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Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee OsteoarthritisA Systematic Review and Meta-analysis

Educational Objective
To review the long-term clinical management of osteoarthritis.
1 Credit CME
Key Points

Question  What is the association of available medications with long-term pain control in knee osteoarthritis?

Findings  In this systematic review and network meta-analysis of 33 pharmacological interventions that included 22 037 patients with knee osteoarthritis in 47 randomized clinical trials lasting at least 12 months, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo, including the 2 medications that were associated with improved pain (celecoxib and glucosamine sulfate).

Meaning  Larger randomized clinical trials are needed to resolve the uncertainty around the long-term efficacy of medications for knee osteoarthritis.


Importance  Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management.

Objective  To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis.

Data Sources and Study Selection  The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer.

Data Extraction and Synthesis  Data at baseline and at the longest available treatment and follow-up of 12 months’ duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed.

Main Outcomes and Measures  The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value.

Results  Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, −0.18 [95% CrI, −0.35 to −0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, −0.29 [95% CrI, −0.49 to −0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, −0.42 [95% CrI, −0.65 to −0.19]), chondroitin sulfate (SMD, −0.20 [95% CrI, −0.31 to −0.07]), and strontium ranelate (SMD, −0.20 [95% CrI, −0.36 to −0.05]).

Conclusions and Relevance  In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis.

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Article Information

Corresponding Author: Lucio C. Rovati, MD, School of Medicine and Surgery, University of Milano – Bicocca, Via Cadore 48, 20900 Monza, Italy (

Accepted for Publication: November 19, 2018.

Author Contributions: Drs Gregori and Rovati had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Gregori, Giacovelli, Rovati.

Acquisition, analysis, or interpretation of data: Minto, Barbetta, Gualtieri, Azzolina, Vaghi.

Drafting of the manuscript: Gregori, Giacovelli, Rovati.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Gregori, Giacovelli, Minto, Barbetta, Azzolina, Vaghi.

Obtained funding: Gregori, Rovati.

Administrative, technical, or material support: Gualtieri.

Supervision: Gregori, Rovati.

Conflict of Interest Disclosures: Drs Giacovelli and Rovati reported participating in clinical trials of glucosamine sulfate and hyaluronic acid as scientists and employees of Rottapharm (a pharmaceutical company). Rottapharm no longer exists and its commercial interests and operations have been taken over by another pharmaceutical company (Mylan). Drs Giacovelli and Rovati are now scientists at Rottapharm Biotech, which is the research and development spin-off of the former Rottapharm company and an independent corporate entity. Rottapharm Biotech is engaged in the development of new drugs for osteoarthritis, but has no commercial or other interest in any marketed drug and, in particular, in glucosamine sulfate, hyaluronic acid, or any other marketed or experimental pharmaceutical agents considered in the present study. Mss Barbetta, Gualtieri, and Vaghi are also scientists and employees of Rottapharm Biotech. No other disclosures were reported.

Funding/Support: This study was supported by grant BIRD 2016 DCTV from the University of Padova and by financial support from Rottapharm Biotech.

Role of the Funders: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Presented in part at the American College of Rheumatology meeting; November 13, 2016; Washington, DC.

Additional Contributions: We are grateful to Lisa Buttle, PhD (Medscript Ltd), for providing editorial assistance. Dr Buttle was not compensated for her contribution.

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