between chondroitin and placebo (narrowing of joint space width over 2 years: 0.00 with chondroitins v –0.14 with placebo; mean difference: 0.14 mm, 95% CI 0.01 to 0.27; P = 0.04). The third subsequent RCT (1583 people with symptomatic knee osteoarthritis) compared four interventions: chondroitin (1200 mg/day), glucosamine (1500 mg/day), combined chondroitin plus glucosamine, and placebo for 6 months. It found no significant difference in the proportion of people who had reduction of 20% in WOMAC pain scores at 6 months between chondroitin alone and placebo (208/318 [65%] with chondroitin v 188/313 [60%] with placebo;P = 0.17).

Harms

The reviews found no important adverse effects. The subsequent RCTs reported minor adverse effects. Treatment-related adverse effects may potentially include upper gastrointestinal symptoms, abdominal pain, and nausea.

Comment

A total of 26 people (24%) withdrew from the subsequent RCT because of lack of efficacy, absence of compliance, increasing pain, or adverse effects (11/60 [18%] with chondroitin v 15/60 [25%] with placebo; reported as not significant, P value not reported). Ten people who did not provide data at the first follow-up were excluded from last observation carried forward analysis.

Clinical guide:

Chondroitin seems to be a safe treatment, but with only marginal improvement in symptoms for osteoarthritis of the knee.

Substantive changes

Chondroitin Two RCTs added, which found no significant difference in pain or function between chondroitin and placebo. Evidence reassessed. Recategorised from Unlikely to be beneficial to Unknown effectiveness as inconclusive results among RCTs.

2007; 2007: 1121.
Published online 2007 September 1.

Corticosteroids (intra-articular)

Summary

PAIN Compared with placebo: Intra-articular corticosteroids may reduce pain compared with placebo at 1–3 weeks in people with osteoarthritis of the knee, but not in the longer term ( low-quality evidence ). Compared with hyalunonan: Intra-articular corticosteroids may be less effective than hyaluronan at reducing pain at 5–13 weeks, although they may be as effective as each other in the shorter term ( very low-quality evidence ).

Benefits

Corticosteroids versus placebo:

We found one systematic review (search date 2006), which found that intra-articular corticosteroids significantly reduced pain at one week compared with placebo (8 RCTs; WMD -21.9, 95% CI -29.9 to -13.9). It also found benefit at two weeks (RR 1.81, 95% CI 1.09 to 3.00) and at three weeks (RR 3.11, 95% CI 1.61 to 6.01) with corticosteroids compared with placebo, but lack of evidence of a sustained effect after 4 weeks.

Corticosteroids versus hyaluronan:

We found one systematic review (search date 2006), which found no significant difference between corticosteroids and hyalruonic acid products in pain at 1 to 4 weeks after injection (3 RCTs, 85 people, WMD -4.90; 95% CI -9.91 to 0.10; P = 0.05). It found that hyaluronic acid products were significantly more effective than corticosteroids in reducing pain at 5 and 13 weeks (3 RCTs, WMD –7.73, 95% CI –12.81 to –2.64; P = 0.003). There were no clinically relevant differences between the various hyaluronic acid preparations.

Harms

We found few reports of serious adverse effects. The systematic review reported the following complications (uncommon) for intra-articular corticosteroids: symptom flare, tissue atrophy, fat necrosis, calcification, steroid arthropathy, and vascular necrosis. A theoretical risk of infection exists, but we found no evidence of this.

Comment

Corticosteroids versus placebo:

The systematic review included single injections of hydrocortisone (25 mg, 2 RCTs and 50 mg), hydrocortisone tertiary-butylacetate (25 mg), methylprednisolone acetate (40 mg), prednisolone acetate (25 mg), triamcinolone hexacetonide (20 mg, 4 RCTs), and triamcinolone acetonide (40 mg, 2 RCTs). Three further RCTs compared placebo versus cortivazol (3.75 mg single dose) versus joint lavage plus placebo versus joint lavage plus cortivazol (3.75 mg single dose); arthroscopy plus methylprednisolone acetate (120 mg single dose) versus arthroscopy plus placebo; and arthroscopic lavage plus methylprednisolone acetate (120 mg single dose) versus arthroscopic lavage plus placebo.

Corticosteroids versus hyaluronan:

The systematic review included methylprednisolone acetate (5 RCTs, 40 mg, 3 weekly injections), triamcinolone hexacetonide (1 RCT, 40 mg, single injection and 1 RCT, 20 mg, single injection), betamethasone acetate (RCTs, dose not specified, 1 or 2 injections). The hyaluronan derivatives used in the RCTs consisted of cross-linked hyaluronan.

Clinical guide:

While corticosteroids are effective for short-term symptom relief for osteoarthritis of the knee, their long-term effectiveness seems low, and no data are available on the effectiveness of repeated courses of treatment.

Substantive changes

Corticosteroids (intra-articular) One systematic review added. Categorisation unchanged (Likely to be beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

Hyaluronan (intra-articular)

Summary

PAIN Compared with placebo: Intra-articular hyaluronan and hyaluronan derivatives may improve pain and function compared with placebo at up to 13 weeks after injection, but may have no longer-term benefits ( low-quality evidence ). Compared with intra-articular corticosteroids: Hyaluronan may be more effective than intra-articular corticosteroids at reducing pain at 5–13 weeks, although they may be as effective as each other in the shorter term ( very low-quality evidence ).

Benefits

Hyaluronan versus placebo:

