Osteoarthritis: New Therapies for an Old Disease

Author: Margaret A. Duston, MD, Adjunct Assistant Professor of Clinical Community and Family Medicine, Dartmouth Medical School, Hanover, NH.

Editor’s Note—The rapidly advancing age of the general population in the United States has magnified the health and social problems resulting from osteoarthritis (OA) and has placed increased stress on the health care system. This article critically reviews many of the newer interventions, medications, and approaches to the management of OA.

Age-related changes in muscle strength, proprioception, and joint laxity may contribute to the development of OA. It is well documented that exercise improves strength, and balance has a large role to play in the initial intervention in OA. The literature is increasingly convincing that the COX-2 agents are living up to their expectations in treating inflammation and pain of OA without increasing the risk of gastropathy in elderly patients. Viscosupplementation has limited benefit but provides an option for the treatment of the osteoarthritic knee. The role of nutraceuticals, glucosamine sulfate in particular, is not certain. There are potential explanations for favorable mechanisms of action in OA. The results of studies now in progress will support or reject the present optimism for glucosamine sulfate. The future of joint resurfacing with chondrocyte transplantation is extremely hopeful.

New Approaches to Osteoarthritis

In 1900, the population of the United States included only 4% who were older than the age of 65. Debility from OA was not a great economic or social problem. In fact, older persons were expected to endure the painful limitations of this condition as part of "the price of aging." Now, however, the elderly population is growing at a faster rate than any other age group, and the population with arthritis related debility is growing even faster. In the United States, 40% of persons older than age 60 years are aware of their arthritis, and 11% are limited by the pain and dysfunction of OA.1 Demographers speculate that in the year 2020, 22% of the population will be older than 65.2 The number of persons in the United States with arthritis will soar to almost 60 million.1 The cost of osteoarthritis debility will be felt throughout society.3

Osteoarthritis has presented great dilemmas to the medical community. There has been no effective treatment. For years, this therapeutic vacuum has drawn all manner of folklore, home remedies, earnest healers, and outright charlatans to compete with physicians and science.4 Further, our own assessment of new medical therapies has been limited by many factors. Poor study design, skewed information from television advertisements, questions of bias, and conflict of interest have clouded the appraisal of new drugs. Cynicism in both the medical and nonmedical communities spawned the joke that new drugs are reviewed in the Wall Street Journal before the New England Journal of Medicine.

But intellectual sophistication and new medical information of recent years have steadied the rocking boat. The public is tiring of antiscience.5 Patients are increasingly savvy, and the medical literature is building a scientifically satisfying understanding of the pathology and therapeutics of OA. As we assess the research, we can see the logic and hope for future.

This review will summarize recent information and advances in the treatment of OA with particular focus on OA of the knee, which is the most commonly debilitating site of OA.6 With this evolving information, physicians can discuss new options in the treatment of OA with the confidence and conviction patients expect.

Pathophysiology of the Problem

OA is a disorder of synovial joints characterized by destruction of articular cartilage and overgrowth of marginal and subchondral bone.7 It is interesting that overall bone mass decreases with age, but increased thickening of the subchondral bone is a consistent finding in OA.8 It is possible that the thicker and stiffer subchondral bone places additional stress on the overlying cartilage during joint loading, causing mechanical failure of the cartilage.9

Typically, the osteoarthritic joint shows fibrillation and loss of articular cartilage. The neighboring bone shows hypertrophic changes, including thickening of the subchondral bone and bone spur formation. The synovium shows patches of inflammation and areas of hypertrophy and the joint capsule is thickened.10 (See Figure 1.) Age changes in cartilage include increased susceptibility for injury and decreased capacity for repair. Osteoarthritis is more complicated than simple aging or "wear and tear" of overuse. The OA cartilage has increased metabolic activity—both increased synthesis and increased catabolism. Metalloproteinases and aggrecanase are catabolic proteins produced at increased rates. The degradation occurs first at the superficial layers of cartilage where the chondrocytes are secreting the enzymes responsible for the breakdown of their own matrix. The chondrocytes appear to attempt matrix repair, but the reduced number of cells, and perhaps the cellular senescence, results in an inadequate response and net loss of matrix.11 The tendons and ligaments undergo age-related changes that may exacerbate OA. The strength of tendons and ligaments and their insertions to bone are reduced with age.12 Increased cross-links may cause increased stiffness of the collagen and make it more prone to fatigue and failure.13 These age-related changes in tendons may contribute to the increase in varus-valgus laxity of the older person.11 The muscle has decreased contractile force related to age. The biologic mechanisms responsible for the decline in strength may be related to neurologic factors, myogenic factors, or a combination of the two.14

Exercise

Most people are eager for self-help directives and exercise programs, but many are fearful that activity will injure the joints. This fear must be addressed and corrected. Multiple studies have demonstrated the value of physical medicine in the prevention and management of OA.

