Comorbidities that impact management of osteoarthritis

INTRODUCTION — Osteoarthritis (OA) is the most common form of arthritis and can often be disabling in adults. Although many drugs are available for the symptomatic treatment of OA, the presence of comorbidities complicates management and remains a practical challenge. Both nonpharmacologic and pharmacologic interventions may require adaptation depending on the comorbidity.

This topic will review the management of OA in patients with common comorbidities. The pathogenesis and risk factors, diagnosis, clinical manifestations, and treatment of OA are presented separately. (See "Pathogenesis of osteoarthritis" and "Epidemiology and risk factors for osteoarthritis" and "Clinical manifestations and diagnosis of osteoarthritis" and "Overview of the management of osteoarthritis" and "Management of knee osteoarthritis" and "Management of moderate to severe knee osteoarthritis".)

BACKGROUND — The prevalence of comorbidities among patients with osteoarthritis (OA) is high. In a meta-analysis with 42 studies, the prevalence of any comorbidity was 67 percent (95% CI 57-74) in individuals with OA versus 56 percent (95% CI 44-68) without OA [1]. The leading chronic conditions among patients with OA included hypertension in 50 percent, cardiovascular disease in 35 percent, peptic ulcer disease in 16 percent, and diabetes in 14 percent. In another meta-analysis, diabetes is also a relatively common comorbidity among patients with OA, with estimates of prevalence of approximately 15 percent [2]. Other studies have shown that the metabolic syndrome is more frequent in patients with OA compared with controls [3,4].

The prevalence of cardiovascular disease (CVD) among patients with OA is also high. A meta-analysis including over 32,000,000 patients with OA found that they were twice as likely to have CVD [5]. Several studies have also suggested that OA is associated with excess mortality risk due to CVD, diabetes mellitus (DM), obesity, cognitive disorders, and disability [6-8] (see "Overview of the management of osteoarthritis", section on 'Mortality'). In addition, pain secondary to OA may promote hypertension, obesity, and CVD by decreasing mobility (sometimes called the "sitting disease"). In an analysis including 10,723 patients with knee OA, the presence of pain had a 37 percent increased association with reduced time-to-morality in an adjusted model [8]. Finally, greater comorbidity burden with cardiac disease, diabetes, or back pain has been shown to contribute to worse pain and physical function in patients with knee and/or hip OA [9]. Findings from a systematic review suggest that having at least one comorbidity is one of the factors associated with a worse evolution of pain over several years [10].

MANAGEMENT CONSIDERATIONS FOR COMORBIDITIES — The presence of comorbidities in patients with osteoarthritis (OA) often impacts treatment choices, particularly with respect to pharmacologic therapy. Among these agents, the use of oral nonsteroidal antiinflammatory drugs (NSAIDs) is often limited due to the increased risk of adverse effects in patients with common comorbidities. When possible, NSAIDs should be used for the shortest period of time, the efficacy decreasing after a couple of weeks, whereas the incidence of side effects increases over time [11]. Otherwise, the same general management principles of OA should apply, in that all patients should also engage in nonpharmacologic measures such as weight management and exercise, braces, walking aids, and psychological interventions as appropriate. It is worth noting that the beneficial effects of exercise and weight loss are not only limited to OA but are also advantageous for several other comorbidities.

We discuss specific considerations when managing OA in the setting of the common comorbidities listed below. Our approach to managing OA patients with comorbidities is generally consistent with those that have been addressed by major guidelines [12-14].

Diabetes mellitus — We avoid the use of oral NSAIDs when treating OA patients with diabetes mellitus (DM), particularly among those with complications such as cardiovascular disease (CVD) and/or kidney disease. Adverse effects of NSAIDs among patients with kidney disease and CVD are discussed in detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs: Acute kidney injury".)

Other oral pharmacologic agents and supplements used in the treatment of OA appear to be safe, but few have been studied specifically in the context of DM. There are some data that support the safety of glucosamine among patients with DM. An analysis of safety data from one randomized trial found that the mean plasma glucose levels in the group of patients taking glucosamine did not differ from baseline at both the three- and six-month follow-up period [15]. Also, a subgroup analysis of hyperglycemic patients at baseline found that mean glucose levels tended to decrease over time with glucosamine compared with placebo. Additional information regarding the use of glucosamine and chondroitin for OA can be found elsewhere. (See "Management of knee osteoarthritis", section on 'Nutritional supplements'.)

