Future Treatment of Osteoarthritis

ABSTRACT

Osteoarthritis represents an advanced stage of disease progression caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and noninflammatory pathways. The burden of this disease will increase in direct proportion to the increase in the older adult population. Research on current and experimental treatment protocols are reviewed, including the effect of hyaluronic acid in both in vitro and in vivo studies, autologous chondrocyte and osteochondral plug implantation, and gene therapy. Disease-modifying osteoarthritis drugs and in vivo studies of glucosamine and chondroitin sulfate are reviewed.

Articular cartilage is an essential component of normal joint function, providing a smooth surface that facilitates joint mobility, as well as shock absorbing and other biomechanical properties that complement those of synovial fluid. Osteoarthritis is characterized by progressive degradation of articular cartilage, accompanied by loss of cartilage function, which ultimately reduces mobility and can cause disabling joint pain.

Current osteoarthritis treatment, which oriented primarily toward preservation of joint function and pain relief through both nonpharmacologic and pharmacologic approaches,¹ has been based on a perception of osteoarthritis as a more or less passive result of injury or wear and tear during a patient’s lifetime. However, over the past 15 years, it has become apparent that osteoarthritis represents the advanced stage of an active, progressive disease process.

Healthy cartilage is a dynamic structure maintained primarily through the activity of chondrocytes, although synovial tissue also exerts an influence over cartilage metabolism, especially in various arthro-ses. The primary component of cartilage is water, which constitutes between 65% and 80% of cartilage volume. The critical biomechanical properties of cartilage, including stiffness, compressibility, elasticity, and resilience, arise directly from its structural components and the interactions between them.

The primary matrix component, collagen, provides stiffness and structural integrity to cartilage. However, its elasticity and compressibility appear to be derived from proteoglycan complexes composed of long molecules of hyaluronic acid, which weave through the collagen matrix and to which are attached large glycosaminoglycan molecules known as aggrecans. In healthy people, the structure of cartilage is maintained in a delicate balance, between synthesis and degradation, through the activity of chondrocytes and synovium.

Osteoarthritis is now understood to be the endpoint of a sustained increase in degradative activity relative to synthetic activity, resulting in loss of cartilage structure and, with it, function. The mechanisms that underlie this imbalance involve both inflammatory and non-inflammatory pathways that appear to be induced as the result of acute and/or chronic injury to the affected cartilage. Improved understanding of these processes has helped identify stages of disease course and potential therapeutic targets for intervention that point toward treatments capable of modifying or arresting osteoarthritis and its antecedents.²

As a result, the goals of osteoarthritis therapy are gradually being expanded beyond the current “pain relief/joint preservation,” possibly to encompass:

• Interfering with the induction of cartilage-degrading mechanisms following acute or chronic injury
• Restoring normal cartilage and joint homeostasis, and arresting disease progression, in osteoarthritis and preosteoarthritis states
• Reversing existing cartilage damage and restoring normal cartilage structure and function in frank osteoarthritis

In this article, we address some of the promising avenues in achieving progress toward these goals, starting with the possible extension of an existing osteoarthritis treatment mode, viscosupplementation, to more active interference with the progression of osteoarthritis. We then summarize current research on possible disease-modifying osteoarthritis drugs. We conclude with a discussion of approaches to cartilage restoration in osteoarthritis and a summary of future directions in osteoarthritis management.

Viscosupplementation: Beyond Pain Relief

One of the most promising avenues toward improved osteoarthritis treatment involves not only a new modality, but also the repositioning and reevaluation of a current modality, viscosupplementation, to reflect current understanding of osteoarthritis etiology and pathophysiology. The important role of hyaluronic acid in cartilage structure and in providing the viscoelastic properties of synovial fluid, as well as observed hyaluronic acid alteration and depletion in osteoarthritis, led to the consideration and subsequent evaluation of intra-articular hyaluronic acid injections in knee osteoarthritis therapy during the 1990s.³

In a meta-analysis of 20 blinded, randomized, controlled studies, Wang et al⁴ concluded that intra-articular hyaluronic acid therapy can reduce symptoms of knee osteoarthritis with few adverse events, despite significant between-study heterogeneity with regard to reported efficacy. The efficacy of viscosupplementation appears to be reduced in patients aged >65 years and in patients with extremely advanced osteoarthritis, involving complete loss of joint space.

