Intraarticular drug delivery in osteoarthritis

Osteoarthritis (OA) is a primarily non-inflammatory, degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, changes in the synovial membrane, and an increased volume of synovial fluid with reduced viscosity and hence changed lubrication properties. As OA is the most common type of arthritis and a leading cause of disability, there is a largely unmet medical need for disease-modifying and symptomatic treatment. Due to the localized nature of the disease, intraarticular (IA) drug injection is an attractive treatment approach for OA. The various glucocorticoid and hyaluronic acid (HA) formulations, which are currently available on the market for IA treatment, provide only short-term pain relief or/and often do not provide adequate pain relief. The available oral drugs for symptomatic treatment also have shortcomings, most notably side effects. Therefore, there is still a large unmet need for novel OA drugs, which provide effective long-term pain relief and/or have disease-modifying properties. To achieve long-term drug exposure, different established formulations such as suspensions and hydrogels, and also novel approaches such as lipid based formulations and nano- or microparticles are currently in development. The development of novel drugs in combination with new formulations for IA treatment of OA, represents a promising approach in this challenging area of research.     

New molecular targets for the treatment of osteoarthritis

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized by destruction of the articular cartilage, subchondral bone alterations and synovitis. Current treatments are focused on symptomatic relief but they lack efficacy to control the progression of this disease which is a leading cause of disability. Therefore, the development of effective disease-modifying drugs is urgently needed. Different initiatives are in progress to define the molecular mechanisms involved in the initiation and progression of OA. These studies support the therapeutic potential of pathways relevant in joint metabolism such as Wnt/β-catenin, discoidin domain receptor 2 or proteinase-activated receptor 2. The dysregulation in cartilage catabolism and subchondral bone remodeling could be improved by selective inhibitors of matrix metalloproteinases, aggrecanases and other proteases. Another approach would favor the activity of anabolic processes by using growth factors or regulatory molecules. Recent studies have also revealed the role of oxidative stress and synovitis in the progression of this disease, supporting the development of a number of inhibitory strategies. Novel targets in OA are represented by genes involved in OA pathophysiology discovered using gene network, epigenetic and microRNA approaches. Further insights into the molecular mechanisms involved in OA initiation and progression may lead to the development of new therapies able to control joint destruction and repair.     

Treatment decisions,side-effect liability and cost-effectiveness in osteoarthritis

Cost-benefit ratios emphasize benefits as much as they do risks but the consequences of not treating also figure in the equation. For osteoarthritis (OA), most drugs designed to alter the progression have either been found wanting or have been withdrawn. That leaves palliation of symptoms as the search for pharmacological intervention to replace the very effective surgery continues. Guidelines to aid in the search succeed in defining alternatives to amelioration but less satisfactority define disease modifiers. Much of this derives from a misunderstanding: OA is not a disease, though it often provokes symptoms, but rather is the final common pathway of all events at a joint. Treatment can therefore be offered only when OA produces symptoms, and that is too late to reverse the process. If prediction were possible, more effective prophylaxis might be developed. The interferences with life content, life space and life span lead to the therapeutic decisions and their cost-effectiveness. Because symptoms in OA often result from secondary inflammation, anti-inflammatory drugs remain appropriate choices, even though simple analgesics suffice in the short term for pain relief alone. That inflammation may also underlie the inception of the process that leads to OA is self-evident and more effective initial treatment might slow the progression, but the symptoms of established OA are a secondary event, long after the historically elusive primary insult, and warrant careful appraisal of cost-effectivness of interventions as part of risk assessment.     

The tolerability of viscosupplementation: low incidence and clinical management of local adverse events

Hylan G-F 20 (Synvisc, Genzyme Biosurgery, Ridgefield, NJ) is a visco supplement indicated for the treatment of pain due to osteoarthritis (OA) of the knee. Overall, the therapy is well tolerated with a low incidence of local and systemic adverse events (AEs). In our large clinical practice, our overall rate of local pain and swelling with treatment is consistent with that of previous reports and the product labeling. Local AEs that do occur with therapy are mostly mild to moderate in nature, transient, and resolve spontaneously or with symptomatic treatment. Local AEs thought to be related to the treatment are clinically manageable and do not result in long-term sequelae, such that their occurrence should not preclude patients from the benefit of OA pain relief with therapy, including continued pain relief with repeat treatment. Based on previous published reports of hylan G-F 20 and our extensive clinical experience, relief of OA knee pain with hylan G-F 20 far outweighs the low risk of local AEs for patients who do not respond to other therapies indicated for the treatment of OA knee pain.     

