Effects of Corticosteroids on Articular Cartilage

A Review of the Literature

ANDREW L. MCDONOUGH

Physical therapists evaluate and treat patients who simultaneously may be receiving corticosteroid compounds to reduce inflammation and pain associated with certain diseases such as rheumatoid arthritis and osteoarthritis. Both beneficial and deleterious effects of corticosteroids on articular cartilage have been reported. Physical therapists and others treating joints with pathological conditions should understand these effects and use this knowledge to establish and modify therapeutic management programs for patients with joint dysfunction. A review of the literature is presented. Key Words: Arthritis, Cortisone, Articular cartilage.

Physical therapists evaluate and treat patients who simultaneously may be receiving systemic or intraarticular corticosteroids (Figure). These compounds are frequently prescribed to reduce inflammation and pain associated with some diseases affecting the musculoskeletal system (eg, rheumatoid arthritis and osteoarthritis). Temporary and permanent changes in soft tissue, bone, and cartilaginous structures have been reported to occur when corticosteroids are administered. Beneficial and deleterious changes occurring in articular cartilage interest clinicians and researchers because the status of this tissue can be used to predict the extent to which a joint will function normally. Because corticosteroids have been shown to have a significant effect on the structural and physiological status of articular cartilage, physical therapists and others treating joints with pathological conditions should understand these effects and use this knowledge to establish and modify therapeutic
Mr. McDonough is Clinical Assistant Professor, Department of Physical Therapy, New York University, 433 First Ave, New York, NY 10010 (USA). This article was submitted May 1, 1980, and accepted September 24,1981.

management programs for patients with joint dysfunction. Following is a review of the literature concerning the effects of certain corticosteroid (cortisone derived) compounds on articular cartilage (Figure). ANTI-INFLAMMATORY ACTION In September 1948, Hench et al clinically studied 23 patients with severe rheumatoid arthritis.1 Compound E, later renamed cortisone or E acetate, was injected intramuscularly. Adrenocorticotropic hormone (ACTH) was also given to some patients. All patients in the study reported some relief of pain in the affected joints, and the investigators noted some objective improvement, including decreased edema and warmth. Withdrawal of cortisone treatment led to return of symptoms in some patients. Other patients experienced delayed relapses, while still other patients experienced partial or complete remission of symptoms for finite periods. Certain side effects were noted after the injections, including alteration in metabolic function and mental status. These findings, which suggest depression of corticoadrenal function, have also been described by others.2 Boland and

Cortisone Cortisone acetate Hydrocortisone Hydrocortisone acetate

Prednisone Prednisolone Prednisolone acetate Triamcinolone

Figure. Commonly prescribed corticosteroid compounds. Volume 62 / Number 6, June 1982 835

Headley, in 1949, reported similar results using cor tisone treatments in four of five patients with severe rheumatoid arthritis.3 Thorn, in 1951, was apparently the first to inject hydrocortisone into a knee joint of a patient with rheumatoid arthritis.4 Prompt local decrease of in flammation was noted. Hollander et al compared the intra-articular effects of cortisone acetate and hydro cortisone acetate in the knee joint; anti-inflammatory effects were noted only with the latter substance5. A total of 700 injections of hydrocortisone in 129 pa tients produced relief of symptoms without unfavor able effects. Similar findings were reported by Zacco et al with relief of symptoms occurring six to eight hours after intra-articular injection of the knee joints and lasting from four days to one month.6 RADIOGRAPHIC EVIDENCE OF DEGENERATION Serious adverse side effects, including structural and physiological alteration of articular cartilage, have been reported to accompany corticosteroid treat ments. In 1958, Chandler and Wright reported radio graphic changes including deterioration of articular cartilage in the knee joints of more than half the patients treated with intra-articular hydrocortisone acetate and hydrocortisone tertiary butylacetate for 48 weeks.7 Reduction in inflammation and pain as sociated with rheumatoid disease apparently enabled patients to engage in activities that led to further damage to articular structures. This suggests that hydrocortisone suppresses local protective mecha nisms (eg, pain). One year later, a similar conclusion was drawn by Chandler et al after they evaluated an apparent avascular arthropathy of the hip joint of a patient who underwent a 12-month regimen of hy drocortisone acetate therapy.8 A total of 900 mg was injected. Other investigators have reported similar findings.9-13 VASCULAR CHANGES The mechanism involved in the sometimes rapid destruction of cartilage after intra-articular cortisone is administered is not well understood. One explana tion is that cortisone and ACTH therapy leads to hypercoaguability of vessels producing thromboem bolic episodes thereby causing a disruption of blood supply to the femoral and humeral heads.13 A second explanation is that the vasculitis induced by steroids causes cartilage destruction.13 Murray believes artic ular disintegration is caused by avascular necrosis, especially in the hip.10 Because steroids are suspected of depressing the pain-warning system, joints are subjected to stresses that would not normally be tolerated given the status of degeneration. Accord