As a result of this study and others, the US Food and Drug Administration has approved 4 branded formulations of purified hyaluronic acid for intra-articular injection in the treatment of osteoarthritis. These formulations are administered weekly for a treatment course of 3 to 5 weeks and differ primarily with regard to hyaluronic acid molecular weight. Note that clinical studies of these agents were guided by concepts of osteoarthritis dominant during the 1990s: osteoarthritis was regarded as generally irreversible, with little or no opportunity to modify disease course; and the primary goal of treatment was pain relief sufficient to permit improved function.

The first indication that intra-articular hyaluronic acid therapy might have broader effects than simple replacement of endogenous hyaluronic acid was the mismatch between in vivo residence time (days) and duration of therapeutic effect (weeks to months). Because the registration studies for hyaluronic acid supplements used pain relief as the primary criterion for efficacy, in the relief of pain this discrepancy first came to light.³ In an animal model of induced arthritis, hyaluronic acid was capable of directly suppressing the activity of afferent nociceptive nerve fibers, as well as movement-evoked pain responses. These effects were not observed with low-molecular-weight (non-viscoelastic) hyaluronic acid, which suggests that the antinociceptive effect may have been derived through “cushioning” of nerve fibers that run through the extracellular matrix.⁵

There is also evidence for direct antinociception by hyaluronic acid through interference with bradykinin-induced pain in rats; the efficacy was directly related to hyaluronic acid molecular weight and may involve specific interactions between hyaluronic acid and hyaluronic acid receptors.⁶ Hyaluronic acid may also ameliorate the effects of substance P, which appears to play several roles in pain transmission.^7,8

Although this article focuses on disease modification rather than pain relief, it should be emphasized that the symptoms of “chronic pain” that many osteoarthritis patients experience, including hyperalgesia and allodynia, are typically unresponsive to conventional analgesic agents and even to opioids.⁵ Therefore, the ability of hyaluronic acid to directly modulate nociception is potentially an important attribute.

There is strong evidence, from both in vitro and in vivo studies, that hyaluronic acid modulates some of the inflammatory and noninflammatory pathways involved in osteoarthritis pathogenesis and progression.³ In a rabbit osteoarthritis model, intra-articular hyaluronic acid treatment reduced the synovial expression of interleukin (IL)-1ß, a critical inducer of inflammatory pathways that promote cartilage degradation, and of matrix metalloproteinase-3, which degrades the extracellular matrix in cartilage.⁹

In other rabbit experiments, hyaluronic acid administration reduced production of the inflammatory signaling molecule nitric oxide, an important mediator of cartilage degradation in osteoarthritis, by the meniscus and synovium, although nitric oxide production in cartilage remained unchanged. Hyaluronic acid treatment also caused a dramatic decrease in chondrocyte apoptosis and in osteoarthritis severity, relative to control animals with osteoarthritis.^10,11 Canine experiments have shown that hyaluronic acid treatment down-regulates expression of tumor necrosis factor (TNF-) and its receptors, as well as the matrix metalloproteinase stromelysin.¹²

In studies on isolated cartilage and cultured chondrocytes from various species in vitro, hyaluronic acid treatment has also been shown to increase chondrocyte proliferation and synthesis of glycosaminoglycan¹³; to increase proteoglycan synthesis in cartilage treated with IL-1 (which induces cartilage degradation)¹⁴; to reduce matrix degradation following exposure to degradative enzymes¹⁵; and to attenuate IL-1ß–induced reduction in collagen gene expression.

Because knee osteoarthritis is a significant contributor to disability and to burden on the health care system, efficacy evaluations on novel osteoarthritis therapies often initially target knee osteoarthritis. Hip osteoarthritis is also a leading cause of disability and increased health care utilization; pilot studies have been performed to evaluate the efficacy of hyaluronic acid in hip osteoarthritis, using 1-3 fluoroscope- or ultrasound-guided injections. All studies have suggested hyaluronic acid efficacy, with decreases that extend for several months in both spontaneous pain and pain while walking, and few adverse events.^16-19 As with knee osteoarthritis, there is some indication that response rates are higher among patients with mild to moderate osteoarthritis than among patients with severe osteoarthritis.¹⁷

There are also published reports of pilot studies of hyaluronic acid supplementation, with encouraging results, in patients with sacroiliac joint syndrome²⁰; and in patients with temporomandibular joint disorders.²¹ Generally, there is no reason that hyaluronic acid should not be equally effective in treating osteoarthritis and osteoarthritis-like syndromes in other synovial joints, including elbow, wrist/hand, ankle, and foot joints.

