Advertisement

OARSI guidelines for the non-surgical management of knee osteoarthritis

Open ArchivePublished:February 14, 2014DOI:https://doi.org/10.1016/j.joca.2014.01.003

      Summary

      Objective

      To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis (OA), intended to inform patients, physicians, and allied healthcare professionals worldwide.

      Method

      Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the OA literature, 29 treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OA Research Society International (OARSI) evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using Assessment of Multiple Systematic Reviews (AMSTAR) criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical sub-phenotypes. Consensus recommendations were produced using the RAND/UCLA Appropriateness Method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical sub-phenotypes and accompanied by 1–10 risk and benefit scores.

      Results

      Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical sub-phenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral non-steroidal anti-inflammatory drugs (NSAIDs; COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical sub-phenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation).

      Conclusion

      These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

      Keywords

      Introduction

      Osteoarthritis (OA) of the knee is a major cause of pain and locomotor disability worldwide. In January 2010, the OA Research Society International (OARSI) published an update to their evidence-based, consensus recommendations for the treatment of OA of the hip and knee
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
      . The 2010 guidelines update followed two previous OARSI guidelines statements
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.
      and included systematic reviews (SRs) of the evidence for relevant therapies and critical appraisals of existing guidelines. Since the publication of the 2010 OARSI guidelines, the evidence base on knee OA treatment has evolved. This guidelines statement aims to incorporate evidence from these recent publications, in addition to the best-available previously published research, to assess where previous treatment recommendations should be modified or expanded to include new OA treatments. Because clinical considerations and availability of evidence between knee OA and hip OA treatments differ, the present guidelines sought to focus specifically on treatment of primary OA of the knee.
      For the present guidelines, we endeavored to enhance the applicability of treatment recommendations by stratifying for relevant co-morbidities, and for the presence of OA in joints other than the knee(s). To synthesize the scientific literature and expert opinion, we adopted the RAND/University of California, Los Angeles Appropriateness method
      • Fitch K.
      • Bernstein S.
      • Aguilar M.D.
      • Burnand B.
      • LaCalle J.R.
      • Lazaro P.
      • et al.
      The RAND/UCLA Appropriateness Method User's Manual.
      and used a modified Delphi method to achieve expert consensus closely integrated with empirical evidence.
      This statement updates the previous OARSI recommendations, incorporating literature published between January 2009 and March 2013, to scrutinize the safety and efficacy of new therapies for OA and reexamine existing therapies in light of recent evidence. These recommendations are intended to be used in conjunction with individual patient and physician's values and judgments to optimize OA treatment for different needs. These guidelines are intended for use by practitioners internationally, based on expert views of the relative safety and efficacy of available treatments for OA, irrespective of healthcare reimbursement policies or popular treatment practices.

      Methodology

      Literature search

      Our strategy was to build on the prior OARSI literature review and guidelines by searching for meta-analyses, SRs and randomized controlled trials (RCTs) in the period subsequent to the 2010 guidelines search. The initial literature search was conducted in the first quarter of 2012, and was based on treatments from the OARSI 2010 guidelines in addition to new treatments proposed by the Osteoarthritis Guidelines Development Group (OAGDG). The search was last updated in March 2013.
      We deployed electronic searches in Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials using relevant subject headings and keywords and then hand-searched the reference lists of all retrieved studies and abstracts presented at pertinent scientific meetings. Publications eligible for inclusion in our literature summary were (1) the most current SRs and/or meta-analyses and (2) any randomized clinical trials published subsequent to those SRs. If multiple SRs were published in a similar time period, all were included. If no SRs or meta-analyses were available, all published RCTs were included.

      Literature summary

      Our approach to summation of the evidence was to update the literature summary for the prior recommendations with high-quality evidence that emerged subsequent to its publication in 2010. We selected the best-available evidence to inform guidelines development. Meta-analyses, SRs and RCTs were considered to be the highest level of evidence. The value of meta-analyses for a literature synthesis is that they provide insight across the range of available RCTs on a topic as well as forest plots, sensitivity analyses and pooled results. The data extraction team produced a summary for each intervention that included description of the study methodology with full citations, any reported safety information, and relevant outcomes including effect sizes.
      The quality and level of evidence available for each treatment modality was graded according to the following:
      Level/type of evidence: The highest level of available evidence used (e.g., SR and/or most current RCT).
      Quality of evidence: The methodological rigor of the highest level of evidence used. Meta-analyses and SRs were assigned a quality rating of “Good”, “Fair”, or “Poor” using the Assessment of Multiple Systematic Reviews Tool (AMSTAR). The Cochrane Risk of Bias Assessment Method was used to rate RCTs.
      Estimated Effect Sizes: If the level of evidence listed above included a meta-analysis, the Estimated Effect Size for pain versus control was stated from that meta-analysis. Only pooled effect sizes reported as a standardized mean difference (SMD) were reported.
      Thus, the expert panel was informed with the prior OARSI guideline publications, subsequent publications generated by the literature search, and a literature summary (Bibliography available as supplement). We provided the literature summary to the OAGDG in August of 2012.

      Composition of the expert panel

      The OAGDG expert panel was composed of 13 voting members and a patient advocate. This group was selected for its diverse expertise and experience in OA management. The panel included seven rheumatologists (NA, FB, GH, DH, KK, TM, FR), two orthopedic surgeons (HK, SL), two physical therapists (SBZ, ER), one primary care practitioner and clinical guidelines methodologist (MU), and one physical therapy and rehabilitation specialist (YH). These members have experience in both academic medicine and private practice, and also have expertise in clinical epidemiology and other research methodology (Appendix 1).

      Management of conflict of interest (COI)

      At the request of the OARSI Ethics Committee, all members of the OAGDG were required to complete a COI questionnaire to report any potential conflicts including consulting, grant support, practice revenue, intellectual property, etc. for each treatment (Appendix 1). During initial rounds of voting, OAGDG members were instructed to recuse themselves from voting on potentially conflicted treatment modalities. At the April 2013 OARSI meeting, OAGDG members updated disclosures and discussed these conflicts in person with an ethics committee member prior to the final round of voting. The Ethics Committee representative made a final determination regarding the level at which a potential conflict would disqualify an OAGDG member from voting on each treatment. Final disclosure and voting recusal results were twice distributed among the OAGDG to verify their accuracy.

      Role of funding source

      This project was commissioned and funded by OARSI, yet was developed independently by the OARSI Treatment Guidelines Committee. The funding source did not participate in the literature search; determination of study eligibility criteria; voting process; data analysis or interpretation; or manuscript preparation. The manuscript was reviewed and approved by OARSI's Executive Committee prior to release for public comment.
      OARSI receives sponsorship from Bioiberica, EMD Serono, Expanscience, Rottapharm/Madaus, Abbvie, Astellas, Bioventus, Boston Imaging Core Lab (BICL), Chondrometrics, Fidia Pharma USA, Flexion, Perceptive Informatics, Merck, Seikagaku, Servier, and Zimmer. No direct medical industry support was used or requested for guideline development. Guidelines development was a budgeted item in OARSI's annual budget.

      Formulation of recommendations

      Role of the expert panel

      The literature summary was released to the OAGDG in August of 2012. An updated literature summary was released in October 2012 to inform subsequent rounds of voting (Bibliography available in supplement). Their role was to use the evidence base along with their expert knowledge, to provide votes on the appropriateness of each treatment modality, according to RAND/UCLA methodology
      • Fitch K.
      • Bernstein S.
      • Aguilar M.D.
      • Burnand B.
      • LaCalle J.R.
      • Lazaro P.
      • et al.
      The RAND/UCLA Appropriateness Method User's Manual.
      , and also an assessment of benefit and risk. The RAND/UCLA methodology is a highly-established approach that was explicitly developed to leverage expert opinion about interventions in situations where the evidence may be incomplete.
      After an initial round of voting that occurred after viewing the evidence, but prior to any discussion, the results were scrutinized by the OAGDG using an online forum to generate discussion and clarifications. Subsequent rounds of voting were performed to with further stratifications of treatment modalities (e.g., non-steroidal anti-inflammatory drugs (NSAIDs) were split into non-selective, selective COX-2 inhibitors, and topical) in October of 2012, March of 2013, and during the OAGDG's face-to-face meeting in April of 2013.

      OA clinical sub-phenotypes

      In order to enhance the specificity of the treatment recommendations for individuals with varying health profiles and OA burden, we defined four clinical sub-phenotypes (Table I). The rationale for these stratifications was that co-morbidities and the presence of OA in other joints might influence treatment choices. However, in all situations the voting was focused on treatment of the knees, and not on treatment of the non-knee joints. The OAGDG also decided on treatments that might merit separate evaluation of symptomatic and structural outcomes.
      Table IStratification into sub-phenotypes
      OA joint typeKnee-only OA: Symptomatic OA in one or both knees only.
      Multiple-joint OA
      Defines a clinical sub-phenotype. Recommendations refer to treatment of the knee(s) in such individuals.
      : Symptomatic OA of the knee(s) in addition to other joints (e.g., hip, hand, spine, etc).
      Co-morbiditiesNo co-morbidities: The individual with OA has no pertinent co-morbid health concerns.
      Co-morbidities: The individual with OA has any of the following pertinent co-morbid health concerns: diabetes; hypertension; CV disease; renal failure; gastrointestinal (GI) bleeding; depression; or physical impairment limiting activity, including obesity.
      • Moderate co-morbidity risk
        For Oral NSAIDs (both non-selective and selective COX-2 inhibitors). Further stratification of risk categories was considered necessary for these treatments given the important safety implications and substantial availability of safety data.
        : The individual with OA has any of the following pertinent co-morbid health concerns: diabetes; advanced age; hypertension; CV disease; renal failure; GI complications; depression; or physical impairment limiting activity, including obesity.
      • High co-morbidity risk
        For Oral NSAIDs (both non-selective and selective COX-2 inhibitors). Further stratification of risk categories was considered necessary for these treatments given the important safety implications and substantial availability of safety data.
        : The individual with OA has risk factors such as history of GI bleed, myocardial infarction, chronic renal failure, etc.
      Defines a clinical sub-phenotype. Recommendations refer to treatment of the knee(s) in such individuals.
      For Oral NSAIDs (both non-selective and selective COX-2 inhibitors). Further stratification of risk categories was considered necessary for these treatments given the important safety implications and substantial availability of safety data.

      Voting and scoring

      For each treatment modality, the OAGDG voted on appropriateness using a nine-point scale (1–9), therapeutic benefit on a 10-point scale (1–10), and overall risk on a 10-point scale (1–10).
      According to the RAND/UCLA Appropriateness Method
      • Fitch K.
      • Bernstein S.
      • Aguilar M.D.
      • Burnand B.
      • LaCalle J.R.
      • Lazaro P.
      • et al.
      The RAND/UCLA Appropriateness Method User's Manual.
      , the panelists ranked the appropriateness of each treatment on a nine-point scale, in which a score in the range 1–3 is considered ‘inappropriate’, 4–6 ‘uncertain’, and 7–9 ‘appropriate’. We then pooled these scores to generate a median appropriateness score for each treatment according to patient sub-phenotype. In addition, according to RAND/UCLA methodology, we classified the presence of ‘disagreement’ among the votes for a treatment modality if greater than one-third fell in the opposite tertile to the median score [e.g., a vote was considered in “Disagreement” if it received an “Appropriate” median vote (≥7) with five of 13 members voting ”Not appropriate” (≤3)]. Finally, we classified a treatment as “Appropriate” if it received a median score of ≥7 without disagreement. A treatment was classified as “Not appropriate” if it received a median vote of ≤3 or lower without disagreement. A treatment receiving a score between 3 and 6, or a treatment with disagreement, was classified as “Uncertain”. An “Uncertain” recommendation can reflect either the ambiguous state of current evidence or equivocal appropriateness either due to a moderately unfavorable risk profile or to limited efficacy. However, the ‘uncertain’ classification is not intended to be a negative recommendation or preclude use of that therapy. Rather it indicates a role for physician–patient interaction in determining whether this treatment may have merit in the context of their individual characteristics, co-morbidities and preferences.
      Each OAGDG member also voted separately on the level of risk and the level of benefit associated with each treatment. Risk was scored from 1 (least risk) to 10 (most risk) and benefit was scored from 1 (no benefit) to 10 (most beneficial). The group's mean risk and benefit scores [along with 95% confidence intervals (CIs)] for each treatment are plotted separately as bar graphs within the guidelines statement (Appendix 2: Annotated Figure).
      The OARSI guidelines report was drafted after a face-to-face meeting and re-vote at the OAGDG meeting at the April 2013 OARSI World Congress. These guidelines provide recommendations according to the median “appropriateness” scores voted upon by a panel of expert physicians and researchers based on their knowledge and the literature summary.
      Figure 1 provides a summary of all treatments voted “Appropriate,” organized by clinical sub-phenotype. The OAGDG's median voting scores for appropriateness, upon which the recommendations are based, are appended in a summary table (Appendix 3). Also included are the OAGDG's mean risk scores, benefit scores, and composite benefit and risk scores for each treatment and clinical sub-phenotype. The composite benefit and risk score is the product of the benefit score (1–10) and the transposed risk score (where 1 = highest and 10 = safety) yielding a range of 1 (worst) to 100 (best).

      Public comment

      The guidelines report draft was disseminated for public comment between September 4th and 18th, 2013. At the conclusion of the public comment period, public responses to the guidelines report were distributed among the OAGDG in order to formulate an appropriate response. Consistent with the OAGDG's prior procedures, it was determined that omission of any research within the committee's original literature summary criteria would necessitate a re-vote on the treatment for which evidence was omitted. Additional evidence for balneotherapy and chondroitin was brought to the attention of the OAGDG during public comment, resulting in an update of the evidence report and a re-vote on each of these interventions by the OAGDG expert panel. To incorporate the new chondroitin evidence, pooled analyses of pain and function outcomes were conducted for randomized clinical trials of chondroitin in knee OA. The balneotherapy evidence was considered too heterogeneous to permit pooled analysis. The finalized guidelines report draft was submitted for publication following approval of the OARSI Executive Committee.

