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Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysisPharmacologic Interventions for Knee OA

Raveendhara R. Bannuru, MD; Christopher H. Schmid, PhD; David M. Kent, MD; Elizaveta E. Vaysbrot, MD; John B. Wong, MD; and Timothy E. McAlindon, MD
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From Center for Treatment Comparison and Integrative Analysis, Predictive Analytics and Comparative Effectiveness Center, and Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, and Center for Evidence Based Medicine and Brown University School of Public Health, Providence, Rhode Island.

Disclaimer: 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 (AHRQ).

Acknowledgment: The authors thank Matthew Sullivan for his contributions to this work.

Grant Support: By the AHRQ (grants F32HS021396 and R01-HS018574; Drs. Bannuru and Schmid, respectively).

Disclosures: Dr. Bannuru reports grants from AHRQ during the conduct of the study. Dr. Wong reports grants from Patient-Centered Outcomes Research Institute and National Institutes of Health National Center for Complementary and Alternative Medicine and nonfinancial support from European League Against Rheumatism outside the submitted work. Dr. McAlindon reports grants from Croma, Flexion Therapeutics, National Institutes of Health, and AHRQ; and personal fees from Bioventus outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1231.

Requests for Single Reprints: Raveendhara R. Bannuru, MD, Center for Treatment Comparison and Integrative Analysis, Division of Rheumatology, Tufts Medical Center, 800 Washington Street, Box 406, Boston, MA 02111; e-mail, rbannuru@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Bannuru, Vaysbrot, and McAlindon: Center for Treatment Comparison and Integrative Analysis, Division of Rheumatology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.

Drs. Kent and Wong: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.

Dr. Schmid: Brown University School of Public Health, 121 South Main Street, Providence, RI 02912.

Author Contributions: Conception and design: R.R. Bannuru, C.H. Schmid, T.E. McAlindon.

Analysis and interpretation of the data: R.R. Bannuru, C.H. Schmid, D.M. Kent, J.B. Wong, T.E. McAlindon.

Drafting of the article: R.R. Bannuru, C.H. Schmid, J.B. Wong.

Critical revision of the article for important intellectual content: R.R. Bannuru, C.H. Schmid, D.M. Kent, E.E. Vaysbrot, J.B. Wong, T.E. McAlindon.

Final approval of the article: R.R. Bannuru, C.H. Schmid, D.M. Kent, E.E. Vaysbrot, J.B. Wong, T.E. McAlindon.

Provision of study materials or patients: R.R. Bannuru.

Statistical expertise: R.R. Bannuru, C.H. Schmid.

Obtaining of funding: R.R. Bannuru.

Administrative, technical, or logistic support: R.R. Bannuru, E.E. Vaysbrot.

Collection and assembly of data: R.R. Bannuru, E.E. Vaysbrot.

Ann Intern Med. 2015;162(1):46-54. doi:10.7326/M14-1231
Text Size: A A A

Background: The relative efficacy of available treatments of knee osteoarthritis (OA) must be determined for rational treatment algorithms to be formulated.

Purpose: To examine the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates relative effects of all treatments against each other.

Data Sources: MEDLINE, EMBASE, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials from inception through 15 August 2014, and unpublished data.

Study Selection: Randomized trials of adults with knee OA comparing 2 or more of the following: acetaminophen, diclofenac, ibuprofen, naproxen, celecoxib, intra-articular (IA) corticosteroids, IA hyaluronic acid, oral placebo, and IA placebo.

Data Extraction: Two reviewers independently abstracted study data and assessed study quality. Standardized mean differences were calculated for pain, function, and stiffness at 3-month follow-up.

Data Synthesis: Network meta-analysis was performed using a Bayesian random-effects model; 137 studies comprising 33 243 participants were identified. For pain, all interventions significantly outperformed oral placebo, with effect sizes from 0.63 (95% credible interval [CrI], 0.39 to 0.88) for the most efficacious treatment (hyaluronic acid) to 0.18 (CrI, 0.04 to 0.33) for the least efficacious treatment (acetaminophen). For function, all interventions except IA corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another.

Limitation: Lack of long-term data, inadequate reporting of safety data, possible publication bias, and few head-to-head comparisons.

Conclusion: This method allowed comparison of common treatments of knee OA according to their relative efficacy. Intra-articular treatments were superior to nonsteroidal anti-inflammatory drugs, possibly because of the integrated IA placebo effect. Small but robust differences were observed between active treatments. All treatments except acetaminophen showed clinically significant improvement from baseline pain. This information, along with the safety profiles and relative costs of included treatments, will be helpful for individualized patient care decisions.

Primary Funding Source: Agency for Healthcare Research and Quality.


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Appendix Figure.

Summary of evidence search and selection.

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Figure 1.

Network of treatment comparisons for pain.

Circle size reflects number of participants, and the line width reflects the number of direct comparisons. No connecting line between 2 treatments indicates that there was no direct comparison. IA = intra-articular.

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Figure 2.

