Osteoarthritis

William S. Wilke

John Carey

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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 it 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 can 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 studied the therapeutic outcomes.

Definition

Osteoarthritis (also known as degenerative arthritis, 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 a primary or an idiopathic phenomenon, or it may be 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 roles in the development of this disease as well. Histologic evidence clearly shows ongoing inflammation and cartilage destruction in osteoarthritis, although not to the same degree as in other arthritides, such as rheumatoid arthritis.1,4,5

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Prevalence and incidence

Osteoarthritis is the most prevalent form of arthritis in the United States, affecting more than 70% of adults between 55 and 78 years of age.5 Women are affected more than men.5,6 Hip osteoarthritis is more common in Western populations, suggesting that race and environmental factors might 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

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Pathophysiology

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 are 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 we have aspirated more than 100 mL of fluid from an acutely swollen knee on more than one occasion. Biopsies of synovium from patients with osteoarthritis show more inflammatory infiltrates 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, such as 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 interleukin-1β and transforming growth factor β, 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. It was previously believed that bone changes occur later in this disease, but newer evidence suggests that subchondral bone changes might 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

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Symptoms, signs, and diagnosis

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 bone tenderness. As the disease progresses, more permanent joint deformities can occur in the forms 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. Newer studies using markers of bone, cartilage, and synovium turnover might help identify patients who have a more rapidly progressive form of joint disease, but they are not recommended in routine clinical practice. 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. They are useful in excluding other causes of the patient's symptoms and in evaluating the extent of joint pathology. However, although radiographs might show osteoid changes such as joint-space narrowing, effusions, bone cysts, and osteophytes, radiographs are limited in sensitivity and in their ability to show nonosseous structures.

Ultrasound, computed tomography, and magnetic resonance imaging (MRI) might 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 and colleagues 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 do not have these signs. Joint malalignment correlates strongly with the presence of the bone marrow lesions.10 In addition, asymptomatic patients with osteoarthritis might have significant abnormalities on MR 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.

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Treatment

Treatments have not been shown to reverse this disease, although some treatments can halt its progression. The goal of treatment is adequate pain relief and preservation of function. The American College of Rheumatology2 (ACR) and the European League Against Rheumatism (EULAR) have published guidelines for managing hip and knee osteoarthritis.

Weight loss, even small amounts, can significantly benefit overweight arthritis patients. Relaxation programs and moderate exercise, good nutrition, and education can all help relieve suffering in arthritis patients. Caring health care professionals can 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

Analgesics and Anti-Inflammatories

Acetaminophen (paracetamol in Europe) is generally recommended as first-line pharmacologic therapy. Acetaminophen is a relatively safe treatment and has significantly lower gastrointestinal (GI), renal, and cardiovascular toxicities 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) can provide significant acute relief in patients with osteoarthritis. However, because 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 agents (e.g., rofecoxib, celecoxib) that specifically inhibit cyclooxygenase-2 (COX-2) are approved in the United States (by the U.S. Food and Drug Administration [FDA]) 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 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 patients with renal or cardiovascular disease.

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.

Nonacetylated Salicylates

Nonacetylated salicylate compounds such as choline magnesium trisalicylate (Trilisate) 500 to 750 mg two or three times daily are 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 COX-2 inhibitors. Salicylate levels can also be measured relatively easily in serum, similar to other pharmaceutical compounds, although this is not routine practice.

Steroids

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 have very long-lasting pain relief from a single injection. This should be performed in a sterile manner by physicians 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 improvement of symptoms 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

Synovial fluid should be aspirated, if possible, with an aseptic technique before injection. The fluid should be sent for the usual studies such as Gram stain, culture, cell count, and differential, and an extensive examination for crystals should be performed by a person familiar with this technique. Other studies may be performed as the situation dictates. Studies such as fluid pH, viscosity, glucose, antinuclear antibody, and rheumatoid factor are unhelpful in most circumstances.

Alternative Treatments

Viscosupplements, although approved by the FDA, appear to provide little more relief than sham injections. Despite the promise for these drugs, well-performed placebo-controlled trials have had disappointing results.16,17 Thus, we do not recommend routine use of intra-articular hyaluronate or its derivatives 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 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 might retard radiographic progression.19 We recommend trying glucosamine and chondroitin sulfate at a dose of 1200 to 1500 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 it is not without its own risks, which include reports of hepatitis transmission and pneumothoraces.

Narcotic Analgesics

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.

Antidepressants

Depression and arthritis are common and often coexist. 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.

Surgery

The efficacy of arthroscopy for osteoarthritis remains controversial. It is 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.

Joint replacements can wear out after an average of 10 to 15 years, although some patients do well for much longer. Newer components and improved techniques might increase the longevity of these replacements in the future. Reoperation after the original replacement surgery may be more complex and can have higher failure and infection rates.