An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution

Background: Osteoarthritis (OA) is the most common chronic degenerative disease, which is characterised by the destruction of the articular cartilage and subchondral bone. The current treatment of OA is based primarily on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. There are disadvantages to routinely using NSAIDs in OA. Topical NSAIDs represent a potentially important advance in this regard as they may be significantly safer than oral NSAIDs. Cutaneous diclofenac solution (Pennsaid^®) was developed for the treatment of symptomatic OA of the knee and contains diclofenac sodium as an active ingredient and dimethyl sulfoxide (DMSO), a penetration enhancer. Objective: To review: i) dermal drug application; ii) the treatment of OA with systemic and topical NSAID therapies; and iii) the clinical efficiency of Pennsaid on the topical treatment of OA of the knee. Methods: A literature search was carried out on skin, topical drug delivery, treatment of OA and assessment of published clinical studies with Pennsaid. Results and discussion: The clinical studies showed that applying the topical diclofenac solution (Pennsaid) to a painful knee with primary OA could provide symptom relief equivalent to oral diclofenac with minimal systemic side effects; however, studies are needed that compare the effectiveness of Pennsaid with different topical forms of diclofenac.     

The tolerability of viscosupplementation: low incidence and clinical management of local adverse events

SUMMARY

Hylan G-F 20 (Synvisc®, Genzyme Biosurgery, Ridgefield, NJ) is aviscosupplement indicated for the treatment of pain due to osteoarthritis (OA) of the knee. Overall, the therapy is well tolerated with a low incidence of local and systemic adverse events (AEs). In our large clinical practice, our overall rate of local pain and swelling with treatment is consistent with that of previous reports and the product labeling. Local AEs that do occur with therapy are mostly mild to moderate in nature, transient, and resolve spontaneously or with symptomatic treatment. Local AEs thought to

be related to the treatment are clinically manageable and do not result in long-term sequelae, such that their occurrence should not preclude patients from the benefit of OA pain relief with therapy, including continued pain relief with repeat treatment. Based on previous published reports of hylan G-F 20 and our extensive clinical experience, relief of OA knee pain with hylan G-F 20 far outweighs the low risk of local AEs for patients who do not respond to other therapies indicated for the treatment of OAknee pain.     

Lumiracoxib: the evidence of its clinical impact on the treatment of osteoarthritis

INTRODUCTION: The symptoms of osteoarthritis (OA) include joint pain, stiffness, and a reduced ability to perform normal daily activities, which result in decreased quality of life. There is currently no known cure or means of preventing the progression of joint damage due to OA. Therefore, treatment focuses on the control of symptoms, including the use of various agents [including nonselective and selective nonsteroidal antiinflammatory drugs (NSAIDs)] to provide pain relief and reduce inflammation. Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor for the treatment of OA. AIMS: To review the evidence for the treatment of OA with lumiracoxib. EVIDENCE REVIEW: There is evidence that lumiracoxib reduces the pain and stiffness associated with OA, and is as effective as nonselective NSAIDs, and the COX-2 inhibitor celecoxib. There is some evidence that lumiracoxib treatment results in a lower incidence of upper gastrointestinal (GI) ulcer complications compared with nonselective NSAIDs. However, evidence suggests that there is no GI benefit in patients receiving concomitant aspirin medication. With the exception of GI ulcers, the evidence indicates that lumiracoxib has a tolerability profile similar to nonselective NSAIDs: low risk of cardiovascular (CV) events and a low incidence of edema. Changes in liver function occur in some patients, largely at doses >100 mg. The cost effectiveness of lumiracoxib compared with nonselective NSAIDs remains to be determined. CLINICAL VALUE: Lumiracoxib is an alternative treatment option for OA which provides effective pain relief without the GI complications associated with nonselective NSAIDs, and with a low risk of CV events. Lumiracoxib is contraindicated in patients with current, previous, or at risk of, hepatic impairment.     

Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a 13-week, randomized, double-blind study vs. placebo and celecoxib