The primary determinant of functional limitation in OA of the knee is quadriceps muscle weakness.15 This is a better predictor of lower limb function than knee pain or radiographic appearance.16 In fact, the x-ray appearance does not predict functional ability at all. Other predictors of function include neurologic defects, such as impaired proprioception,17 disabling medical conditions,18 depression, and anxiety.19

Many patients go into physical therapy (PT) with more positive determination and resolve if they know the facts about the relationship of quadriceps weakness and OA. Reduced quadriceps strength is found in both symptomatic and asymptomatic OA. One might counter that the pain of the OA leads to disuse, atrophy, and weakness, but the interesting point of several studies is that asymptomatic women have significant quadriceps weakness. The weakness precedes pain.15

A contributing factor to the weakened quadriceps in painless knee OA is impaired propioception. Damage in the joint affects the joint receptors. The afferent information to muscle and muscle spindles is interrupted. This deficiency decreases motor drive to the muscle and alters propioception. The encouraging news is that resistance training has been shown to improve the reflex propioception and decrease disability in addition to the expected muscle strength increase.20

More than 13 randomized clinical trials have tested the effect of conditioning and strengthening exercises on the pain and debility of OA.19 From these we have learned that weight loss, though helpful in pain management, is frequently not successful without exercise. Almost every study has shown improvement in pain and debility—even in low intensity and unsupervised environments. The largest trial, an 18-month study of 439 people, demonstrated that those who exercised in a group, under supervision and direction, profited the most. But all who exercised, even those on the self-directed home program, fared better than those who had only education.21 Interestingly, there was a direct correlation between the faithfulness to the regular exercise program and the degree of improvement. Strengthening is less successful in those with more severe structural damage or joint laxity.22

The mechanism for the beneficial effects of exercise remain unclear. Benefits of decreased pain and improved function (walking time, stair climbing, and stability) are found even in patients without increases in strength. It should be noted that personal care and attention alone results in decreased pain and increased subjective functional improvement. However, the improvements after exercise are significant even after correcting for the improvement from the personal attention alone.

PT is an important and underused modality in the management of OA. Referral to PT should be considered in any patient with OA pain, loss of joint motion, muscle weakness, instability, or malalignment. Physicians are sometimes frustrated by patients who make no distinction between a work-style causing strain and a prescribed therapeutic exercise program for strengthening. The office time taken in explaining this difference and reviewing the objectives of therapy is well worth the effort. It is important for the arthritic person to see the value of both improved body mechanics in everyday life and embrace the therapeutic program. Even the benefits from total joint replacement have been shown to be contingent on the preoperative physical function.23,24 If the patient realizes this early in the course of OA, he or she can improve his or her outcome from every later intervention.

Isotonic exercises appear to be most beneficial. Isometric exercises are reserved for those who find the standard exercises painful. The goal is to progress to a combination of isotonic and isometric exercises, including stair stepping, such that these can be performed regularly and safely after instruction. Aerobic exercise may be recommended in conjunction with strength training.25 Guidelines for appropriate exercise are available from the Arthritis Foundation (www.arthritis.org. Accessed June 11, 2001). This organization has developed the PACE (People with Arthritis Can Exercise) video series and Pathways To Better Living educational materials. The Arthritis Help Book by Lorig and Fries is available in bookstores or from the Arthritis Foundation and provides a great deal of interesting and practical information on arthritis care and management for both patients and physicians.26 (See Table 1.)

Table 1. Nonpharmacologic Measures for the Management of Knee OA
• Strengthening of the knee extensors
• Weight loss if overweight
• Aerobic exercise program
• Education and social support
• Proper well-cushioned shoes, heel-wedges if angular deformity present
• Cane or other assistive device for more advanced disease
Adapted from: Hochberg M, et al. American College of Rheumatology subcommittee
on osteoarthritis guidelines for the medical management of osteoarthritis: Part II.
Osteoarthritis of the knee. Arthritis Rheum. 1995;38:1541-1546.