Intraarticular glucocorticoid injections pose a theoretical risk to patients with DM by potentially raising blood glucose to hyperglycemic levels. However, patients generally experience an isolated increase in blood glucose for one to two days after the injection which rarely poses a significant clinical risk when DM is well controlled. For insulin-dependent diabetic patients in whom an intraarticular injection is warranted, self-monitoring of blood glucose should be performed for up to three to five days after the injection. In a case–crossover study of 40 patients with type 1 or 2 DM, the fasting blood glucose level was increased one and two days after a glucocorticoid injection for common conditions in the hand and wrist (eg, trigger finger, carpal tunnel syndrome, OA), especially in insulin-dependent diabetic patients. Fasting blood glucose concentration did not differ after the second post-injection day. [16]. In another study with 23 patients with DM, an extraarticular wrist injection of 10 mg of triamcinolone acetonide increased blood glucose levels during five days after injection as compared with morning blood glucose levels pre-injection [17]. Insulin-dependent patients experienced greater changes from baseline compared with non-insulin–dependent patients. Additional information regarding the use of intraarticular glucocorticoid injections in the management of knee OA is discussed separately. (See "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections'.)

Poorly controlled hypertension — We generally limit the use of oral NSAIDs in OA patients with hypertension to those whose hypertension is well controlled and who have preserved kidney function. All NSAIDs at therapeutic doses can increase blood pressure in both normotensive and hypertensive individuals. Cyclooxygenase (COX)-2 inhibitor NSAIDs seem to have the more pro-hypertensive effects than nonselective NSAIDs [18]. In a meta-analysis which measured the hypertensive effects of various nonselective NSAIDs, indomethacin, naproxen, and piroxicam appeared to have a greater effect on increasing blood pressure relative to ibuprofen and sulindac [19]. NSAID use may also reduce the effect of all antihypertensive drugs except calcium channel blockers. A detailed discussion of the effect of NSAIDs on blood pressure is presented separately. (See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

Although acetaminophen is no longer a preferred agent in the management of OA, it is not contraindicated in OA patients with hypertension. While there have also been some studies suggesting an increased effect on blood pressure with acetaminophen [20], the data are mixed, with most studies reporting no effect [15,21-23]. (See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

Intraarticular glucocorticoid injections do not appear to have a significant effect on blood pressure, based largely on data from patients with rheumatoid arthritis [24-26]. However, considering the known effects of systemic glucocorticoids on blood pressure, the blood pressure may be evaluated for the three to five days after the injection in patients with poorly controlled hypertension.

Cardiovascular disease — In patients with CVD, the use of both selective and nonselective NSAIDs should be avoided [27]. For those patients in whom an NSAID is necessary, the choice is influenced by other factors which include the presence of other comorbidities and the cost to the patient. (See "NSAIDs: Adverse cardiovascular effects", section on 'Patients with known coronary heart disease' and "NSAIDs: Therapeutic use and variability of response in adults", section on 'NSAID use and comorbidities' and "NSAIDs: Adverse cardiovascular effects", section on 'NSAID characteristics'.)

Regular NSAID use should also be avoided in patients taking low-dose aspirin for cardiovascular protection. In patients on aspirin who require NSAIDs on an occasional short-term basis, aspirin should be taken at least two hours before the NSAID. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)

Patients with OA and walking disability are at increased risk of death from cardiovascular causes [6]. Thus, management of OA in patients with CVD should focus on approaches that will improve walking disability [6]. Nonpharmacologic therapies including exercises, braces, education, and the use of assistive devices such as canes should be emphasized. Moreover, cardiovascular rehabilitation programs that increase physical activity have a positive impact on both CVD and OA. The benefits and risks of exercise in patients with CVD as well as an approach to prescribing exercise are discussed in detail separately. (See "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease".)