      Recommendations

      Non-pharmacological interventions

      Acupuncture

      Recommendation:
      • Uncertain
      Rationale:
      The efficacy of acupuncture for peripheral joint OA has been tested in numerous clinical trials. Trials using waiting list- or usual care control groups, have generally found a clinically relevant benefit, but those using a sham-acupuncture have been less positive
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • Lao L.
      • Yoo J.
      • Wieland S.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      . A recent pooled analysis of 16 RCTs found statistically significant benefit of acupuncture in sham-controlled trials, though this did not reach the investigators' threshold for clinical significance
      • Manheimer E.
      • Cheng K.
      • Linde K.
      • Lao L.
      • Yoo J.
      • Wieland S.
      • et al.
      Acupuncture for peripheral joint osteoarthritis.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): 0.28 (0.11–0.45)
        • Manheimer E.
        • Cheng K.
        • Linde K.
        • Lao L.
        • Yoo J.
        • Wieland S.
        • et al.
        Acupuncture for peripheral joint osteoarthritis.
        .
      • Function (SMD): 0.28 (0.09–0.46)
        • Manheimer E.
        • Cheng K.
        • Linde K.
        • Lao L.
        • Yoo J.
        • Wieland S.
        • et al.
        Acupuncture for peripheral joint osteoarthritis.
        .
      Figure thumbnail fx1

      Balneotherapy/spa therapy

      Recommendation:
      • Appropriate: individuals with multiple-joint OA and relevant co-morbidities
      • Uncertain: individuals without relevant co-morbidities
      • Uncertain: individuals with knee-only OA
      Rationale:
      Balneotherapy (defined as the use of baths containing thermal mineral waters) includes practices such as Dead Sea salt or mineral baths, sulfur baths, and radon-carbon dioxide baths. Two 2009 SRs and a 2009 RCT demonstrated benefit of balneotherapy for pain when compared with controls, but the methodologic quality of trials was poor and both reviews concluded that additional large and well-designed RCTs are needed
      • Falagas M.E.
      • Zarkadoulia E.
      • Rafailidis P.I.
      The therapeutic effect of balneotherapy: evaluation of the evidence from randomised controlled trials.
      • Harzy T.
      • Ghani N.
      • Akasbi N.
      • Bono W.
      • Nejjari C.
      Short- and long-term therapeutic effects of thermal mineral waters in knee osteoarthritis: a systematic review of randomized controlled trials.
      • Sherman G.
      • Zeller L.
      • Avriel A.
      • Friger M.
      • Harari M.
      • Sukenik S.
      Intermittent balneotherapy at the Dead Sea area for patients with knee osteoarthritis.
      . No significant safety concerns were found to be associated with balneotherapy, though reporting of adverse events was patchy among included trials
      • Harzy T.
      • Ghani N.
      • Akasbi N.
      • Bono W.
      • Nejjari C.
      Short- and long-term therapeutic effects of thermal mineral waters in knee osteoarthritis: a systematic review of randomized controlled trials.
      • Forestier R.
      • Desfour H.
      • Tessier J.M.
      • Francon A.
      • Foote A.M.
      • Genty C.
      • et al.
      Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial.
      . In the voting, balneotherapy was considered appropriate only for the sub-phenotype with multiple-joint OA and co-morbidities, due to paucity of treatment alternatives for that group.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Fair.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx2

      Biomechanical interventions

      Recommendation:
      • Appropriate
      Rationale:
      We recommend use of biomechanical interventions as directed by an appropriate specialist. A 2011 SR and three recent RCTs evaluated the effectiveness of knee braces, knee sleeves, and foot orthoses in conservative management of knee OA
      • Raja K.
      • Dewan N.
      Efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis: a systematic review.
      • Bennell K.L.
      • Bowles K.A.
      • Payne C.
      • Cicuttini F.
      • Williamson E.
      • Forbes A.
      • et al.
      Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial.
      • van Raaij T.M.
      • Reijman M.
      • Brouwer R.W.
      • Bierma-Zeinstra S.M.
      • Verhaar J.A.
      Medial knee osteoarthritis treated by insoles or braces: a randomized trial.
      • Erhart J.C.
      • Mundermann A.
      • Elspas B.
      • Giori N.J.
      • Andriacchi T.P.
      Changes in knee adduction moment, pain, and functionality with a variable-stiffness walking shoe after 6 months.
      . One review suggested that knee braces and foot orthoses were effective in decreasing pain, joint stiffness, and drug dosage and also improved physical function, with insignificant adverse events
      • Raja K.
      • Dewan N.
      Efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis: a systematic review.
      . The conclusions were limited due to the heterogeneity and poor quality of available evidence. Results regarding lateral wedge insoles varied, with one RCT demonstrating no symptomatic or structural benefits
      • Bennell K.L.
      • Bowles K.A.
      • Payne C.
      • Cicuttini F.
      • Williamson E.
      • Forbes A.
      • et al.
      Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial.
      and another asserting their appropriateness as a possible alternative to valgus bracing for conservative medial knee OA treatment
      • van Raaij T.M.
      • Reijman M.
      • Brouwer R.W.
      • Bierma-Zeinstra S.M.
      • Verhaar J.A.
      Medial knee osteoarthritis treated by insoles or braces: a randomized trial.
      . One recent RCT found that variable-stiffness walking shoes reduced adduction movement and pain and improved function after 6 months of wear, though this benefit was not statistically significant when compared to constant-stiffness footwear
      • Erhart J.C.
      • Mundermann A.
      • Elspas B.
      • Giori N.J.
      • Andriacchi T.P.
      Changes in knee adduction moment, pain, and functionality with a variable-stiffness walking shoe after 6 months.
      .
      Quality assessment:
      • Level of evidence: SR of RCTs and non-randomized clinical trials.
      • Quality of evidence: Fair.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx3

      Cane (walking stick)

      Recommendation:
      • Appropriate: knee-only OA
      • Uncertain: multiple-joint OA
      Rationale:
      A single-blind RCT concluded that canes, in comparison with usual disease management, could be used to diminish pain and improve function and some aspects of quality of life in participants with knee OA
      • Jones A.
      • Silva P.G.
      • Silva A.C.
      • Colucci M.
      • Tuffanin A.
      • Jardim J.R.
      • et al.
      Impact of cane use on pain, function, general health and energy expenditure during gait in patients with knee osteoarthritis: a randomised controlled trial.
      . A substantial increase in energy expenditure in the first month of cane use was no longer a factor for concern by the end of the second month. There was a lack of evidence regarding cane use for individuals with multiple-joint type OA. This treatment could be inappropriate for some such individuals, as cane use to relieve knee pain may increase weight-bearing load on other affected joints (e.g., contralateral hand and hip joints), though further research is needed to confirm this.
      Quality assessment:
      • Level of overall evidence: Single-blind RCT.
      • Quality of overall evidence: Fair.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx4

      Crutches

      Recommendation:
      • Uncertain
      Rationale:
      There is insufficient evidence at this time to support the use of crutches as an appropriate alternative to cane use.
      Level of Evidence: Expert consensus of OAGDG.
      Quality of evidence: No available trials.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx5

      Electrotherapy/neuromuscular electrical stimulation

      Recommendation:
      • Not appropriate
      Rationale:
      A 2012 SR and meta-analysis demonstrated conflicting efficacy data for neuromuscular electrical stimulation and concluded that additional studies were needed to determine the efficacy of this intervention
      • Giggins O.
      • Fullen B.
      • Coughlan G.
      Neuromuscular electrical stimulation in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
      . A recent RCT showed no significant additive effect of electromyograph (EMG) biofeedback to strengthening exercise for pain, function and muscle strength in 40 participants with knee OA
      • Yilmaz O.O.
      • Senocak O.
      • Sahin E.
      • Baydar M.
      • Gulbahar S.
      • Bircan C.
      • et al.
      Efficacy of EMG-biofeedback in knee osteoarthritis.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Fair.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx6

      Exercise (land-based)

      Recommendation:
      • Appropriate
      Rationale:
      Four recent meta-analyses found small but clinically relevant short-term benefits of land-based exercise for pain and physical function in knee OA
      • Jansen M.J.
      • Viechtbauer W.
      • Lenssen A.F.
      • Hendriks E.J.
      • de Bie R.A.
      Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
      • Iversen M.D.
      Rehabilitation interventions for pain and disability in osteoarthritis: a review of interventions including exercise, manual techniques, and assistive devices.
      • Fransen M.
      • McConnell S.
      • Hernandez-Molina G.
      • Reichenbach S.
      Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthritis and Cartilage/OARS,.
      • Fransen M.
      • McConnell S.
      Exercise for osteoarthritis of the knee.
      . Meta-analyses investigating t'ai chi found strong favorable benefits of t'ai chi for improving pain and physical function in individuals with knee OA
      • Bannuru R.R.
      • Abariga S.
      • Wang C.
      How effective is tai chi mind-body therapy for knee osteoarthritis? A systematic review and meta-analysis.
      • Kang J.W.
      • Lee M.S.
      • Posadzki P.
      • Ernst E.
      T'ai chi for the treatment of osteoarthritis: a systematic review and meta-analysis.
      . The duration and type of exercise programs included in these meta-analyses varied widely, but interventions included a combination of elements including strength training, active range of motion exercise, and aerobic activity. Results were generally positive among land-based exercise type, and did not significantly favor any specific exercise regimens
      • Jansen M.J.
      • Viechtbauer W.
      • Lenssen A.F.
      • Hendriks E.J.
      • de Bie R.A.
      Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
      • Iversen M.D.
      Rehabilitation interventions for pain and disability in osteoarthritis: a review of interventions including exercise, manual techniques, and assistive devices.
      • Fransen M.
      • McConnell S.
      • Hernandez-Molina G.
      • Reichenbach S.
      Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthritis and Cartilage/OARS,.
      • Fransen M.
      • McConnell S.
      Exercise for osteoarthritis of the knee.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): Ranges from 0.34 (0.19–0.49)
        • Jansen M.J.
        • Viechtbauer W.
        • Lenssen A.F.
        • Hendriks E.J.
        • de Bie R.A.
        Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
        to 0.63 (0.39–0.87)
        • Bannuru R.R.
        • Abariga S.
        • Wang C.
        How effective is tai chi mind-body therapy for knee osteoarthritis? A systematic review and meta-analysis.
        .
      • Function (SMD): 0.25 (0.03–0.48)
        • Jansen M.J.
        • Viechtbauer W.
        • Lenssen A.F.
        • Hendriks E.J.
        • de Bie R.A.
        Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
        .
      Figure thumbnail fx7

      Exercise (water-based)

      Recommendation:
      • Appropriate
      Rationale:
      A 2007 SR investigating water-based exercise in knee and hip OA found small to moderate short-term benefits for function and quality of life, but only minor benefits for pain
      • Bartels E.M.
      • Lund H.
      • Hagen K.B.
      • Dagfinrud H.
      • Christensen R.
      • Danneskiold-Samsoe B.
      Aquatic exercise for the treatment of knee and hip osteoarthritis.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs and quasi-randomized trials.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain or Function: Not available.
      Figure thumbnail fx8

      Strength training

      Recommendation:
      • Appropriate
      Rationale:
      A 2011 meta-analysis and SR demonstrated moderate effect sizes of strength training for reducing pain and improving physical function compared with controls
      • Jansen M.J.
      • Viechtbauer W.
      • Lenssen A.F.
      • Hendriks E.J.
      • de Bie R.A.
      Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
      . Strength training programs primarily incorporate resistance-based lower limb and quadriceps strengthening exercises. Both weight-bearing and non-weight-bearing interventions were included, as well as group and individual programs. Participants experienced similarly significant improvement with each of these programs.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): 0.38 (0.23–0.54)
        • Jansen M.J.
        • Viechtbauer W.
        • Lenssen A.F.
        • Hendriks E.J.
        • de Bie R.A.
        Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
        .
      • Function (SMD): 0.41 (0.17–0.66)
        • Jansen M.J.
        • Viechtbauer W.
        • Lenssen A.F.
        • Hendriks E.J.
        • de Bie R.A.
        Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
        .
      Figure thumbnail fx9

      Self-management and education

      Recommendation:
      • Appropriate
      Rationale:
      A 2011 meta-analysis and a 2005 meta-analysis found moderate benefits of self-management programs for chronic musculoskeletal pain conditions on measures of pain and disability
      • Du S.
      • Yuan C.
      • Xiao X.
      • Chu J.
      • Qiu Y.
      • Qian H.
      Self-management programs for chronic musculoskeletal pain conditions: a systematic review and meta-analysis.
      • Chondosh J.
      • Morton S.C.
      • Mojica W.
      • Maglione M.
      • Suttorp M.J.
      • Hilton L.
      • et al.
      Meta-analysis: chronic disease self-management programs for older adults.
      . Analysis of arthritis-related disability showed only modest benefit. Recent randomized clinical trials indicated significant clinical benefits of self-management
      • Ravaud P.
      • Flipo R.M.
      • Boutron I.
      • Roy C.
      • Mahmoudi A.
      • Giraudeau B.
      • et al.
      ARTIST (osteoarthritis intervention standardized) study of standardised consultation versus usual care for patients with osteoarthritis of the knee in primary care in France: pragmatic randomised controlled trial.
      • Hurley M.V.
      • Walsh N.E.
      • Mitchell H.
      • Nicholas J.
      • Patel A.
      Long-term outcomes and costs of an integrated rehabilitation program for chronic knee pain: a pragmatic, cluster randomized, controlled trial.
      and suggested feasibility of implementation in primary care by means of group sessions
      • Hansson E.E.
      • Jonsson-Lundgren M.
      • Ronnheden A.M.
      • Sorensson E.
      • Bjarnung A.
      • Dahlberg L.E.
      Effect of an education programme for patients with osteoarthritis in primary care–a randomized controlled trial.
      and telephone-based sessions
      • Allen K.D.
      • Oddone E.Z.
      • Coffman C.J.
      • Datta S.K.
      • Juntilla K.A.
      • Lindquist J.H.
      • et al.
      Telephone-based self-management of osteoarthritis: a randomized trial.
      . Another RCT expressed reservations about the efficacy and practicality of such interventions
      • Ackerman I.N.
      • Buchbinder R.
      • Osborne R.H.
      Challenges in evaluating an Arthritis Self-Management Program for people with hip and knee osteoarthritis in real-world clinical settings.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Sizes for
      • Pain (SMD): Ranges from 0.06 (0.02–0.10)
        • Chondosh J.
        • Morton S.C.
        • Mojica W.
        • Maglione M.
        • Suttorp M.J.
        • Hilton L.
        • et al.
        Meta-analysis: chronic disease self-management programs for older adults.
        to 0.29 (0.17–0.41)
        • Du S.
        • Yuan C.
        • Xiao X.
        • Chu J.
        • Qiu Y.
        • Qian H.
        Self-management programs for chronic musculoskeletal pain conditions: a systematic review and meta-analysis.
        .
      Figure thumbnail fx10