While the extension of viscosupplementation to osteoarthritis in other synovial joints is encouraging, demonstration that hyaluronic acid could modify or even arrest the pathophysiological processes that precede the onset of frank osteoarthritis would potentially be a more significant development. A number of studies, most recently among Swedish female soccer players, have shown that acute knee injury dramatically increases the risk of subsequent osteoarthritis.²² This is believed to be the consequence of rapid, but persistent, changes that promote cartilage breakdown following injury to the affected joints.^23,24

Animal studies have recently shown that the rate of programmed cell death (apoptosis) among chondrocytes following acute injury is much higher in younger animals, which suggests that the relationship between injury and subsequent cartilage degradation and osteoarthritis is strongest early in life.²⁵ Because of this, the most appropriate evaluation of the ability of viscosupplementation to delay or prevent the onset of osteoarthritis may be in younger adults who have recently suffered an acute injury to the knee joint.

Progress on Disease-Modifying Osteoarthritis Drugs

The elucidation of the inflammatory and noninflammatory mechanisms that promote the development and progression of osteoarthritis has led to excitement about the potential to attenuate or arrest these processes pharmacologically. The development of effective disease-modifying osteoarthritis drugs promises to sharply reduce anticipated osteoarthritis-related morbidity, disability, and health care burden, including the need for surgical approaches in end-stage disease, among the aging populations in developed countries.

The potential for successful agent development in this arena has led regulatory agencies to acknowledge that it may be possible to grant a disease-modifying osteoarthritis drug indication to drugs that demonstrate the ability to arrest or delay osteoarthritis progression.²⁶ This possibility has led osteoarthritis experts to consider the objective parameters that would best define efficacy in putative disease-modifying osteoarthritis drugs.^26,27

A working group within the Group for the Respect of Ethics and Excellence in Science (GREES) has suggested that at this point, radiographic evidence for reduced joint-space narrowing provides the best objective measure of effectiveness of disease-modifying osteoarthritis drugs and should be used as a primary endpoint in clinical studies. However, the GREES group also emphasized the need to include as co-primary endpoints objective measures of pain and function, which are the outcomes that most directly determine patients’ perception of disease burden. Secondary endpoints should include response rates, with “response” defined in terms of joint-space narrowing progression and objective measures of increased pain and reduced function.²⁶

The GREES group considered time to total joint replacement surgery as perhaps the most relevant clinical endpoint, but rejected its use in clinical studies because of the potential for bias due to economic factors or patient views of surgery. The group also stressed the need to refine magnetic resonance image–based assessments of osteoarthritis progression because of the potential to provide more detailed structural information than joint-space narrowing, as well as the need to use biochemical markers of cartilage degradation and joint remodeling to define disease state criteria objectively. It was suggested that validation of these “experimental” measures of osteoarthritis progression could be facilitated by their use in proof-of-concept studies or as secondary endpoints in early-stage clinical trials.²⁶

Nutraceuticals: Coming of Age in Osteoarthritis?

The use of self-prescribed over-the-counter nutritional and herbal supplements to treat or prevent disease has increased greatly in recent years. In support of such use, proponents of various “alternative” preparations cite anecdotal and, in some cases, clinical study evidence for their efficacy, as well as their cost-effectiveness vs. prescription medications, with regard to both the actual product price and the cost and inconvenience of the required physician visit.

Critics point out the general paucity of evidence from well-designed, controlled, blinded clinical trials with objectively defined efficacy endpoints; the lack of information on adverse events and drug-drug interactions; and the reluctance on the part of companies marketing these agents to fund studies that would support claims of efficacy and safety.

Two of the most popular nutraceuticals, glucosamine and chondroitin sulfate, are aimed at the growing osteoarthritis market, marketed on the basis of joint protection or similar claims. Glucosamine is an aminosaccharide that provides a substrate for chondrocyte synthesis of glycosaminoglycans and proteoglycans in vivo, while chondroitin sulfate is a long, unbranched chain of sulfated and unsulfated glucuronic acid and N-acetylgalactosamine residues. Chondroitin sulfate is found in several types of proteoglycan molecules, including aggrecans, within articular cartilage.²⁸

Studies of glucosamine in vitro suggest that it may act primarily as a substrate for glycosaminoglycan synthesis and as a promoter of protein synthesis, increasing the level of proteoglycan production; a possible alternative or additive mechanism involves enhancement of synovial hyaluronic acid production, which down-regulates degradative pathways.²⁸ In addition, glucosamine has been found to prevent activation of human chondrocytes by IL-1ß, inhibiting the release of the proinflammatory mediators cyclooxygenase-2 (which produces prostaglandin E2), IL-6, and nitric oxide. This suggests that glucosamine may directly interfere with at least some of the inflammatory pathways leading to cartilage degradation.²⁹

