Response of Joint Structures to Inactivity and to Reloading After Immobilization

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1 Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 2, April 15, 2003, pp DOI /art , American College of Rheumatology SPECIAL ARTICLE Response of Joint Structures to Inactivity and to Reloading After Immobilization KENNETH D. BRANDT Introduction The studies described herein were aimed at providing a better understanding of the effects on joint structures of immobilization and remobilization. Some of the effects of immobilization in animal models have been reviewed and have been contrasted with those seen in animal models of osteoarthritis (OA). The response of articular tissues to remobilization and reloading of the joint has been examined and the effect of nonsteroidal antiinflammatory drug (NSAID) administration on these responses has been described. Although the observations described here are based on research performed primarily in animals, and a caveat exists with respect to their generalizability to humans, they illuminate our knowledge and suggest research questions that, when answered, will better inform clinicians regarding approaches to rehabilitation of humans after prolonged immobilization of diarthrodial joints. Synovial Joint Anatomy Synovial joints are meant to move. Although chronic overloading of the joint (as in performance of jobs that require repeated kneeling, bending, and lifting heavy loads) or an acute overload (e.g., joint trauma) may lead to OA, immobility is also detrimental. In OA, the most striking pathologic change is the progressive loss of articular cartilage over the habitually loaded areas of the joint surface. OA, however, is not a disease of only a single tissue articular cartilage but of an organ, the synovial joint. OA involves all of the tissues of the joint, i.e., the synovium, subchondral bone, capsule, Presented at the International Conference on Health Promotion and Disability Prevention for Individuals and Populations with Rheumatic Disease: Evidence for Exercise and Physical Activity, St. Louis, MO, September Supported in part by NIH grants AR and AR Kenneth D. Brandt, MD: Indiana University School of Medicine and Indiana University Multipurpose Arthritis and Musculoskeletal Diseases Center, Indianapolis, Indiana. Address correspondence to Kenneth D. Brandt, MD, 1110 W Michigan Street, LO 545 Indianapolis, IN 46202, kbrandt@iupui.edu. Submitted for publication May 17, 2002; accepted in revised form October 18, periarticular muscle, ligaments, and the sensory nerves whose termini lie within these tissues. OA represents failure of the joint. The articular cartilage that covers the ends of the bones within every synovial joint fulfills 2 functions. First, it provides a smooth bearing surface so that the 2 bones glide over each other virtually without effort (with synovial fluid as a lubricant, the coefficient of friction of cartilage moving across cartilage is some 15 times lower than that of two ice cubes sliding across each other). Second, articular cartilage transmits load from 1 bone to the next within the joint, minimizing the concentration of force (i.e., stress), thereby preventing damage to the underlying bone. OA interferes with the ability of the cartilage to serve these functions. In OA, the collagen network of the cartilage, whose macromolecular organization serves to constrain the highly hydrophilic proteoglycans (PGs) within the extracellular matrix, is damaged (1). Damage to the fibrillar network may, in fact, be the earliest change in OA; evidence strongly suggests that it is irreversible. Effects of Joint Disuse In contrast to OA, the changes in articular cartilage that result from disuse unless immobilization is prolonged are reversible (2). The remainder of this article focuses on the consequences of immobilization on joint structures. Most of the information presented relates to the effects of inactivity on articular cartilage and periarticular muscle, areas with which the author and his colleagues have had extensive research experience. Effects on cartilage. Studies of the effects of immobilization of the hind limb of normal adult dogs have been instructive: immobilization in an orthopedic cast, with about 90 flexion of the hip and 90 flexion of the knee to prevent weight bearing, results in striking changes in the articular cartilage. Within only a matter of weeks, the thickness of the cartilage may be reduced by as much as 50%; the concentration and content of PGs (which provide the tissue with compressive stiffness) may be reduced by as much as 50%; and the normal constitutive level of PG synthesis, which maintains the PG concentration of nor- 267

2 268 Brandt mal articular cartilage throughout the lifetime of the animal, is strikingly reduced (2). The importance of abnormal joint loading in the development of OA and of the effects of reducing or eliminating the abnormal loading are illustrated by studies of the effects of immobilization of the knee in an experimental model of OA the canine anterior cruciate ligament (ACL) deficiency model (1). Dogs that were permitted free ambulation in a pen for 12 weeks after transection of the ACL developed osteophytes, fibrillation of the articular cartilage, a decrease in PG concentration, and an increase in the net rate of PG synthesis (reflecting the phenomenon of hypertrophic repair) in the unstable knee (3). Furthermore, the proportion of total cartilage PGs present in the culture medium after incubation of slices of articular cartilage from the unstable knee was twice as great at that seen in cultures of normal canine articular cartilage. In contrast, osteophytes, which are normally prominent after cruciate ligament transection, did not develop when the limb was immobilized immediately after ACL transection, and the articular