      Transcutaneous electrical nerve stimulation (TENS)

      Recommendation:
      • Uncertain: knee-only OA
      • Not appropriate: multiple-joint OA
      Rationale:
      A 2009 SR found inconclusive results regarding the effect of TENS for pain relief in knee OA
      • Rutjes A.W.
      • Nuesch E.
      • Sterchi R.
      • Kalichman L.
      • Hendriks E.
      • Osiri M.
      • et al.
      Transcutaneous electrostimulation for osteoarthritis of the knee.
      . Due to the low methodological quality and high heterogeneity of included trials, no effect size was reported as a primary result. The review found no evidence to suggest that TENS was unsafe. A recent RCT revealed no statistically significant difference for pain between TENS and a sham TENS procedure
      • Atamaz F.C.
      • Durmaz B.
      • Baydar M.
      • Demircioglu O.Y.
      • Iyiyapici A.
      • Kuran B.
      • et al.
      Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy in knee osteoarthritis: a double-blind, randomized, controlled, multicenter study.
      .
      Quality assessment:
      • Level of evidence: SR of randomized or quasi-randomized clinical trials.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): 0.07 (−0.32–0.46)
        • Rutjes A.W.
        • Nuesch E.
        • Sterchi R.
        • Kalichman L.
        • Hendriks E.
        • Osiri M.
        • et al.
        Transcutaneous electrostimulation for osteoarthritis of the knee.
        .
      • Function (SMD): 0.34 (0.14–0.54)
        • Rutjes A.W.
        • Nuesch E.
        • Sterchi R.
        • Kalichman L.
        • Hendriks E.
        • Osiri M.
        • et al.
        Transcutaneous electrostimulation for osteoarthritis of the knee.
        .
      Figure thumbnail fx11

      Weight management

      Recommendation:
      • Appropriate
      Rationale:
      A 2007 SR and meta-analysis found reductions in pain and physical disability for overweight participants with knee OA after a moderate weight reduction regime
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis.
      . The analysis supported the notion that a weight loss of 5% should be achieved within a 20-week period—that is, 0.25% per week—for the treatment to be efficacious.
      Quality assessment:
      • Level of overall evidence: SR and meta-analysis of RCTs.
      • Quality of overall evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): 0.20 (0.0–0.39)
        • Christensen R.
        • Bartels E.M.
        • Astrup A.
        • Bliddal H.
        Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis.
        .
      • Function (SMD): 0.23 (0.04–0.42)
        • Christensen R.
        • Bartels E.M.
        • Astrup A.
        • Bliddal H.
        Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis.
        .
      Figure thumbnail fx12

      Ultrasound

      Recommendation:
      • Uncertain: knee-only OA
      • Not appropriate: multiple-joint OA
      Rationale:
      Two 2010 SRs suggested a possible beneficial effect of ultrasound for knee OA; however, the quality of the analyzed evidence was low
      • Rutjes A.W.
      • Nuesch E.
      • Sterchi R.
      • Juni P.
      Therapeutic ultrasound for osteoarthritis of the knee or hip.
      • Loyola-Sanchez A.
      • Richardson J.
      • MacIntyre N.J.
      Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis.
      . No safety risks were reported to be associated with ultrasound. A 2012 RCT found no significant differences between the groups for pain or function
      • Ulus Y.
      • Tander B.
      • Akyol Y.
      • Durmus D.
      • Buyukakincak O.
      • Gul U.
      • et al.
      Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): Ranges from 0.49 (0.18–0.79)
      • Loyola-Sanchez A.
      • Richardson J.
      • MacIntyre N.J.
      Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis.
      to 0.49 (0.23–0.76)
      • Rutjes A.W.
      • Nuesch E.
      • Sterchi R.
      • Juni P.
      Therapeutic ultrasound for osteoarthritis of the knee or hip.
      .
      Figure thumbnail fx13

      Pharmacological interventions

      Acetaminophen (paracetamol)

      Recommendation:
      • Appropriate: individuals without relevant co-morbidities
      • Uncertain: individuals with relevant co-morbidities
      Rationale:
      A 2010 SR and meta-analysis abstract found a low-level effect of acetaminophen for OA pain, suggesting usefulness as a short-term analgesic
      • Bannuru R.R.D.U.
      • McAlindon T.E.
      Reassessing the role of acetaminophen in osteoarthritis: systematic review and meta-analysis.
      . However, both this review and a 2012 safety review indicated increased risk of adverse events associated with acetaminophen use, including GI adverse events and multi-organ failure
      • Craig D.G.
      • Bates C.M.
      • Davidson J.S.
      • Martin K.G.
      • Hayes P.C.
      • Simpson K.J.
      Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity.
      . These recent findings suggest greater risk associated with acetaminophen use (particularly when used for extended durations) than previously thought. Thus, we recommend conservative dosing and treatment duration consistent with approved prescribing limits.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): 0.18 (0.11–0.25)
      • Bannuru R.R.D.U.
      • McAlindon T.E.
      Reassessing the role of acetaminophen in osteoarthritis: systematic review and meta-analysis.
      .
      Figure thumbnail fx14

      Avocado soybean unsaponfiables (ASU)

      Recommendation:
      • Uncertain
      Rationale:
      A 2008 SR and meta-analysis comparing ASU with oral placebo in 644 patients with knee and hip OA demonstrated a small benefit for pain in favor of ASU that was more evident in knee OA
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): 0.39 (0.01–0.76)
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials.
      .
      Figure thumbnail fx15

      Capsaicin

      Recommendation:
      • Appropriate: knee-only OA without relevant co-morbidities
      • Uncertain: multi-joint OA and individuals with relevant co-morbidities
      Rationale:
      Citing a previous SR
      • Mason L.
      • Moore R.A.
      • Derry S.
      • Edwards J.E.
      • McQuay H.J.
      Systematic review of topical capsaicin for the treatment of chronic pain.
      and RCT
      • Kosuwon W.
      • Sirichatiwapee W.
      • Wisanuyotin T.
      • Jeeravipoolvarn P.
      • Laupattarakasem W.
      Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo.
      , a 2011 comparative efficacy review concluded that topical capsaicin was superior to placebo for 50% pain reduction (number needed to treat 8.1) but associated with increased local adverse events [54% vs 15%; relative risk (RR) 3.6 (95% CI: 2.6–5.0)] and withdrawals due to adverse events [13% vs 3%; RR 4.0 (95% CI: 2.3–6.8)]
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      .
      Quality assessment:
      • Level of evidence: SR of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain and Physical function: Not available.
      Figure thumbnail fx16

      Corticosteroids (intra-articular injection)

      Recommendation:
      • Appropriate
      Rationale:
      Two recent SRs demonstrated clinically significant short-term decreases in pain
      • Bannuru R.R.
      • Natov N.S.
      • Obadan I.E.
      • Price L.L.
      • Schmid C.H.
      • McAlindon T.E.
      Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
      • Bellamy N.
      • Campbell J.
      • Robinson V.
      • Gee T.
      • Bourne R.
      • Wells G.
      Intraarticular corticosteroid for treatment of osteoarthritis of the knee.
      . Short-term effects were found to be significantly greater than those of intra-articular hyaluronic acid. The reviews concluded that for longer duration of pain relief, clinicians should consider other treatment options.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain: Not available.
      Figure thumbnail fx17

      Chondroitin (for symptom relief)

      Recommendation:
      • Uncertain

      Chondroitin (for disease modification)

      Recommendation:
      • Not appropriate
      Rationale:
      Four SRs examined the efficacy of chondroitin for knee OA
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      • Reichenbach S.
      • Sterchi R.
      • Scherer M.
      • Trelle S.
      • Burgi E.
      • Burgi U.
      • et al.
      Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
      • Hochberg M.C.
      • Zhan M.
      • Langenberg P.
      The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate.
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      . Results differed regarding symptom relief, with some reviews finding no significant benefit of chondroitin over placebo for pain and others finding large effect sizes in favor of chondroitin. A high degree of heterogeneity and small, poor quality included trials in one meta-analysis made definitive assessment difficult
      • Reichenbach S.
      • Sterchi R.
      • Scherer M.
      • Trelle S.
      • Burgi E.
      • Burgi U.
      • et al.
      Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
      . Effect sizes for pain were small to non-existent [e.g., 0.01 (95% CI: −0.07–0.13)] in stratified analyses of large-scale, high-quality trials
      • Reichenbach S.
      • Sterchi R.
      • Scherer M.
      • Trelle S.
      • Burgi E.
      • Burgi U.
      • et al.
      Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
      . Another meta-analysis showed no statistically significant benefit of chondroitin when compared with placebo
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      . Results were also mixed regarding disease modification, with only some studies showing statistically significant decreases in joint-space narrowing (JSN) over longer (2-year) follow-up
      • Hochberg M.C.
      • Zhan M.
      • Langenberg P.
      The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate.
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): Ranges from 0.13 (0.00–0.27)
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      to 0.75 (0.50–0.99)
      • Reichenbach S.
      • Sterchi R.
      • Scherer M.
      • Trelle S.
      • Burgi E.
      • Burgi U.
      • et al.
      Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
      .
      Estimated Effect Size for reduction in rate of decline of minimum joint-space width (SMD): Ranges from 0.26 (0.14–0.38)
      • Hochberg M.C.
      • Zhan M.
      • Langenberg P.
      The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate.
      to 0.30 (0.00–0.59)
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      .
      Figure thumbnail fx18

      Diacerein

      Recommendation:
      • Uncertain
      Rationale:
      A 2010 SR and meta-analysis found a small but statistically significant short-term benefit of diacerein for pain compared with placebo, despite a large degree of heterogeneity among included trials
      • Bartels E.M.
      • Bliddal H.
      • Schondorff P.K.
      • Altman R.D.
      • Zhang W.
      • Christensen R.
      Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis and Cartilage/OARS.
      . The review also found a significantly increased risk of diarrhea among those receiving diacerein [RR = 3.51 (95% CI: 2.55–4.83, P < 0.001)]. The study authors suggested that diacerein may still be a safer alternative to NSAIDs, which are associated with more severe adverse events, but also concluded that more high-quality trials are needed to confirm the efficacy of diacerein and rule out publication bias.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): 0.24 (0.08–0.39)
        • Bartels E.M.
        • Bliddal H.
        • Schondorff P.K.
        • Altman R.D.
        • Zhang W.
        • Christensen R.
        Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis and Cartilage/OARS.
        .
      • Function (SMD): 0.14 (0.03–0.25)
        • Bartels E.M.
        • Bliddal H.
        • Schondorff P.K.
        • Altman R.D.
        • Zhang W.
        • Christensen R.
        Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis and Cartilage/OARS.
        .
      Figure thumbnail fx19

      Duloxetine

      Recommendation:
      • Appropriate: individuals without co-morbidities
      • Appropriate: individuals with multiple-joint OA and relevant co-morbidities
      • Uncertain: knee-only OA with relevant co-morbidities
      Rationale:
      A 2012 SR and a 2011 RCT comparing duloxetine with oral placebo found duloxetine efficacious and tolerable for chronic pain associated with OA
      • Citrome L.
      • Weiss-Citrome A.
      A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed?.
      • Frakes E.P.
      • Risser R.C.
      • Ball T.D.
      • Hochberg M.C.
      • Wohlreich M.M.
      Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial.
      . Pooled analysis found that 16.3% of the patients who received duloxetine withdrew due to adverse events compared with 5.6% of those receiving placebo
      • Citrome L.
      • Weiss-Citrome A.
      A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed?.
      . The most commonly reported adverse events included nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis. While duloxetine was considered appropriate for most clinical sub-phenotypes, associated adverse events and availability of more targeted therapies predicated uncertain appropriateness for individuals with knee-only OA and co-morbidities.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Fair.
      Estimated Effect Size for Pain: Not available.
      Figure thumbnail fx20

      Glucosamine (for symptom relief)

      Recommendation:
      • Uncertain

      Glucosamine (for disease modification)

