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Meta-Analysis
. 2012 Nov 14;11(11):CD007323.
doi: 10.1002/14651858.CD007323.pub3.

Doxycycline for osteoarthritis of the knee or hip

Bruno R da Costa  1 , Eveline Nüesch, Stephan Reichenbach, Peter Jüni, Anne W S Rutjes
Affiliations
Meta-Analysis

Doxycycline for osteoarthritis of the knee or hip

Bruno R da Costa et al. Cochrane Database Syst Rev. .

Abstract

Background: Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. This is an update of a Cochrane review first published in 2009.

Objectives: To examine the effects of doxycycline compared with placebo or no intervention on pain and function in people with osteoarthritis of the hip or knee.

Search methods: We searched CENTRAL (The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, with an update performed at 16 March 2012. In addition, we checked conference proceedings, reference lists, and contacted authors.

Selection criteria: We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in people with osteoarthritis of the knee or hip.

Data collection and analysis: We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios (RR) for binary outcomes.

Main results: We identified one additional trial (232 participants) and included two trials (663 participants) in this update. The methodological quality and the quality of reporting were considered moderate. At end of treatment, clinical outcomes were similar between the two treatment groups, with an effect size of -0.05 (95% confidence interval (CI) -0.22 to 0.13), corresponding to a difference in pain scores between doxycycline and control of -0.1 cm (95% CI -0.6 to 0.3 cm) on a 10-cm visual analogue scale, or 32% versus 29% improvement from baseline (difference 3%; 95% CI -5% to 10%). The effect size for function was -0.07 (95% CI -0.25 to 0.10), corresponding to a difference between doxycycline and control of -0.2 (95% CI -0.5 to 0.2) on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability subscale with a range of 0 to 10, or 24% versus 21% improvement (difference 3%; 95% CI -3% to 10%). The difference in changes in minimum joint space narrowing assessed in one trial was in favour of doxycycline (-0.15 mm; 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units (95% CI -0.44 to -0.02). More participants withdrew from the doxycycline group compared with placebo due to adverse events (RR 2.28; 95% CI 1.06 to 4.90). There was no evidence that participants in the doxycycline group experienced more serious adverse events than those in the placebo group, but the estimate was imprecise (RR 1.07; 95% CI 0.68 to 1.68).

Authors' conclusions: In this update, the strength of evidence for effectiveness outcomes was improved from low to moderate and we confirmed that the symptomatic benefit of doxycycline is minimal to non-existent, while the small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. The CIs of the summary estimates now exclude any clinically relevant difference in improvement of symptoms and the small benefit in terms of joint space narrowing does not outweigh the harms.

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Conflict of interest statement

None.

