Roth Because of the significant adverse events associated with oral or systemic NSAIDs, it is imperative to seek pharmaco- logic options with more favorable benefit-risk ratios. Safety concerns are even greater in special populations, such as older adults and those with gastrointestinal, cardiovascular, or renal risk factors. Therefore, the issue of reducing systemic exposure has special relevance in such populations.8 This article reviews recent studies evaluating the relative safety of oral NSAID formulations and strategies for balancing the risks of NSAIDs against their well established efficacy in individuals with osteoarthritis. Mechanisms of action and available formulations The analgesic, anti-inflammatory, and antipyretic effects of NSAIDs are a result of the ability of these agents to inhibit cyclo-oxygenase (COX) enzymes, which catalyze the conversion of arachidonic acid to prostaglandins, which are fatty acids involved in the generation of pain, fever, and inflammation.7,9 Currently available NSAIDs can be divided into two categories, ie, nonselective NSAIDs, which inhibit both COX-1 and COX-2, and COX-2 selective NSAIDs. The COX-1 isoenzyme is widely and constitutively expressed in many tissues.9,10 It plays an important role in renal and gastrointestinal function, and is located on mono- cytes and platelets, in the endothelium, and on renal collect- ing tubules and seminal vesicles.9 These expression patterns explain the gastrointestinal and renal adverse events observed with the use of nonselective NSAIDs, in that COX-1 inhi- bition reduces the cytoprotective effects of this enzyme on gastrointestinal function and renal physiology.9 Furthermore, COX-1 inhibition prevents the formation of proaggregatory thromboxane A2, which can result in decreased platelet aggregation, and thereby occlusive thrombi, but also can lead to excessive bleeding.9,11 In contrast with COX-1, the COX-2 isoenzyme is pre- dominantly involved in pathophysiologic states, such as inflammation and tumorigenesis, and appears substantially more prevalent in injured or inflamed tissues.9,10 Found in higher concentrations in the kidney, brain, and reproduc- tive organs, COX-2 is mainly expressed in parenchymal cells.10 COX-2 inhibition suppresses some inflammatory mediators involved in the progression of atherogenesis and ischemic myocardial damage, and appears to alter the balance between antithrombotic prostacyclin and prothrom- botic thromboxane A2, increasing the risk of thrombosis.9,11 COX-2 selective NSAIDs, notably celecoxib, have a recognized dose-related risk of cardiovascular events, but 126 submit your manuscript | www.dovepress.com Dovepress Dovepress nonselective NSAIDs, such as diclofenac or ibuprofen, also confer cardiovascular risk.12 Oral NSAID therapy in osteoarthritis: key safety issues The most ubiquitous and problematic adverse event associ- ated with oral (systemic) NSAIDs is gastropathy, which confers a significant risk of decreased work time, disability, and medical costs. Increased risk of mortality from gastroin- testinal bleeding, stomach, and bowel perforations is also of significant concern. Thus, although cardiovascular and renal vascular complications pose significant risks, they are com- paratively less frequent than gastrointestinal complications. All three categories of events are associated with significant morbidity and mortality, and necessitate careful selection of patients for oral NSAID therapy to minimize risk. Gastrointestinal adverse events The most common adverse events associated with oral (systemic) NSAID therapy are those of the gastrointestinal system.13 A recent international, multicenter study of 3293 consecutive candidates for NSAID treatment of osteoarthritis showed that 86.6% were at increased gastrointestinal risk, and 22.3% were considered at high risk for gastrointestinal events.14 The risk of gastric events increases with age, ris- ing precipitously at age 60 years.15 Additional risk factors for gastrointestinal toxicity include history of ulcers (par- ticularly bleeding ulcers), high NSAID dose, Helicobacter pylori infection (which increases ulcer risk by approximately 1.8-fold), and concurrent use of antiplatelet agents and aspirin, both of which are commonly used by older adults.15 NSAIDs and H. pylori have synergistic effects on risk; in a meta-analysis of 16 studies involving 1625 NSAID users, the odds ratio (OR) for peptic ulcer disease in H. pylori- positive NSAID users was 61.1 (95% confidence interval [CI] 9.98–373), compared with H. pylori-negative nonusers.16 Both nonselective and COX-2 selective NSAIDs are associated with some elevated gastrointestinal risk. However, the risk is significantly greater for nonselective NSAIDs.13,17 Oral nonselective NSAIDs can cause serious upper and lower gastrointestinal effects, including bleeding, perforation, obstruction, stricture, anemia, and hypoalbuminemia.8 Of patients receiving nonselective NSAID therapy, 10%–30% develop peptic ulcers;13 a study in more than 2000 patients hospitalized for peptic ulcer demonstrated that the mortality rate in patients using nonselective NSAIDs was approxi- mately 35%, and was double the rate of that in patients not taking NSAIDs.17 More common gastrointestinal adverse Clinical Interventions in Aging 2011:6