      Recommendation:
      • Not appropriate
      Rationale:
      Two SRs comparing glucosamine with placebo for OA found mixed results regarding the efficacy of glucosamine for pain relief and physical function
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      • Towheed T.E.
      • Maxwell L.
      • Anastassiades T.P.
      • Shea B.
      • Houpt J.
      • Robinson V.
      • et al.
      Glucosamine therapy for treating osteoarthritis.
      . One review found no statistically significant benefit of glucosamine for pain
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      and the other found a positive effect for pain that did not reach statistical significance when confined to studies with adequate allocation concealment
      • Towheed T.E.
      • Maxwell L.
      • Anastassiades T.P.
      • Shea B.
      • Houpt J.
      • Robinson V.
      • et al.
      Glucosamine therapy for treating osteoarthritis.
      . The most recent meta-analysis
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      included a large, NIH-funded RCT (GAIT study) that had a null result for glucosamine for pain relief
      • Clegg D.O.
      • Reda D.J.
      • Harris C.L.
      • Klein M.A.
      • O'Dell J.R.
      • Hooper M.M.
      • et al.
      Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
      . Regarding disease modification, a SR found no statistically significant differences in minimum JSN between glucosamine and placebo at 1-year follow-up, though a moderate effect was detected at 3 years
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      . A 2011 safety review found that long-term use of glucosamine was not associated with cardiovascular (CV) safety risks
      • Palma Dos Reis R.
      • Giacovelli G.
      • Girolami F.
      • Andre R.
      • Bonazzi A.
      • Rovati L.C.
      Crystalline glucosamine sulfate in the treatment of osteoarthritis: evidence of long-term cardiovascular safety from clinical trials.
      . Two more meta-analyses found no increase in overall adverse events relative to placebo
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      • Towheed T.E.
      • Maxwell L.
      • Anastassiades T.P.
      • Shea B.
      • Houpt J.
      • Robinson V.
      • et al.
      Glucosamine therapy for treating osteoarthritis.
      . Small pooled effect sizes (especially for the large high-quality studies), inconsistency in results between industry-sponsored and independent trials, and heterogeneity among studies generated uncertainty as to the appropriateness of glucosamine.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): Ranges from 0.17 (0.05, 0.28)
      • Wandel S.
      • Juni P.
      • Tendal B.
      • Nuesch E.
      • Villiger P.M.
      • Welton N.J.
      • et al.
      Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
      to 0.47 (0.23–0.72)
      • Towheed T.E.
      • Maxwell L.
      • Anastassiades T.P.
      • Shea B.
      • Houpt J.
      • Robinson V.
      • et al.
      Glucosamine therapy for treating osteoarthritis.
      .
      Estimated Effect Size for reduction in rate of decline of minimum joint-space width (SMD): 0.08 (−0.12–0.27)
      • Lee Y.H.
      • Woo J.H.
      • Choi S.J.
      • Ji J.D.
      • Song G.G.
      Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
      .
      Figure thumbnail fx21

      Hyaluronic acid (intra-articular injection)

      Recommendation:
      • Uncertain: knee-only OA
      • Not appropriate: multiple-joint OA
      Rationale:
      A recent SR demonstrated small but significant efficacy of intra-articular hyaluronic acid for knee OA pain by week 4 with a peak at week 8 (reaching moderate clinical significance) and residual benefit until 24 weeks
      • Bannuru R.R.
      • Natov N.S.
      • Dasi U.R.
      • Schmid C.H.
      • McAlindon T.E.
      Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and Cartilage/OARS.
      . Another review found moderate benefits of IAHA for pain and physical function in knee OA, though sensitivity analyses including larger trials or trials with adequate blinding found only small effect size for pain
      • Rutjes A.W.
      • Juni P.
      • da Costa B.R.
      • Trelle S.
      • Nuesch E.
      • Reichenbach S.
      Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.
      . A third review comparing IAHA with intra-articular corticosteroids (IACS) found that while IACS provided greater benefit for pain 2 weeks after injection, IAHA provided greater benefit at 12 and 26 weeks
      • Bannuru R.R.
      • Natov N.S.
      • Obadan I.E.
      • Price L.L.
      • Schmid C.H.
      • McAlindon T.E.
      Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
      . Inconsistent conclusions among the meta-analyses and conflicting results regarding IAHA's safety influenced panel votes.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for
      • Pain (SMD): Ranges from 0.37 (0.28–0.46)
        • Rutjes A.W.
        • Juni P.
        • da Costa B.R.
        • Trelle S.
        • Nuesch E.
        • Reichenbach S.
        Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.
        to 0.46 (0.28–0.65)
        • Bannuru R.R.
        • Natov N.S.
        • Dasi U.R.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and Cartilage/OARS.
        .
      • Physical function: 0.33 (0.22–0.43)
        • Rutjes A.W.
        • Juni P.
        • da Costa B.R.
        • Trelle S.
        • Nuesch E.
        • Reichenbach S.
        Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.
        to 0.31 (0.11–0.51)
        • Bannuru R.R.
        • Natov N.S.
        • Dasi U.R.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and Cartilage/OARS.
        .
      Figure thumbnail fx22

      NSAIDs (oral non-selective NSAIDs)

      Recommendation:
      • Appropriate: individuals without co-morbidities
      • Uncertain: individuals with moderate co-morbidity risk
      • Not appropriate: individuals with high co-morbidity risk
      Gastroprotection:
      • We do not recommend proton-pump inhibitor (PPI) co-prescription with non-selective oral NSAIDs for those with no co-morbidity risk. For those with moderate or high co-morbidity risk receiving oral non-selective NSAIDs, we recommend PPI co-prescription, though we strongly advise against using oral NSAIDs altogether for individuals with high co-morbidity risk.
      Rationale:
      A 2011 comparative effectiveness review indicated that NSAIDs are associated with increased risk of serious GI, CV, and renal harms compared with placebo
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      . Nevertheless, the CV safety of naproxen appeared moderately superior to that of any COX-2 selective NSAID in two SRs of RCTs. Among currently marketed NSAIDs, diclofenac is associated with the highest rate of hepatic laboratory abnormalities. Due to serious safety risks associated with oral NSAID use, we recommend conservative dosing and treatment duration consistent with approved prescribing limits.
      The 2011 Cochrane review found that co-prescribing of PPIs, misoprostol, and H2-antagonists reduced the risk of endoscopically detected gastroduodenal ulcers compared with placebo in persons prescribed non-selective NSAIDs
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): 0.37 (0.26–0.49)
      • Lee C.
      • Hunsche E.
      • Balshaw R.
      • Kong S.X.
      • Schnitzer T.J.
      Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis.
      .
      Figure thumbnail fx23

      NSAIDs (oral COX-2 inhibitors)

      • Appropriate: individuals without co-morbidities
      • Appropriate: multiple-joint OA with moderate co-morbidity risk
      • Uncertain: knee-only OA with moderate co-morbidity risk
      • Not appropriate: individuals with high co-morbidity risk
      Gastroprotection:
      • We do not recommend PPI co-prescription with COX-2 selective oral NSAIDs for those with no co-morbidity risk. For individuals with moderate co-morbidity risk, we advocate neither for nor against PPI co-prescription. For individuals with high co-morbidity risk receiving oral COX-2 selective NSAIDs, we recommend PPI co-prescription, though we strongly advise against using oral NSAIDs altogether for such individuals.
      Rationale:
      A 2011 comparative effectiveness review found that relative to non-COX-2 selective NSAIDs, selective COX-2 inhibitors were better or comparably tolerated, though rates of serious adverse events were similar
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      . Celecoxib was associated with a lower risk of ulcer complications (RR 0.23, 95% CI: 0.07–0.76) compared with non-selective NSAIDs but a moderately higher risk of CV complications. Due to serious safety risks associated with oral NSAID use, we recommend conservative dosing and treatment duration consistent with US approved prescribing limits.
      Quality assessment based on Chou et al.
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      and Lee et al.
      • Lee C.
      • Hunsche E.
      • Balshaw R.
      • Kong S.X.
      • Schnitzer T.J.
      Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis.
      :
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain: 0.44 (0.33–0.55)
      • Lee C.
      • Hunsche E.
      • Balshaw R.
      • Kong S.X.
      • Schnitzer T.J.
      Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis.
      .
      Figure thumbnail fx24

      NSAIDs (topical)

      Recommendation:
      • Appropriate: individuals with knee-only OA
      • Uncertain: individuals with multiple-joint OA
      Rationale:
      A 2011 Cochrane comparative effectiveness review found comparable efficacy of topical and oral NSAIDs for knee OA
      • Chou R.
      • McDonagh M.S.
      • Nakamoto E.
      • Griffin J.
      Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
      . Topical NSAIDs were associated with lower risk of GI adverse events but higher risk of dermatological adverse events compared with oral NSAIDs. Overall, topical NSAIDs were considered to be safer and better tolerated compared with oral NSAIDs.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain: Not available.
      Figure thumbnail fx25

      Opioids (transdermal)

      Recommendation:
      • Uncertain
      Rationale:
      A 2009 SR and meta-analysis examining the efficacy of opioids for knee and hip OA found small effect sizes for pain and physical function for transdermal fentanyl
      • Nuesch E.
      • Rutjes A.W.
      • Husni E.
      • Welch V.
      • Juni P.
      Oral or transdermal opioids for osteoarthritis of the knee or hip.
      . Patients receiving some form of opioid therapy were four times as likely as patients receiving placebo to withdraw due to adverse events (RR 4.05, 95% CI: 3.06–5.38) and more than three times as likely to experience a serious adverse event (RR 3.35, 95% CI: 0.83–13.56). Thus, the study concluded that opioids offered limited usefulness in the long term.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain (SMD): Ranges from 0.22 (0.03–0.42) to 0.36 (0.26–0.47)
      • Nuesch E.
      • Rutjes A.W.
      • Husni E.
      • Welch V.
      • Juni P.
      Oral or transdermal opioids for osteoarthritis of the knee or hip.
      .
      Figure thumbnail fx26

      Opioids (oral)

      Recommendation:
      • Uncertain
      Rationale:
      Analyses of pain relief from a 2009 SR found a moderate effect size for codeine over placebo, a small to moderate benefit for oxycodone, and a small benefit for morphine in patients with OA of the knee or hip
      • Nuesch E.
      • Rutjes A.W.
      • Husni E.
      • Welch V.
      • Juni P.
      Oral or transdermal opioids for osteoarthritis of the knee or hip.
      . A 2006 review also found a small but statistically significant benefit for tramadol over placebo
      • Cepeda M.S.
      • Camargo F.
      • Zea C.
      • Valencia L.
      Tramadol for osteoarthritis.
      . However, patients receiving some form of opioid therapy were four times as likely as patients receiving placebo to withdraw due to adverse events (RR 4.05, 95% CI: 3.06–5.38) and more than three times as likely to experience a serious adverse event (RR 3.35, 95% CI: 0.83–13.56)
      • Nuesch E.
      • Rutjes A.W.
      • Husni E.
      • Welch V.
      • Juni P.
      Oral or transdermal opioids for osteoarthritis of the knee or hip.
      .
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain: Ranges from 0.36 (0.26–0.47) to 0.51 (0.01–1.01)
      • Nuesch E.
      • Rutjes A.W.
      • Husni E.
      • Welch V.
      • Juni P.
      Oral or transdermal opioids for osteoarthritis of the knee or hip.
      .
      Figure thumbnail fx27

      Risedronate

      Recommendation:
      • Not appropriate
      Rationale:
      Risedronate was evaluated primarily on its disease-modifying efficacy, as the majority of available evidence targets this outcome. A 2012 SR found that higher doses of risedronate (15 mg/d) did not reduce the signs or symptoms of OA, but did reduce the marker of cartilage degradation (CTX-II), which may contribute to attenuation of radiological progression of OA
      • Iwamoto J.
      • Takeda T.
      • Sato Y.
      • Matsumoto H.
      Effects of risedronate on osteoarthritis of the knee.
      . The review concluded that further RCTs would be needed to assess the efficacy of risedronate for symptoms, function, and progression of knee OA.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Poor.
      Estimated Effect Size for Pain: Not available.
      Figure thumbnail fx28

      Rosehip

      Recommendation:
      • Uncertain
      Rationale:
      A 2008 SR and meta-analysis of three small trials found a positive effect of rosehip powder for pain when compared with placebo, but the reviewers concluded that further evaluation in larger-scale trials is necessary due to the paucity of available data
      • Christensen R.
      • Bartels E.M.
      • Altman R.D.
      • Astrup A.
      • Bliddal H.
      Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?–a meta-analysis of randomized controlled trials.
      . Safety results from one included study did not provide conclusive results.
      Quality assessment:
      • Level of evidence: SR and meta-analysis of RCTs.
      • Quality of evidence: Good.
      Estimated Effect Size for Pain: 0.37 (0.13–0.60)
      • Christensen R.
      • Bartels E.M.
      • Altman R.D.
      • Astrup A.
      • Bliddal H.
      Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?–a meta-analysis of randomized controlled trials.
      .
      Figure thumbnail fx29