Glucosamine has also been evaluated in several randomized studies using placebo or active controls. The largest of the double-blind, placebo-controlled studies was conducted by Rovati,³⁰ who randomized 252 patients with knee osteoarthritis to oral glucosamine or placebo. The response rate (for predefined reductions in pain or movement limitation) was 55% for glucosamine vs. 38% for placebo (P<.05), and glucosamine was nearly as well tolerated as placebo.

In a large comparative study, Müller-Fassbender et al³¹ randomized 199 patients with symptomatic knee osteoarthritis to oral glucosamine or ibuprofen for 4 weeks. At 4 weeks, the rate of response (predefined reduction on the Lequesne Index of osteoarthritis severity) was nearly equivalent between the two groups (48% for glucosamine vs. 52% for ibuprofen, P=.67).

In addition to the efficacy results, the Müller-Fassbender study illustrated 2 aspects of the glucosamine-ibuprofen comparison that have been reproduced in other studies. The first is the time course of symptomatic improvement. Ibuprofen-treated patients demonstrated greater symptomatic relief early (at about 1 week), but the level of relief remained stable from 2 to 4 weeks; in contrast, glucosamine-treated patients took longer to achieve levels comparable to ibuprofen, but continued to improve through the end of the trial.^28,31

The second is the pattern of adverse events. Glucosamine has been consistently well tolerated in randomized studies, with adverse event rates similar to placebo; all adverse events have been mild (mostly gastrointestinal upset). The observed rates of adverse events for ibuprofen (mostly gastrointestinal related) have been significantly (3 to 6 times) greater than those for glucosamine in comparative studies.^28,31

In vitro studies of chondroitin sulfate have shown that it promotes proteoglycan production and inhibits collagen breakdown in chondrocytes, possibly by serving as a substrate for proteoglycan synthesis. It has also been proposed that the sulfate moiety of both chondroitin sulfate and glucosamine sulfate may contribute significantly to their in vivo activity, enabling more robust incorporation of sulfur, which helps stabilize the extracellular matrix.²⁸

Chondroitin sulfate has not been evaluated as extensively as glucosamine in controlled clinical studies, but several trials have demonstrated highly significant reduction in osteoarthritis symptoms vs. placebo. In the single published comparison with a nonsteroidal anti-inflammatory drug (NSAID) (diclofenac), chondroitin sulfate demonstrated less-rapid, but more persistent, symptomatic relief, with benefit lasting up to 3 months after the final treatment; in contrast, symptoms reappeared rapidly after treatment cessation in patients receiving diclofenac.^28,32 An issue specific to chondroitin sulfate is the variability among commercial preparations with regard to molecular weight and structure. Depending on the specific preparation used, intestinal absorption and bioavailability may vary significantly.²⁸

In a review of the clinical use of glucosamine and chondroitin sulfate, Brief et al²⁸ conclude that both agents have demonstrated efficacy with regard to reduction of joint pain/tenderness and improved mobility, as well as a reduced side effect profile compared with NSAIDs and no evidence of toxicity. However, they caution that all studies to date have been short-term and that a number of questions about these agents remain unanswered, such as those regarding longer term safety and efficacy, as well as product purity and optimal formulation, dosage, dosage form, and route of administration.

The lack of conclusive evidence from well-designed prospective studies for the long-term efficacy and safety of these agents in preventing or treating osteoarthritis will probably continue to prevent professional organizations and advocacy groups from supporting their use.

Other Disease-Modifying Osteoarthritis Agents Under Evaluation

Several other agents with potential disease-modifying effects in osteoarthritis are under evaluation. One approach involves direct inhibition of matrix metalloproteinases, which are responsible for degrading collagen, proteoglycans, and other matrix components in osteoarthritis. One matrix metalloproteinase inhibitor, Ro 32-3555, which specifically targets collagenase, has demonstrated the ability to inhibit joint-space narrowing and osteophyte formation in a mouse model.³³

While direct targeting of degradative enzymes may be useful in modifying the course of osteoarthritis, it may ultimately be more fruitful to target entire pathways, especially those induced by IL-1ß and TNF-, through inhibition of receptor binding and/or signal transduction. Two agents currently under investigation, diacerein and green tea polyphenols, interfere with IL-1ß–induced signal transduction through the NF-kB activation pathway.³⁴