OBJECTIVE: To determine the efficacy and safety of lumiracoxib for knee osteoarthritis (OA). METHODS: This was a 13-week, multicentre, randomized, double-blind, double-dummy, placebo-controlled study. Males or females aged >/= 18 years with primary knee OA received lumiracoxib 100 mg od, lumiracoxib 100 mg od with a loading dose of 200 mg od for the first two weeks, celecoxib 200 mg od, or placebo. MAIN OUTCOME MEASURES: Co-primary variables, assessed at week 13, were OA pain intensity in the target knee, patient's global assessment of disease activity and the WOMAC total score. Other variables included OMERACT-OARSI responder rates and WOMAC subscale scores. Safety and tolerability were evaluated. RESULTS: All active treatments were superior to placebo for all co-primary variables. No significant differences were observed between any active treatments. Mean reductions from baseline to week 13 for lumiracoxib 100mg od, 100mg od with loading dose, celecoxib and placebo, respectively, were: OA pain intensity in the target knee: 26.8, 26.2, 26.6 and 21.4mm (all p < 0.01 vs. placebo); patient's global assessment of disease activity: 25.1, 21.9, 22.9 and 18.9 mm (all p < 0.05 vs. placebo); WOMAC total score: 15.2, 14.8, 14.7 and 11.3 (all p < 0.01 vs. placebo). Lumiracoxib was superior to placebo and similar to celecoxib for OMERACT-OARSI response and WOMAC subscale scores. Lumiracoxib was well tolerated. The incidence of adverse events was similar across groups. CONCLUSIONS: Lumiracoxib 100 mg od provided effective relief from the pain of knee OA, with efficacy similar to celecoxib 200 mg od, and was well tolerated.     

The pathobiology of osteoarthritis and the rationale for using the chondroitin sulfate for its treatment

Structure-modifying osteoarthritis (OA) drugs are agents that reverse, retard, or stabilize the pathology of OA, thereby providing symptomatic relief in the long-term treatment. The objective of this review is to evaluate the literature on chondroitin sulfate (CS) with respect to the pathobiology of OA to ascertain whether this agent should be classified as a symptomatic slow-acting drug (SYSADOA), a compound that has a slow onset of action and improve OA symptoms after a couple of weeks. CS exhibits a wide range of biological activities and from a pharmacological point of view it produces a slow but gradual decrease of the clinical symptoms of OA and these benefits last for a long period after the end of treatment. Many literature data show that CS could have an anti-inflammatory activity and a chondroprotective action by modifying the structure of cartilage. These properties are also related to the oral adsorption of this molecule as high-molecular mass compounds having clusters of sulfate groups and high charge density capable of exert their chondroprotective activity in vivo.     

The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii

Background and Purpose: L-DOPA is generally considered to alleviate the symptoms of Parkinson''s disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA-binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS).Experimental Approach: We examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock-down of OA1 in the NTS, using shRNA against OA1.Key Results: Using a specific OA1 antibody, OA1-positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine-induced bradycardic responses without affecting blood pressure responses.Conclusion and Implications: OA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.     

Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis

Recent literature and animal research has provided insight to potentially new analgesic targets for managing osteoarthritis (OA) pain. Primary afferent neurons located in affected joints express excessive amounts of abnormally functioning sodium (Na) channels on their surface in response to the inflammatory process. These Na channels may play an integral role in production of pain and hyperalgesia. Hence, the authors set out to conduct a 2-week, open-label, multicenter proof-of-concept study to evaluate the effectiveness and safety of lidocaine patch 5% monotherapy in adults with OA pain of the knee (n = 20). Patients with OA of one or both knees who were experiencing inadequate pain relief (defined as an average daily pain intensity of > 4 on a 0 to 10 pain scale) with their current analgesic regimen (i.e. APAP, NSAIDs, COX-2 inhibitors, tramadol) were enrolled and had all analgesic medications discontinued. Treatment with the lidocaine patch 5% resulted in significant improvements in the Western Ontario and McMaster Universities OA Index (WOMAC) pain, stiffness, physical function subscales and composite index (48.4, 41.1, 47.0, and 46.8% improvements respectively, p < 0.01). In addition, significant improvement was noted for pain intensity, pain relief, and pain interference with quality of life as measured by the Brief Pain Inventory (p < 0.05). The lidocaine patch 5% was generally well tolerated and no patients discontinued due to treatment-related adverse events. Given the open-label design, lack of a control group, and small sample size, the findings from our pilot study need to be confirmed by larger randomized controlled trials. Topical lidocaine patch 5% may provide clinicians with a novel, non-systemic therapy for OA pain with a unique mechanism of action.     

Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics

ABSTRACT

Introduction: Osteoarthritis (OA) is a leading cause of pain and disability among adults with a current prevalence of around 15% and a predicted prevalence of 35% in 2030 for symptomatic OA. It is increasingly recognized as a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity. Current therapeutic regimens for OA are only partially effective and often have significant associated toxicities. There are no disease-modifying drugs approved by the regulatory bodies.

Areas covered: We reviewed the opportunities within key OA pathogenetic mechanism: cartilage catabolism/anabolism, pathological remodeling of subchondral bone and synovial inflammation to identify targeted disease-modifying osteoarthritis drugs, based on compounds currently in Phase II and III stages of clinical development in which x-ray and/or MRI was used as the structural outcome with/without symptomatic outcomes according to regulatory requirements.