      Discussion

      These OARSI 2013 guidelines for the management of knee OA represent an update to the previous OARSI publications in 2010 and 2008
      • Zhang W.
      • Nuki G.
      • Moskowitz R.W.
      • Abramson S.
      • Altman R.D.
      • Arden N.K.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
      and used the original evidence and set of evaluated treatments as the base for a literature update. Their purpose is to disseminate a framework for treatment of knee OA to professionals involved in the management of this disorder, as well as patients, provider organizations and regulatory bodies. The guidelines were also developed for an International context, reflecting the constituency and perspective of OARSI, the sponsoring organization. These guidelines should be used in conjunction with individual patients' values and clinical judgment.
      We used the RAND/UCLA approach as a methodology for measuring expert opinion and reaching a classification for appropriateness of each treatment modality
      • Fitch K.
      • Bernstein S.
      • Aguilar M.D.
      • Burnand B.
      • LaCalle J.R.
      • Lazaro P.
      • et al.
      The RAND/UCLA Appropriateness Method User's Manual.
      . This well-established approach leverages expert opinion in relation to their synthesis of contemporary evidence. One advantage for the field of OA treatment is that it was explicitly developed to measure expert opinion in situations where the evidence may be incomplete. The outcome of the voting process, according to this methodology, is a designation for each putative therapy of “Appropriate,” “Uncertain” or “Inappropriate.” Among these, the implication of the term “Uncertain” was viewed as unclear by reviewers. To clarify, the “Uncertain” classification is not intended here to be a negative recommendation or to preclude use of that therapy. Rather it requires a role for physician–patient interaction in determining whether this treatment may have merit in the context of its risk-benefit profile and the individual characteristics, co-morbidities and preferences of the patient.
      Our guidelines diverge from the previous OARSI guidelines in 2010 and 2008 as well as from recent American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) guidelines by focusing specifically on treatment of OA of the knee. The decision was made to examine knee OA separately due to disparities in available evidence between hip OA and knee OA and differences in best treatment practices between these conditions. The current guidelines aim to identify the best-available treatment practices for knee OA, irrespective of differing healthcare policies and treatment standards internationally. Thus, this update of the OARSI guidelines also excluded cost effective analysis, evaluating treatments solely based upon their safety and efficacy profiles.
      Our guidelines also provide separate recommendations for each of four clinical sub-phenotypes. These were assessed separately in order to best capture heterogeneous health profiles and OA disease types. One limitation of this method is that the research literature was not surveyed for OA sites beyond the knee and hip. Thus, recommendations for individuals with multiple-joint OA may not take into account all evidence regarding other joint sites. Expert opinion of the OAGDG panel was used to support recommendations in these instances. However, these guidelines' recommendations pertain to treatment of knee OA specifically, even when making recommendations for individuals with OA in multiple-joint sites. For all considered treatments, best-available evidence of efficacy and safety in knee OA was evaluated.
      Our expert panel (OAGDG) represented a range of clinical disciplines that included rheumatologists (NA, FB, GH, DH, KK, TM, FR), orthopedic surgeons (HK, SL), a primary care physician (MU), physical therapists (SBZ, ER), a physiatrist (YH), and a clinical epidemiologist (TM) (Appendix 1). The OAGDG also solicited ongoing input from a patient advocate (RK), who attended the April 2013 OAGDG meeting and provided continuing feedback and oversight via the development group's online discussion forum. Our team also included an evidence-based methodologist (RB) who organized the development of the evidence report used by the OAGDG panel. Panel voting was conducted with oversight from OARSI's Ethics Committee. OAGDG members with perceived financial conflicts of interest were recused from voting following written and oral disclosures, with final decisions made by an Ethics Committee representative present at the OAGDG's April 2013 face-to-face meeting. Despite recusals, a majority of practicing clinicians were present within the voting at all times. Thus, the results of voting are unlikely to have lacked sufficient voter expertise for any treatment.
      The present statement also incorporated treatments not addressed in the prior OARSI guidelines such as risedronate and duloxetine. Treatments such as ASU, rosehip, electrotherapy, and ultrasound were not included in the 2008 OARSI recommendations but have since been discussed in the 2010 evidence update and assessed within our current guidelines. The present guidelines focused primarily on the non-surgical management of knee OA, though we recommend referral for consideration of orthopedic surgical interventions after more conservative treatment options have been exhausted. To examine the symptomatic slow-acting drug for OA (SYSDOA) effect, glucosamine and chondroitin were assessed separately for disease modification and for symptom relief. Other treatments received one score for overall efficacy, as other treatments were judged to lack sufficient evidence to merit separate assessment for disease modification effect and symptomatic effect.
      In comparison to the previous OARSI guidelines published in 2008, recommendations for some treatments have changed. Though the method of assessing treatment appropriateness has changed between guidelines versions, complicating straightforward comparison, it nevertheless appears that recent evidence has increased safety concerns regarding use of treatments such as acetaminophen and opioids (both oral and transdermal), while evidence for use of treatments such as duloxetine, balneotherapy, and land-based exercises such as t'ai chi has strengthened. These differences are updates to previous OARSI guidelines following the development of new treatment options and greater available evidence for existing treatments.
      While many of the recommendations in this guidelines statement agree with those published in other OA guidelines, our recommendations differ notably from others in a number of ways. Although our recommendations are based on best-available evidence, the current evidence contains some areas of inconsistency. With regard to non-pharmaceutical treatments, our recommendations were largely similar to other recent guidelines published by the American Academy of Orthopaedic Surgeons (AAOS), ACR, and EULAR, consistently recommending exercise programs for individuals with knee OA as well as weight loss programs for overweight individuals with knee OA. For this guidelines statement, exercise modalities were divided into three groups (land-based, water-based, and strength training) to provide greater specificity than other OA guidelines in assessing their distinct benefits and risks and to evaluate their relative appropriateness for different clinical sub-phenotypes. In other areas of non-pharmacological treatment, our guidelines differed more substantially from others. For electrotherapeutic modalities, AAOS provided an “Inconclusive” recommendation, while these guidelines recommend against the use of TENS and provide an “Uncertain” recommendation for EMG-biofeedback. While ACR conditionally recommends acupuncture for knee OA, and AAOS does not recommend acupuncture, our guidelines provide an “Uncertain” recommendation regarding acupuncture, highlighting the lack of strong available evidence regarding its use. Recommendations regarding biomechanical interventions were also mixed; AAOS provided an inconclusive recommendation regarding force braces, and both AAOS and EULAR recommended against the use of wedged insoles, while ACR conditionally recommended the use of medially wedged insoles. Rather than providing recommendations individually for specific biomechanical modalities, these guidelines recommend the use of biomechanical interventions as directed by an appropriate specialist.
      With regard to pharmaceutical treatment modalities, our guidelines also differ from others in several areas. AAOS's 2013 guidelines provided “Inconclusive” recommendations for both acetaminophen and intra-articular corticosteroids, citing for IACS a “lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm.” In contrast, our guidelines coincide with ACR's 2012 guidelines in recommending both APAP (for those without relevant co-morbidities) and IACS as appropriate, finding the potential benefits to outweigh associated risks in certain clinical scenarios. Regarding glucosamine and chondroitin, AAOS recommended against use of both treatments and ACR recommended against chondroitin and conditionally against glucosamine. Our guidelines provide greater specificity than previous guidelines by evaluating these treatments separately for symptomatic relief and disease modification. Our group responded more favorably (voting “Uncertain”) for the symptomatic efficacy of each of these two treatments than for the disease-modifying use of each (voting “Not appropriate”). The contrasting assessments of glucosamine and chondroitin's symptomatic versus disease-modifying efficacy may indicate the source of some of the inconsistency in the perceived value of these treatments among other recent guidelines. Regarding hyaluronic acid treatment, AAOS recommended against the use of IAHA, citing a lack of efficacy. Our guidelines offer a stance similar to that of ACR, providing an “Uncertain” recommendation for IAHA for individuals with knee-only OA. Despite safety and efficacy concerns of IAHA raised by one meta-analysis, a number of analyses revealed positive effect sizes for pain. Oral NSAIDs (both non-selective and COX-2 selective) were conditionally recommended by ACR, which was also reflected in our guidelines through the use of clinical sub-phenotypes. Conversely, AAOS strongly recommended both oral and topical NSAIDs. ACR guidelines conditionally recommend against topical capsaicin use, while we considered it appropriate in patients without relevant co-morbidities. Finally, the ACR provided negative or uncertain recommendations for the use of duloxetine, while these guidelines considered duloxetine appropriate for those without co-morbidities and those with multiple-joint OA and provided an “Uncertain” recommendation for duloxetine in individuals with knee-only OA and co-morbidities.
      Limitations of our guidelines include the scope of treatments addressed. These guidelines were developed based on the previous guidelines report and expanded where the OAGDG felt sufficient new evidence was available to merit inclusion (based on number and quality of available trials). Our guidelines did not consider treatments included in the previous OARSI 2010 guidelines such as vitamin E and calcitonin, as well as interventions included in the AAOS guidelines, such as platelet-rich plasma therapy and growth factor injections. Treatment duration and duration of benefit were not voted on separately for limited versus extended course for pharmaceutical treatments due to the lack of clarity in available evidence. Other treatments not included in our guidelines include lavage and debridement (considered for inclusion but removed due to consistent evidence of ineffectiveness), strontium (recently received a recommendation to restrict use by the European Medicines Agency and not approved by US FDA)

      European Medicines Agency. Recommendation to restrict the use of Protelos/Osseor (strontium ranelate) [press release].

      , and licofelone (not currently approved by the European Medicines Agency or US FDA). Manual therapy was not included in these guidelines due to insufficient available evidence. Unlike ACR, we did not include patellar taping or psychosocial intervention for knee OA. However, our guidelines also contain many treatment modalities not addressed by other (ACR) guidelines, such as ASU, risedronate, diacerein, and rosehip. In addition, these guidelines divided various treatments (e.g., NSAIDs, opioids, and exercise) into sub-categories to better assess considerations such as delivery method, drug mechanism or other factors, aiming to provide specific and actionable treatment recommendations. Our guidelines are also unique in that the recommendations considered the risk, benefit, and appropriateness of each treatment individually for the specific sub-phenotypes described in our methods. One limitation of these categories is that not every treatment had available research for all clinical sub-phenotypes. In such cases, expert consensus was relied upon via the RAND/UCLA voting method. The role of expert opinion and voters' enthusiasm for treatment modalities may also explain some instances where the panel's voting diverged from effect sizes presented in the evidence. The four clinical sub-phenotypes were assessed separately for every treatment considered in order to best capture heterogeneous health profiles and OA disease types.

      Conflict of interest

      Full disclosure statements from all members of the OARSI Guidelines Development Group are shown in Appendix 1. These were reviewed by the OARSI Ethics Committee. No potential conflicts of interest were identified that should preclude any member of the committee participating in this critical appraisal. No OAGDG members are employees of any pharmaceutical or medical device company. OAGDG members were recused from voting on select treatments where potential conflicts arose, as described in the report Methodology section. Corporate members of OARSI are also listed in Appendix 1. The data extraction team included five members of the Division of Rheumatology, Tufts Medical Center, Boston, MA, USA: Raveendhara Bannuru MD, FAGE, Elizaveta Vaysbrot, MD, Matthew Sullivan, BA, Elena Manning, BS, and Bryan Bourdeau, BS. Dr Bannuru is supported by a F32 HS021396 grant from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. Elizaveta Vaysbrot, Matthew Sullivan, Elena Manning, and Bryan Bourdeau have no conflicts of interest to disclose.

      Role of the funding source

      These guidelines were commissioned by the OARSI and sponsored by a grant from OARSI. This report is endorsed by the Board of Directors of OARSI; it was developed independently by the OARSI Guidelines Development Group.

      Acknowledgments

      The authors would like to thank Elizaveta Vaysbrot and Elena Manning for data collection and Diann Stern for logistics support throughout the project. We thank patient representative Robin Katzanek for her guidance. Financial support for data collection at Tufts Medical Center came from an OARSI grant.

      Appendix 1.

      Tabled 1Disclosure of potential conflicts of interest
      Name & specialty (in author-list order)Consulting fees, honoraria, research or institutional support, educational grants, equipment, services or expensesResearch grants/contractsService with organization with interests comparable to OARSIRecused from voting on the following treatment modalities
      T. McAlindon

      Rheumatologist; Epidemiologist
      Flexion Therapeutics|Consulting, Samumed|Consulting, Abbvie|Consulting, Sanofi|Consulting, Myrtus|Licensing feeNIH, CromaCo-editor for Arthritis & RheumatismHyaluronic acid
      R. BannuruNoneAHRQ|F32 HS021396 grantNoneNot a voter
      M. SullivanNoneNoneNoneNot a voter
      N. Arden
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Rheumatologist
      Merck|Consultancy, Roche|Consultancy, Smith and Nephew|Consultancy, Pfizer|Speaker Bureau, Flexion|Consultancy, Bioiberica|Consultancy, Speaker bureauNIHR|Outcomes of Arthroplasty and Biomedical Research Unit, NIH|Hip morphology, ARUK|VIDEO, project and equipment grantsNoneChondroitin

      Hyaluronic acid

      All surgery
      F. Berenbaum
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Rheumatologist
      Pfizer|Advisory board, Expanscience|Advisory board, UCB|Advisory board, Servier|Advisory board, research support, symposium, TRB Chemedica|research support, Sanofi|Advisory board, Abbott|Advisory boardAgence Nationale RechercheFrench Society of RheumatologyNSAIDs
      S. Bierma-Zeinstra
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Physical therapist; Epidemiologist





      S. Bierma-Zeinstra (disclosure cont'd)
      NoneDutch Arthritis Association|research in corticosteroids for OA, OA vascular pathology, early OA diagnosis, brace vs osteotomy treatment, & OA stepped care; The Netherlands Organization for Health Research and Development|research in identification, prevention of knee OA, OA phenotyping, treatment cost-effectiveness (ACL rupture, viscosupplementation, surgery vs conservative treatment in lumbar stenosis), corticosteroids for trochanteric pain syndrome, ankle injury complications, exercise after injury, & exercise therapy for patellofemoral pain syndrome; Nuts Ohra|research in X-ray OA diagnosis, OA pain medication, & statines & OA; EU FP7|markers for early detection & progression of OANoneGlucosamine
      G. Hawker
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Rheumatologist
      Women's College Hospital|Physician in Chief of Medicine|Salary Support Award, Women's College Hospital Foundation|FM Hill Chair in Academic Women's Medicine.