Diacerein, currently in phase II studies for osteoarthritis therapy, reduces chondrocyte apoptosis and inhibits nitric oxide synthesis in canine chondrocytes in vitro.³⁵ The activity of diacerein in vivo may be due primarily to its active metabolite, rhein, which has been found to down- regulate certain matrix metalloproteinases and up-regulate an endogenous inhibitor of matrix metalloproteinases, tissue inhibitor of metalloproteinase-1.³⁶ Both diacerein and rhein reduced the synthesis of factors associated with bone remodeling in isolated osteoblast cells from osteoarthritis patients.³⁷

Diacerein has demonstrated some degree of efficacy in placebo-controlled studies of knee and hip osteoarthritis. In a 16-week study of knee osteoarthritis, diacerein produced significantly greater pain reduction and reduction in osteoarthritis severity scores than placebo (P<.05).³⁸ In a long-term (3-year) study of hip osteoarthritis, significantly fewer patients receiving diacerein demonstrated progression by joint-space narrowing than those receiving placebo; among patients who completed the study, the mean joint-space narrowing was significantly less for patients receiving diacerein than for patients receiving placebo. However, diacerein demonstrated only limited effect on osteoarthritis symptoms.³⁹ Diacerein was well tolerated in both studies; the most frequent adverse event was transient change in bowel habits.^38,39

Green tea polyphenols were originally shown in a mouse model of osteoarthritis induction to inhibit the development of osteoarthritis and reduce the expression of inflammatory mediators.⁴⁰ One of the active components of the green tea polyphenol fraction, epigallocatechin-3-gallate, has been found to inhibit a range of IL-1ß–induced effects in human chondrocytes in vitro. These effects include suppression of nitric oxide synthase expression and production, as well as inhibition of cyclooxygenase-2 release.

The activities of epigallocatechin-3-gallate appear to be mediated through the suppression of 2 signal transduction pathways, the NF-kB pathway and a specific mitogen-activated protein kinase pathway, which suggests the potential of this compound to ameliorate a range of degradative processes in osteoarthritis.^41-43 As yet, no human clinical studies of green tea polyphenols or derivatives have been performed.

Approaches to Cartilage Restoration

The restoration of normal cartilage structure and function following damage resulting from osteoarthritis or preosteoarthritis disease processes is the ultimate goal of osteoarthritis therapy. The use of locally administered recombinant growth factors and/or cytokine inhibitors to promote cartilage synthesis and inhibit degradation has been discussed as a potential approach to cartilage restoration. However, the chronic nature of osteoarthritis, combined with the short in vivo residence time of many of these agents, would probably necessitate multiple treatments. The high cost of recombinant proteins (compared with oral agents) and the invasive nature of this type of therapy are also significant drawbacks.⁴⁴

For that reason, some researchers are investigating the use of gene therapy to effect local in situ production of important promoters of cartilage repair and regeneration, such as transforming growth factor-ß, insulin-like growth factor, and bone morphogenetic proteins.⁴⁴ Two broad approaches to such therapy are possible: in ex vivo gene therapy, cells are removed from the patient and returned after inserting a desired gene sequence; in vivo gene therapy uses a virus or other vector to introduce genes to cells in situ.

In preliminary proof-of-concept studies, both approaches have shown promise. In one ex vivo experiment, a bone morphogenetic protein gene was introduced into isolated rat bone marrow cells using a viral vector (a process known as transduction). Reintroduction of these cells into femurs with artificial lesions resulted in complete healing, with the new bone indistinguishable from existing bone.⁴⁵ In a study of in vivo gene therapy, gene sequences for a marker protein were successfully transduced using a viral vector into chondrocytes within rabbit articular cartilage. In this study, it was interesting to note that chondrocytes in cartilage defects were transduced at higher rates than chondrocytes in healthy cartilage.⁴⁶

Another potentially useful approach to permanent cartilage restoration is the introduction of adult mesenchymal stem cells, isolated from bone marrow, into the joint compartment. Adult mesenchymal stem cells retain the ability to differentiate into a range of mesodermal tissues, including bone, cartilage, and muscle. This technology is currently in the concept stage; perhaps the most challenging hurdle involves identification, selection, and isolation of the stem cell population that would be introduced.⁴⁷

Two surgical approaches are currently used to repair and regenerate full-thickness cartilage defects. The first is implantation of autologous osteochondral plugs, which are derived from non-weight bearing articular cartilage near the site of the defect. In the first study of this procedure, Yamashita et al⁴⁸ reported that 12 patients with femoral condyle cartilage defects who received autologous plug repair showed good results at 2-year follow-up.⁴⁹ Such implantation is probably most appropriate for defects 2 cm in diameter.