Expert opinion: Given the heterogeneity of the OA disease process and complex overlapping among these phenotypes, a ‘one size fits all’ approach used in most clinical trials would unlikely be practical and equally effective in all patients, as well as in all anatomical OA sites. On the other hand, it is a challenge to develop a targeted drug with high activity, specificity, potency, and bioavailability in the absence of toxicity for long-term use in this chronic disease of predominantly older adults. Further research and insight into evaluation methods for drug-targeted identification of early OA and specific characterization of phenotypes, improvement of methodological designs, and development/refinement of sensitive imaging and biomarkers will help pave the way to the successful discovery of disease-modifying drugs and the optimal administration strategies in clinical practice.     

Analgesic efficacy of sustained release paracetamol in patients with osteoarthritis of the knee

AIMS: Paracetamol is widely recommended as the initial treatment for pain associated with osteoarthritis (OA). A sustained release (SR) paracetamol formulation (Panadol Extend) was compared with standard immediate release (IR) paracetamol (Panadol) in patients with knee pain secondary to OA. The primary parameter for assessment of efficacy was patient-assessed global pain relief as determined on day 8 of the treatment period. METHODS: A double-blind, double-dummy, randomized study was conducted. Patients (n=403) were treated for 7 days with paracetamol 4 g day(-1) (SR paracetamol, two 665 mg tablets taken three times daily; IR paracetamol, two 500 mg tablets taken four times daily). Patients completed daily pain measurements and assessed global pain relief at the end of the study. Therapeutic noninferiority was defined on the basis of achieving statistical noninferiority for global pain relief. RESULTS: Analysis of the primary parameter for the intention to treat population showed that the difference in proportion of patients (SR-IR paracetamol) achieving a successful response on day 8 was -0.7%; 90% CI (-8.82%, 7.45%), P=0.890. For the per protocol population the difference in proportion was -3.0%; 90% CI (-11.61%, 5.66%), P=0.571. As the lower bound of the 90% CI for the treatment difference in each case was greater than the prespecified value (-15%), SR paracetamol was considered to be statistically noninferior to IR paracetamol in terms of pain relief. The treatments were not significantly different for any of the secondary parameters in either populations. CONCLUSIONS: SR paracetamol taken three times daily was statistically and therapeutically noninferior to IR paracetamol taken four times daily in patients with knee pain due to OA. SR paracetamol may be more convenient for patients with chronic pain and has the potential to enhance compliance and therefore pain relief.     

'Natural remedies' in the treatment of osteoarthritis

Osteoarthritis (OA) is a common, chronic and painful condition. It is the most common of all rheumatic disorders and is destined to become one of the most prevalent and costly diseases in our society. The conventional therapeutic options employed in the management of OA are simple analgesics and NSAIDs, but these options frequently produce sub-optimal benefit and are associated with an adverse-safety profile. Unsurprisingly patients are looking to alternative and complementary medicine. The aim of this article was to review the available literature on the effectiveness and safety of 'natural remedies' for the treatment of OA. Computerised literature searches were carried out for systematic reviews and randomised controlled trials examining the role of 'natural remedies' in the treatment of OA. There have been few randomised controlled trials of 'natural remedies' that have satisfied the internationally agreed standards. There was, however, evidence of efficacy for glucosamine, chondroitin sulfate and possibly avocado/soybean unsaponifiables for the symptomatic relief of OA. To date, it is not established whether any of the 'natural remedies' are capable of chondroprotection. Even if 'natural remedies' are only modestly effective, they are widely available and well tolerated, suggesting that they may play a significant role in the management of OA in the elderly.     

A review of current animal models of osteoarthritis pain

Osteoarthritis (OA) is a complex disease plagued by a significant unmet need for treatment. To date, no disease- modifying OA drugs (DMOADs) exist and the available symptom-modifying OA drugs (SMOADs) have limitations. Although a complete understanding of the mechanisms of OA pain in humans is lacking, animal models have helped provide insight into the multifaceted origin and manifestation of OA pain. Success in discovering new therapeutics will likely require reliance on good animal models. This review summarizes the animal models available for studying pain associated with OA.     