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Conclusions

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 patients who have a more rapidly progressive illness, and it 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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Summary

  • Whether it is primary or secondary, osteoarthritis is characterized by loss and erosion of cartilage, subchondral sclerosis, and overgrowth of bone.
  • The pathogenesis of osteoarthritis is driven by heredity, prior insults to the joint, and mild-to-moderate local inflammation.
  • The diagnosis of osteoarthritis is made on the basis of signs and symptoms of joint swelling, pain, and hypertrophy in characteristic joints and is confirmed by x-ray.
  • Primary treatment of osteoarthritis includes joint protection, strengthening the muscles around the joint, weight loss for hip and knee osteoarthritis, and acetaminophen.
  • Nonsteroidal anti-inflammatory drugs are safest when used intermittently.

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References

  1. Creamer P, Hochberg MC. Osteoarthritis. Lancet. 1997, 350: 503-508.
  2. Altman RD, Hochberg MC, Moskowitcz RW, Schnitzer TJ. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000, 43: 1905-1915.
  3. Jordan KM, Arden NK, Doherty M, et al: EULAR recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003, 62: 1145-1155.
  4. Garnero P, Delmas PD. Biomarkers in osteoarthritis. Curr Opin Rheumatol. 2003, 15: 641-646.
  5. Brooks P. Inflammation as an important feature of osteoarthritis. Bull World Health Organ. 2003, 81: 689-690.
  6. Felson DT, Zhang Y, Hannan MT, et al: The incidence and natural history of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum. 1995, 38: 1500-1505.
  7. Pelletier JP, Martel-Pelletier J. The Novartis-ILAR Rheumatology Prize 2001 Osteoarthritis: From molecule to man. Arthritis Res. 2002, 4: 13-19.
  8. Ehrlich GE. The rise of osteoarthritis. Bull World Health Organ. 2003, 81: 630.
  9. Mainil-Varlet P, Aigner T, Brittberg M, et al: Histological assessment of cartilage repair: A report by the Histology Endpoint Committee of the International Cartilage Repair Society (ICRS). J Bone J Surg Am. 2003, 85A: (suppl 2): 45-57.
  10. Felson DT, McLaughlin S, Goggins J, et al: Bone marrow edema and its relation to progression of knee osteoarthritis. Ann Intern Med. 2003, 139: 330-336.
  11. Sturmer T, Brenner H, Koenig W, Gunther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis. 2004, 63: 200-205.
  12. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al: Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med. 1994, 331: 69-73.
  13. Mandell BF. COX-2 inhibitors: Balancing the hope, the hype, and the concern. Cleve Clin J Med. 2001, 68: 899.
  14. Gaffney K, Ledingham J, Perry JD. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: Factors influencing the clinical response. Ann Rheum Dis. 1995, 54: 379-381.
  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: 370-377.
  16. Felson DT, Anderson JJ. Hyaluronate sodium injections for osteoarthritis: Hope, hype, and hard truths. Arch Intern Med. 2002, 162: 245-247.
  17. Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis. JAMA. 2003, 290: 3115-3121.
  18. Richy F, Bruyere O, Ethgen O, et al: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis. Arch Intern Med. 2003, 163: 1514-1522.
  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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Suggested Readings

  • Altman RD, Hochberg MC, Moskowitcz RW, Schnitzer TJ. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000, 43: 1905-1915.
  • Brooks P. Inflammation as an important feature of osteoarthritis. Bull World Health Organ. 2003, 81: 689-690.
  • Felson DT, Anderson JJ. Hyaluronate sodium injections for osteoarthritis: Hope, hype, and hard truths. Arch Intern Med. 2002, 162: 245-247.
  • Gaffney K, Ledingham J, Perry JD. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: Factors influencing the clinical response. Ann Rheum Dis. 1995, 54: 379-381.
  • Jordan KM, Arden NK, Doherty M, et al: EULAR recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003, 62: 1145-1155.
  • 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.
  • Mainil-Varlet P, Aigner T, Brittberg M, et al: Histological assessment of cartilage repair: A report by the Histology Endpoint Committee of the International Cartilage Repair Society (ICRS). J Bone J Surg Am. 2003, 85A: (suppl 2): 45-57.
  • Mandell BF. COX-2 inhibitors: Balancing the hope, the hype, and the concern. Cleve Clin J Med. 2001, 68: 899.
  • Richy F, Bruyere O, Ethgen O, et al: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: A comprehensive meta-analysis. Arch Intern Med. 2003, 163: 1514-1522.
  • Sturmer T, Brenner H, Koenig W, Gunther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis. 2004, 63: 200-205.