Foreword

Osteoarthritis is a leading cause of disability worldwide and is the most common form of arthritis.¹ Although estimates vary considerably, it is believed that between 10 million and 16 million people in the United States are affected by this degenerative condition.²Because many adults with this disease are limited in their ability to perform the functions of everyday life, osteoarthritis takes a heavy emotional toll on its victims. Patients living with osteoarthritis are more likely to report high degrees of emotional distress, to feel that their lives are limited by their disease, and to rate their health as poor than are individuals unaffected by the disease.¹

The costs to society are considerable, as well. Osteoarthritis ranks as one of the top 10 most expensive medical conditions in the United States. Direct health care costs in 1997 were $16 billion.² However, that does not take into account indirect costs. Many adults with osteoarthritis are limited in their ability to perform simple daily tasks, with 50% of those with osteoarthritis of the knee reporting that they are either unable to walk, stoop, or crouch or have great difficulty doing so.¹ Thus, it is not surprising that patients with osteoarthritis are more likely to lose time at work or retire because of their disability. Although this economic burden is difficult to quantify, it is nonetheless substantial.¹

Others may lose time at work helping to care for a relative or spouse with osteoarthritis. As more members of the baby boomer generation enter their “golden years,” this problem is expected to grow exponentially.

To sustain the current level of health care in the coming decades, it is imperative to address the issues surrounding the management of many of the more expensive medical conditions. Whenever possible, surgeons must try to discover the pathologic processes underlying these diseases to prevent or forestall their occurrence. Surgeons must attempt to find less costly, more effective treatment interventions, and to keep people healthy and active as they age. This supplement presents the latest findings on the epidemiology, etiology, and pathophysiology of osteoarthritis; discusses currently available treatment options and management strategies; examines a relevant case study; and reviews possible future treatment options, important clinical research, and ongoing clinical trials.

The first article reviews the epidemiology of knee and hip osteoarthritis. A number of difficulties arise when trying to assess the prevalence and incidence of osteoarthritis in the population, including the failure to agree on criteria for diagnosis, the need to rely on clinical evaluation rather than radiographic assessment for broad-based population estimates, and the well-recognized disparity between diagnosis based on radiographic evidence and patient-reported symptoms of pain and disability.^3,4 Age and female gender appear to be risk factors for the development of both knee and hip osteoarthritis, and interesting data are emerging from studies around the world that suggest that ethnic and environmental components are involved, as well. Although data from the Framingham study have been proven invaluable and studies performed in Iceland on genetic markers for the disease are beginning to offer data, much remains to be done in this area.^1,5

In the second article, Bert Mandelbaum, MD, Team Physician for the US Soccer Team, Pepperdine University, Santa Monica, California, explores the etiology and pathophysiology of osteoarthritis. The relative roles played by aberrant cartilage physiology and the biomechanical contributions of injury and malalignment are examined, and the concept of chondropenia is discussed. Surgeons’ understanding of the pathophysiology of this disease has progressed considerably from the days when it was accepted as a normal part of the aging process.

Although surgeons have long known that osteoarthritis is a disease characterized by the degeneration of articular cartilage with proliferation and remodeling of subchondral bone,^6,7 they are only now beginning to see that its roots may involve a disruption in the synovial lining cell-signaling process that normally regulates remodeling of joint tissues.⁸ Dysregulation of this process may lead to destruction or incomplete repair of cartilage and set the stage for the development of osteoarthritis.^8,9

Surgeons are beginning to uncover the molecular foundations of these processes, investigating the role of matrix metalloproteinases and gap junctions to determine exactly where and why the pathologic course begins. Changes in intercellular communication may play an important role in the early development of osteoarthritis. The synovial tissue from patients with osteoarthritis has 4 times the number of gap junctions than do tissue from unaffected patients. However, whether this is a cause or a consequence of the disease has yet to be determined.⁸ The role of cytokines, such as interleukin-1b, in this process also are being explored and add weight to the hypothesis that gap junctions are a critical element in the degeneration of the joint.¹⁰ Overall, evidence suggests that gap junctions may be a reasonable therapeutic target.⁸

Surgeons also are developing a better sense of the risk factors involved in osteoarthritis. Women experience higher rates of all forms of arthritis than men and are more than twice as likely to develop osteoarthritis of the knee.^6,11 Eighteen percent of women between the ages of 63 and 74 years have osteoarthritis of the knee compared with only 8% of men in that age group. The risk of osteoarthritis also is increased in those who are physically inactive, overweight, or obese.¹¹ Age is another risk factor,⁶ with individuals aged 18 to 44 years having a 19% prevalence of all forms of arthritis, compared with a 42.1% prevalence in those aged 45 to 64 years, and a 58.8% prevalence in those .65 years.⁵