Patients with OA of 1 knee have been shown to have impaired motion of the hip and ankle too. The involvement of the contiguous joints is most often asymptomatic.27,28 With the regional alterations in mind, the mechanics of the feet must be taken into account when advising patients on knee exercise. Well-fitting, wide, deep, supportive shoes are always required for walking. Shock-absorbing insoles can reduce knee pain, and heel wedges can correct abnormal biomechanics of OA.29 Fluoroscopy has shown that knee braces will distract the tibial and femoral condyles resulting in decreased pain while the brace is worn.30 Long-lasting benefit was not shown. Finally, the 1995 American College of Rheumatology (ACR) Guidelines also recommend that overweight persons with hip or knee OA lose weight. A randomized open trial assessing a walking program with and without weight loss provides data demonstrating pain improvement in the group losing body fat.31

Viscosupplementation

Most patients who have heard of hyaluronin injections picture a liquid rubber substance keeping the bones separated in a bouncy mobility. This is not entirely wrong. The hyaluronin is a high molecular weight protein, coiled in an entangled network.32 There is some physical chemical contribution to joint lubrication. The elasticity and viscosity buffer the load transmission across the joint surface. However, this protein, which is synthesized in the synovial joint lining, works to decrease pain and inflammation through other mechanisms.33 Its half-life in the joint space is too short to account for a long-acting benefit by its physical presence only.34

In a healthy joint, the hyaluronin is produced in low load states. It is continually synthesized by the lining synovialcytes and is a normal constituent of synovial fluid. In OA, the hyaluronin is of lower molecular weight and less concentrated. The hyaluronin imparts anti-inflammatory and pain-blocking properties by molecular exclusion. In the OA joint, the decreased amount of hyaluronin permits increase in inflammatory cells and pain mediators.35,36 The rationale for injections of synthetic hyaluronin, or viscosupplementation, includes restoration of elasticity and viscosity.37 Its anti-inflammatory effect appears to be related to the molecular weight of the injected substance. The substance also decreases the firing rate of nociceptors, thus decreasing pain perception.38 Finally, in normalizing physical and chemical properties of the joint, the hyaluronin may permit more endogenous secretion of hyaluronin by the joint-lining cells.39 This may explain the extended duration of benefit from the injection series. This would also suggest that the greatest benefit from injection would be early in the course of OA while the joint still has a well-functioning synovial lining. Ironically, hyaluronin is often sought in the case of advanced OA in patients who cannot tolerate the stress of surgery.40 Certainly, it has been seen to "buy time" in many cases.

The indication for use of hyaluronin injections is after a trial of exercise, nonpharmacologic modalities, and simple analgesics. (See Table 2.) Not all patients benefit from hyaluronin injections.41,42 The product has a good safety record. Systemic reactions are extremely rare. There is a 6% reported incidence of local reactions. The swollen joint is rarely severe or long lasting.43 The greatest concern is differentiating the pseudosepsis reaction from a joint infection.44 Some believe that inflammation is more likely if the product extravasates outside the joint. For this reason, joint aspiration followed by injection may have the dual benefit of increasing the concentration of the hyaluronin in the joint and assuring that the injection is, indeed, in the joint space.45 The hyaluronin is derived from rooster comb. Patients allergic to avian products may be allergic to hyaluronin injections.46

Table 2. Pharmacologic Therapy for Patients with Osteoarthritis
Oral
Acetaminophen
COX-specific inhibitors
Selective NSAID plus misoprostol or proton pump inhibitor
Nonacetylated salicylate
Pure analgesics
      Tramdol
      Opiates
Intra-articular
      Glucocorticoids
      Hyaluronan
Topical
      Cappsaicin
      Methylsalicylate
Adapted from: American College of Rheumatology Subcommittee
on Osteoarthritis Guidelines: Recommendations for the medical management
of osteoarthritis of the hip and knee: 2000 update. Arthritis
Rheum. 2000;43(9):1905-1915.

Within the orthopedic and rheumatologic communities, there are widely ranging opinions on the usefulness of viscosupplementation.47,48 However, the fact that up to 50% of hyaluronate-treated patients reported decreased pain and increased mobility for 6 months postinjection with few side effects, no serious adverse events, no drug interactions,49 and that repeat courses of viscosupplementation may be successful and well tolerated.50 All argue in favor of a trial of this therapy for knee OA.