We found two systematic reviews and two subsequent RCTs. The first systematic review (search date 2006) compared intra-articular hyaluronan and hyaluronan derivatives versus intra-articular placebo. It found that hyaluronan significantly improved weight-bearing pain compared to placebo between 1 and 26 weeks(1 to 4 weeks postinjection [22 RCTs]: WMD –7.7, 95% CI –11.3 to –4.1, P < 0.0001; 5 to 13 weeks postinjection [17 RCTs]: WMD –13.0, 95% CI –17.8 to –8.2, P < 0.00001); 14 to 26 weeks postinjection [9 RCTs]: WMD –9.0, 95% CI –14.8 to –3.2, P = 0.002). There was no improvement at 45 to 52 weeks postinjection [3 RCTs]. It found a significant improvement in the Lequesne Index at 1 to 4 weeks postinjection (4 RCTs, WMD –0.8, 95% CI –1.5 to –0.2, P = 0.02) and at 5 to 13 weeks postinjection (4 RCTs, WMD –1.4, 95% CI –2.0 to –0.7, P < 0.0001), but no significant difference at 14 to 26 weeks post-injection or later. The second review (search date 2004, 11 RCTs, 1443 people)compared hyaluronan injection with placebo and only included trials in which pain was measured by visual analogue scales for active treatment and placebo. It reported that hyaluronic acid injections were moderately effective in relieving knee pain in patients with osteoarthritis at 5 to 7 and 8 to 10 weeks post-injection, but not at 15 to 22 weeks (visual analogue pain score difference between hyaluronic acid injections and placebo: 4.4 at 1 week, 95% CI 1.1 to 7.2 v 17.7 at 5 to 7 weeks, 95% CI 7.5 to 28.0 v 18.1 at 8 to 12 weeks, 95% CI 6.3 to 29.9; P value not reported). The first subsequent RCT (255 people with knee osteoarthritis) compared “appropriate care” with or without either a single or repeat course of a hyaluronan derivative over one year. It found that either single or repeated treatments of the hyaluronan derivative significantly reduced WOMAC pain scores compared with appropriate care. It also found no significant difference between single or repeated treatments of hyaluronan (difference between single course and appropriate care –27.5, P < 0.0001; difference between repeat course and appropriate care –21.0, P = 0.0042; difference between single course and repeat course –6.5, P = 0.6593). The second subsequent RCT (106 people with radiologically confirmed knee osteoarthritis) compared hyaluronan derivative injections versus saline injections. It found that hyaluronan derivative injections produced significantly greater mean improvement in WOMAC pain scores compared with saline after 3 weeks (mean reduction in WOMAC pain scores: 8 with hyaluronan derivative v 3 with saline; P < 0.02) However, differences did not persist at 6 weeks (mean reduction in WOMAC pain scores: 8 for hyaluronan derivative v 8 for saline).

Hyaluronan versus corticosteroids:

See benefits of corticosteroids (intra-articular).

Harms

The systematic reviews did not find any significant differences between the hyaluronan/hyaluronan derivative and placebo groups for overall serious adverse events, potentially treatment-related adverse events, local skin reactions, or gastro-intestinal complaints. . The subsequent RCTs reported adverse effects that were mainly mild to moderate in intensity, and reported no difference in the likelihood of advese effects between active and control treatments.

Comment

Because hyaluronan and hyaluronan derivative products differ in their molecular weight, concentration, treatment schedule, and mode of production, the systematic review also presented the results by product. The hyaluronan derivatives used in the RCTs consisted of cross-linked hyaluronan. The authors of the review noted that the class-based analysis could either underestimate or overestimate the performance of individual products. Given the heterogeneity in effects across the product classes, readers were advised to review by product analyses.

Clinical guide:

There is a large body of evidence to suggest that that hyaluronan injections provide clinically important relief from symptoms of osteoarthritis of the knee for up to 6 months after initial injections. However, there is no evidence on the effectiveness of subsequent courses of hyaluronan, and if diminishing returns exist.

Substantive changes

Hyaluronan Two systematic reviews and two RCTs added. Categorisation unchanged (Likely to be beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

Joint bracing

Summary

PAIN Compared with control: We don't know whether joint bracing reduces pain at 6–12 months compared with control ( very low-quality evidence ). FUNCTION Compared with control: Joint bracing may improve function compared with control at 6–12 months in people with osteoarthritis of the knee (very low-quality evidence).

Benefits

We found one systematic review and one subsequent RCT. The systematic review (search date 2002, 1 RCT, 119 people with varus gonarthrosis), which compared three treatments: unloader knee brace, neoprene sleeve, and control (medical treatment only). The RCT found was of low quality, and there was a difference in the baseline characteristics between the groups. Efficacy data could not be extracted owing to incomplete data presented on the outcome measures. However, it reported that the knee brace increased WOMAC score improvement compared with the neoprene sleeve at 6 months, and the neoprene sleeve improved WOMAC score compared with control.The subsequent RCT (117 people, uni-compartmental knee osteoarthritis) compared conservative treatment with or without additional brace treatment. After 12 months, treatment with a knee brace increased walking distance (difference between groups 1.3 kilometres, (95% CI 0.2 to 2.4; P < 0.05); there were no other significant differences between groups.

Harms

The systematic review did not report on adverse events. The subsequent RCT found that bracing was associated with bad fit and skin irritatation in about 3% of people.

Comment

There is evidence that physical supports can offer some benefit; however, considerable expert advice is required before use, and correct usage over the long term needs to be monitored.

Substantive changes

Joint bracing One RCT added. Categorisation unchanged (Likely to be beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

Taping

Summary

PAIN Compared with no tape or control tape: Therapeutic tape reduces pain at 3–6 weeks compared with no tape or a control tape in people with osteoarthritis of the knee ( moderate-quality evidence ).

Benefits

One RCT (87 people, aged > 50 years with osteoarthritis of the knee) compared three groups: therapeutic tape, control tape, and no tape. It found a significant reduction in pain in the therapeutic tape group compared with the other groups after 3 weeks' treatment (pain on movement: mean difference in change on a 0–10 visual analogue scale [VAS]; no tape v control tape 0.8, 95% CI 0 to 1.6; no tape v therapeutic tape 2.1, 95% CI 1.2 to 3.0; control tape v therapeutic tape 1.3, 95% CI 0.3 to 2.4 and effect size 1.19; pain on worst activity: mean difference in change: no tape v control tape +0.6, 95% CI –0.4 to +1.5; no tape v therapeutic tape 2.0, 95% CI 1.0 to 3.1; control tape v therapeutic tape 1.5, 95% CI 0.3 to 2.7 and effect size 1.00). The beneficial effects of therapeutic tape on pain and disability were maintained 3 weeks after stopping treatment.

Harms

The RCT reported minor skin irritations (8/29 [28%] with therapeutic tape v 1/29 [3%] with control tape; significance not reported). All participants continued to wear tape as prescribed.

Comment

There is evidence that physical supports can offer some benefit; however, considerable expert advice is required before use, and correct usage over the long term needs to be monitored.

Substantive changes

2007; 2007: 1121.
Published online 2007 September 1.