ingly, Steinberg et al recommended limiting the use of intra-articular steroids to three or four injections over a few weeks, followed by conservative manage ment to control potential degenerative joint changes.12 Severe degenerative arthritis, however, also has been reported in patients with no history of steroid ther apy.10 Based on routine follow-up of 100 patients' records over a seven-year period, Hollander and as sociates reported a less than 1 percent incidence of accelerated destruction.14 BIOCHEMICAL, PHYSIOLOGICAL, AND ULTRASTRUCTURAL CHANGES Deleterious effects of cortisone acetate were re ported by Layton who noted that high doses inhibited the synthesis of chondroitin sulfate in the skin of intact rats.15 Using radiosulfate uptake as a measure of chondroitin sulfate synthesis in xiphoid cartilage, Clark and Umbreit reported similar findings in vi tro.16 Synthesis increased, however, when hydrocor tisone and its acetate salt were administered to normal adult male rats. Thomas reported similar findings in 1964.17 Intramuscular injection of cortisone in rabbits de layed the recovery of papain-treated ear cartilage, causing the ears to remain collapsed.18 In this study, cortisone was found to inhibit and delay synthesis and deposition of chondroitin sulfate, an important matrix constituent that imparts major morphological and functional characteristics to hyaline cartilage. Thomas et al showed that pretreatment of rabbits with prednisolone completely blocked the lytic effects of hypervitaminosis A,19 whose action is indistin guishable from that of papain.20 These findings indi cate that cortisone (and its derivatives) has the effect of stabilizing lysosomes to prevent cartilage break down.21-23 Whitehouse's 1961 study on the somites of threeday-old chick embryos treated in vitro with cortisone and hydrocortisone showed depression of cartilage growth and reduced radiosulfate uptake into chon droitin sulfate; DNA content was not inhibited.24 This shows that cortisone's primary effect is to inhibit sulfation rather than simply inhibiting cell reproduc tion or reducing cell vitality. In a similar study, Lash and Whitehouse made similar observations.25 Struc tural analogues were also tested. Prednisone and prednisolone severely depressed radiosulfate uptake while 6 -methylprednisolone did not. In 1972, Mankin et al arrived at essentially the same conclusion after treating rabbits with daily intramuscular injec tions of cortisone acetate for up to nine weeks.26 Similar findings were also reported by Shaw and Lacey using daily intra-articular or intramuscular methylprednisolone.27 In the same experiment, rab bits given papain to induce arthritis showed no signs of repair when pretreated with corticosteroids. PHYSICAL THERAPY

