Cyclooxygenase-2 (COX-2) inhibitor therapy should be cautiously used in patients with osteoarthritis (OA) due to an increased risk for gastrointestinal- and cardiovascular-related adverse events, according to a systematic review and meta-analysis published in Drugs and Aging.

Researchers sought to assess the safety of COX-2 inhibitors (including celecoxib, rofecoxib, etoricoxib, and valdecoxib) in patients with OA. A total of 40 trials were identified in a literature search and examined in this systematic review and meta-analysis. Primary outcomes of interest were occurrence of gastrointestinal, cardiac, vascular, nervous system, hepatobiliary, renal and urinary, and skin and subcutaneous tissue disorders, as well as overall severe and serious adverse events, drug-related adverse events, and mortality.

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Included studies were published between 1999 and 2017 and had a follow-up time ranging from 6 weeks to 24 months. Anatomic regions examined were knee (59%), hip (5%), knee or hip (32%), any OA (2%), and unspecified (2%).

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Overall, the use of COX-2 inhibitors was associated with an increased risk for drug-related adverse events compared with placebo (relative risk [RR], 1.26; 95% CI, 1.09-1.46). In particular, the use of COX-2 inhibitors vs placebo was more likely to increase the risk for upper gastrointestinal complications (eg, dyspepsia, gastritis, and heartburn; RR, 1.19; 95% CI, 1.03-1.38). Among cardiovascular concerns, hypertension risk increased by 45% overall; this increase was no longer significant when rofecoxib was removed from the analysis (RR, 1.21; 95% CI, 0.80-1.83). In addition, the risk for heart failure and edema increased by nearly 70% with the use of COX-2 inhibitors (RR, 1.67; 95% CI, 1.21-2.29).

The occurrence of nervous system or dermatological disorders was comparable in patients treated with COX-2 inhibitors or placebo, and too few studies reported on renal and hepatic disorders to be included in the meta-analysis.

The investigators noted several limitations to this study, including a lack of suitable adverse event data, and the lack of data on particular patient subgroups. (eg, patients with coronary artery bypass graft surgery or rheumatoid arthritis).

“COX-2 inhibitors were associated with an increased risk [for] upper gastrointestinal [adverse events], especially abdominal pain,” noted the review authors. “Our results confirm that a cautious approach to the use of…COX-2 inhibitors for the management of pain and inflammation in OA is advisable.”

Multiple authors report conflicts of interest. For the complete list of disclosures, please view the full text of the study online.


Curtis E, Fuggle N, Shaw S, et al. Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis. Drugs Aging. 2019;36(suppl):25-44.