surface did not develop fibrillation, but remained intact. On the other hand, articular cartilage from the immobilized limb exhibited striking atrophic changes: its PG content was diminished, in association with a decrease in the rate of net PG synthesis to a level only about 60% of that seen in normal cartilage. Cartilage from knees that had been immobilized after ACL transection, therefore, resembled that from dogs with an intact ACL whose knee had been immobilized, i.e., immobilization prevented the development of OA (4). Although protracted immobilization of a joint leads eventually to fibro-fatty ankylosis with obliteration of the joint space, if the animal is permitted to ambulate on all fours after removal of the cast after a shorter period of immobilization, rapid and complete reversal of all of the above changes occurs. Within only a few weeks, the cartilage thickness, histologic changes, PG concentration, extractability of PGs from the matrix (an indication of matrix integrity), and cartilage biomechanics all return to normal (1). It is widely considered that articular cartilage can not heal. The above experiments, however, demonstrate not only healing but complete restitution of the changes induced by immobilization. It is likely that this reversal occurs because immobilization, although it strikingly depletes the cartilage matrix of PGs, does not irreversibly damage the collagen network (as occurs in OA). Therefore, the new PGs that are synthesized in abundance after the cast is removed and loading of the joint is resumed, remain constrained within the extracellular matrix and, therefore, restore the biomechanical integrity of the cartilage. If the dog is not permitted to reload the limb normally after removal of the cast (and induction of cartilage atrophy), but an attempt is made to accelerate the rehabilitation process by imposing a regimen of running on a treadmill, newly synthesized PGs are not effectively deposited within the matrix and the cartilage defects persist indefinitely (although a marked increase in the net rate of PG synthesis occurs immediately upon reloading of the limb) (5). Indeed, the newly synthesized PGs may be recovered in large quantities from the synovial fluid of the remobilized joint. Furthermore, followup studies over intervals as long as 18 months strongly suggest that the failure to reconstitute the extracellular matrix under these conditions is permanent. It should be emphasized that the irreversible damage to the articular cartilage that occurs under such circumstances may be induced by a loading regimen that, for a normal joint, would be relatively trivial treadmill running for as little as 30 minutes per day, 5 days per week, at only 4 miles per hour. These loading forces, which are so mild that they produce no discernible changes in the morphology, biochemistry, or metabolism of normal canine articular cartilage, are sufficient to produce the long-lasting chondropathy described above. These results raise the possibility that some patients who are considered clinically to have posttraumatic OA may, in fact, have postrehabilitation OA as a consequence of excessively enthusiastic efforts to reimpose loading on atrophic articular cartilage before the PGs in the extracellular matrix have been replenished sufficiently to protect the chondrocytes from mechanical damage. Role of periarticular muscles. Other studies have shed light on the importance of the periarticular musculature in maintaining the integrity of normal articular cartilage. In the canine immobilization model described above and also in humans who are placed in an orthopedic cast not only the articular cartilage, but the subchondral bone and periarticular muscles undergo rapid, and often profound disuse atrophy. In adult dogs in whom the hip and knee joints were normal but in whom weight bearing by 1 hind limb was eliminated as a result of amputation of the ipsilateral paw, changes developed in the articular cartilage and subchondral bone of the ipsilateral knee that were qualitatively, quantitatively, and temporally identical to those that occur after immobilization of the intact hind limb in an orthopedic cast (6). In this model, the range of motion of the ipsilateral knee has been shown to be nearly normal, strongly suggesting that joint movement alone is insufficient to maintain the integrity of the cartilage, but that the contraction of the periarticular muscles (hamstrings, quadriceps) that normally occurs with the stance phase of gait is required. That conclusion is reinforced by the observation that the atrophy of articular cartilage and subchondral bone produced in the knees of rabbits by immobilization in a cast was prevented by electrical stimulation of the quadriceps with an electrode inserted into the muscle through the cast (7). Consistent with the above conclusion, in vitro studies have shown that static compressive loading results in a reversible reduction in the level of PG synthesis in normal human articular cartilage, whereas cyclic loads of reasonable magnitude (as would occur physiologically with muscle contraction, e.g., with walking) have been shown by several investigators to stimulate PG synthesis by the chondrocytes (8). It is well recognized that periarticular muscle atrophy is a feature of OA. Physical examination of the patient with knee OA often reveals quadriceps atrophy. The loss of muscle bulk is generally attributed to disuse, consequent