Insoles

Summary

PAIN Different insoles compared with each other: We don't know which type of insole is most effective at reducing pain in people with medial knee osteoarthritis ( very low-quality evidence ). FUNCTION Different insoles compared with each other: We don't know which type of insole is most effective at improving function in people with medial knee osteoarthritis (very low-quality evidence).

Benefits

We found one systematic reviewand three subsequent RCTs. The systematic review (search date 2002, 3 RCTs, 334 people with medial femoro-tibial osteoarthritis of the knee) compared different types of insoles. The results could not be pooled owing to heterogeneity of the studies identified. Overall, the studies found no significant differences in pain or function for any of the comparisons (laterally wedged insole versus neutral insole over 6 months, subtalar strapped insole versus lateral wedge insole over 8 weeks, and subtalar strapped insole versus a sock-type support over 8 weeks). The first subsequent RCT also compared different types of insoles: subtalar strapped lateral wedged insoles with elevations of 8, 12, and 16 mm over 2 weeks. All groups were given acemetacine 30 mg twice daily. It found that the 12 mm insole significantly improved the remission score on the Lequesne Index compared with the 16 mm insole only (1 RCT; 62 women with medial compartment osteoarthritis of the knee; P = 0.029). The second subsequent RCT compared subtalar strapped lateral wedged 12 mm insoles made from sponge rubber or urethane over 4 weeks. All groups were given acemetacine 30 mg twice daily. The RCT found that people using urethane insoles had significantly greater improvement in the percentage of remission scores on the Lequesne Index compared with people using rubber insoles (1 RCT; 84 females with medial compartment osteoarthritis of the knee; P = 0.001). The third subsequent RCT compared subtalar strapped lateral wedged insoles for less than 5 hours, 5–10 hours, or greater than 10 hours each day, and treatment with a placebo subtalar strapping band without a lateral wedge over 2 weeks. The insole had an elevation of 12 mm and was made from urethane. All groups were given acemetacine 30 mg twice daily. It found that wearing insoles for 5–10 hours or over 10 hours daily significantly improved remission scores on the Lequesne Index compared with placebo (1 RCT; 81 females with medial compartment osteoarthritis of the knee; P = 0.001 for 5–10 hours v placebo; P = 0.001 for > 10 hours v placebo).All of the subsequent RCTs comparing subtalar strapped lateral wedged insoles involved randomisation by birth date. In the studies comparing different forms of subtalar strapped lateral wedged insoles, participants were instructed to use the insoles without shoes in their home for 3–6 hours daily. The authors noted that this was done because most of the participants were Japanese housewives who spent a considerable proportion of each day not wearing footwear while in their homes.

Harms

The systematic review found limited evidence that a strapped insole increased adverse effects compared with a lateral wedge insole.The adverse effects included popliteal pain, low back pain, and foot sole pain. In no cases was the adverse effect so serious that the participant stopped wearing the insole. The subsequent RCTs comparing different forms of subtalar strapped lateral wedged insoles found that adverse effects were more common in the 16 mm elevated insole compared with the 8 mm (P = 0.003), and the 12 mm elevated insole (P = 0.005); and with the rubber insole compared with the urethane insole (P = 0.028). The most common adverse effect was foot pain. The other RCTs did not report on adverse effects.

Comment

None.

Substantive changes

Insoles One systematic review added. Categorisation unchanged (Unknown effectiveness).

2007; 2007: 1121.
Published online 2007 September 1.

Simple analgesics

Summary

PAIN Compared with placebo: Paracetamol may reduce pain compared with placebo in the short term in people with osteoarthritis of the knee ( very low-quality evidence ). Compared with oral NSAIDs: Paracetamol may be less effective than oral NSAIDs at reducing pain in people with osteoarthritis of the knee (very low-quality evidence).

Benefits

Simple analgesics versus placebo:

We found one systematic review (search date 2005, 7 RCTs, 1966 people with osteoarthritis), which compared paracetamol with placebo. Five RCTs included in the review (1835 people) found that paracetamol significantly reduced overall pain compared with placebo (NNT 16; SMD –0.13, 95% CI –0.22 to –0.04). Two RCTs showed no significant effect of paracetamol compared with placebo. One included RCT with dichotomous outcomes (44 people) found that paracetamol was significantly better than placebo for pain response and pain in motion (rest pain improvement: 2/22 [4%] with placebo v 16/22 [72%] with paracetamol, NNT 4, 95% CI 2 to 24; pain on motion improvement: 4/22 [9%] with placebo v 15/22 [66%] with paracetamol, NNT 5, 95% CI 2 to 24).

Simple analgesics versus oral NSAIDs:

We found two systematic reviews The first systematic review compared NSAIDs versus paracetamol (search date 2001, 3 RCTs, 404 people with osteoarthritis of the knee). Two of the RCTs found that NSAIDs significantly reduced pain measured on a VAS at rest. The third RCT reported only “patient preference” for the NSAID or paracetamol (59% for NSAID v 29% for paracetamol v 12% for no preference). The second systematic review (search date 2005, 12 RCTs, 4020 people with osteoarthritis) compared paracetamol with a range of NSAIDs. It found that NSAIDs were significantly more effective than paracetamol for rest pain (3 RCTs of ibuprofen, diclofenac, diclofenac plus misoprostol, celecoxib, naproxen, 573 people, SMD –0.20, 95% CI –0.36 to –0.03; 4 RCTs of ibuprofen, diclofenac plus misoprostol, rofecoxib, naproxen, 594 people, SMD –0.19, 95% CI –0.35 to –0.03) and overall pain (8 RCTs of ibuprofen, diclofenac, diclofenac plus misoprostol, celecoxib, naproxen, 2358 people, SMD –0.25, 95% CI –0.33, –0.17; 7 RCTs of ibuprofen, diclofenac with misoprostol, rofecoxib, naproxen, 1812 people, SMD –0.31, 95% CI –0.40 to –0.21). The review found no significant differences between NSAIDs and paracetamol for pain on motion (2 RCTs of ibuprofen, diclofenac, Arthrotec, celecoxib, naproxen, 270 people, SMD 0.04, 95% CI –0.20, –0.28; 2 RCTs of ibuprofen, diclofenac with misoprostol, rofecoxib, naproxen, 271 people, SMD –0.03, 95% CI –0.27 to –0.21).

Harms

Simple analgesics versus placebo:

The systematic review found no significant difference in frequency of adverse events between the paracetamol and placebo groups.