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PRACTICE Collin's and Aniline's 1959 investigation of costal cartilage of hypophysectomized rats treated with hydrocortisone snowed inhibition of sulfate fixation.28 The same investigation by Denko and Bergenstal performed two years later produced similar findings.29 An inhibition of the stimulatory effect of growth hormone and weight loss were additionally reported in the latter study. Using tritiated glycine (glycine 3H) as an indicator of amino acid incorporation in protein synthesis in cartilage matrices, Mankin and Conger injected hydrocortisone acetate in rabbit knees.30 Their data showed a rapid and profound decrease in glycine incorporation that appeared to depend on dosage. With smaller doses, recovery occurred within three days while with larger doses, recovery took about two weeks. Maximum decline occurred about six hours after injection. A similar experiment, using glycine 14 C, as the amino acid indicator, showed a definite decrease in the rate of protein synthesis within two hours.31 The rate of the effect of intra-articular injection on synthesis was about twice that of the observed rate for corticosteroids given by intramuscular route. Others have reported changes in the ultrastructure of cartilage matrix within four hours of subcutaneous injection of cortisone acetate in three-week-old mice.32 Changes included alteration of the rough endoplasmic reticulum and the Golgi apparatus, which appears consistent with inhibition of the synthesis of protein polysaccharides. Changes in membrane permeability may explain this occurrence. Behrens et al made the same observations in similar experiments in 1975.33 BIOMECHANICAL AND HISTOLOGICAL CHANGES In 1969, Kopta and Blosser investigated the effects of intra-articular methylprednisolone acetate on the knee joints of adult rabbits that had undergone arthrotomy and meniscectomy.34 After surgery, the knee joints were injected monthly for six months. (Mechanical and histological analyses of the articular cartilage were performed at the end of the experiment.) Findings showed that the elasticity of the tibial articular cartilage was markedly reduced. Microscopic degenerative changes were progressively more evident including loss of protein polysaccharide in the matrix; decreased number of chondrocytes; multiple Assuring of the matrix; clumping of collagen stain; and finally, by the sixth month, appearance of large cysts containing amorphous debris and degenerated chondrocytes and mucoprotein. These findings indicated a breakdown in protein synthesis. Systemic effects included nystagmus, vertigo, and marked adrenal atrophy. More recently, investigators (Roach et al35 and Lutfi and Kosel36) reported the same findings when comparing the effects of corticosteroids and salicylates on the articular cartilage of rabbits. DISCUSSION Since Thorn, in 1951, first injected hydrocortisone into the knee joint of a patient with rheumatoid arthritis, the anti-inflammatory effects of intra-articular corticosteroid compounds have been established.4 Corticosteroids have not only offered relief but partial or complete remission of symptoms associated with this and other conditions. Because their action is prompt and effective in reducing inflammation, clinical use of steroids has been well established. This treatment, however, has serious side effects including altered metabolic and mental status,1 weight loss,29 gross radiographic abnormalities,7-13 loss of elasticity of articular cartilage,34 biochemical alterations,15,18-33 degeneration of tissue, microscopic34 and ultrastructural changes of chondrocytes and matrix.33 Because of these sometimes serious side effects, clinicians attempt to balance the treatment program of patients suffering from joint dysfunction and other related problems by using judiciously administered chemical treatments combined with physical therapeutic treatments including exercise and manipulation. At times, medications and exercise are used concurrently to maintain joint flexibility, soft tissue continuity, and strength and to preserve function. Exercise has been shown to affect articular cartilage positively by maintaining its structure and physiologic status.37-39 Conversely, the lack of exercise (eg, immobilization) secondary to acute inflammation and pain or the use of therapeutic immobilization devices (eg, casts, splints, and braces) has demonstrated essentially negative effects. Changes produced by immobilization include the degeneration and eventual death of chondrocytes and reduced production of matrix components when immobilization is sufficiently prolonged.40-42 Abundant information appears in the literature on the effects of corticosteroids1-14,17,22,24-27,30-36 and exercise 37-39 used separately. Little investigation has been reported on the inter-relationship between these two treatments. Few investigators have studied the effects of different types of exercise on articular structures. Clinicians, such as physical therapists, recognize the importance of choosing appropriate exercises (eg, active, passive, or resistive) to promote recovery from illness, but the effects of specific exercises on hyaline cartilage that is simultaneously treated with corticosteroids have received little study; the advisability of exercising while receiving intra-articular steroids has not yet been clearly established in clinical or laboratory studies. One situation that requires study is that of the athlete who is given corticosteroids for an acute or chronic injury to reduce inflammation.