3 Loading and Unloading of Joints 269 to unloading of the extremity because of the joint pain that results from weight bearing. There is no reason to question that paradigm. However, it has recently become apparent that another cause of quadriceps atrophy may exist in subjects with knee OA. In one study, community-dwelling elderly individuals from central Indiana were identified who exhibited quadriceps weakness (as documented by isokinetic dynamometry) in association with radiographic changes of knee OA, in the absence of a history of joint pain. These subjects were not taking NSAIDs nor did they perceive a need to seek care from a health professional for their knee arthritis (although they did so for other reasons). Indeed, they felt that physically they were doing as well as, or better than, their peers. Notably, despite their quadriceps weakness, they did not exhibit quadriceps atrophy, as defined by dual-energy x-ray absorptiometry measurements of lower extremity lean tissue mass. Indeed, because of their obesity, muscle mass in the thigh was greater in these subjects with asymptomatic OA than in age- and sex-matched controls (9). Among subjects in the same study with no radiographic evidence of OA in the baseline examination, those with the most marked quadriceps weakness were those who were most likely to develop incident radiographic OA on followup examination 3 years later. These data suggest that quadriceps weakness is not only a consequence of OA but, in some individuals, may precede and represent a risk factor for knee OA. When the presence of radiographic knee OA (with or without knee pain) was modeled as a function of sex, body weight, age, and lower-extremity strength, each 10 poundfoot increase in quadriceps strength was associated with a 20% reduction in the risk of radiographic OA and a 29% reduction in the odds of symptomatic knee OA. A relatively small increase in quadriceps strength (20% of the mean value for men, 25% of the mean value for women) was predicted by the authors to result in a 20 30% decrease in the odds of having knee OA (9). A number of studies point to the importance of the quadriceps muscle as a stabilizer of the knee joint. Subjects without knee OA in whom the quadriceps was exercised to the point of fatigue were shown to temporarily exhibit anteroposterior knee laxity, until quadriceps strength was restored. Similarly, anteroposterior laxity of the knee in individuals without knee OA is greater when the quadriceps is relaxed than when it is contracted (10). Quadriceps weakness alters the mechanical loading of the articular cartilage. Furthermore, by decelerating the leg in the swing phase of gait prior to heelstrike, quadriceps contraction plays a major role in resisting the force of gravity on the lower extremity. Experimental paralysis of the quadriceps in normal subjects may produce a sharp heelstrike transient, with a several-fold increase in the forces acting at the knee milliseconds after heelstrike (11). Rabbits that were subjected to repeated acute impact loading of the knee rapidly developed damage of articular cartilage and subchondral bone (12); however, impulsive loads of even greater magnitude, if applied gradually, produced no damage (Radin E, personal communication). When a joint is loaded very rapidly, insufficient time exists for the periarticular muscles (such as the quadriceps) to absorb the load through eccentric contraction (13,14). Effects of medications. A large number of in vitro studies, conducted with chondrocyte cultures or organ slices, have shown that some, but not all, NSAIDs may affect cartilage matrix synthesis (15). These effects have been observed with concentrations of the drug in the culture medium that approximate those attained in serum or synovial fluid of patients who are treated with the drug, although variables such as protein binding and clearance from the joint space are not adequately taken into account in such studies. Based on effects on chondrocyte metabolism observed under such experimental conditions, results have led some investigators to classify NSAIDs as chondrodestructive, neutral, or chondroprotective. It should be emphasized, however, that a paucity of supporting evidence exists from in vivo studies in animal models of OA because the animal species commonly used in models of OA (e.g., dog, mouse, guinea pig, rabbit) are exquisitely sensitive to the gastrointestinal adverse effects of cyclooxygenase (COX) inhibition and commonly develop gastric ulceration and die before the pathologic changes of OA become established. Because of the variable effects of the drug on synovial inflammation (which may contribute to damage in the OA joint), clearance of the drug from joint tissues, and the possibility that the analgesia produced by the drug may accelerate joint damage (analgesic arthropathy), it is not possible to predict the consequences of systemic administration of an NSAID in vivo on the basis of in vitro data. Notably, the recent development of NSAIDs that are highly selective inhibitors of COX-2 and do not inhibit COX-1 in therapeutic doses, thereby affording greater gastrointestinal tract safety than nonselective NSAIDs, now provides an opportunity to examine the possibility that such agents may modify pathologic changes in the OA joint. Nonetheless, it should be noted that studies in animal models of OA have shown that administration of aspirin in doses sufficient to achieve a serum salicylate concentration of mg/dl results in acceleration and exacerbation of the pathologic changes of OA (16). In support of the in vivo findings, in vitro studies have shown marked suppression of PG synthesis in normal and OA cartilage exposed to reasonable concentrations of salicylate (17,18). When aspirin was administered orally to dogs for 6 weeks while 1 hind limb was immobilized in a cast, the decreases in uronic acid content and in the net rate of PG synthesis in articular cartilage from the immobilized knee were significantly greater than those in cartilage from immobilized knees of dogs that had not received aspirin (19). Notably, the serum salicylate concentrations achieved in those studies are seen commonly in humans treated with antiinflammatory doses of aspirin. Although the above-mentioned study indicated that aspirin therapy could have an adverse effect in vivo on cartilage of an immobilized joint, continued aspirin administration after removal of the cast (i.e., during the striking increase in PG synthesis by the chondrocyte that oc-