Summary of risk-of-bias assessment: direct and indirect evidence for each pairwise comparison.

Only comparisons with at least 5 direct head-to-head trials were plotted. The numbers inside the bars indicate the number of trials within each comparison that had low, unclear, or high risk of bias. The x-axis illustrates the percentage of trials with low, unclear, or high risk of bias for each comparison. IA = intra-articular.

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Pharmacologic Interventions for Knee Osteoarthritis
Posted on January 29, 2015
Donald M. Marcus, MD
Baylor College of MedicinePharmacologic Interventions for Knee Osteoarthritis
Conflict of Interest: None Declared
In their complex review of pharmacologic interventions for treatment of knee osteoarthritis (1), Bannuru et al. reported that intraarticular hyaluronic acid had the highest effect size for relief of pain compared to an oral placebo. That comparison is misleading because the appropriate control for intraarticular hyaluronic is an intraarticular placebo injection. Although the authors and the accompanying editorial (2) note that the apparent efficacy of hyaluronic acid may result from the stronger placebo effect of an injection, the comparison with an oral placebo gives unwarranted credibility to the efficacy of hyaluronic acid, and it is subject to misinterpretation. For example, a commentary by a physician in an online medical newsletter (3) ignored the issue of placebo effects, and called into question recommendations against the use of hyaluronic acid. Another online newsletter (4) cited the biggest benefit from hyaluronic acid and failed to consier data from other reviews and guidelines.
The best evidence is that intraarticular hyaluronic acid has no clinically meaningful benefit for knee osteoarthritis compared to an intraarticular placebo injection (5). The guidelines of the American Academy of Orthopedic Physicians contains a strong recommendation against the use of hyaluronic acid for treatment of knee osteoarthritis (6). The review by Bannuru et al. provides no basis for reconsidering current guidelines.
Despite the lack of evidence supporting its use, injections of hyaluronic acid for knee osteoarthritis are used widely. It is unfortunate that this paper may well be misquoted in other popular health media and in advertisements as providing evidence for the benefits of hyaluronic acid.
1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectivenesss of pharmacologic interventions for knee osteoarthritis. Ann Int Med 2015; 162: 46-54.
2. Mandl LA, Losina E. Relative efficacy of knee osteoarthritis treatments: Are all placebos created equal? Ann Int med 2015; 162:71-2.
3. Altman R. Next round on hyaluronic acid: Better even than acetaminophen? New data call AAOS recommendations into question? http://www.medpagetoday.com/Rheumatology/Arthritis /49 1/23/2015.
4. Norton A. Knee arthritis drugs beat placebos, but study finds no clear winner. Health Day http://consumerhealthday.com January 6, 2015, accesed January 26, 2015.
5. Rutjes AWS, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for osteoarhritis of the knee. Ann Intern Med 2012; 157:180-91.
6. American Academy of Orthopedic Surgeons. Treament of osteoarthritis of the knee:evidence-based guidelines. 2nd edition. Rosement, IL: American Academy of Orthopedic Surgeons; 2013. Accessed at www.aaos.org January 29, 2015
Author's Response
Posted on February 26, 2015
Raveendhara R. Bannuru, MD; David M. Kent, MD; and Timothy E. McAlindon, MD
Tufts Medical Center
Conflict of Interest: None Declared
We thank Dr. Marcus for his insightful comments and wholeheartedly agree that all articles should be faithfully reported and not spun to meet marketing agendas. We agree that comparison of intra-articular hyaluronic acid to intra-articular placebos is scientifically valuable, but we also maintain that comparison to oral placebo is valuable as well. Both comparisons give valid estimates of treatment effect—but with different meanings. The former measures an explanatory treatment effect that might be a better measure of the incremental effect due to the biological activity of hyaluronic acid over and above a (potentially) pharmacodynamically inactive saline injection. The latter, however, gives a more pragmatic measure, which is likely to be a better indicator of the degree of relief a patient will feel—since it incorporates all modes of intra-articular hyaluronic acid activity. For the purposes of comparative effectiveness research, we feel the comparison to oral placebo provides a better evidentiary basis for clinical decision making.

Our network meta-analysis enabled us to estimate the comparative effectiveness of intra-articulars relative to oral agents, and rank these effects in a way that has clinical utility.1 The fact that the derived comparative effect may incorporate a component of a placebo response should prompt thought and discussion as to how to reformulate how we think about its role in therapy and practice of medicine. Therefore, we should think carefully before making strong negative recommendations for therapeutic products that have good comparative effectiveness, especially for conditions for which use of the limited number of alternatives is often precluded by comorbid contra-indications. These complex considerations may explain why there are differences between consensus recommendations from different groups in regard to products such as HA.2-4

1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Annals of internal medicine. Jan 6 2015;162(1):46-54.
2. Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. The Journal of the American Academy of Orthopaedic Surgeons. Sep 2013;21(9):577-579.
3. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis care & research. Apr 2012;64(4):465-474.
4. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. Mar 2014;22(3):363-388.

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