Figures

1
1
Flow chart.
2
2
Methodological characteristics and source of funding of the included trial. (+) indicates low risk of bias, (?) unclear and (‐) a high risk of bias on a specific item.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 1 Pain.
1.2
1.2. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 2 Physical function.
1.3
1.3. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 3 Minimum joint space width.
1.4
1.4. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 4 Number of patients withdrawn due to adverse events.
1.5
1.5. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 5 Number of patients experiencing any adverse event.
1.6
1.6. Analysis
Comparison 1 Doxycycline versus placebo, Outcome 6 Number of patients experiencing any serious adverse events.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Brandt 2005 {published and unpublished data}
    1. Brandt KD, Mazzuca SA. Experience with a placebo‐controlled randomized clinical trial of a disease‐modifying drug for osteoarthritis: the doxycycline trial. Rheumatic Diseases Clinics of North America 2006;32(1):217‐34, xi‐xii. - PubMed
    1. Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA, Yocum DE, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo‐controlled, double‐blind trial. Arthritis and Rheumatism 2005;52(7):2015‐25. - PubMed
    1. Chakr R, Brandt KD, Ang DC, Mazzuca SA. Varus malalignment diminishes the structure‐modifying effects of doxycycline (doxy) in patients with knee osteoarthritis. Arthritis and Rheumatism 2009;60(Suppl 10):829.
    1. Hellio Le Graverand MP, Brandt KD, Mazzuca SA, Katz BP, Buck R, Lane KA, et al. Association between concentrations of urinary type II collagen neoepitope (uTIINE) and joint space narrowing in patients with knee osteoarthritis. Osteoarthritis Cartilage 2006;14(11):1189‐95. - PubMed
    1. Mazzuca SA, Brandt KD, Chakr R, Lane KA. Varus malalignment negates the structure‐modifying benefits of doxycycline in obese women with knee osteoarthritis. Osteoarthritis and Cartilage 2010;18(8):1008‐11. - PMC - PubMed
Snijders 2011 {published data only}
    1. Snijders GF, Ende CH, Riel PL, Hoogen FH, Broeder AA. Doxycycline has no symptom modifying effects in knee osteoarthritis: results from a randomized placebo controlled trial. Annals of the Rheumatic Diseases 2011; Vol. 70, issue Suppl 3:140. - PubMed
    1. Snijders GF, Ende CH, Riel PL, Hoogen FH, Broeder AA. The effects of doxycycline on reducing symptoms in knee osteoarthritis: results from a triple‐blinded randomised controlled trial. Annals of the Rheumatic Diseases 2011;70(7):1191‐6. [PUBMED: 21551510] - PubMed
    1. Dissel JT. Placebo controlled study on the effect of 6 months treatment with doxycycline on pain and function in patients with osteoarthritis of the knee [Placebo gecontroleerd onderzoek naar het effect van 6 maanden behandeling met doxycycline op pijn en functie in patiënten met artrose van de knie]. Nederlands Trial Register (www.trialregister.nl/trialreg/index.asp) 2007.

References to studies excluded from this review

Brandt 1995 {published data only}
    1. Brandt KD. Modification by oral doxycycline administration of articular cartilage breakdown in osteoarthritis. Journal of Rheumatology 1995;22(Suppl 43):149‐51. - PubMed
Smieja 2001 {published data only}
    1. Smieja M, MacPherson DW, Kean W, Schmuck ML, Goldsmith CH, Buchanan W, et al. Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis. Annals of the Rheumatic Diseases 2001;60(12):1088‐94. - PMC - PubMed