Simple analgesics versus oral NSAIDs:

The first systematic review did not report on adverse events. The second systematic review found no significant difference between NSAIDs and paracetamol for total number of withdrawals caused by adverse events and the total number of patients experiencing any adverse event. There was no significant difference in the number of patients reporting gastrointestinal events when NSAIDS (including COX-2 inhibitors) were compared to paracetamol. When ibuprofen or naproxen were compared to paracetamol, the relative risk was 1.47 (95% CI 1.08 to 2.00).

Comment

The authors of the first systematic review noted that the trials were of short duration, and studied a relatively small number of highly-selected people with osteoarthritis. This precludes the ability to detect the less common, but more significant adverse events.

Clinical guide:

There is a large body of evidence showing that simple analgesics are likely to offer safe and clinically effective short-term pain relief for people with large-joint osteoarthritis.

Substantive changes

Simple analgesics One systematic review added.[P] Categorisation unchanged (Likely to be beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

NSAIDs (topical)

Summary

PAIN Compared with placebo: Topical NSAIDs may be more effective than placebo at reducing pain at 1–8 weeks in people with osteoarthritis of the knee ( low-quality evidence ). Compared with oral NSAIDs: Topical NSAIDs may be as effective as oral NSAIDs at reducing pain in people with osteoarthritis of the knee ( very low-quality evidence ). FUNCTION Compared with placebo: Topical NSAIDs are more effective than placebo at improving function at 6–8 weeks in people with osteoarthritis of the knee ( moderate-quality evidence ). ADVERSE EFFECTS Compared with oral NSAIDs: Topical NSAIDs may be less likely to cause gastrointestinal adverse effects than oral NSAIDs at 4–12 weeks (very low-quality evidence). Topical NSAIDs are associated with skin irritation. NOTE We found no clinically important results about the effects of topical NSAIDs for periods of longer than 12 weeks.

Benefits

Topical NSAIDs versus placebo:

We found two systematic reviews and three subsequent RCTs. The first systematic review found that topical NSAIDs significantly reduced pain compared with placebo in weeks 1 and 2 (effect size 0.41, 95% CI 0.18 to 0.63; P < 0.05), but not in weeks 3 and 4 (effect size +0.08, 95% CI –0.04 to +0.2; P value not reported).The second systematic review (search date 2005, 3 RCTs, 790 people with osteoarthritis of the knee) evaluated only trials involving topical diclofenac. It found that topical diclofenac significantly reduced WOMAC pain scores and improved WOMAC stiffness and physical function scores over 8.5 weeks (mean) compared with placebo (pain scores: SMD –0.33, 95% CI –0.48 to –0.18; stiffness: SMD –0.30, 95% CI –0.45 to –0.15; physical function: SMD –0.35, 95% CI –0.50 to –0.20). The first subsequent RCT found that a 5% ibuprofen cream significantly increased the proportion of people responding to treatment (defined as a reduction in pain on movement of at least 23% or at least 18 mm from baseline on a 100 mm visual analogue scale [VAS]) compared with a placebo cream over 7 days (50 people aged 40–75 years with osteoarthritis of the knee of grade 2 to 3 as judged by Kellgren and Lawrence criteria; AR for response: 21/25 [84%] with ibuprofen v 10/25 [40%] with placebo; P = 0.0015). The second subsequent RCT (216 people with radiologically confirmed primary knee osteoarthritis) compared topical diclofenac solution versus vehicle control solution over 6 weeks. It found that topical diclofenac significantly improved pain score compared with vehicle control (effect size [unclear if odds ratio or relative risk] 0.41, 95% CI 0.14 to 0.68, P = 0.003;NNT for 50% reduction in pain 5, 95% CI 3 to 17; P = 0.004). There were also significant improvements in physical function and patients’ global assessments compared with placebo (physical function effect size [unclear if odds ratio or relative risk]: 0.44, 95% CI 0.16 to 0.71, P = 0.001; patient global assessment effect size [unclear if odds ratio or relative risk]: 0.47, 95% CI 0.19 to 0.74, P = 0.0001). The third subsequent RCT (238 people with knee osteoarthritis) compared diclofenac gel or placebo gel applied 4 times daily over 3 weeks. It found that diclofenac gel significantly reduced pain intensity, and improved overall response and WOMAC scores compared with placebo (mean difference in pain intensity between groups 9, P = 0.006; overall response rate at 3 weeks: 62% with diclofenac gel v 46% with placebo; mean difference in WOMAC pain score between groups 9, P = 0.0002).

Topical NSAIDs versus oral NSAIDs:

We found one RCT comparing the same NSAID in topical and oral formulations, and two RCTs comparing one topical NSAID versus a different oral NSAID. The first RCT was an equivalence trial comparing topical diclofenac (75 mg/day, 1.5% diclofenac sodium in a carrier containing 45.5% DMSO) with oral diclofenac (three 50 mg capsules/day) for 12 weeks. It found that oral diclofenac significantly improved WOMAC function score (equivalence trial, 622 people, aged 40–85 years; mean difference: 90, 95% CI 24 to 156; P = 0.008) compared with topical diclofenac from baseline to 12 weeks. However, there were no significant differences in changes in WOMAC pain (mean difference: +16.4, 95% CI –3.4 to +36.1; P = 0.1) or patient global assessment (mean difference [100 mm VAS]: +4.5, 95% CI –0.5 to +9.6; P = 0.08). As all of the differences fell within the prespecified equivalence range, the study concluded that there were no clinically relevant differences between the two treatments. The second RCT (235 people with mild osteoarthritis of the knee) compared topical piroxicam gel versus oral ibuprofen 1200 mg daily over 4 weeks. It found no significant difference in pain relief between the two groups. The third RCT (290 people with osteoarthritis of the knee) compared three groups: eltenac 1% gel; oral diclofenac 100 mg/day; and a placebo gel group over 4 weeks. It found no significant difference between the treatment groups for pain, measured on a 100 mm VAS or the Lequesne Index score.

Harms

Topical NSAIDs versus topical placebo:

The main adverse effect of topical treatment was local skin irritation; systemic adverse effects were no more common than with placebo.