      Nothing to declare
      Operating grants from the Canadian Institutes of Health Research|Canadian Arthritis Network|Cochrane Collaboration/writing paper with Adelphi, a marketing company who worked for Pfizer on a survey of physicians regarding factors that influence their perceptions of OA severity – unpaidNoneNone
      Y. Henrotin
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Physical therapy & rehabilitation
      Bioiberica; BioXtract; Danone; Nestle; Pierre Fabre; Grunenthal; Expanscience; Artialis; Tilman; Merck; Ibsa|Honoraria. Patent ownership: Artialis|Biomarkers; Kit immunoassays|Development & commercialization of biomarkers of cartilage degradation & inflammationWalloon Government-Belgium|First Post-Doc RW/5291 PROMART-Recherche de nouveaux biomarqueurs (2007–2009).165.765; First Post-Doc RW/716609 CARTIMAT: Recherche de nouveaux biomateriaux; FIRST Entreprise - 73.726,4 Euros, European commission|FP7 D-Board, rd; Bioiberica & Expanscience|unrestricted educational grantsNoneChondroitin
      D. Hunter
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Rheumatologist
      DonJoy|Royalties;

      Merck Serono|Consulting, Flexion Therapeutics|Consulting
      Australian Research Council|Future Fellowship, NIH|POMA, NHMRC|project grantsBone and Joint Decade International Coordinating Council, Advisory editor for Arthritis Care and Research, Associate Editor for International Journal of Rheumatic DiseasesBiomechanical interventions
      H. Kawaguchi
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Orthopedic surgeon
      Teijin Pharma Co., Ltd.|Consulting feeNoneBMC Musculoskeletal Disorders|Associate Editor, Japanese Orthopaedic Association|Committee Member, Japanese Society for Bone and Mineral Metabolism|Committee Member, Journal of Orthopaedic Science|Editorial Board, Journal of Bone &Mineral Metabolism|Editorial Board, Japanese Society of Cartilage Metabolism|Comm. MemberHyaluronic acid
      R. Katzanek

      Patient advocate
      Nothing to declareNoneNoneN/A
      K. Kwoh

      Rheumatologist
      Novartis|Advisory Board and DSMB, NIH|DSMB, Express Scripts|Consulting, Pfizer|RA Quality Measures RoundtableNIH|NIAMS P60AR054731 PITT-MCRC for rheumatic and musculoskeletal diseases; NIAMS N01AR-2-2260 Clinical centers for the Osteoarthritis Initiative; NHLBI HHSN26820100002 Pivotal OAI MRI Analyses (POMA); NIAMS R01AR056630 Single- vs Double-Bundle ACL Reconstruction: A Prospective Randomized Trial; NINR R01NR010904 Promoting Physical Activity in Older Adults with Co-morbidity; CDC|U48DP001918 Health Promotion and Disease Prevention Research CenterArthritis Foundation|Public Health CommitteeGlucosamine

      Risedronate
      S. Lohmander
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Orthopedic surgeon
      Merck Serono|Advisory board, Informed Medical Decision Making|Speaker honorarium, Össur Advisory Board, Abbott Consultancy, Flexion Therapeutics Advisory Board, Allergan Consultancy, Medivir Consultancy, Merrimack Pharmaceuticals Consultancy, Servier ConsultancySwedish Research Council|Lund University, Swedish Rheumatism Association|Lund University, Medical faculty|Lund UniversityNoneBiomechanical interventions
      F. Rannou
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Rheumatologist
      Sanofi Aventis, Pfizer, Rottapharm, Pierre Fabre, Genzyme, Merck, Genévrier, Expanscience, Negma, Servier|Consulting/Advisory boardAP-HP|Non-pharmacological treatments in rheumatic diseases, GSK|HO-1 inducer molecules in cartilage, Fondation de l'Avenir|Molecular mapping of IVD in scoliosisMember of the Eular Scientific CommitteeNSAIDs

      Hyaluronic acid

      ASU

      Diacerein
      E. Roos
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.


      Physical therapist
      National Welfare Board, Sweden|Reviewer, National board for preventive medicine, Denmark|Board member, Össur|Lecture fees, Finnish Orthopedic Society|Lecture fees, Studentlitteratur|Royalties, Munksgaard|Royalties, Osteoarthritis and Cartilage|Associate EditorSouthern Health Care Region, Denmark|RCT on exercise vs pharma, Danish Rheumatism Association|Knee OA prevention and treatmentNoneNone
      M. Underwood

      Primary care practitioner; primary care research
      Travel, Accommodation and Conference fee waiver from OARSI to attend OAGDG meetings concurrent with annual scientific meetingNIHR Programme grants|Improving outcomes from the treatment of back pain; Improving self-management of chronic pain, NHS HTA Programme|Prevention of Fall Injury Trial (Pre-FIT); Adherence to strengthening activities in rheumatoid arthritis of the hand (SARAH); Older People's Exercise intervention in Residential and nursing Accommodation (OPERA), National Centre for Osteopathic Research|Investigating osteopath's attitudes to managing and assessing risk in clinical settings and patient's experiences and responses, Research for Patient Benefit|Improving Patient Choice in Treating Low Back Pain (IMPACT - LBP).

      NHS Health Technology Assessment Programme. Facet joint feasibility study.
      National Institute for Health and Care Excellence (NICE)|Chair of Headache Guideline Development Group (2010–12).

      Chair NICE Accreditation Advisory Committee (2013)

      NICE Strategy Board, in attendance (2013)
      Acupuncture
      OARSI's Congress sponsors and corporate members for 2013 include the following: Bioiberica; EMD Serono; Expanscience; Rottapharm/Madaus; Abbvie; Astellas; Bioventus; Boston Imaging Core Lab (BICL); Chondrometrics; Fidia Pharma USA, Inc.; Flexion; Perceptive Informatics; Merck; Seikagaku; Servier; Zimmer. No direct medical industry support was used or requested for guideline development. Guidelines development was a budgeted item in OARSI's annual budget.
      Panel member has an editorial position with the Osteoarthritis and Cartilage journal.

      Appendix 2.

      Appendix 3.

      Table AAppropriateness voting data
      Appropriateness scores
      No co-morbiditiesCo-morbidities
      MedianAppropriate (Y/N/U)Disagreement?MedianAppropriate (Y/N/U)Disagreement?
      Non-pharmaceutical treatments
      AcupunctureKnee5UncertainNo4.5UncertainNo
      Multi-joint4.5UncertainNo4.5UncertainNo
      BalneotherapyKnee5UncertainNo6UncertainNo
      Multi-joint6UncertainNo7YesNo
      Biomechanical interventionsKnee7YesNo7YesNo
      Multi-joint7YesNo7YesNo
      Cane (walking stick)Knee7YesNo7YesNo
      Multi-joint6UncertainNo6UncertainNo
      CrutchesKnee6UncertainNo6UncertainNo
      Multi-joint5UncertainNo5.5UncertainNo
      Electrotherapy/neuromuscular electrical stimulationKnee3NoNo3NoNo
      Multi-joint3NoNo3NoNo
      Exercise (land-based)Knee8YesNo8YesNo
      Multi-joint8YesNo8YesNo
      Exercise (water-based)Knee7YesNo7YesNo
      Multi-joint8YesNo8YesNo
      Strength trainingKnee8YesNo8YesNo
      Multi-joint8YesNo7YesNo
      Self-management and educationKnee8YesNo9YesNo
      Multi-joint9YesNo9YesNo
      TENSKnee5UncertainNo5UncertainNo
      Multi-joint3NoNo3NoNo
      Weight managementKnee8YesNo8YesNo
      Multi-joint8YesNo9YesNo
      UltrasoundKnee4UncertainNo4UncertainNo
      Multi-joint3NoNo3NoNo
      Pharmaceutical treatments
      Acetaminophen (paracetamol)Knee7YesNo6UncertainNo
      Multi-joint7YesNo6UncertainNo
      ASUKnee4UncertainNo4UncertainNo
      Multi-joint5UncertainNo5UncertainNo
      CapsaicinKnee7YesNo6UncertainNo
      Multi-joint6UncertainNo6UncertainNo
      Corticosteriods (intra-articular injection)Knee7YesNo7YesNo
      Multi-joint7YesNo7YesNo
      Chondroitin: symptom reliefKnee5UncertainNo5UncertainNo
      Multi-joint5UncertainNo5UncertainNo
      Chondroitin: disease modificationKnee3NoNo3NoNo
      Multi-joint3NoNo3NoNo
      DiacereinKnee4UncertainNo4UncertainNo
      Multi-joint4UncertainNo4UncertainNo
      DuloxetineKnee7YesNo6UncertainNo
      Multi-joint7YesNo7YesNo
      Glucosamine: symptom reliefKnee5.5UncertainNo5.5UncertainNo
      Multi-joint5.5UncertainNo5.5UncertainNo
      Glucosamine: disease modificationKnee3NoNo3NoNo
      Multi-joint3NoNo3NoNo
      Hyaluronic acid (intra-articular injection)Knee5UncertainNo4UncertainNo
      Multi-joint3NoNo3NoNo
      NSAIDs (topical)Knee8YesNo7YesNo
      Multi-joint6UncertainNo6UncertainNo
      Opioids: transdermalKnee4UncertainNo4UncertainNo
      Multi-joint5UncertainNo4UncertainNo
      Opioids: oralKnee5UncertainNo4UncertainNo
      Multi-joint5UncertainNo6UncertainNo
      RisedronateKnee3NoNo3NoNo
      Multi-joint3NoNo3NoNo
      RosehipKnee5UncertainNo5UncertainNo
      Multi-joint5UncertainNo5UncertainNo
      For each treatment modality, the OAGDG voted on appropriateness using a nine-point scale (1–9).
      Definitions: No co-morbidities: The individual with OA has no pertinent co-morbid health concerns. Co-morbidities: The individual with OA has any of the following pertinent co-morbid health concerns: diabetes; hypertension; CV disease; renal failure; GI bleeding; depression; or physical impairment limiting activity, including obesity. Knee: Symptomatic OA in one or both knees only. Multi-joint OA: Symptomatic OA of the knee(s) in addition to other joints (e.g., hip, hand, spine, etc).
      Disagreement: An appropriateness vote was considered to be in ‘disagreement’ if greater than one-third of votes fell in the opposite tertile to the median score [e.g., a vote was considered in “Disagreement” if it received an “Appropriate” median vote (≥7) with five of 13 members voting ”Not appropriate” (≤3)].
      Table BRisk scores, benefit scores, and composite risk and benefit scores
      Risk scoresBenefit scoresBenefit and risk scores
      No co-morbiditiesCo-morbiditiesNo co-morbiditiesCo-morbiditiesNo co-morbiditiesCo-morbidities
      Mean (1–10)Mean (1–10)Mean (1–10)Mean (1–10)(1–100)(1–100)
      Non pharmaceutical treatments
      AcupunctureKnee1.92.33.13.028.026.3
      Multi-joint1.92.33.13.028.026.3
      BalneotherapyKnee1.31.54.24.240.340.0
      Multi-joint1.31.64.54.543.241.9
      Biomechanical interventionsKnee1.52.05.65.657.050.4
      Multi-joint1.62.14.74.737.641.8
      Cane (walking stick)Knee1.61.65.05.046.946.9
      Multi-joint1.81.84.24.038.336.9
      CrutchesKnee1.71.74.44.340.840.1
      Multi-joint1.81.83.73.833.834.5
      Electrotherapy/neuromuscular electrical stimulationKnee2.02.12.52.422.221.3
      Multi-joint2.02.11.91.917.317.2
      Exercise (land-based)Knee1.21.96.66.864.661.4
      Multi-joint1.32.16.46.561.958.3
      Exercise (water-based)Knee1.52.35.96.256.054.2
      Multi-joint1.52.26.26.559.056.7
      Strength trainingKnee1.41.86.96.866.662.0
      Multi-joint1.62.26.06.056.353.1
      Self management and educationKnee1.21.54.95.148.148.4
      Multi-joint1.21.55.25.250.349.5
      TENSKnee1.81.83.23.229.128.9
      Multi-joint1.81.82.42.422.021.8
      Weight managementKnee1.21.56.16.359.460.2
      Multi-joint1.21.56.26.460.160.4
      UltrasoundKnee1.31.52.83.027.628.6
      Multi-joint1.41.42.42.522.924.4
      Pharmaceutical treatments
      Acetaminophen (paracetamol)Knee3.44.54.54.434.028.3
      Multi-joint3.54.74.64.534.828.6
      Avocado soybean unsaponfiablesKnee1.61.83.53.533.232.6
      Multi-joint1.61.83.63.634.033.4
      CapsaicinKnee2.62.85.15.142.641.8
      Multi-joint2.93.14.74.737.937.2
      Corticosteriods (intra-articular injection)Knee2.83.66.56.453.847.1
      Multi-joint2.83.65.25.342.739.2
      Chondroitin: symptom reliefKnee1.11.33.83.937.838.0
      Multi-joint1.11.33.84.037.838.9
      Chondroitin: disease modificationKnee1.11.32.72.727.026.5
      Multi-joint1.11.42.62.526.123.7
      DiacereinKnee3.84.03.73.726.625.7
      Multi-joint3.84.03.83.827.826.3
      DuloxetineKnee4.04.75.35.437.234.0
      Multi-joint4.04.75.65.639.335.4
      Glucosamine: symptom reliefKnee1.41.73.93.937.436.3
      Multi-joint1.51.74.04.038.037.2
      Glucosamine: disease modificationKnee1.41.72.72.726.325.3
      Multi-joint1.41.72.52.524.523.6
      Hyaluronic acid (intra-articular injection)Knee3.13.84.14.232.430.5
      Multi-joint3.33.93.03.123.022.1
      NSAIDs (topical)Knee2.73.56.05.949.844.7
      Multi-joint2.93.85.25.242.236.9
      Opioids: transdermalKnee4.86.15.24.931.724.2
      Multi-joint4.96.15.35.132.325.0
      Opioids: oralKnee5.56.55.65.430.724.0
      Multi-joint5.66.55.75.430.724.0
      RisedronateKnee3.23.32.72.720.920.4
      Multi-joint3.23.32.82.721.520.4
      RosehipKnee1.81.93.33.430.330.7
      Multi-joint1.81.93.33.430.330.7
      For each treatment modality, the OAGDG voted on therapeutic benefit on a 10-point scale (1–10) and overall risk on a 10-point scale (1–10). The composite benefit and risk score is the product of the benefit score (1–10) and the transposed risk score (where 1 = highest and 10 = safety) yielding a range of 1 (worst) to 100 (best).
      No co-morbidities: The individual with OA has no pertinent co-morbid health concerns. Co-morbidities: The individual with OA has any of the following pertinent co-morbid health concerns: diabetes; hypertension; cardiovascular disease; renal failure; GI bleeding; depression; or physical impairment limiting activity, including obesity. Knee: Symptomatic OA in one or both knees only. Multi-joint: Symptomatic OA of the knee(s) in addition to other joints (e.g. hip, hand, spine, etc).
      Table COral NSAIDs voting data
      TreatmentOA typeAppropriateness voteVoting disagreement?Percent voting in favor of gastroprotection
      Co-morbidity riskCo-morbidity riskCo-morbidity risk
      No co-morbiditiesModerate riskHigh riskNo co-morbiditiesModerate riskHigh riskNo co-morbiditiesModerate riskHigh risk
      Oral NSAIDs (non-selective)Knee-only OA7.05.02.0NoNoNo33%92%100%
      Multi-joint OA7.54.02.0NoNoNo67%92%92%
      Oral NSAIDs (COX-2 inhibitors)Knee-only OA7.06.03.0NoNoNo18%50%100%
      Multi-joint OA7.07.03.0NoNoNo36%50%91%
      TreatmentOA TypeRisk scoresBenefit scoresBenefit and risk scores
      Co-morbidity riskCo-morbidity riskCo-morbidity risk
      No co-morbiditiesModerate riskHigh riskNo co-morbiditiesModerate riskHigh riskNo co-morbiditiesModerate riskHigh risk
      Oral NSAIDs (non-selective)Knee-only OA4.66.17.85.95.65.240.729.717.3
      Multi-joint OA4.66.17.86.25.65.342.830.918.6
      Oral NSAIDs (COX-2 inhibitors)Knee-only OA4.66.16.66.05.75.446.638.324.7
      Multi-joint OA3.84.76.66.46.15.846.838.825.4
      For each treatment modality, the OAGDG voted on appropriateness using a nine-point scale (1–9), on therapeutic benefit on a 10-point scale (1–10) and overall risk on a 10-point scale (1–10). The composite benefit and risk score is the product of the benefit score (1–10) and the transposed risk score (where 1 = highest and 10 = safety) yielding a range of 1 (worst) to 100 (best).
      Definitions: No co-morbidities: The individual with OA has no pertinent co-morbid health concerns. Co-morbidities: The individual with OA has any of the following pertinent co-morbid health concerns: diabetes; hypertension; CV disease; renal failure; GI bleeding; depression; or physical impairment limiting activity, including obesity. Knee-only OA: Symptomatic OA in one or both knees only. Multi-joint OA: Symptomatic OA of the knee(s) in addition to other joints (e.g., hip, hand, spine, etc).
      Disagreement: An appropriateness vote was considered to be in ‘disagreement’ if greater than one-third of votes fell in the opposite tertile to the median score [e.g., a vote was considered in “Disagreement” if it received an “Appropriate” median vote (≥7) with five of 13 members voting ”Not appropriate” (≤3)].

