Osteoarthritis, which is the most common form of arthritis in the United States and other Western countries, is increasing in incidence as the population ages and is likely to rise further with the obesity epidemic. Significant disability and loss of function are associated with this disease, and its management is an enormous cost to the health care system. Progress in prevention and treatment has been slow, related in part to the insidious onset and generally slow progression of the disease.^1-3 As a result, clinical trials may take many years to show a significant disease benefit. Therefore, despite its being the most prevalent form of arthritis, few long-term clinical trials have been done on therapeutic outcomes.

Osteoarthritis (also known as degenerative or hypertrophic arthritis, or age-related arthritis) implies an inflamed joint by its very name, but for a long time the role of inflammation in osteoarthritis has been somewhat controversial. The pathology reflects the result of joint disease, with loss and erosion of articular cartilage, subchondral sclerosis, and bone overgrowth (osteophytes). Rather than one uniform disease, osteoarthritis may be either a primary or idiopathic phenomenon or secondary to some other disorder. Osteoarthritis is also commonly seen as a secondary form of arthritis in patients with other inflammatory arthritides, such as rheumatoid arthritis. Mechanical and genetic factors play a role in the development of this disease as well. Histologic evidence clearly shows that there is ongoing inflammation and cartilage destruction in osteoarthritis, although not to the same degree as in other arthritides, such as rheumatoid arthritis.^1,4,5

Osteoarthritis is the most prevalent form of arthritis in the United States, affecting more than 70% of adults between 55 and 78 years old.⁵ Women are affected more than men.^5,6 Hip osteoarthritis is more common in Western populations, suggesting that race and environmental factors may also be important.⁵ The incidence of symptomatic knee osteoarthritis is 1% per year, with a radiographic incidence of 2% per year. The rate of radiographic progression has been estimated at about 4% per year.⁶

Understanding the metabolic pathways at the molecular level has greatly enhanced our understanding of the tissue factors involved.⁷

Although the role of inflammation in osteoarthritis has been unclear for a long time, significant progress has been made in more recent years. The molecular pathways involved are being more clearly defined, and this is an area of intense ongoing research. Studies also show that there is ongoing inflammation and synovitis that result in permanent joint damage.^1,5,8 At times, this may be more striking, with flares of symptoms or joint effusions. Effusions can be very large at times, and the authors have aspirated >100 mL of fluid from an acutely swollen knee on more than one occasion. Biopsies of synovium from patients with osteoarthritis show a more inflammatory infiltrate than normal controls do.

Some patients appear to have a more hereditary form of this disease. The striking features are usually seen in women who, shortly after menopause, develop distal (Heberden's nodes) and proximal (Bouchard's nodes) interphalangeal joint involvement in their hands, which eventually leads to the characteristic bony swelling, and correlates with the presence of radiographic knee involvement.⁸ Previous trauma or other prior joint insults like inflammation, infection, or avascular necrosis increase the risk of developing osteoarthritis at that anatomic site.^1,8

Histologically, articular cartilage comprises chondrocytes and their extracellular matrices. Three distinct zones are recognizable—superficial, middle, and deep. Mechanical or inflammatory injury that disrupts these zones can lead to irreparable damage and to further inflammation and cartilage degradation as the body attempts to heal itself. In essence, there is a defective repair mechanism, resulting in scarring, thinning, and erosion of the articular cartilage in the joints of subjects with osteoarthritis.⁹ Several cytokines, such as IL-1-beta and transforming growth factor-beta, proteases (the most important of which is matrix metalloprotease), and nitric oxide synthetase all appear to be essential for cartilage degradation in the pathogenesis of osteoarthritis. While it was previously thought that bone changes occur later in this disease, newer evidence suggests that subchondral bone changes may take place earlier than previously suspected.¹⁰ Increased production of bone and cartilage degradation products has been shown to herald more rapid disease progression.⁴

Stiffness, joint pain, and swelling are the earliest symptoms of osteoarthritis. In contrast to inflammatory arthritis, the pain of osteoarthritis is often exacerbated by activity or weight-bearing and relieved by rest. Early symptoms are usually of an insidious nature and often do not correlate well with radiographic abnormalities. Later, extensive bone changes, muscle weakness, and loss of joint integrity can lead to more dramatic joint deformity and disability. Physical findings include painful limitation of movement, bony crepitus, and, occasionally, joint effusions and joint line or bony tenderness. As the disease progresses, more permanent joint deformities can occur in the form of contractures, osteophytes, and loss of joint function.