4 270 Brandt curs immediately following restoration of joint loading) did not preclude the reversal of cartilage atrophy if the dog was then allowed to ambulate freely. However, if the dog was subjected to treadmill running after cast removal (when the chondrocytes are particularly vulnerable to the increase in loading because the cushioning extracellular matrix in which they are embedded has been depleted of PGs) the reduction in uronic acid content of cartilage from the immobilized knee persisted and was significantly more severe if the animal had received aspirin than if it had not (19). Benefits of Immobilization Despite the adverse effects on joint tissues that occur as a consequence of immobilization, immobilization may also have its advantages: for example, it may protect against some types of chemically induced damage to articular cartilage. The extent of chondrocyte death after intraarticular injection of the metabolic poison sodium iodoacetate was significantly reduced if guinea pigs were immobilized immediately after the injection. Neither osteophytes nor fibrillation of the articular cartilage developed in any of the animals that were constrained in this manner (20). Hence, unloading the joint during a period of severe damage to the chondrocytes may be chondroprotective. If the insult to the cartilage is reversible, such temporary unloading may permit recovery of the damaged chondrocytes and facilitate subsequent repair of the tissue. Future Directions High interest exists today within the pharmaceutical industry and in regulatory agencies in the development of drugs whose principal effect is aimed not at symptomatic relief, but at alteration of the fundamental pathogenetic processes within the OA joint (chiefly in the articular cartilage but, to a lesser extent, in the underlying bone). In animal models, a number of agents have been shown to prevent the development of OA when administered prophylactically or to slow the progression of joint damage when administered therapeutically. No drug, however, has yet been convincingly shown to have such effect in humans. Based on the above observations, it would seem important to take into account the level of periarticular muscle strength in assessing the therapeutic benefit of putative disease-modifying OA drugs (DMOADs) in a clinical trial. Given the results of the studies described above, it is possible that DMOAD effects of a drug could be overwhelmed by an unfavorable mechanical environment and, conversely, that a physical therapy regimen that improved muscle strength could enhance the therapeutic effect of a DMOAD. In patients with OA, short-term clinical trials have shown improvement in knee pain and function after exercise interventions aimed at increasing leg strength (21 23). Although some studies have shown that the symptomatic benefit is lost rapidly after cessation of training, other studies have shown that the benefits of such programs can be long lasting. Whether exercises to strengthen the periarticular muscles can prevent the development of knee OA or the progression of pathologic changes in joints in which OA is already established, or can decrease the risk for joint pain or disability, is currently under evaluation in a randomized, placebo-controlled trial. The results of the studies discussed above, and other studies, suggest several important research questions. What is the most effective and efficient way to remobilize a joint after a period of unloading sufficient to induce atrophy of joint structures? Will electrical stimulation of muscle during the period of immobilization prevent the atrophic changes in joints of humans? What are the quantitative considerations, with respect to magnitude and frequency of loading, needed to reverse the atrophy of joint structures after immobilization, i.e., what is the dose-response curve? Evidence shows that depletion of cartilage matrix proteoglycans by immobilization increases the susceptibility of chondrocytes to the effects of some NSAIDs. What effect do selective COX-2 inhibitors, which have become the NSAID of choice for many physicians treating OA pain, have on the metabolism of chondrocytes in cartilage whose extracellular matrix has been depleted as a result of immobilization? Does exercise have a role in the primary prevention of radiographic or symptomatic OA? In joints in which structural changes of OA are already present, can strengthening the periarticular muscles slow the progression of cartilage damage? If so, will this be of clinical benefit? REFERENCES 1. Mow VC, Hung CT. Mechanical properties of normal and osteoarthritic articular cartilage, and the mechnaobiology of chondrocytes. In: Brandt KD, Doherty M, Lohmander SL, editors. Osteoarthritis, 2nd ed. Oxford: Oxford University Press; In press. 2. Palmoski MJ, Brandt KD. Development and reversal of the proteoglycan aggregation defect in normal canine knee cartilage after immobilization. Arthritis Rheum 1979;22: Adams ME, Brandt KD. Hypertrophic repair of canine articular cartilage in osteoarthritis after anterior cruciate ligament transection. J Rheumatol 1991;18: Palmoski MJ, Brandt KD. Immobilization of the knee prevents osteoarthritis after anterior cruciate ligament transection. Arthritis Rheum 1982;25: Palmoski MJ, Brandt KD. Running inhibits the reversal of atrophic changes in canine knee cartilage after removal of a leg cast. Arthritis Rheum 1981;24: Palmoski MJ, Colyer RA, Brandt KD. Joint motion in the absence of normal loading does not maintain normal articular cartilage. 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