Topical NSAIDs versus oral NSAIDs:

The RCT comparing topical versus oral diclofenac found a higher incidence of withdrawals caused by skin irritation with topical diclofenac (10% with topical diclofenac v 0.3% with oral diclofenac; P < 0.0001), but topical diclofenac significantly reduced withdrawals caused by gastrointestinal adverse events compared with oral diclofenac (6% with topical diclofenac v 16% with oral diclofenac; P = 0.0001). It also found fewer overall withdrawals caused by adverse events with topical diclofenac than with oral diclofenac (21% with topical diclofenac v 25% with oral diclofenac; significance assessment not performed). Gastrointestinal adverse events were reported in the RCT that compared piroxicam gel with oral ibuprofen, and there was no statistical difference in the type and incidence of adverse events for either drug group. The study comparing eltenac gel with oral diclofenac or placebo found a significantly lower frequency of gastrointestinal events in the eltenac group compared with diclofenac (P = 0.037).

Comment

The evidence is poor, with most studies being short term, including a mixture of patient groups, and comparing different agents. The withdrawal rate in the second subsequent RCT comparing diclofenac versus vehicle control was quite high (45/164 [27%] with diclofenac v 53/162 [33%] with vehicle control). The RCT comparing topical versus oral diclofenac also had a high withdrawal rate (129/311 [41%] with topical diclofenac v 116/311 [37%] with oral diclofenac), but analysed 97% (604/622) of participants using the last-observation-carried-forward method. The RCTs comparing different NSAIDs in oral and topical formulations are difficult to interpret, because it is difficult to disentangle the effects of the different drugs from the different routes of administration.

Clinical guide:

Topical NSAIDs seem effective for short-term use (< 2 weeks), but there is insufficient evidence to determine the effectiveness of long-term use.

Substantive changes

NSAIDs topical One systematic review and two RCTs added. Categorisation unchanged (Likely to be beneficial).

2007; 2007: 1121.
Published online 2007 September 1.

Capsaicin

Summary

We found no clinically important results about the effects of capsaicin in people with osteoarthritis of the knee alone.

Benefits

We found no systematic review or RCTs of capsaicin in which the data for osteoarthritis of the knee were provided separately.

Harms

We found no RCTs.

Comment

Clinical guide:

There is currently no evidence about the effects of capsaicin as a treatment of osteoarthritis of the knee.

Substantive changes

No new evidence

2007; 2007: 1121.
Published online 2007 September 1.

Education to aid self management

Summary

PAIN Compared with usual care: Educational programmes to aid self-management do not reduce pain at 12 months compared with usual care in people with osteoarthritis of the knee ( moderate-quality evidence ). FUNCTION Compared with usual care: Educational programmes to aid self-management may not improve function compared with usual care at 9–12 months ( low-quality evidence ).

Benefits

We found no systematic review but found three RCTs. The first RCT compared a primary care-based patient education programme versus a waiting list control over 12 months. The education programme consisted of a home visit and four 1-hour group teaching sessions. The unit of randomisation was the primary care practice. The RCT found no significant difference in health-related quality-of-life (SF-36) or WOMAC scores at 12 months (22 practices, 193 people aged > 45 years; mean difference in SF-36 general health score: +2.6, 95% CI –3.8 to +8.9; mean difference for WOMAC pain: –0.1, 95% CI –1.4 to +1.2; mean difference for WOMAC disability: –1.4, 95% CI –6.0 to +3.2). The second RCT compared an 18-week nurse-directed self management education intervention (aimed at reducing NSAID use and increasing non-drug management of symptoms) or waiting list control (routine care). It found that self management education significantly reduced reliance on NSAIDs compared with routine care over 12 months (4 health maintenance organisations randomised, 186 people, mean aged > 60 years; reduced reliance in NSAIDs defined as using paracetamol initially rather than NSAIDs, switching from NSAIDs to other analgesics, or reducing or discontinuing NSAID use; AR: 26% with education v 5% with routine care; P = 0.014). However, it found no significant difference in WOMAC pain and function scores between self management education and routine care at 12 months (mean pain score: 12.9 with education v 12.7 with routine care; reported as not significant, P value not reported; mean function score: 43.7 with education v 44.0 with routine care; reported as not significant, P value not reported). The third RCT (100 people with radiological evidence of knee osteoarthritis) compared pharmacological treatment plus a programme of therapeutic education and functional readaptation versus pharmacological treatment alone. It found that the education-and-functional-readaptation programme plus pharmacological treatment significantly improved WOMAC functional scores compared with pharmacological treatment alone after 9 months (mean difference between groups 8.5, P = 0.035). It also found that analgesic use increased significantly in people receiving education compared with pharmological treatment alone (P = 0.036).

Harms

The RCTs did not report on adverse effects.

Comment

We found one systematic review, which found few well-designed RCTs, and the participants in many RCTs were not representative of those in the general population. Studies of individual education in the systematic review also included biofeedback, exercises, and social support. One trial, which found a large improvement for pain and disability, was excluded from the analysis because its results were so different from the others. It also included exercise in the intervention. The remaining nine trials had no significant heterogeneity of results.

Clinical guide:

While the evidence on patient education and self management for knee osteoarthritis is limited, it is likely that the benefits of education are in improved patient knowledge, satisfaction with decision making, involvement in decision making, and forming of treatment preferences, all of which are often of benefit to the patient and health professional.

Substantive changes

Education to aid self management One RCT added. Categorisation unchanged (Unknown effectiveness).

2007; 2007: 1121.
Published online 2007 September 1.

Glucosamine

Summary

PAIN Compared with placebo: Glucosamine may be no more effective than placebo at reducing pain in people with osteoarthritis of the knee ( very low-quality evidence ). Compared with oral NSAIDs: Glucosamine reduces pain compared with oral NSAIDs in people with osteoarthritis of the knee ( moderate-quality evidence ). FUNCTION Compared with placebo: Glucosamine may not improve function compared with placebo in people with osteoarthritis of the knee (very low-quality evidence). ADVERSE EFFECTS Glucosamine may be less likely than NSAIDs to produce adverse effects.

Benefits

We found four systematic reviews and one subsequent RCT.