The second technique is autologous chondrocyte implantation, which involves harvesting chondrocytes from an unaffected joint in a patient with osteoarthritis, expanding the chondrocyte population using in vitro cell culture techniques, and reimplanting the cultured chondrocytes at the defect site. This technology, which has been commercialized, involves sending the harvested chondrocytes to a central facility where they are grown to produce about 12 million cells. The cultured chondrocytes are then provided to the surgeon, who reinserts them at the defect site, following debridement to a healthy border, beneath a periosteal cap.⁵⁰

The results of autologous chondrocyte implantation have been encouraging. Among the initial cohort of patients, 96% of those receiving autologous chondrocyte implantation for an isolated femoral condyle defect reported excellent or good results at a mean follow-up of 4.1 years post-surgery.⁵¹ More recent results have generally confirmed these observations and have supported the extension of autologous chondrocyte implantation to other joints; the commercial provider of autologous chondrocyte implantation technology maintains a “cartilage repair registry” that permits ongoing analysis of autologous chondrocyte implantation results and sequelae.⁵²

Although these technologies appear to provide robust restoration of cartilage structure and function, they appear to be most useful in the treatment of isolated, relatively small full-thickness cartilage defects, rather than as remediation for the extensive remodeling associated with osteoarthritis. However, because of the high rate of progression to osteoarthritis among patients who experience defects as the result of acute or chronic injury, the ability to provide functional restoration is not trivial.⁵² It remains to be seen whether the progression to osteoarthritis will be reduced among patients receiving autologous chondrocyte implantation or autologous osteochondral transplants, but demonstration of this effect would alter the treatment paradigm for acute cartilage injury.

An alternative approach to surgical restoration is tissue engineering — the use of an artificial matrix or scaffold that will support ingrowth and colonization by surrounding chondrocytes, which ultimately replace the artificial matrix with natural extracellular matrix. Encouraging results have been reported for arthroscopic implantation of carbon fiber pads that provide structural strength as well as scaffolding into human knees with articular defects. Although few details have been provided, the pads became filled with a compliant, fibrous matrix.⁵³

Artificial matrices can also incorporate growth factors and/or cells to encourage more rapid creation of a normal matrix and tissue. The implantation of a collagen sponge impregnated with bone morphogenetic protein-2 was found to promote the growth of cartilage in full-thickness articular defects in rabbits. Compared to the tissue regenerated using untreated sponges, use of the bone morphogenetic protein-2-containing sponge resulted in cartilage that was more histologically normal and better integrated with surrounding cartilage.⁵⁴ In a mouse system, chondrocytes incorporated into a polymeric sponge produced cartilage that was more normal when they were pretreated with platelet-derived growth factor than when they were untreated.⁵⁵

Conclusion

The burden of osteoarthritis, in terms of disability, reduced productivity, and reduced quality of life, as well as direct medical costs, is likely to rise sharply with the aging of the population in the absence of better options for long-term prevention and management. It is fortunate that the identification of new therapeutic targets and modalities has been made possible by the improved understanding of osteoarthritis pathophysiology and the underlying role of signaling pathways in osteoarthritis development and progression.

In the near term, osteoarthritis treatment should be improved through the extension of viscosupplementation into new joints, as well as the use of this technique to limit osteoarthritis onset and progression. In addition, the availability of new disease-modifying osteoarthritis agents and more appropriate evidence-based use of glucosamine and chondroitin sulfate will help provide improved outcomes for patients with or at risk for osteoarthritis.

In the longer term, improved disease state management will most likely stem from interrupting the progression from cartilage injury to symptomatic osteoarthritis, using medical approaches, as well as surgical implantation of autologous chondrocytes and cartilage. Ultimately, optimal treatment of both preosteoarthritis and existing disease will almost certainly involve a combined approach that synthesizes advances in tissue engineering, gene therapy, and disease-modifying osteoarthritis agent development into focused treatment plans based on a consideration of each patient’s genetic background, risk factors, and medical history.

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Authors

From the Hughston Clinic, PC, Columbus, Ga. The authors thank Stephen Collins, MS, from Hatboro, Pa, for his help with content development.