Although age and obesity together constitute the most important risk factor for the development of osteoarthritis, injuries that occur during youth may set the stage for later disease. Athletes appear to be at increased risk for developing osteoarthritis, and injuries incurred during high school sports can resonate years later. In a study performed in 1,321 former medical students of Johns Hopkins University, the incidence of osteoarthritis was 13.9% among those who had sustained knee injuries during adolescence and young adulthood compared with only 6% in their uninjured colleagues.¹²

A Swedish study corroborated these findings, with evidence of long-lasting biochemical response to injury. In patients who had injured the anterior cruciate ligament or the meniscus, concentrations of stromelysin-1 and tissue inhibitor of metalloproteinases-1 were increased 25-fold immediately after the injury. Although these markers gradually decreased with time, increased levels were still evident 18 years after the initial injury.¹³

The third article in this supplement, by Jason C. Snibbe, MD, of the Beverly Hills Orthopedic Group, Beverly Hills, California, and Ralph A. Gambardella, MD, of the Kerlan-Jobe Orthopaedic Clinic in Los Angeles, California, reviews currently available treatment options. Although there is no cure for osteoarthritis, therapeutic interventions have improved over the past decade. The goal of most therapies is to diminish pain and reduce inflammation and effusion so that the quadriceps may be strengthened and functional ability enhanced.

Education is the cornerstone of treatment for patients with osteoarthritis. Nonpharmacologic modalities include weight loss, supports and braces, and physiotherapy. Exercise programs can improve joint proprioception, quadriceps strength, and performance of activities of daily living.¹⁴

Most patients, however, require some kind of pharmacologic intervention. In addition to the long-time, standard pain killers, such as analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), the cyclooxygenase (COX)-2 inhibitors, such as celecoxib, are now available. These agents have less severe gastrointestinal adverse effects than the more traditional NSAIDs, because they are selective for COX-2, whereas traditional NSAIDs target both COX-1 and COX-2.¹⁵ However, celecoxib should not be used in patients who have had an allergic reaction to sulfonamides. Acetaminophen is recommended for the treatment of osteoarthritis in patients with impaired renal function because NSAIDs also are associated with renal toxicity in some patients; however, acetaminophen has been known to cause hepatic toxicity when doses exceed 4 g/day. Topical NSAIDs have been advocated as safe alternatives to systemic NSAIDs.¹⁵

Intra-articular corticosteroid injections reduce inflammation, which decreases pain and increases joint mobility. However, repeated injections may encourage cartilage degradation, and thus application of this therapy is limited. Furthermore, such treatment cannot prevent pain that results from weight bearing forces across the joint. These injections often are used to treat acute and chronic inflammatory conditions, but are contraindicated when infection is present or suspected. Injection-related flare that sometimes occurs in the treated joint can be alleviated with ice.¹⁵

New procedures, such as viscosupplementation with hyaluronic acid, reduce pain and may target the underlying pathophysiology, helping to forestall or even prevent more drastic measures. Hyaluronic acid, which is normally synthesized and secreted into the joint space by the type B synoviocytes, has both viscous and elastic properties and serves as a shock absorber during fast movements and as a lubricant during slow movements. Hyaluronic acid also reduces the release of arachidonic acid from synovial fibroblasts.

Production of hyaluronic acid appears to be impaired in osteoarthritic joints. It is believed that intra-articular injection of hyaluronic acid affects the synthesis of the naturally occurring substance by synovial fibroblasts, possibly enhancing endogenous chondrocyte hyaluronic acid and proteoglycan production. The beneficial effects on pain may be accomplished through direct inhibition of nociceptors or by binding substance P.¹⁵ Decreases in the production and activity of proinflammatory mediators and matrix metalloproteinases, and alteration of immune cell function may play roles as well. As with cortico-steroid injections, local inflammatory reactions sometimes occur after treatment but are usually mild and self-limited.¹⁶ The approximate incidence of side effects per injection is 1%. Severe local reactions occur in 0.2% of procedures but usually respond quickly to aspiration and corticosteroid injection.¹⁶

Conservative treatment with analgesics or NSAIDs is generally recommended in mild osteoarthritis, whereas viscosupplementation is reserved for patients with mild-to-moderate osteoarthritis of the knees with significant symptoms that have failed to be controlled by traditional nonpharmacologic and pharmacologic treatments, or for patients who cannot tolerate anti-inflammatory medications.¹ However, this approach may be less conservative than it appears, because the safety of long-term NSAID use is questionable.