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Athletes receive intra-articular injections and return to full intensity participation within days or even hours of injection. One possible outcome is that the deleterious effects of corticosteroids on articular cartilage may be exacerbated by exercise or manipulation. Moreover, responses to exercises may differ when the exercises are performed in weight-bearing positions as compared to nonweight-bearing positions. (In the former, joint compression forces produced by muscular contraction may be augmented by ground reaction forces, while in the latter, ground reaction forces are not a factor.) Increases in both the intra-articular forces and the diffusion pressure in the cartilage matrix may drive steroid-laden synovial fluid in an accelerated fashion, which would hasten the negative effects of steroids. Conversely, joint motion may have an ameliorating effect on intrasynovial steroid concentrations by permitting the compound to be flushed from the joint capsule into general circulation before deleterious effects on chondrocytes and other matrix components occur. In the absence of clear evidence to demonstrate either theory is correct, physical therapists and others treating joint dysfunction should question their patients concerning

past and present use of corticosteroids and closely monitor the effects of adjunctive procedures, such as exercise or manipulation, until sufficient data is available. SUMMARY A review of the literature has been presented concerning the effects of corticosteroid compounds on articular cartilage. Substantial evidence demonstrates that significant adverse histostructural, histochemical, and ultrastructural changes occur in articular cartilage leading to a decrease in synthesis of matrix components, disorganization of various strata, and impairment or loss of function. Because corticosteroid therapy is often a component of a total therapeutic management program that may also include various forms of exercise or manipulative procedures, the potential relationship between these treatments was discussed. Data on this relationship are currently unavailable; therefore, physical therapists should be aware of the effects of corticosteroids on articular cartilage and closely monitor patient performance so that treatment programs may be modified as required.

REFERENCES
1. Hench PS, Kendall EL, Slocumb CH, et al: Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med 85:545-666, 1950 2. Sprague RG, Power MH, Mason HL, et al: Observations on the physiologic effects of cortisone and ACTH in man. Arch Intern Med 85:199-258, 1950 3. Boland EN, Headley NE: Effects of cortisone acetate on rheumatoid arthritis. JAMA 141:301, 1949 4. Thorn, quoted by Hollander JL, Jessar RA, Brown CY: Hydrocortisone injected into arthritic joints. JAMA 147:16291635, 1951 5. Hollander JL, Jessar RA, Brown CY: Hydrocortisone injected into arthritic joints. JAMA 147:1629-1635, 1951 6. Zacco M, Richardson EM, Crittendon JO, et al: Disposition of intra-articularly injected hydrocortisone acetate, hydrocortisone and cortisone acetate in arthritis: 1. Concentration in synovial fluid and cells. J Clin Endocrinol Metab 1 4 : 7 1 1 718, 1954 7. Chandler GN, Wright V: Deleterious effects of intra-articular hydrocortisone. Lancet 2:661-663, 1958 8. Chandler GN, James DT, Wright V, et al: Charcot's arthropathy following intra-articular hydrocortisone. Br Med J 1:952-953, 1959 9. Sweetnam DR, Mason RM, Murray RO: Steroid arthropathy of the hip. Br Med J 1:1392-1394, 1960 10. Murray RO: Steroids and the skeleton. Radiology 77:729743, 1961 11. Alarcon-Segovia D, Ward LE: Charcot-like arthropathy in rheumatoid arthritis. JAMA 193:1052-1054, 1965 12. Steinberg CL, Duthrie RB, Piva AE: Charcot-like arthropathy following intra-articular hydrocortisone. JAMA 181:851852, 1962 13. Miller RT, Restifo RA: Steroid arthropathy. Radiology 86:652-657, 1966 14. Hollander JL, Jessar RA, Brown EM: Intrasynovial corticosteroid therapy: A decade of use. Bull Rheum Dis 11:239240, 1961 15. Layton L: Cortisone inhibition of mucopolysaccharide synthesis in the intact rat. Arch Biochem Biophys 32:224-225, 1951 16. Clark IC, Umbreit NW: Effect of cortisone and other steroids upon in vitro synthesis of chondroitin sulfate. Proc Soc Exp Biol Med 86:558-651, 1954 17. Thomas L: The effects of papain, vitamin A, and cortisone on cartilage matrix in vivo. Biophys J 4(suppl):207-213, 1964 18. Thomas L: Reversible collapse of rabbit ears after intravenous papain, and prevention of recovery by cortisone. J Exp Med 104:245-252, 1956 19. Thomas L, McClusky RT, Weissman G: Prevention by cortisone of the changes in cartilage induced by an excess of vitamin A in rabbits. Am J Pathol 42:271-279, 1963 20. Fell HB, Thomas L: Comparison of the effects of papain and vitamin A on cartilage. J Exp Med 111:719-743, 1960 21. Houck JC, Patel YM: Proposed mode of action of corticosteroids on the connective tissue. Nature (London) 206:158160, 1965 22. Lack CH: Increased vascular permeability, chondrolysis and cortisone. Proceedings of the Royal Society of Medicine 55:113-116, 1962 23. Katz WA: Rheumatoid Disease Diagnosis and Management, Philadelphia, PA, J.B. Lippincott Co, 1977, pp 8 8 2 - 8 8 3 24. Whitehouse MW: Effect of cortisone and related compounds on biogenesis of cartilage. Nature (London) 189:37-39, 1961 25. Lash JW, Whitehouse MW: Effects of steroid hormones and some anti-inflammatory agents upon in vitro chondrogenesis. Lab Invest 10:388-396, 1961 26. Mankin HJ, Zarins A, Jaffee WJ: The effect of systemic corticosteroids on rabbit articular cartilage. Arthritis Rheum 15:593-599, 1972 27. Shaw NE, Lacey E: The influence of corticosteroids on normal and papain-treated articular cartilage in the rabbit. J Bone Joint Surg [Am] 55:197-205, 1973