Additional references

Altman 1996
    1. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage 1996;4(4):217‐43. - PubMed
Buckland‐Wright 1995
    1. Buckland‐Wright JC, Macfarlane DG, Williams SA, Ward RJ. Accuracy and precision of joint space width measurements in standard and macroradiographs of osteoarthritic knees. Annals of the Rheumatic Diseases 1995;54(11):872‐80. - PMC - PubMed
Chinn 2000
    1. Chinn S. A simple method for converting an odds ratio to effect size for use in meta‐analysis. Statistics in Medicine 2000;19(22):3127‐31. - PubMed
Clegg 2006
    1. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. New England Journal of Medicine 2006;354(8):795‐808. - PubMed
Cohen 1988
    1. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd Edition. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988.
da Costa 2012
    1. Costa BR, Rutjes AWS, Johnston BC, Reichenbach S, Nüesch E, Tonia T, Gemperli A, Guyatt G, Jüni P. Methods to convert continuous outcomes into odds ratios of treatment response and numbers needed to treat: meta‐epidemiological study. International Journal of Epidemiology 2012; Vol. 41, issue 5:1445‐59. - PubMed
Dickersin 1994
    1. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309(6964):1286‐91. - PMC - PubMed
Dieppe 2005
    1. Dieppe P. Disease modification in osteoarthritis: are drugs the answer?. Arthritis and Rheumatism 2005;52(7):1956‐9. - PubMed
Egger 2001
    1. Egger M, Smith GD. Principles of and procedures for systematic reviews. In: Egger M, Smith GD, Altman DG editor(s). Systematic Reviews in Health Care: Meta‐Analysis in Context. London: BMJ Books, 2001:23‐42.
Egger 2003
    1. Egger M, Juni P, Bartlett C, Holenstein F, Sterne J. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technology Assessment (Winchester, England) 2003;7(1):1‐76. - PubMed
European Commission 2010
    1. European Commission. Guidelines on Medical Devices. Clinical Investigations: Serious Adverse Event Reporting Under Directives 90/385/EEC and 93/42/EEC, 2010. ec.europa.eu/health/medical‐devices/files/meddev/2_7_3_en.pdf. (accessed 7 October 2012).
Golub 1993
    1. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Kawai T, Hamasaki T, et al. inventors, Kuraray Co, Ltd. assignee. Method to reduce connective tissue destruction. United States patent 5,258,371 Nov 3, 1993.
Greenwald 1994
    1. Greenwald RA. Treatment of destructive arthritis disorders with MMP inhibitors. Annals of the New York Academy of Sciences 1994;731:181‐98. - PubMed
Guyatt 2008
    1. Guyatt G, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Schunemann HJ. GRADE: what is "quality of evidence" and why is it important to clinicians?. BMJ 2008;336:995‐8. - PMC - PubMed
Guyatt 2011
    1. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso‐Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence ‐ imprecision. Journal of Clinical Epidemiology 2011;64:1283‐93. - PubMed
Gøtzsche 2007
    1. Gøtzsche PC, Hróbjartsson A, Maric K, Tendal B. Data extraction errors in meta‐analyses that use standardized mean differences. JAMA 2007;298(4):430‐7. - PubMed
Hellio 2009
    1. Hellio Le Graverand‐Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed?. Osteoarthritis Cartilage 2009;17(11):1393‐401. - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. - PMC - PubMed
Higgins 2011
    1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Juni 2001
    1. Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6. - PMC - PubMed
Juni 2006
    1. Juni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approach to treating the individual. Best Practice and Research. Clinical Rheumatology 2006;20(4):721‐40. - PubMed
Lequesne 1995
    1. Lequesne M. Quantitative measurements of joint space during progression of osteoarthritis: chondrometry. In: Kuettner K, Goldberg V editor(s). Osteoarthritic Disorders. Rosemont (IL): American Academy of Orthopaedic Surgeons, 1995:427‐44.
Mazzuca 2006
    1. Mazzuca SA, Brandt KD, Katz BP, Lane KA, Buckwalter KA. Comparison of quantitative and semiquantitative indicators of joint space narrowing in subjects with knee osteoarthritis. Annals of the Rheumatic Diseases 2006;65(1):64‐8. - PMC - PubMed
Merle‐Vincent 2007
    1. Merle‐Vincent F, Vignon E, Brandt K, Piperno M, Coury‐Lucas F, Conrozier T, et al. Superiority of the Lyon schuss view over the standing anteroposterior view for detecting joint space narrowing, especially in the lateral tibiofemoral compartment, in early knee osteoarthritis. Annals of the Rheumatic Diseases 2007;66(6):747‐53. - PMC - PubMed
Nuesch 2009a
    1. Nuesch E, Rutjes AW, Husni E, Welch V, Juni P. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews 2009;7(4):CD003115. [DOI: 10.1002/14651858.CD003115.pub3; PUBMED: 19821302] - DOI - PubMed