Pharmaceuticals

The statistics indicate that patients taking nonsteroid anti-inflammatory drugs (NSAIDs) have a prevalence of peptic ulcer disease 10- to 30-fold greater than the general population.51 The estimated 13 million people using conventional NSAIDs each year account for staggering statistics of NSAID-related human and financial cost: 107,000 hospitalizations, 76,000 deaths,52 and an annual financial toll of $380 million.53

Synovial hypertrophy and inflammation are frequently used for this purpose. Nonacetylated salicylates (Salsalate or choline magnesium salicylate) do not have antiprostaglandin associated GI or platelet function and can be used when gastropathy is a concern. However, these agents may be associated with ototoxicity and central nervous system toxicity. Finally, GI toxicity can be reduced by using a nonsteroid drug with the least effect on the COX-1 enzymes while still inhibiting the pro-inflammatory COX-2 enzymes. The ACR Guidelines remind us that if a patient is at serious risk of an upper GI adverse event, gastroprotective agents should be used even with COX-2 selective agents. (See Table 3.)

Table 3. Risk Factors for an Upper GI Adverse Event
• Age 65 or older
• Comorbid medical conditions
• Oral glucocorticoids
• History of peptic ulcer disease
• History of upper GI bleed
• Anticoagulation
Adapted from: Hochberg M, et al. American College of Rheumatology
subcommittee on osteoarthritis guidelines for the medical management of osteoarthritis:
Part II. Osteoarthritis of the knee. Arthritis Rheum. 1995;38:1541-1546.

Control of inflammation in OA is often necessary and the analgesia of NSAIDs is often helpful.58 However, it should not be thought that control of the pain is required for success of the physical medicine and exercise interventions. Although treatment of pain is important, there is evidence to suggest that pain management does not affect functional ability.59,60

Patients heady with TV images of grandmothers running on beaches or dancing the night away are often unaware that COX-2 agents share some of the same non-GI toxicities as the nonselective agents. (See Table 4.) Due to inhibition of renal prostaglandins, all NSAIDs decrease renal blood flow, cause fluid retention, and increase the risk of renal failure.61 These risks are greater in elderly patients.11 The COX-2 selective agent, rofecoxib, may have a higher incidence of fluid retention and systolic hypertension than many agents.62 As with any NSAID, the risk of renal toxicity is increased in the face of renal insufficiency, decreased blood volume (as with diuretics), cirrhosis, and congestive heart failure. Central nervous system effects (dizziness, drowsiness, anxiety, confusion) may occur with any NSAID. Interference with other drugs such as ACE inhibitors, some antihypertensives, lithium, and methotrexate must be considered. Increase in INR, prothrombin time, and increased bleeding risk do occur even with the COX-2 selective agents.63 Of course, allergic reactions can occur. In particular, there is warning of celecoxib reaction in persons sensitive to sulfonamides.62

Table 4. COX Isoforms Related to GI and Renal NSAID Effects
COX-1(constitutive enzyme) COX-2 (inducible enzyme)
Protects normal gastric mucosa Promotes inflammation, pain, fever
Maintains normal platelet function Promotes dysregulated proliferation at inflammatory site
Maintains normal renal function Maintains normal renal function
Promotes vascular flow, tissue repair

In short, the COX-2 agents have not "revolutionized" arthritis management. The COX-2 agents have given us one more tool to use judiciously.

Nutraceuticals

Glucosamine and chondroitin sulfate have been of medical interest since as early as 1969. In recent years, there have been reports of favorable effects in OA. The interest sky-rocketed with the 1992 publication of "The Arthritis Cure," popular in the lay press, which extolled the value of these agents in cartilage maintenance.64

Clinical trials of therapeutic agents for arthritis have always been partially obscured by very high rates of placebo effect. Frequent placebo benefit has always been observed in arthritis literature.65 In some rheumatoid arthritis study trials, the improvement has not been limited to subjective reports of pain relief. "Objective" parameters of improvements in erythrocyte sedimentation rate and blood count have been observed. So, against this background, reports of modest pain improvement in glucosamine-treated patients have been fairly unimpressive. The rheumatology community in particular has been very skeptical of this agent.54

Most of the glucosamine studies have been short term and flawed in design. Little data are available about the pharmacokinetics of glucosamine. Its fate after GI absorption is poorly tracked. After oral, IM, or IV administration, it is broken down to D-glucosamine and sulfate. From the oral route, it is excreted in feces and urine in equal amounts. It is incorporated into plasma-binding proteins as opposed to nonspecific binding to plasma proteins. Based on studies in only 2 subjects, the half-life is believed to be 26 hours and bioavailability 26%.66