Glucosamine versus placebo:

The first systematic review (search date 1999, 6 RCTs, 911 people with osteoarthritis of the knee) found a moderate effect size for glucosamine compared with placebo in Lequesne Index, WOMAC, and pain (0.44, 95% CI 0.24 to 0.64; measured on a Likert scale or visual analogue scale [VAS]; VAS scale range not reported), but this was diminished when only high-quality or large trials were considered. The second systematic review (search date 2002, 7 RCTs [including 3 RCTs from the first review], 1020 people with osteoarthritis of the knee) found that glucosamine significantly reduced WOMAC scores compared with placebo (2 RCTs, SMD 0.30, 95% CI 0.11 to 0.49). Two of the RCTs found that pain (measured on a VAS; VAS scale range not reported) was significantly reduced in people taking glucosamine compared with placebo (P = 0.01 in 1 RCT and P < 0.001 in the other); however, two RCTs found no significant difference between glucosamine and placebo (P = 0.89 in 1 RCT and P = 0.77 in the other). The third systematic review (search date 2005) included RCTs in people with osteoarthritis of the knee (13 RCTs, 1992 people) and RCTs in people with osteoarthritis at multiple sites or unspecified sites (4 RCTs, 182 people). Although overall analyses suggested that glucosamine reduced pain compared with placebo, analyses of only the RCTs with adequate allocation concealment found no significant difference in pain between glucosamine and placebo (8 RCTs, 1111 people, including 1 RCT in 23 people with osteoarthritis of the knee, hip, or both; SMD –0.19, 95% CI –0.50 to +0.11), or WOMAC function scores (6 RCTs, including 1 RCT in 23 people with osteoarthritis of the knee, hip, or both; SMD –0.07, 95% CI –0.21 to +0.08). The fourth systematic review (search date 2005, 2 RCTs) found that glucosamine significantly delayed structural progression in knee osteoarthritis compared with placebo (RR 0.46, 95% CI 0.28 to 0.73; NNT 9, 95% CI 6 to 20). The subsequent RCT (1583 people with symptomatic knee osteoarthritis) compared four interventions: glucosamine (1500 mg/day), chondroitin sulfate (1200 mg/day), combined chondroitin sulphate with glucosamine and placebo for 24 weeks ). It found no significant difference between glucosamine and placebo in the proportion of people with a 20% decrease in WOMAC pain score at 24 weeks (203/317 [64%] with glucosamine v 188/313 [60%] with placebo; P = 0.30).

Glucosamine versus oral NSAIDs (NSAIDs):

One systematic review (search date 2005, 4 RCTs, 737 people with osteoarthritis of the knee) compared glucosamine versus oral NSAIDs. Three of the RCTs reported on pain; they found that glucosamine significantly reduced pain (measured on a VAS) compared with NSAIDs (SMD –0.40, 95% CI –0.60 to –0.19).

Harms

Glucosamine versus placebo:

The first review did not report on adverse events. The second review found no difference between treatment and placebo groups in adverse events in people with osteoarthritis of all sites (RR 0.80, 95% CI 0.59 to 1.08). The third review found no significant difference in adverse events between glucosamine and placebo (14 RCTs; RR 0.97, 95% CI 0.88 to 1.08). The fourth review stated that abdominal pain, dyspepsia, diarrhoea, and increased blood pressure were the most common adverse events reported with glucosamine, but found no significant difference in adverse events between glucosamine and placebo (RR 1.02 95% CI 0.93 to 1.11).

Glucosamine versus oral NSAIDs:

Glucosamine was less likely than NSAIDs to produce adverse reactions (4 RCTs; RR [fixed effects] 0.29, 95% CI 0.19 to 0.44). The review did not report on the types of adverse events experienced. See harms of oral NSAIDs.

Comment

Subgroup analyses in the third review by type of glucosamine preparation used found that Rotta preparation glucosamine significantly improved pain (pooling all measures) compared with placebo (7 RCTs, 730 people, including 3 RCTs in 140 people with osteoarthritis at multiple or unspecified sites; SMD –1.31, 95% CI –1.99 to –0.64). For the non-Rotta preparations there was no difference in pain (pooling all measures) compared with placebo (8 RCTs, 751 people, including 1 RCT in 23 people with osteoarthritis of the knee, hip, or both; SMD –0.15, 95% CI –0.35 to +0.05). It found no significant difference in WOMAC measured pain, stiffness, and function between the groups for either preparation.

Clinical guide:

There is conflicting evidence on the effectiveness of glucosamine for osteoarthritis of the knee. Until this conflict is clearly resolved conclusions regarding its effectiveness cannot be drawn.

Substantive changes

Glucosamine One systematic review and one subsequent RCT added. Categorisation unchanged (Unknown effectiveness).

2007; 2007: 1121.
Published online 2007 September 1.

Opioid analgesics

Summary

PAIN Compared with placebo: Opioid analgesics reduce pain compared with placebo in people with osteoarthritis of the knee ( moderate-quality evidence ). ADVERSE EFFECTS Adverse effects of opioids include constipation, nausea, vomiting, drowsiness, hypotension, and respiratory depression at higher doses, and tolerance and dependence with regular use. They are not recommended as first-line treatment of osteoarthritis. NOTE We found no clinically important results about the effects of opioid analgesics compared with NSAIDs in people with osteoarthritis of the knee.

Benefits

Opioid analgesics versus placebo:

We found one systematic review and one subsequent RCT. The systematic review (search date 2005, 3 RCTs, 749 people with osteoarthritis, primarily of the knee) compared tramadol versus tramadol plus paracetamol versus placebo. It found that tramadol significantly reduced pain intensity and total WOMAC score compared with placebo (pain intensity WMD –8.47, 95% CI –12.05 to –4.90; WOMAC score WMD –0.34, 95% CI –0.49 to –0.19; RR 1.37, 95% CI 1.22 to 1.55). The subsequent RCT (399 people with osteoarthritis, 211 with osteoarthritis of the knee) compared transdermal fentanyl (25 µg/hour) with placebo over 6 weeks. It found that fentanyl significantly improved visual analogue pain scores and WOMAC pain scores compared to placebo (VAS mean change from baseline: –23.6 for fentanyl v –17.9 for placebo, P = 0.025; change from baseline in overall WOMAC scores: –3.9 for fentanyl v –2.4 for placebo, P = 0.009).

Opioid analgesics versus oral NSAIDs:

We found no RCTs.

Opioid analgesics versus each other:

One systematic review evaluated three RCTs that compared tramadol versus dihydrocodeine, dextropropoxyphene, and pentazocine. It found that tramadol increased the likelihood of a moderate improvement by 38% compared with dextropropoxyphene, and by 150% compared with pentazocine (absolute data or P value not reported).