Among pharmacologic treatments that are commonly used to treat OA, we prefer local treatments including topical agents (eg, topical NSAIDs, capsaicin) and intraarticular glucocorticoid injections rather than systemic therapies for patients with CVD. However, when appropriate, other systemic therapies used in the treatment of OA such as duloxetine can be used in patients with CVD. (See "Management of knee osteoarthritis", section on 'Topical NSAIDs' and "Management of knee osteoarthritis", section on 'Topical capsaicin' and "Management of moderate to severe knee osteoarthritis", section on 'Duloxetine' and "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections'.)

There are limited data regarding cardiovascular effects with analgesics other than NSAIDs, most of which are limited to acetaminophen. As mentioned above, acetaminophen is no longer a preferred agent for the treatment of OA [28]. There are conflicting data on the effect of acetaminophen on cardiovascular disease [28-31]. A large population-based study including 10,878 patients over the age of 65 who were exposed to acetaminophen during a 10-year period found that there was no associated increased risk of myocardial infarction or stroke [30,31]. However, a systemic review which included four observational studies with data on adverse cardiovascular events found a dose-response increase with acetaminophen in the risk ratio of cardiovascular adverse events in each of the studies [28]. (See "Management of knee osteoarthritis", section on 'Acetaminophen'.)

Opioids have been associated with an increased risk of myocardial infarction when used long-term and should only be limited to short-term use in OA patients with severe and disabling symptoms in whom other interventions have failed [32]. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Monitoring for adverse effects'.)

Chronic kidney disease — We avoid the use of NSAIDs in the management of OA patients with chronic kidney disease, especially stages 3 and 4, given the risk of contributing to chronic kidney disease progression. A detailed discussion of the NSAIDs and their effect on kidney function is presented separately. (See "NSAIDs: Acute kidney injury" and "Management of chronic pain in advanced chronic kidney disease", section on 'Drugs that should be avoided'.)

Among pharmacologic treatments that are commonly used to treat OA, we prefer local treatments including topical agents (eg, topical NSAIDs, capsaicin) and intraarticular glucocorticoid injections rather than systemic therapies in patients with chronic kidney disease. (See "Management of knee osteoarthritis", section on 'Topical NSAIDs' and "Management of moderate to severe knee osteoarthritis", section on 'Limited role of intraarticular glucocorticoid injections'.)

Peptic ulcer disease — The recurrence of ulcer complications with continued use of NSAIDs is well-established and is contraindicated when treating OA patients with active peptic ulcer disease (eg, active bleeding or perforation). (See "Overview of complications of peptic ulcer disease", section on 'Discontinue NSAIDs'.)

In patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease who require NSAIDs, we combine an NSAID with a gastroprotective agent (eg, a proton pump inhibitor). COX-2 inhibitors may be safer than nonselective NSAIDs for reduction in the risk of gastrointestinal bleeding but are still associated with an increased risk. The relative gastrointestinal toxicity of different NSAIDs and prevention of NSAID-induced gastroduodenal damage are discussed in detail separately. (See "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

Obesity — The importance of weight loss should be emphasized for all OA patients who are overweight or obese. Obesity is associated with lower-limb and hand OA and can worsen pain and functional disability [33,34]. Obesity also has a direct mechanical effect on weightbearing joints, as do various substances in adipose tissue such as adipokines or inflammatory proteins (see "Pathogenesis of osteoarthritis", section on 'Risk factors'). The approach to the management of obesity is discussed separately. (See "Obesity in adults: Overview of management".)

Weight loss has been shown to reduce both pain and disability in patients with knee OA. As an example, in a randomized trial with 399 patients with knee OA and obesity, the association of diet-induced weight loss (≥10 percent) and physical exercise for 18 months was more effective on pain and mobility than each intervention alone [35]. In a meta-analysis of 19 randomized trials of patients with knee or hip OA, weight reduction was found to provide small to moderate improvement in pain and disability [36]. There is also some evidence to suggest that weight loss may have a structural effect on OA. In a study with 112 patients with obesity, weight loss was associated with reduced medial-tibial cartilage volume loss (but not lateral and patella cartilage) and improved knee symptoms (pain, stiffness, and function) [37].