Nuesch 2009c
    1. Nuesch E, Trelle S, Reichenbach S, Rutjes AWS, Burgi E, Scherer M, et al. The effects of the exclusion of patients from the analysis in randomised controlled trials: meta‐epidemiological study. BMJ 2009;339:b3244. [DOI: 10.1136/bmj.b3244; PUBMED: 19736281] - DOI - PMC - PubMed
Ornetti 2009
    1. Ornetti P, Brandt K, Hellio‐Le Graverand MP, Hochberg M, Hunter DJ, Kloppenburg M, et al. OARSI‐OMERACT definition of relevant radiological progression in hip/knee osteoarthritis. Osteoarthritis Cartilage 2009;17(7):842‐9. - PMC - PubMed
Pham 2004
    1. Pham T, Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al. OMERACT‐OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage 2004;12(5):389‐99. - PubMed
Pogue 1997
    1. Pogue JM, Yusuf S. Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta‐Analysis. Controlled Clinical Trials 1997;18:580‐593. - PubMed
Reichenbach 2007
    1. Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. Meta‐analysis: chondroitin for osteoarthritis of the knee or hip. Annals of Internal Medicine 2007;146(8):580‐90. - PubMed
Reichenbach 2010
    1. Reichenbach S, Rutjes AW, Nuesch E, Trelle S, Juni P. Joint lavage for osteoarthritis of the knee. Cochrane Database of Systematic Reviews 2010;12(5):CD007320. [DOI: 10.1002/14651858.CD007320.pub2; PUBMED: 20464751] - DOI - PubMed
RevMan 2011 [Computer program]
    1. The Nordic Cochrane Centre. The Cochrane Collaboration. Review Manager (RevMan). Version 5.1. Copenhagen: The Nordic Cochrane Centre. The Cochrane Collaboration, 2011.
Rubin 2000
    1. Rubin BK, Tamaoki J. Macrolide antibiotics as biological response modifiers. Current Opinion in Investigational Drugs 2000;1(2):169‐72. - PubMed
Rucker 2008
    1. Rücker G, Schwarzer G, Carpenter JR, Schumacher M. Undue reliance on I(2) in assessing heterogeneity may mislead. BMC Medical Research Methodology 2008;8(1):79. - PMC - PubMed
Rutjes 2009a
    1. Rutjes AW, Nuesch E, Sterchi R, Kalichman L, Hendriks E, Osiri M, et al. Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database of Systematic Reviews 2009;7(4):CD002823. [DOI: 10.1002/14651858.CD002823.pub2; PUBMED: 19821296] - DOI - PMC - PubMed
Rutjes 2009b
    1. Rutjes AW, Nuesch E, Reichenbach S, Juni P. S‐Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews 2009;7(4):CD007321. [DOI: 10.1002/14651858.CD007321.pub2; PUBMED: 19821403] - DOI - PMC - PubMed
Rutjes 2010
    1. Rutjes AW, Nuesch E, Sterchi R, Juni P. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews 2010;20(1):CD003132. [DOI: 10.1002/14651858.CD003132.pub2; PUBMED: 20091539] - DOI - PubMed
Rutjes 2012
    1. Rutjes AW, Jüni P, Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta‐analysis. Annals of Internal Medicine 2012;157(3):180‐91. - PubMed
Shapiro1997
    1. Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Archives of Dermatology 1997;133(10):1224‐30. - PubMed
Shlopov 1999
    1. Shlopov BV, Smith GN Jr, Cole AA, Hasty KA. Differential patterns of response to doxycycline and transforming growth factor beta1 in the down‐regulation of collagenases in osteoarthritic and normal human chondrocytes. Arthritis and Rheumatism 1999;42(4):719‐27. - PubMed
Smith 1996
    1. Smith GN Jr, Brandt KD, Hasty KA. Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity. Arthritis and Rheumatism 1996;39(2):235‐44. - PubMed
Towheed 2005
    1. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database of Systematic Reviews 2005;18(2):CD002946. [DOI: 10.1002/14651858.CD002946.pub2] - DOI - PMC - PubMed
Vlad 2007
    1. Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: why do trial results differ?. Arthritis and Rheumatism 2007;56(7):2267‐77. - PubMed
Wandel 2010
    1. Wandel S, Juni P, Tendal B, Nuesch E, Villiger PM, Welton NJ, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta‐analysis. BMJ (Clinical research ed.) 2010;341:c4675. [PUBMED: 20847017] - PMC - PubMed
Yu 1992
    1. Yu LP Jr, Smith GN Jr, Brandt KD, Myers SL, O'Connor BL, Brandt DA. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis and Rheumatism 1992;35(10):1150‐9. - PubMed
Zhang 2011
    1. Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, Roemer F, McCulloch C, Felson DT. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis and Rheumatism 2011;63(3):691‐9. - PMC - PubMed

References to other published versions of this review

Nuesch 2009b
    1. Nuesch E, Rutjes AW, Trelle S, Reichenbach S, Juni P. Doxycycline for osteoarthritis of the knee or hip. Cochrane Database of Systematic Reviews 2009;7(4):CD007323. [DOI: 10.1002/14651858.CD007323.pub2; PUBMED: 19821404] - DOI - PubMed

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