Harms

Common adverse effects associated with lower doses of opioid analgesics include constipation, nausea, vomiting, and drowsiness, while higher doses can result in hypotension and respiratory depression. Regular use of opioid analgesics may lead to tolerance and dependence. Tramadol is less addictive than other opioid analgesics and gives rise to less constipation and less respiratory depression.

Opioid analgesics versus placebo:

The systematic review found that tramadol increased the risk of developing major adverse events by 2.6 times (95% CI 2.0 to 3.6) compared with placebo (tramadol: 143/710 [20%]; placebo: 49/626 [8%]; NNTH 8, 95% CI 7 to12).The RCT found that the most common adverse effects associated with transdermal fentanyl were nausea and vomiting (nausea: 19% with placebo v 44% with fentanyl; vomiting: 3% with placebo v 28% with fentanyl). Other adverse effects most frequently reported included somnolence, dizziness, headache, application site reactions, and constipation.

Opioid analgesics versus each other:

The systematic review found that tramadol caused significantly more adverse events than dextropropoxyphene (tramadol: 48/135 [36%]; dextropropoxyphene: 14/129 [11%]; NNTH 6, 95% CI 4.4 to 12). It also found that tramadol caused fewer adverse events than pentazocine (tramadol: 9/30 [30%]; pentazocine: 11/30 [37%]; P value not reported).

Comment

Clinical guide:

Opioids offer an additional option for pain relief for osteoarthritis of the knee. However, the adverse effects of the opioid analgesics mean that these are not recommended as first-line treatment.

Substantive changes

Opioid analgesics One systematic review and one RCT added. Categorisation changed to Tradeoff between benefits and harms.

2007; 2007: 1121.
Published online 2007 September 1.

Osteotomy

Summary

PAIN Compared with knee replacement: High tibial osteotomy may be as effective at reducing pain at 1–5 years compared with unicompartmental knee replacement in people with osteoarthritis of the knee ( low-quality evidence ). FUNCTION Compared with knee replacement: High tibial osteotomy may be as effective at improving function at 1–5 years compared with unicompartmental knee replacement in people with osteoarthritis of the knee ( low-quality evidence ). NOTE We found no clinically important results about the effects of osteotomy compared with conservative treatment.

Benefits

Osteotomy versus conservative treatment:

We found no systematic review or RCTs (see comment below).

Osteotomy versus knee replacement:

We found one systematic review comparing high tibial osteotomy (HTO) versus unicompartmental knee replacement (UKR). The review (search date 2004, 2 RCTs, 100 people with osteoarthritis of the knee) did not perform a meta-analysis because of the heterogeneity of the studies. Overall, the review did not find any significant differences between the groups for pain or function. Subgroup analysis from the first RCT included in the review (100 people randomised aged 55–70 years with medial osteoarthritis of the knee, grades I–III according to Ahlback's classification; subgroup analysis on 59 people with strictly unilateral knee pain) found overall clinical improvement from baseline on the British Orthopaedic Association score, pain during walking, and the ability to ascend and descend steps in both treatment groups. On comparing treatments after 1 year, it found no significant difference between the groups (British Orthopaedic Association score: +8 with HTO v +7 with UKR; pain during walking [Borg scale]: –2.5 with HTO v –2.8 with UKR; reported as not significant). There was also no significant difference between the groups in pain on walking at 5 years (mean score: 0 in both groups; reported as not significant). The second RCT (60 people, aged > 60 years with medial unicompartmental osteoarthritis of the knee) included in the review found no significant difference at latest follow-up (range 7–10 years) in knee scores (mean scores: 76 with HTO v 74 with UKR using the Knee Society Clinical Rating System; higher scores represent a worse outcome; P = 0.77). It found no significant difference in functional score (mean functional score: 71 with HTO v 59 with UKR; P = 0.22).

Harms

Osteotomy versus knee replacement:

The review reported more revisions after HTO than after UKR, but this increase did not reach significance (1 RCT, AR: 10/32 [31%] with HTO v 6/30 [20%] with UKR; RR 1.56, 95% CI 0.64 to 3.70). Complications included deep vein thrombosis (both groups) and wound infections (with osteotomy).

Comment

We also identified a number of observational studies (non-comparative cohorts and case series). Of these studies, only one compared osteotomy versus another technique (osteotomy v UKR). It found that UKR had better results than osteotomy and that these results were sustained over long periods. The other observational studies found that osteotomy was effective in subgroups with appropriate site of osteoarthritis, severity of disease, and degree of physical activity.

Clinical guide:

Osteotomy offers an alternative surgical option to total knee replacement, especially in younger and more physically active people with osteoarthritis of the knee.

Substantive changes

2007; 2007: 1121.
Published online 2007 September 1.

Total knee replacement

Summary

PAIN Unicompartmental prostheses compared with tricompartmental prostheses: Unicompartmental prostheses may be as effective at reducing pain at 5 years compared with tricompartmental prostheses ( low-quality evidence ). Patellar resurfacing compared with no resurfacing: Patellar resurfacing as part of knee replacement surgery may not improve pain at 2 years compared with no resurfacing (low-quality evidence). FUNCTION Unicompartmental prostheses compared with tricompartmental prostheses: Unicompartmental prostheses may be as effective at improving function at 5 years compared with tricompartmental prostheses (low-quality evidence). Sacrifice of posterior crucuate ligament compared with no sacrifice: Sacrifice of the posterior cruciate ligament during knee replacement improves joint mobility and function at 5 years compared with no sacrifice of the ligament ( high-quality evidence ). Patellar resurfacing compared with no resurfacing: We don't know whether patellar resurfacing as part of knee replacement surgery improves function at 6 months to 2 years compared with no resurfacing (low-quality evidence).

Benefits

Unicompartmental versus tricompartmental prostheses:

We found one systematic review (search date 2004, 1 RCT, 94 people, 102 knees), which found little difference between unicompartmental knee replacement (UKR) and tricompartmental knee replacement (TKR) in pain at 5 years (mean Bristol Knee Score: 91.1 with UKR v 86.7 with TKR; significance assessment not performed). It found that UKR increased the proportion of knees rated good or excellent for knee function at 5 years, but this increase did not reach significance (measured on the Bristol Knee Score; 34/45 [76%] with UKR v 26/46 [57%] with TKR; RR 1.34, 95% CI 0.99 to 1.81). The trial may have lacked power to detect a meaningful difference for this outcome. It also found that UKR significantly increased the proportion of people with a range of motion greater than 120° after 5 years compared with TKR (31/45 [69%] with UKR v 8/46 [17%] with TKR; P < 0.001).