Synovial fluid analyses and laboratory investigations are generally not diagnostic. Their utility lies mainly in excluding other causes for the patient's symptoms or other common forms of arthritis such as crystal deposition diseases. Although newer studies using markers of bone, cartilage, and synovium turnover may help identify patients who have a more rapidly progressive form of joint disease, they are not recommended in routine clinical practice at this time. Data on high-sensitivity, C-reactive protein have been reported, with somewhat conflicting findings. Elevated levels of C-reactive protein appear to correlate best with symptoms of pain and stiffness rather than extent or progression of disease.¹¹

Radiographic studies are reserved for patients with symptoms. Again, they are useful in excluding other causes of the patient's symptoms and to evaluate the extent of joint pathology. However, although radiographs may show osteoid changes such as joint-space narrowing, effusions, bone cysts, and osteophytes, radiographs are limited in sensitivity and in their ability to visualize nonosseous structures.

Ultrasound, computed tomography, and magnetic resonance imaging (MRI) may show more extensive joint detail. Although changes in soft tissue and cartilage are better visualized by MRI than by radiographs, and MRI is more sensitive for picking up early bone changes, this is generally unhelpful to the practicing physician. Felson et al have shown that men with osteoarthritis of the knee who have MRI evidence of subchondral "bone bruising" or marrow edema experience a more rapid progression of their disease than men who have none. Joint malalignment correlates strongly with the presence of the bone marrow lesions.¹⁰ In addition, asymptomatic patients with osteoarthritis may have significant abnormalities on MRI imaging, making abnormal findings even harder to interpret.¹² These more-expensive imaging modalities are usually reserved for evaluating other possible causes of symptoms, such as meniscal tears and tumors. Until it can be shown that a therapeutic intervention can significantly prevent or retard the progression of this disease, the role of these imaging modalities in osteoarthritis is of limited value.

Treatments to date have not been shown to reverse this disease although some may halt its progression. Presently, the goal of management is adequate pain relief and preservation of function. Guidelines have been published for the management of hip and knee osteoarthritis by both the American College of Rheumatology² (ACR) and, more recently, the European League Against Rheumatism (EULAR).³

Weight loss, even small amounts, can significantly benefit overweight patients. Relaxation programs and moderate exercise, good nutrition, and education can all help relieve suffering in arthritis patients. Caring healthcare professionals can help to alleviate worry and help a patient to achieve realistic goals. Devices such as canes, supports, and braces can take some stress off the affected joint. Avoiding aggravating factors such as trauma, excessive weight gain, or overly strenuous exercise is essential. Other analgesic therapies, such as heating pads or ice packs, also alleviate suffering. Care should be taken, as in all pain-related illnesses, to treat concomitant aggravating factors such as psychosocial stress or other painful maladies, such as secondary bursitis.^2,3,5

Acetaminophen (paracetamol in Europe) is generally recommended as first-line pharmacologic therapy. Acetaminophen is a relatively safe treatment with significantly lower gastrointestinal (GI), renal, and cardiovascular toxicity than other medications. When taken on a regular basis, doses of 500 to 750 mg three to four times daily can provide substantial relief. Care should be taken not to exceed 4 g/day.^2,3 Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide significant acute relief in subjects with osteoarthritis. However, as osteoarthritis occurs more commonly in older patients who often have other comorbidities, the use of NSAIDs is limited by their potential for or actual side effects. Notably, they can cause or worsen GI hemorrhage, renal insufficiency, congestive heart failure, and hypertension. Several new agents (eg, rofecoxib, celecoxib) that specifically inhibit cyclooxygenase-2 (COX-2) have recently been approved by the Food and Drug Administration in the United States and in Europe for use in arthritis patients. Although they are more expensive than over-the-counter generic drugs, they have a better GI safety profile. The concern with these newer agents, as for the older NSAIDs, is that there may be an increased risk of cardiovascular events for patients taking these medications.¹³ Indeed, one of these agents rofecoxib (Vioxx) was recently withdrawn from the market because of evidence documenting such side effects. Whether these findings are specific to rofecoxib or represent a class effect, remains to be determined. They should be used with extreme caution or not at all in people with renal or cardiovascular disease. Nonacetylated salicylate compounds such as choline magnesium trisalicylate (Trilisate) 500 to 750 mg two or three times daily are also effective therapies for many patients, and we have had success using this group of drugs. These medications have fewer adverse GI effects than regular aspirin compounds or NSAIDs and provide a less expensive alternative to the newer COX-2 inhibitors. Salicylate levels can also be measured relatively easily in serum, similar to other pharmaceutical compounds, though this is not routine practice. Topical aspirin or NSAID preparations, which are more widely available in Europe, are an alternative to oral medications. However, the incidence of side effects from NSAIDs is often dose-related, and thus they should probably be reserved for acute flares or more recalcitrant disease.