Although the potential for adverse events is evaluated seriously with all newly introduced agents or medical procedures, few stop to consider that >16,500 deaths in the United States occur annually as the result of prescription and over-the-counter anti-inflammatory drug use.¹⁷ In addition, >103,000 patients are hospitalized each year as the result of using NSAIDs.¹⁷ It may be time to rethink the current treatment paradigm.

Snibbe and Gambardella also examine the importance of injection technique and a postinjection protocol, and present critical data from clinical trials of hyaluronic acid in patients with osteoarthritis, perhaps most importantly, critical arguments on the most appropriate use of this therapeutic intervention are aired.

The fourth article in this supplement is a case study, presented by Jennifer Solomon, MD, and Vijay Vad, MD, of the Hospital for Special Surgery, New York, New York. Solomon and Vad review the history of a 55-year-old woman with osteoarthritis in both knees and details appropriate therapeutic interventions, beginning with patient education, weight loss, activity modification, exercise, and physical therapy, and moving on to a discussion of pharmacologic treatment. The benefits of a conservative and individualized approach to disease management are discussed.

The fifth and final article in the supplement, by Champ L. Baker, Jr., MD, of the Hughston Clinic PC, in Columbus, Georgia, discusses the future direction of osteoarthritis treatment. Current therapies have been targeted toward pain relief and preservation of joint function, and are based primarily on the model of osteoarthritis as a disease of wear and tear. The new paradigm of osteoarthritis has given hope that the progression of this disease may be slowed or prevented, or even reversed, with therapeutic interventions and has caused us to shift our attention to other therapeutic targets. The use of viscosupplementation in joints other than the knee is considered and its possible antinociceptive and chondroprotective qualities are discussed.

Although there is a 70% to 80% response rate in patients, with relief of pain for up to 6 months and a low incidence of local side effects with viscosupplementation,¹⁸ to date, this procedure has been approved for use only in the knees. However, a recent study has investigated its application in shoulders affected by osteoarthritis. The response rate among patients was 69%, with an average duration of benefit of 7 months. Other studies of viscosupplementation in this joint are underway. Results from pilot studies of viscosupplementation in the hip, sacroiliac joint, and temporomandibular joint have been promising, as well.

Recent findings on the inflammatory and noninflammatory mechanisms involved in the development and progression of osteoarthritis offer hope that surgeons may soon be able to attenuate or arrest these processes. The development of disease-modifying osteoarthritis drugs would have a tremendous impact on the toll exacted by this disease. Criteria for assessing effectiveness of disease-modifying osteoarthritis drugs are outlined and several agents with disease-modifying potential are explored, including those that target matrix metalloproteinases, green tea polyphenols, and diacerein, a cartilage-targeted therapy that reduces DNA fragmentation in the chondrocyte.¹⁹ The role of nutraceuticals such as glucosamine and chondroitin sulfate in disease modification is examined.

Out on the frontiers of medical research are cell-based and gene-based therapies. Therapeutic use of locally administered recombinant growth factors and/or cytokine inhibitors to promote cartilage formation and inhibit degradation may someday prove valuable; however, the high cost of recombinant proteins and the chronic nature of osteoarthritis may limit use of this technique.

Another potentially promising ap-proach involves the introduction of adult mesenchymal stem cells into the joint compartment. However, the task remains to identify and isolate chondrogenic stem cells. Genes with products that stimulate chondrogenesis and inhibit the breakdown of the matrix offer another possible therapeutic target, and these are being investigated, as well.²⁰ In addition, new surgical techniques may help stimulate formation of healthy cartilage using autologous chondrocyte or osteochondral plug implantation. Initial testing in autologous chondrocyte implantation has been encouraging.

The coming decades offer a tremendous challenge in the field of osteoarthritis. With the growth in the numbers of those at greatest risk — the elderly — and the epidemic of obesity in this country, the incidence of osteoarthritis is expected to rise dramatically. But as surgeons’ understanding of the pathophysiology of this disease deepens, opportunities arise to identify appropriate targets and develop effective therapies to intervene in the earlier stages of the disease and end the cycle of cartilage destruction and increasing disability. It is hoped that the information offered in this supplement may help further those endeavors.

References

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Author

From the University of Colorado Health Sciences Center, Denver, Colo.