      References

        • Zhang W.
        • Nuki G.
        • Moskowitz R.W.
        • Abramson S.
        • Altman R.D.
        • Arden N.K.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January 2009.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2010; 18 (Epub 2010/02/23. http://dx.doi.org/10.1016/j.joca.2010.01.013. PubMed PMID: 20170770): 476-499
        • Zhang W.
        • Moskowitz R.W.
        • Nuki G.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2008; 16 (Epub 2008/02/19. http://dx.doi.org/10.1016/j.joca.2007.12.013. PubMed PMID: 18279766): 137-162
        • Zhang W.
        • Moskowitz R.W.
        • Nuki G.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2007; 15 (Epub 2007/08/28. http://dx.doi.org/10.1016/j.joca.2007.06.014. PubMed PMID: 17719803): 981-1000
        • Fitch K.
        • Bernstein S.
        • Aguilar M.D.
        • Burnand B.
        • LaCalle J.R.
        • Lazaro P.
        • et al.
        The RAND/UCLA Appropriateness Method User's Manual.
        Rand, Santa Monica2001
        • Manheimer E.
        • Cheng K.
        • Linde K.
        • Lao L.
        • Yoo J.
        • Wieland S.
        • et al.
        Acupuncture for peripheral joint osteoarthritis.
        Cochrane Database Syst Rev. 2010; (Epub 2010/01/22. http://dx.doi.org/10.1002/14651858.CD001977.pub2. PubMed PMID: 20091527; PubMed Central PMCID: PMCPMC3169099): CD001977
        • Falagas M.E.
        • Zarkadoulia E.
        • Rafailidis P.I.
        The therapeutic effect of balneotherapy: evaluation of the evidence from randomised controlled trials.
        Int J Clin Pract. 2009; 63 (Epub 2009/07/03. http://dx.doi.org/10.1111/j.1742-1241.2009.02062.x. PubMed PMID: 19570124): 1068-1084
        • Harzy T.
        • Ghani N.
        • Akasbi N.
        • Bono W.
        • Nejjari C.
        Short- and long-term therapeutic effects of thermal mineral waters in knee osteoarthritis: a systematic review of randomized controlled trials.
        Clin Rheumatol. 2009; 28 (Epub 2009/02/20. http://dx.doi.org/10.1007/s10067-009-1114-2. PubMed PMID: 19225707): 501-507
        • Sherman G.
        • Zeller L.
        • Avriel A.
        • Friger M.
        • Harari M.
        • Sukenik S.
        Intermittent balneotherapy at the Dead Sea area for patients with knee osteoarthritis.
        Isr Med Assoc J: IMAJ. 2009; 11 (Epub 2009/05/13. PubMed PMID: 19432036): 88-93
        • Forestier R.
        • Desfour H.
        • Tessier J.M.
        • Francon A.
        • Foote A.M.
        • Genty C.
        • et al.
        Spa therapy in the treatment of knee osteoarthritis: a large randomised multicentre trial.
        Ann Rheum Dis. 2010; 69 (Epub 2009/09/08. http://dx.doi.org/10.1136/ard.2009.113209. PubMed PMID: 19734131; PubMed Central PMCID: PMCPMC2927613): 660-665
        • Raja K.
        • Dewan N.
        Efficacy of knee braces and foot orthoses in conservative management of knee osteoarthritis: a systematic review.
        Am J Phys Med Rehabil/Assoc Acad Physiatr. 2011; 90 (Epub 2011/01/29. http://dx.doi.org/10.1097/PHM.0b013e318206386b. PubMed PMID: 21273902): 247-262
        • Bennell K.L.
        • Bowles K.A.
        • Payne C.
        • Cicuttini F.
        • Williamson E.
        • Forbes A.
        • et al.
        Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial.
        BMJ (Clinical Research Ed). 2011; 342 (Epub 2011/05/20. http://dx.doi.org/10.1136/bmj.d2912. PubMed PMID: 21593096; PubMed Central PMCID: PMCPMC3100910): d2912
        • van Raaij T.M.
        • Reijman M.
        • Brouwer R.W.
        • Bierma-Zeinstra S.M.
        • Verhaar J.A.
        Medial knee osteoarthritis treated by insoles or braces: a randomized trial.
        Clin Orthop Relat Res. 2010; 468 (Epub 2010/02/24. http://dx.doi.org/10.1007/s11999-010-1274-z. PubMed PMID: 20177839; PubMed Central PMCID: PMCPMC2881986): 1926-1932
        • Erhart J.C.
        • Mundermann A.
        • Elspas B.
        • Giori N.J.
        • Andriacchi T.P.
        Changes in knee adduction moment, pain, and functionality with a variable-stiffness walking shoe after 6 months.
        J Orthop Res: Off Publ Orthop Res Soc. 2010; 28 (Epub 2010/01/09. http://dx.doi.org/10.1002/jor.21077. PubMed PMID: 20058261): 873-879
        • Jones A.
        • Silva P.G.
        • Silva A.C.
        • Colucci M.
        • Tuffanin A.
        • Jardim J.R.
        • et al.
        Impact of cane use on pain, function, general health and energy expenditure during gait in patients with knee osteoarthritis: a randomised controlled trial.
        Ann Rheum Dis. 2012; 71 (Epub 2011/12/01. http://dx.doi.org/10.1136/ard.2010.140178. PubMed PMID: 22128081): 172-179
        • Giggins O.
        • Fullen B.
        • Coughlan G.
        Neuromuscular electrical stimulation in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
        Clin Rehabil. 2012; 26 (Epub 2012/02/11. http://dx.doi.org/10.1177/0269215511431902. PubMed PMID: 22324059): 867-881
        • Yilmaz O.O.
        • Senocak O.
        • Sahin E.
        • Baydar M.
        • Gulbahar S.
        • Bircan C.
        • et al.
        Efficacy of EMG-biofeedback in knee osteoarthritis.
        Rheumatol Int. 2010; 30 (Epub 2009/08/21. http://dx.doi.org/10.1007/s00296-009-1070-9. PubMed PMID: 19693508): 887-892
        • Jansen M.J.
        • Viechtbauer W.
        • Lenssen A.F.
        • Hendriks E.J.
        • de Bie R.A.
        Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review.
        J Physiother. 2011; 57 (Epub 2011/03/16. http://dx.doi.org/10.1016/s1836-9553(11)70002-9. PubMed PMID: 21402325): 11-20
        • Iversen M.D.
        Rehabilitation interventions for pain and disability in osteoarthritis: a review of interventions including exercise, manual techniques, and assistive devices.
        Orthop Nurs/Natl Assoc Orthop Nurses. 2012; 31 (Epub 2012/03/27. http://dx.doi.org/10.1097/NOR.0b013e31824fce07. PubMed PMID: 22446803): 103-108
        • Fransen M.
        • McConnell S.
        • Hernandez-Molina G.
        • Reichenbach S.
        Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthritis and Cartilage/OARS,.
        Osteoarthritis Research Society. 2010; 18 (Epub 2010/03/02. http://dx.doi.org/10.1016/j.joca.2010.01.003. PubMed PMID: 20188228): 613-620
        • Fransen M.
        • McConnell S.
        Exercise for osteoarthritis of the knee.
        Cochrane Database Syst Rev. 2008; (Epub 2008/10/10. http://dx.doi.org/10.1002/14651858.CD004376.pub2. PubMed PMID: 18843657): CD004376
        • Bannuru R.R.
        • Abariga S.
        • Wang C.
        How effective is tai chi mind-body therapy for knee osteoarthritis? A systematic review and meta-analysis.
        Osteoarthritis Cartilage. 2012; 20 (Osteoarthritis Research Society International World Congress; 2012 Apr 26–29; Barcelona, Spain): S281-S282
        • Kang J.W.
        • Lee M.S.
        • Posadzki P.
        • Ernst E.
        T'ai chi for the treatment of osteoarthritis: a systematic review and meta-analysis.
        BMJ Open. 2011; 1 (Epub 2011/10/25. http://dx.doi.org/10.1136/bmjopen-2010-000035. PubMed PMID: 22021734; PubMed Central PMCID: PMCPMC3191392): e000035
        • Bartels E.M.
        • Lund H.
        • Hagen K.B.
        • Dagfinrud H.
        • Christensen R.
        • Danneskiold-Samsoe B.
        Aquatic exercise for the treatment of knee and hip osteoarthritis.
        Cochrane Database Syst Rev. 2007; (Epub 2007/10/19. http://dx.doi.org/10.1002/14651858.CD005523.pub2. PubMed PMID: 17943863): CD005523
        • Du S.
        • Yuan C.
        • Xiao X.
        • Chu J.
        • Qiu Y.
        • Qian H.
        Self-management programs for chronic musculoskeletal pain conditions: a systematic review and meta-analysis.
        Patient Educ Couns. 2011; 85 (Epub 2011/04/05. http://dx.doi.org/10.1016/j.pec.2011.02.021. PubMed PMID: 21458196): e299-310
        • Chondosh J.
        • Morton S.C.
        • Mojica W.
        • Maglione M.
        • Suttorp M.J.
        • Hilton L.
        • et al.
        Meta-analysis: chronic disease self-management programs for older adults.
        Ann Intern Med. 2005; 143 (Epub 2005/09/21. PubMed PMID: 16172441): 427-438
        • Ravaud P.
        • Flipo R.M.
        • Boutron I.
        • Roy C.
        • Mahmoudi A.
        • Giraudeau B.
        • et al.
        ARTIST (osteoarthritis intervention standardized) study of standardised consultation versus usual care for patients with osteoarthritis of the knee in primary care in France: pragmatic randomised controlled trial.
        BMJ (Clinical Research Ed). 2009; 338 (Epub 2009/02/25. http://dx.doi.org/10.1136/bmj.b421. PubMed PMID: 19237406; PubMed Central PMCID: PMCPMC2651104): b421
        • Hurley M.V.
        • Walsh N.E.
        • Mitchell H.
        • Nicholas J.
        • Patel A.
        Long-term outcomes and costs of an integrated rehabilitation program for chronic knee pain: a pragmatic, cluster randomized, controlled trial.
        Arthritis Care Res. 2012; 64 (Epub 2011/09/29. http://dx.doi.org/10.1002/acr.20642. PubMed PMID: 21954131): 238-247
        • Hansson E.E.
        • Jonsson-Lundgren M.
        • Ronnheden A.M.
        • Sorensson E.
        • Bjarnung A.
        • Dahlberg L.E.
        Effect of an education programme for patients with osteoarthritis in primary care–a randomized controlled trial.
        BMC Musculoskelet Disord. 2010; 11 (Epub 2010/10/26. http://dx.doi.org/10.1186/1471-2474-11-244. PubMed PMID: 20969809; PubMed Central PMCID: PMCPMC2987970): 244
        • Allen K.D.
        • Oddone E.Z.
        • Coffman C.J.
        • Datta S.K.
        • Juntilla K.A.
        • Lindquist J.H.
        • et al.
        Telephone-based self-management of osteoarthritis: a randomized trial.
        Ann Intern Med. 2010; 153 (Epub 2010/11/03. http://dx.doi.org/10.7326/0003-4819-153-9-201011020-00006, http://dx.doi.org/10.1059/0003-4819-153-9-201011020-00006. PubMed PMID: 21041576): 570-579
        • Ackerman I.N.
        • Buchbinder R.
        • Osborne R.H.
        Challenges in evaluating an Arthritis Self-Management Program for people with hip and knee osteoarthritis in real-world clinical settings.
        J Rheumatol. 2012; 39 (Epub 2012/03/03. http://dx.doi.org/10.3899/jrheum.111358. PubMed PMID: 22382340): 1047-1055
        • Rutjes A.W.
        • Nuesch E.
        • Sterchi R.
        • Kalichman L.
        • Hendriks E.
        • Osiri M.
        • et al.
        Transcutaneous electrostimulation for osteoarthritis of the knee.
        Cochrane Database Syst Rev. 2009; (Epub 2009/10/13. http://dx.doi.org/10.1002/14651858.CD002823.pub2. PubMed PMID: 19821296): CD002823
        • Atamaz F.C.
        • Durmaz B.
        • Baydar M.
        • Demircioglu O.Y.
        • Iyiyapici A.
        • Kuran B.
        • et al.
        Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy in knee osteoarthritis: a double-blind, randomized, controlled, multicenter study.
        Arch Phys Med Rehabil. 2012; 93 (Epub 2012/03/31. http://dx.doi.org/10.1016/j.apmr.2011.11.037. PubMed PMID: 22459699): 748-756
        • Christensen R.
        • Bartels E.M.
        • Astrup A.
        • Bliddal H.
        Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis.
        Ann Rheum Dis. 2007; 66 (Epub 2007/01/06. http://dx.doi.org/10.1136/ard.2006.065904. PubMed PMID: 17204567; PubMed Central PMCID: PMCPMC1856062): 433-439
        • Rutjes A.W.