Systemic steroids are not indicated in the management of osteoarthritis. However, local intra-articular injection of corticosteroids can provide significant relief of pain and stiffness, and despite the evidence in randomized trials, clearly some patients can have very long-lasting pain relief from a single injection. This should be performed in a sterile manner by persons experienced with this technique; side effects such as infection, bruising, lipodystrophy, and osteonecrosis are rare with careful technique. Most of the benefit in randomized, double-blind, placebo-controlled trials seems to have occurred soon after the injection, and symptom improvement may be greatest in those with joint effusion.^14,15 Intra-articular triamcinolone 40 mg injections every 3 months for 1 to 2 years showed no effect on radiographic progression.¹⁵ Aspiration of synovial fluid, if possible, should be performed with an aseptic technique before injection, and the fluid should be sent for the usual studies such as Gram's stain, culture, cell count, and differential, and an extensive examination for crystals should be performed by a person familiar with this technique. Other studies can be performed as the situation dictates. Studies such as fluid pH, viscosity, glucose, antinuclear antibody, and rheumatoid factor are unhelpful in most circumstances.

Viscosupplements though approved by the FDA for use, appear to provide little more relief than sham injections. Despite the promise for these drugs, well-performed placebo-controlled trials have had disappointing results to date.^16,17 Thus, we do not recommend routine use of intra-articular hyaluronate or its derivatives, at this time, until there is stronger evidence that they are clearly beneficial.

Many patients with osteoarthritis use alternative therapies in an attempt to relieve their suffering. Natraceuticals have shown some promise in this regard. Glucosamine and chondroitin sulfate are by far the most studied agents in this category and have been shown in several studies to be as effective as acetaminophen and NSAIDs, with significantly fewer adverse effects. These agents appear to significantly alleviate pain and suffering by an as-yet unknown mechanism. They have a slow onset of action (placebo-controlled trials show that it takes several weeks to see an effect in the treated groups), and they appear to have a more sustained post-treatment effect than NSAIDs or analgesics.^1,3,18,19 A 3-year, placebo-controlled trial showed that glucosamine may retard radiographic progression.¹⁹ We recommend trying glucosamine and/or chondroitin sulfate at a dose of 1,200 to 1,500 mg daily in most patients with osteoarthritis, given that the safety profile and efficacy are similar to those of NSAIDs and acetaminophen. Acupuncture, although used by many patients, appears to be no better than sham needling in controlled trials,⁵ and is not without its own risks, which include reports of hepatitis transmission and pneumothoraces.

Narcotic analgesics should be reserved for patients with severe joint disease and intolerable suffering who are not candidates for other therapeutic interventions or for whom other therapeutic interventions have failed. Short courses, however, can be used effectively. Less-potent medications, such as the new combination tramadol/acetaminophen, should be tried first, reserving narcotic medications for those who still have severe pain. Usual precautions should be taken when prescribing these, such as counseling patients about their correct use and addictive potential.

Depression and arthritis are common and often coexist. It has been shown that treatment of depressive symptoms in older adults with arthritis resulted in significantly less pain and depression and overall improvement in health and quality of life.²⁰ Thus, care should be taken to evaluate and treat patients for concomitant depression when managing their arthritis.

The efficacy of arthroscopy for osteoarthritis remains controversial. It is presently under review by the ACR and is not recommended in the 2003 EULAR guidelines.^2,3 Progress in joint replacement surgery has been remarkable in the past few decades, particularly for knee and hip arthritis. Arthroplasty is now used to treat many patients with severe osteoarthritis, especially those who are appropriate surgical candidates and for whom more conservative measures have failed. Presently, joint replacements may wear out after an average of 10 to 15 years, although some patients may do well for many more. Newer components and improved techniques may increase the longevity of these replacements in the future. Reoperation after the original replacement surgery may be more complex and have higher failure and infection rates.

Osteoarthritis is the most common form of arthritis in the United States. The incidence increases with advancing age. Many patients can achieve significant relief of their symptoms with appropriate care. Current therapies are being investigated to see if they improve the long-term outcomes of this disease. Ongoing research is aiming to identify those patients who have a more rapidly progressive illness, and is evaluating disease-specific molecular pathways as potential new targets for intervention. Advances in joint replacement surgery have made this an excellent treatment for many patients with more severe disease.

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15. Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee. Arthritis Rheum. 2003;48:370-77.



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19. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357:251-256.



20. Lin EHB, Katon W, Von Korff M, et al. Effect of improving depression care on pain and functional outcomes among older adults with arthritis: a randomized, controlled trial. JAMA. 2003;290:2428-2434.

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