How could glucosamine work as a modifier of OA? The strength of the cartilage matrix depends upon large aggregating proteoglycans. Aggrecan, one of the major structural components of cartilage, provides properties of compressibility and elasticity.67 In OA, aggrecan is the first matrix component to undergo measurable loss. This loss appears to be due to an increased rate of degradation.68 The initial cleavage of the intact cartilage is thought to be accomplished by the enzyme aggrecanase. From this, the degenerative process begins. (See Figure 2.) Small tangential clefts on the surface of the joint lead to deeper vertical clefts with splitting and fibrillation. Progressive degeneration of the cartilage follows. In vitro, glucosamine inhibits aggrecanase. This interruption of aggrecanase activity is a mechanism by which glucosamine could alter, or even reverse, the degeneration process.69 Other researchers have suggested glucosamine might increase proteoglycan synthesis, depress catabolic activity through nonaggrecanase modalities, or inhibit inflammation through cartilage-unrelated effects.70 However, these theories, in relation to clinical use of glucosamine, are not fully accepted and may yet undergo correction or revision as new information unfolds.

A recent 3-year multicenter trial of glucosamine sulfate in OA of the knee was published in Lancet.71 This study reported improvement in x-ray defined knee medial joint space loss and improvement in pain and functional parameters in the patients taking glucosamine sulfate as compared to placebo. This study has legitimized the interest in glucosamine in the medically conservative community.72 It has not established a certainty of glucosamine benefit but has encouraged further scientific study of this substance. McAldindon and associates query whether future long-term, well-designed studies will support the finding of clinically significant glucosamine benefit. The National Institute of Health has a multicenter trial under way to address some of these questions.73 We wait for "the other shoe to drop."

Information regarding adverse effects of glucosamine sulfate is scant. Except for sporadic letters to the editor and rare case reports, we have little evidence of deleterious effects from these agents.74 There is very little scientific information available regarding chondroitin sulfate. The studies of glucosamine have all been related to the sulfate, not hydrochloride, N-acetyl, or chlorhydrate salt, which are sometimes in the commercial products. Data on the purity and amount of product in each capsule do not exist. The Dietary Supplement Health and Education Act legislated in 1994 by the US Congress severely limits federal government regulation of vitamins, herbs, or dietary supplements. There is wide latitude for unsubstantiated claims. Even if the practitioner holds faith in glucosamine as a therapeutic agent, no one can assure the legitimacy of the over-the-counter product. At this point, the situation is truly "buyer beware."67

So, what can you offer to the patient in your office asking your blessing as he or she takes "over-the-counter" formulations of glucosamine/chondroitin sulfate? The patient can be assured that there is little likelihood of toxicity or adverse event due to glucosamine. He or she can be advised to select the glucosamine sulfate formulation from a reputable pharmaceutical firm. If no pain relief is appreciated in the first 12 weeks of therapy, the value of continuing therapy is doubtful. Finally, the patient is advised to continue to "check-in" as new and reliable information will be accumulating over the next few years.

Joint Resurfacing

The future of resurfacing cartilage with autologous cells is hopeful. We have long known that injury that causes cartilage surface defects rarely heals completely. Trauma-induced divots on the cartilage surface fill in with fibrocartilage or scar tissue. This evolves into OA and functional debility.75

Attempts to repair the injury with transplanted chondrocytes have been reported for years.76 The drawbacks include the fate of the donor site and the difficulty of expanding the cell population in vitro. In a patient who already has OA, finding an uninvolved donor site can be difficult. Harvesting the cartilage cells results in a defect at the donor site, and this site may then evolve into OA. The culturing of the harvested cells may result in de-differentiation of the cells. If this occurs, the chondrocytes will no longer organize and produce matrix.

Recent research suggests that the periosteum may offer hope as an excellent source of chondrocytes for transplant. These cells form hyaline cartilage as part of postfracture repair. Now studies have shown that periosteal cells taken from adults can be cultured.77 These cells continue to express their normal traits despite the age of the donor.78 The cells are easily accessible, expandable, and phenotypically stable. Under appropriate conditions, they form tissue close to that of hyaline cartilage. This is a promising finding making the possibility of cell transfer a more practical option in the future.

Conclusion

The demands placed on the health care system by the aging population are many. Continued advances in the understanding of the changes of aging and the pathology of OA are combining to enlighten us on a rational approach to the management of OA. The use of physical, nutritional, and pharmaceutical intervention may in the future prevent or slow the progress of OA. The strides made in cellular biology and chondrocyte transplantation offers extraordinary hope for an entirely different approach to advanced OA. Patients and physicians have a great deal to discuss in the continuing medical care of OA. We have come a long way from the "nothing can be done; just learn to live with it" mentality of a few years ago.

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