        • Nuesch E.
        • Sterchi R.
        • Juni P.
        Therapeutic ultrasound for osteoarthritis of the knee or hip.
        Cochrane Database Syst Rev. 2010; (Epub 2010/01/22. http://dx.doi.org/10.1002/14651858.CD003132.pub2. PubMed PMID: 20091539): CD003132
        • Loyola-Sanchez A.
        • Richardson J.
        • MacIntyre N.J.
        Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2010; 18 (Epub 2010/07/20. http://dx.doi.org/10.1016/j.joca.2010.06.010. PubMed PMID: 20637297): 1117-1126
        • Ulus Y.
        • Tander B.
        • Akyol Y.
        • Durmus D.
        • Buyukakincak O.
        • Gul U.
        • et al.
        Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
        Int J Rheum Dis. 2012; 15 (Epub 2012/04/03. http://dx.doi.org/10.1111/j.1756-185X.2012.01709.x. PubMed PMID: 22462424): 197-206
        • Bannuru R.R.D.U.
        • McAlindon T.E.
        Reassessing the role of acetaminophen in osteoarthritis: systematic review and meta-analysis.
        Osteoarthritis Cartilage. 2010; 18 (Osteoarthritis Research Society International World Congress; 2010 Sep 23–26; Brussels, Belgium): S250
        • Craig D.G.
        • Bates C.M.
        • Davidson J.S.
        • Martin K.G.
        • Hayes P.C.
        • Simpson K.J.
        Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity.
        Br J Clin Pharmacol. 2012; 73: 285-294
        • Christensen R.
        • Bartels E.M.
        • Astrup A.
        • Bliddal H.
        Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2008; 16 (Epub 2007/11/29. http://dx.doi.org/10.1016/j.joca.2007.10.003. PubMed PMID: 18042410): 399-408
        • Mason L.
        • Moore R.A.
        • Derry S.
        • Edwards J.E.
        • McQuay H.J.
        Systematic review of topical capsaicin for the treatment of chronic pain.
        BMJ (Clinical Research Ed). 2004; 328 (Epub 2004/03/23. http://dx.doi.org/10.1136/bmj.38042.506748.EE. PubMed PMID: 15033881; PubMed Central PMCID: PMCPMC404499): 991
        • Kosuwon W.
        • Sirichatiwapee W.
        • Wisanuyotin T.
        • Jeeravipoolvarn P.
        • Laupattarakasem W.
        Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo.
        J Med Assoc Thai = Chotmaihet Thangphaet. 2010; 93 (Epub 2010/10/27. PubMed PMID: 20973322): 1188-1195
        • Chou R.
        • McDonagh M.S.
        • Nakamoto E.
        • Griffin J.
        Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review.
        (Rockville MD)2011 Oct
        • Bannuru R.R.
        • Natov N.S.
        • Obadan I.E.
        • Price L.L.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.
        Arthritis Rheum. 2009; 61 (Epub 2009/12/02. http://dx.doi.org/10.1002/art.24925. PubMed PMID: 19950318): 1704-1711
        • Bellamy N.
        • Campbell J.
        • Robinson V.
        • Gee T.
        • Bourne R.
        • Wells G.
        Intraarticular corticosteroid for treatment of osteoarthritis of the knee.
        Cochrane Database Syst Rev. 2006; (Epub 2006/04/21. http://dx.doi.org/10.1002/14651858.CD005328.pub2. PubMed PMID: 16625636): CD005328
        • Wandel S.
        • Juni P.
        • Tendal B.
        • Nuesch E.
        • Villiger P.M.
        • Welton N.J.
        • 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 (Epub 2010/09/18. http://dx.doi.org/10.1136/bmj.c4675. PubMed PMID: 20847017; PubMed Central PMCID: PMCPMC2941572): c4675
        • Reichenbach S.
        • Sterchi R.
        • Scherer M.
        • Trelle S.
        • Burgi E.
        • Burgi U.
        • et al.
        Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
        Ann Intern Med. 2007; 146 (Epub 2007/04/18. PubMed PMID: 17438317): 580-590
        • Hochberg M.C.
        • Zhan M.
        • Langenberg P.
        The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate.
        Curr Med Res Opin. 2008; 24 (Epub 2008/10/02. http://dx.doi.org/10.1185/03007990802434932. PubMed PMID: 18826751): 3029-3035
        • Lee Y.H.
        • Woo J.H.
        • Choi S.J.
        • Ji J.D.
        • Song G.G.
        Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
        Rheumatol Int. 2010; 30 (Epub 2009/06/23. http://dx.doi.org/10.1007/s00296-009-0969-5. PubMed PMID: 19544061): 357-363
        • Bartels E.M.
        • Bliddal H.
        • Schondorff P.K.
        • Altman R.D.
        • Zhang W.
        • Christensen R.
        Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials. Osteoarthritis and Cartilage/OARS.
        Osteoarthritis Research Society. 2010; 18 (Epub 2009/10/28. http://dx.doi.org/10.1016/j.joca.2009.10.006. PubMed PMID: 19857509): 289-296
        • Citrome L.
        • Weiss-Citrome A.
        A systematic review of duloxetine for osteoarthritic pain: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed?.
        Postgrad Med. 2012; 124 (Epub 2012/02/09. http://dx.doi.org/10.3810/pgm.2012.01.2521. PubMed PMID: 22314118): 83-93
        • Frakes E.P.
        • Risser R.C.
        • Ball T.D.
        • Hochberg M.C.
        • Wohlreich M.M.
        Duloxetine added to oral nonsteroidal anti-inflammatory drugs for treatment of knee pain due to osteoarthritis: results of a randomized, double-blind, placebo-controlled trial.
        Curr Med Res Opin. 2011; 27 (Epub 2011/10/25. http://dx.doi.org/10.1185/03007995.2011.633502. PubMed PMID: 22017192): 2361-2372
        • Towheed T.E.
        • Maxwell L.
        • Anastassiades T.P.
        • Shea B.
        • Houpt J.
        • Robinson V.
        • et al.
        Glucosamine therapy for treating osteoarthritis.
        Cochrane Database Syst Rev. 2005; (Epub 2005/04/23. http://dx.doi.org/10.1002/14651858.CD002946.pub2. PubMed PMID: 15846645): CD002946
        • Clegg D.O.
        • Reda D.J.
        • Harris C.L.
        • Klein M.A.
        • O'Dell J.R.
        • Hooper M.M.
        • et al.
        Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.
        New Engl J Med. 2006; 354 (Epub 2006/02/24. http://dx.doi.org/10.1056/NEJMoa052771. PubMed PMID: 16495392): 795-808
        • Palma Dos Reis R.
        • Giacovelli G.
        • Girolami F.
        • Andre R.
        • Bonazzi A.
        • Rovati L.C.
        Crystalline glucosamine sulfate in the treatment of osteoarthritis: evidence of long-term cardiovascular safety from clinical trials.
        Open Rheumatol J. 2011; 5 (Epub 2012/01/05. http://dx.doi.org/10.2174/1874312901105010069. PubMed PMID: 22216067; PubMed Central PMCID: PMCPMC3245483): 69-77
        • Bannuru R.R.
        • Natov N.S.
        • Dasi U.R.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and Cartilage/OARS.
        Osteoarthritis Research Society. 2011; 19 (Epub 2011/03/30. http://dx.doi.org/10.1016/j.joca.2010.09.014. PubMed PMID: 21443958): 611-619
        • Rutjes A.W.
        • Juni P.
        • da Costa B.R.
        • Trelle S.
        • Nuesch E.
        • Reichenbach S.
        Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.
        Ann Intern Med. 2012; 157 (Epub 2012/08/08. http://dx.doi.org/10.7326/0003-4819-157-3-201208070-00473. PubMed PMID: 22868835): 180-191
        • Lee C.
        • Hunsche E.
        • Balshaw R.
        • Kong S.X.
        • Schnitzer T.J.
        Need for common internal controls when assessing the relative efficacy of pharmacologic agents using a meta-analytic approach: case study of cyclooxygenase 2-selective inhibitors for the treatment of osteoarthritis.
        Arthritis Rheum. 2005; 53 (Epub 2005/08/06. http://dx.doi.org/10.1002/art.21328. PubMed PMID: 16082648): 510-518
        • Nuesch E.
        • Rutjes A.W.
        • Husni E.
        • Welch V.
        • Juni P.
        Oral or transdermal opioids for osteoarthritis of the knee or hip.
        Cochrane Database Syst Rev. 2009; (Epub 2009/10/13. http://dx.doi.org/10.1002/14651858.CD003115.pub3. PubMed PMID: 19821302): CD003115
        • Cepeda M.S.
        • Camargo F.
        • Zea C.
        • Valencia L.
        Tramadol for osteoarthritis.
        Cochrane Database Syst Rev. 2006; (Epub 2006/07/21. http://dx.doi.org/10.1002/14651858.CD005522.pub2. PubMed PMID: 16856101): CD005522
        • Iwamoto J.
        • Takeda T.
        • Sato Y.
        • Matsumoto H.
        Effects of risedronate on osteoarthritis of the knee.
        Yonsei Med J. 2010; 51 (Epub 2010/03/02. http://dx.doi.org/10.3349/ymj.2010.51.2.164. PubMed PMID: 20191005; PubMed Central PMCID: PMCPMC2824859): 164-170
        • Christensen R.
        • Bartels E.M.
        • Altman R.D.
        • Astrup A.
        • Bliddal H.
        Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?–a meta-analysis of randomized controlled trials.
        Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society. 2008; 16 (Epub 2008/04/15. http://dx.doi.org/10.1016/j.joca.2008.03.001. PubMed PMID: 18407528): 965-972
      1. European Medicines Agency. Recommendation to restrict the use of Protelos/Osseor (strontium ranelate) [press release].

      Linked Article

      • Corrigendum to ‘2014 OARSI Guidelines for the Non-Surgical Management of Knee Osteoarthritis’ [Osteoarthritis and Cartilage 22 (2014) 363–388]
        Osteoarthritis and CartilageVol. 23Issue 6
        • Preview
          The authors have identified discrepancies in some of the figures of the manuscript “OARSI guidelines for the non-surgical management of knee osteoarthritis,” published in the March 2014 issue of Osteoarthritis and Cartilage; 22(3):363–88. After completing our diligence in ascertaining the nature and cause of these discrepancies, we have discovered errors in some of the figures depicting the risk and benefit scores. These arose from a line shift error in the programming code embedded in the excel spreadsheet that we used to generate the figures.
        • Full-Text
        • PDF
        Open Archive
      • Comments on “OARSI guidelines for the non-surgical management of knee osteoarthritis”
        Osteoarthritis and CartilageVol. 22Issue 6
        • Preview
          To the Editor: The 2014 OARSI Guidelines1 for the management of hip and knee osteoarthritis (OA) with pharmacological therapies are indeed improved by reference to the 2008/2010 OARSI recommendations because the presence or absence of co-morbidities is taken into account.
        • Full-Text
        • PDF
        Open Archive
      • Response to Letter to the Editor entitled “Comments on ‘OARSI guidelines for the non-surgical management of knee osteoarthritis’”
        Osteoarthritis and CartilageVol. 22Issue 6
        • Preview
          We thank Prof. du Souich for commending the 2014 guidelines for the management of knee OA for taking into account the role of co-morbidities in its treatment recommendations1 and wholeheartedly share his views on the importance of considering co-morbidities and the risk of drug–drug interactions in those with multiple morbidity. Indeed, our decision to formulate treatment guidelines more tailored to patient characteristics was predicated on these important issues. Prof. du Souich's emphasis on safety in treating at-risk individuals resonates with our own view, and, taken together with reliable data supporting their effectiveness, is the basis for our emphasis on non-pharmacological interventions for patients in the high risk group, namely strength training and aerobic exercise (land-based or water-based), weight management, biomechanical interventions, and self-management and education.
        • Full-Text
        • PDF
        Open Archive