Tricompartmental prostheses:

We found one systematic review in a mixed population; the osteoarthritis of the knee data were not presented separately (see comment below).

Unicompartmental or bicompartmental prostheses:

We found one systematic review in a mixed population; the osteoarthritis of the knee data were not presented separately (see comment below).

Retention or removal of posterior cruciate ligament in total knee replacement:

We found one systematic review (reported in two articles, search date 2004, 8 RCTs, 576 people). It found that sacrifice of the posterior cruciate ligaments improved range of movement, and improved the Hospital for Special Surgery joint score (range of movement: WMD –4.38, 95% CI –8.60 to –0.16; joint score: WMD –1.64; 95% CI –3.13to –0.14).

Patellar resurfacing in people receiving total knee replacement:

We found two RCTs. The first RCT (56 people with knee osteoarthritis undergoing posterior-stabilised total knee replacement) found no significant difference in clinical American Knee Society scores between patellar resurfacing and no patellar resurfacing over 2 years (91.6 with resurfaced v 90.5 unsurfaced; reported as not significant, P value not reported). It found a significant improvement in functional Knee Society scores with resurfacing compared with no resurfacing at 6 months (83.7 with resurfaced v 82.1 with unsurfaced; P = 0.034) The second RCT (50 people with knee osteoarthritis undergoing total knee replacement) found no significant difference in mean AKSS knee scores, WOMAC pain, stiffness or physical function scores, or pain visual analogue scales at 18 to 24 months (AKSS knee score: 83.2 with resurfaced v 83.4 with unsurfaced, P = 0.968; WOMAC pain scores: 2.4 v 3.3, P = 0.359; WOMAC stiffness: 1.7 v 2.0 , P = 0.511; WOMAC physical function: 17.4 v 15., P = 0.614; pain VAS: 8.3 with resurfaced v 12.6 with unsurfaced, P = 0.495). However, there were minor but significant benefits in Knee Society function score at 24 months (63.6 with resurfaced v 79.2 with unsurfaced, P = 0.008).

Harms

Death:

In one 6-year cohort of 338,736 US Medicare patients, the death rate within 30 days of hospital admission for total knee replacement was 2147 (0.63%). The same cohort study reported a mean mortality of 1.5% a year (no comparative data available). One observational study (208 people) found no significant increase in the risk of death after knee replacement for women (standardised mortality ratio 1.03, 95% CI 0.76 to 1.37) or men (standardised mortality ratio 1.14, 95% CI 0.68 to 1.80) after a mean follow-up of 6 years (range 0–20 years).

Thrombosis:

The review that compared UKR versus TKR reported that 2% (1/45) of people who received UKR had clinical evidence of deep vein thrombosis compared with 10% (5/49) of people who received TKR, but this difference did not reach significance (1 RCT, RR 0.22, 95% CI 0.03 to 1.79). We found one controlled clinical trial and one RCT that reported rates of venous thrombosis. They both found that about 24% of people who had a total knee replacement developed a deep vein thrombosis.

Revision and infection:

This is considered the main long-term risk. The first review found a revision rate of 3.8% during 4.1 years' follow-up after tricompartmental replacements. The second review found a revision rate of 9.2% over 4.6 years for unicompartmental prostheses and 7.2% over 3.6 years for bicompartmental prostheses. The review that compared UKR versus TKR found a revision rate of 2/50 (4%) for UKR and 1/52 (2%) for TKR at 5 years. Large patient register-based studies in Sweden found that the cumulative 10-year risk for revision surgery because of infection had fallen to less than 1%. Most implant revision surgery was because of aseptic loosening. For unicompartmental osteoarthritis, UKR was an effective alternative to total knee replacement.

Postoperative pain:

This was rarely recorded, but seemed to be absent or mild in most people.

Wound infection:

We found no good evidence on the frequency of wound infections. One large retrospective cohort study found lower complication rates in centres with a higher volume of procedures.

Comment

We found hundreds of observational studies that reported the time to prosthesis failure or revision surgery, but less evidence on pain and function outcomes. Studies have shown that total knee replacement is a highly effective treatment for osteoarthritis of the knee, but no RCT data exist on selection criteria for surgery. We found insufficient evidence from observational studies on the effects of obesity on knee replacement outcomes. We found limited evidence from observational studies that knee replacement is effective in elderly people.

Tricompartmental prostheses:

One systematic review identified 154 studies (4 RCTs, 130 cohort studies, 20 studies where the design could not be determined) of 37 different tricompartmental prostheses used in 9879 people (63% with osteoarthritis, mean follow up of 4.1 years). Good or excellent outcomes were reported in 89% of people (improved function 5 years after surgery; pain relief after 5 years; mortality at 30 days and at 1 year; thromboembolism by 30 days after surgery; no failure of knee prosthesis).

Unicompartmental or bicompartmental prostheses:

One systematic review identified no RCTs but found 18 cohort studies on bicompartmental prostheses (884 people, 31% with osteoarthritis), and 46 cohort studies on unicompartmental prostheses (2391 people, 75% with osteoarthritis). The review found that both unicompartmental and bicompartmental procedures were effective based on a global knee rating scale that includes measures of pain, function, and range of movement (80% of people having unicompartmental procedures v 73% of people having bicompartmental procedures reported a good or excellent outcome after a mean follow-up period of 4.6 years for unicompartmental procedures and 3.6 years for bicompartmental procedures). Unicompartmental studies published in or after 1987 found a greater percentage of people achieving good or excellent results compared with studies published before 1987, despite significantly longer follow up periods (75% before 1987 v 84% after 1987; P < 0.05).

Clinical guide:

There is clinical consensus that knee replacement offers effective and long-term symptom relief for people with knee osteoarthritis. However, total knee replacement represents irreversible major surgery with no guarantee of success. Therefore, people should be aware of other medical treatments, and of potential problems of surgery before having total knee replacement. Nevertheless, the consensus is that total knee replacement represents the most clinically effective treatment for people with severe osteoarthritis of the knee.

Substantive changes

Total knee replacement Two RCTs added. Categorisation unchanged (Likely to be beneficial).


Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group