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28. Collins EJ, Aniline J: The response of costal cartilage to changes in hormonal environment. Experientia 15:116-117, 1959 29. Denko CW, Bergenstal DM: Effects of growth hormone and corticosteroids on S 35 fixation in cartilage. Endocrinology 69:769-777, 1961 30. Mankin HJ, Conger KA: The acute effects of intra-articular hydrocortisone on articular cartilage in rabbits. J Bone Joint Surg [Am] 48:1383-1388, 1966 31. Mankin HJ, Conger KA: The effect of Cortisol on articular cartilage of rabbits: 1. Effect of a single dose of Cortisol on glycine-C14 incorporation. Lab Invest 15:794-800, 1966 32. Silberberg M, Silberberg R, Hasler M: Fine structure of articular cartilage in mice receiving cortisone acetate. Arch Pathol and Laboratory Medicine 82:559-582, 1966 33. Behrens F, Shepard N, Mitchell N: Alteration of rabbit cartilage by intra-articular injections of glucocorticoids. J Bone Joint Surg [Am]57:70-75, 1975 34. Kopta JA, Blosser JA: Elasticity of articular cartilage: Effects of intra-articular steroid administration and medical meniscectomy. Clin Orthop 64:21-32, 1969 35. Roach JE, Tomblin W, Eyring EJ: Comparison of the effects of steroid, aspirin and sodium salicylate on articular cartilage. Clin Orthop 106:350-356, 1975 36. Lutfi AM, Kosel K: Effect of intra-articularly administered corticosteroids and salicylates on the surface of articular cartilage. J Anat 1 2 7 : 3 9 3 - 4 0 2 , 1 9 7 8 37. Saaf J: Effect of exercise on articular cartilage. Acta Orthop Scand 20 (suppl 7):1-83, 1950 38. Lanier RR: The effects of exercise on the knee joints of inbred mice. Anat Rec 94:311 - 3 1 9 , 1946 39. Ekholm R, Norbck B: On the relationship between articular changes and function. Acta Orthop Scand 21:81 - 9 8 , 1951 40. Hall MC: Cartilage changes after experimental immobilization of the knee joint of the young rat. J Bone Joint Surg [Am] 45:35-44, 1963 41. Sood SC: A study of the effects of experimental immobilization on rabbit articular cartilage. J Anat 108:497-507, 1971 42. Enneking WF, Horowitz M: The intra-articular effects of immobilization on the human knee. J Bone Joint Surg [Am] 54:973-985, 1972

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