SPECIAL POPULATIONS

Older age — In older adults with osteoarthritis (OA), optimizing drug therapy is more challenging. Analgesics have pharmacokinetics characteristics different from those of younger patients and the risk of toxicity is increased. Pharmacologic therapies that are sometimes used to treat OA symptoms which may be more likely to result in adverse effects include nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, and opioids. (See "Drug prescribing for older adults".)

The metabolism of acetaminophen in older patients is highly variable and may be reduced in frail older patients due to a decreased volume of distribution and intrinsic conjugative activity of the liver [38]. Thus, older adults may be at increased risk of hepatotoxicity, and the maximum daily dose should likely be reduced to between 2 and 3 g/day (see "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs", section on 'Hepatic toxicity'). NSAIDs have also been shown to increase the risk of gastrointestinal, cardiovascular, and renal adverse effects in older adults [38] (see "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'). Opioid use in older adults is associated with an increased risk of cognitive impairment, delirium, or injuries (eg, falls, fractures) and may also increase the risk of cardiovascular events, pneumonia, hospitalization, and mortality [38,39]. (See "Treatment of chronic non-cancer pain in older adults", section on 'Opioids'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoarthritis".)

SUMMARY AND RECOMMENDATIONS

●Background – The presence of comorbidities in patients with osteoarthritis (OA) often impacts treatment choices, particularly with respect to pharmacologic therapy. (See 'Background' above and 'Management considerations for comorbidities' above.)

●Management considerations for comorbidities

•Diabetes mellitus – We avoid the use of oral nonsteroidal antiinflammatory drugs (NSAIDs) when treating OA patients with diabetes mellitus (DM), particularly among those with complications such as cardiovascular disease (CVD) and/or kidney disease. (See 'Diabetes mellitus' above and "NSAIDs: Adverse cardiovascular effects" and "NSAIDs: Acute kidney injury".)

Intraarticular glucocorticoid injections pose a theoretical risk to patients with DM by potentially raising blood glucose to hyperglycemic levels. However, patients generally experience an isolated increase in blood glucose for one to two days after the injection, which rarely poses a significant clinical risk when DM is well controlled. For insulin-dependent diabetic patients in whom an intraarticular injection is warranted, self-monitoring of blood glucose should be performed for up to three to five days after the injection. (See 'Diabetes mellitus' above.)

•Poorly controlled hypertension – We generally limit the use of oral NSAIDs in OA patients with hypertension to those whose hypertension is well controlled and who have preserved kidney function. (See 'Poorly controlled hypertension' above.)

•Cardiovascular disease – In patients with CVD, the use of both selective and nonselective NSAIDs should be avoided. For those patients in whom an NSAID is necessary, the choice is influenced by other factors which include the presence of other comorbidities and the cost to the patient. (See 'Cardiovascular disease' above and "NSAIDs: Adverse cardiovascular effects", section on 'Patients with known coronary heart disease' and "NSAIDs: Therapeutic use and variability of response in adults", section on 'NSAID use and comorbidities' and "NSAIDs: Adverse cardiovascular effects", section on 'NSAID characteristics'.)

•Chronic kidney disease – We avoid the use of NSAIDs in the management of OA patients with chronic kidney disease, especially stages 3 and 4, given the risk of contributing to chronic kidney disease progression. (See 'Chronic kidney disease' above.)

•Peptic ulcer disease – In patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease who require NSAIDs, we combine an NSAID with a gastroprotective agent (eg, a proton pump inhibitor). (See "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

•Obesity – The importance of weight loss should be emphasized for all OA patients who are overweight or obese. Obesity is associated with lower-limb and hand OA and can worsen pain and functional disability. (See 'Obesity' above and "Management of knee osteoarthritis", section on 'Weight loss'.)

•Older age – In older adults with OA, optimizing drug therapy is more challenging. Analgesics have pharmacokinetics characteristics different from those of younger patients and the risk of toxicity is increased. Pharmacologic agents for treating OA-related pain which may be more likely to result in adverse effects include NSAIDs, acetaminophen, and opioids. (See 'Older age' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Francis Berenbaum, MD, PhD, who contributed to an earlier version of this topic review.