Topical lidocaine patch 5% may target a novel underlying pain mechanism in osteoarthritis

SUMMARY

Recent literature and animal research has provided insight to potentially new analgesic targets for managing osteoarthritis (OA) pain. Primary afferent neurons located in affected joints express excessive amounts of abnormally functioning sodium (Na) channels on their surface in response to the inflammatory process. These Na channels may play an integral role in production of pain and hyperalgesia. Hence, the authors set out to conduct a 2-week, open-label, multicenter proof-of-concept study to evaluate the effectiveness and safety of lidocaine patch 5% monotherapy in adults with OA pain of the knee (?n = 20). Patients with OA of one or both knees who were experiencing inadequate pain relief (defined as an average daily pain intensity of > 4 on a 0 to 10 pain scale) with their current analgesic regimen (i.e. APAP, NSAIDs, COX-2 inhibitors, tramadol) were enrolled and had all analgesic medications discontinued. Treatment with the lidocaine patch 5% resulted in significant improvements in the Western Ontario and McMaster Universities OA Index (WOMAC) pain, stiffness, physical function subscales and composite index (48.4, 41.1, 47.0, and 46.8% improvements respectively, p < 0.01). In addition, significant improvement was noted for pain intensity, pain relief, and pain interference with quality of life as measured by the Brief Pain Inventory (?p < 0.05). The lidocaine patch 5% was generally well tolerated and no patients discontinued due to treatment-related adverse events. Given the open-label design, lack of a control group, and small sample size, the findings from our pilot study need to be confirmed by larger randomized controlled trials. Topical lidocaine patch 5% may provide clinicians with a novel, non-systemic therapy for OA pain with a unique mechanism of action.     

Chondroitin sulphate for symptomatic osteoarthritis: critical appraisal of meta-analyses

ABSTRACT

Background: Chondroitin sulphate (CS) is an important structural component of cartilage and is approved and regulated as a symptomatic slow-acting drug for osteoarthritis (OA) (SYSADOA) in Europe and some other countries. Although numerous studies have shown the clinical benefits of CS to decrease pain, improve functional disability, reduce non-steroidal anti-inflammatory drug (NSAID) or acetaminophen consumption, and good tolerability with an additional carry-over effect, there are still some concerns regarding its effectiveness in treating OA.

Purpose: To examine the data provided by meta-analyses to clarify the effectiveness of CS as a symptomatic treatment for OA.

Methods: A MEDLINE database search was conducted for appropriate meta-analyses published between 1997 and 2007. Five meta-analyses that limited their analysis to randomised controlled trials (RCTs) comparing CS with placebo or no-treatment control arms were retrieved.

Results: Four meta-analyses showed significant clinical effects of CS compared with placebo for pain and function measures and one demonstrated greater reduction of analgesic co-medication in patients assigned to the active treatment. In one meta-analysis, the 20 trials included in the study showed a high degree of heterogeneity and the conclusion that CS showed minimal symptomatic benefits was based on the analysis of only three trials. One meta-analysis showed that pain relief after CS treatment steadily increased between 4 and 12 weeks of treatment, whereas the time course of pain relief after treatment with NSAIDs decreased. Two meta-analyses reported consistently higher frequencies of side effects in the placebo group than in patients treated with CS.

Conclusion: Data provided by these meta-analyses indicate that CS has a slight to moderate efficacy in the symptomatic treatment of OA, with an excellent safety profile.     

Potential directions for drug development for osteoarthritis

Background: Osteoarthritis (OA) is a frustrating disease for both patient and physician because neither cause nor cure is known and there are currently no disease-modifying drugs. Objective: To review current therapeutic approaches as well as new findings regarding OA pathoetiology that could form the basis of future direction for the development of drugs to prevent or slow down disease progression. Methods: After reviewing disease progression in human OA, as demonstrated by histological analyses, the reasons for cartilage erosion are explored and possible therapeutic approaches are highlighted. Results/conclusions: OA may be an epigenetic disease. This new concept can explain many aspects of the disease and provide reasons why therapeutic approaches until now have met with little success.     

Differences in cardiovascular safety with non‐steroidal anti‐inflammatory drug therapy—A nationwide study in patients with osteoarthritis

Osteoarthritis (OA) and the non‐steroidal anti‐inflammatory drugs (NSAIDs) used to relieve OA‐associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged ≥18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non‐fatal myocardial infarction and non‐fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533 502 patients included, 64.3% received NSAIDs and 38 226 (7.2%) experienced a cardiovascular event during follow‐up. Compared with non‐use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 (95% confidence interval, 1.74‐2.08); celecoxib, 1.47 (1.34‐1.62); diclofenac, 1.44 (1.36‐1.54); ibuprofen, 1.20 (1.15‐1.25); and naproxen, 1.20 (1.04‐1.39). Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs: 0.81 [CI: 0.74‐0.90]) and naproxen (HRs: 0.81 [0.68‐0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low‐dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs: 1.12 (1.07‐1.19) and 1.16 (0.92‐1.42), respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief.