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Effects of Corticosteroids on Articular CartilageA R e v i e w o f t h e L i te r a tu r eA N D R E W L. MCDONOUGH

Physical therapists evaluate and treat patients who simultaneously may bereceiving corticosteroid compounds to reduce inflammation and pain associatedwith certain diseases such as rheumatoid arthritis and osteoarthritis. Bothbeneficial and deleterious effects of corticosteroids on articular cartilage havebeen reported. Physical therapists and others treating joints with pathologicalconditions should understand these effects and use this knowledge to establishand modify therapeutic management programs for patients with joint dysfunc-tion. A review of the literature is presented.

Key Words: Arthritis, Cortisone, Articular cartilage.

Physical therapists evaluate and treat patients whosimultaneously may be receiving systemic or intra-articular corticosteroids (Figure). These compoundsare frequently prescribed to reduce inflammation andpain associated with some diseases affecting the mus-culoskeletal system (eg, rheumatoid arthritis and os-teoarthritis). Temporary and permanent changes insoft tissue, bone, and cartilaginous structures havebeen reported to occur when corticosteroids are ad-ministered. Beneficial and deleterious changes occur-ring in articular cartilage interest clinicians and re-searchers because the status of this tissue can be usedto predict the extent to which a joint will functionnormally. Because corticosteroids have been shownto have a significant effect on the structural andphysiological status of articular cartilage, physicaltherapists and others treating joints with pathologicalconditions should understand these effects and usethis knowledge to establish and modify therapeutic

management programs for patients with joint dys-function. Following is a review of the literature con-cerning the effects of certain corticosteroid (cortisonederived) compounds onarticular cartilage (Figure).ANTI-INFLAMMATORY ACTION

In September 1948, Hench et al clinically studied23 patients with severe rheumatoid arthritis.1 Com-pound E, later renamed cortisone or E acetate, wasinjected intramuscularly. Adrenocorticotropic hor-mone (ACTH) was also given to some patients. Allpatients in the study reported some relief of pain inthe affected joints, and the investigators noted someobjective improvement, including decreased edemaand warmth. Withdrawal of cortisone treatment ledto return of symptoms in some patients. Other pa-tients experienced delayed relapses, while still otherpatients experienced partial or complete remission ofsymptoms for finite periods. Certain side effects werenoted after the injections, including alteration in met-abolic function and mental status. These findings,which suggest depression of corticoadrenal function,have also been described by others.2 Boland and

CortisoneCortisone acetateHydrocortisoneHydrocortisone acetate

PrednisonePrednisolonePrednisolone acetateTriamcinolone

Figure. Commonly prescribed corticosteroid compounds.

M r. McDonough is Clinical Assistant Professor, Department ofPhysical Therapy, New York University, 433 First Ave, New York,NY 10010 (USA).This article was submitted May 1, 1980, andaccepted September24,1981.

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Headley, in 1949, reported similar results using cortisone treatments in four of five patients with severerheumatoid arthritis.3Thorn, in 1951, was apparently the first to injecthydrocortisone into a knee joint of a patient withrheumatoid arthritis.4 Prompt local decrease of inflammation wa s noted. Hollander et al compared theintra-articular effects of cortisone acetate and hydro

cortisone acetate in the knee joint; anti-inflammatoryeffects were noted only with the latter substance 5. Atotal of 700 injections of hydrocortisone in 129 patients produced relief of symptoms without unfavorable effects. Similar findings were reported by Zaccoet al with relief of symptoms occurring six to eighthours after intra-articular injection of the knee joint sand lasting from four days to one m onth.6

RADIOGRAPHIC EVIDENCE OFDEGENERATION

Serious adverse side effects, including structuraland physiological alteration of articular cartilage,hav e been reported to accom pany co rticosteroid treatments. In 1958, Chandler and Wright reported radiographic changes including deterioration of articularcartilage in the knee joints of more than half thepatients treated with intra-articular hydrocortisoneacetate and hydrocortisone tertiary butylacetate for48 weeks.7 Reduction in inflammation and pain associated with rheumatoid disease apparently enabledpatients to engage in activities that led to furtherdamage to articular structures. This suggests thathydrocortisone suppresses local protective mechanisms (eg, pain). One year later, a similar conclusionwas drawn by Chandler et al after they evaluated anapparent avascular arthropathy of the hip joint of apatient who underwent a 12-month regimen of hydrocortisone acetate therapy.8 A total of 900 mg wasinjected. Other investigators have reported similarfindings.9-13

VASCULAR CHANGESThe mechanism involved in the sometimes rapid

destruction of cartilage after intra-articular cortisoneis administered is not well understood. One explanation is that cortisone and ACTH therapy leads tohypercoaguability of vessels producing thromboembolic episodes thereby causing a disruption of bloodsupply to the femoral and humeral heads. 13 A secondexplanation is that the vasculitis induced by steroidscauses cartilage destruction.13 Murray believes articular disintegration is caused by avascular necrosis,especially in the hip.10 Because steroids are suspectedof depressing the pain-warning system, joints aresubjected to stresses that would not normally betolerated given the status of degeneration. Accord

ingly, Steinberg et al recommended limiting the useof intra-articular steroids to three or four injectionsover a few weeks, followed by conservative m anagement to control potential degen erative joint ch anges. 12Severe degenerative arthritis, however, also has beenreported in patients with no history of steroid therapy.10 Based on routine follow-up of 100 patients'records over a seven-year period, Hollander and associates reported a less than 1 percent incidence ofaccelerated destruction.14BIOCHEMICAL, PHYSIOLOGICAL, ANDULTRASTRUCTURAL CHANGES

Deleterious effects of cortisone acetate were reported by Layton wh o noted that high doses inhibitedthe synthesis of chondroitin sulfate in the skin ofintact rats.15 Using radiosulfate uptake as a measureof chondroitin sulfate synthesis in xiphoid cartilage,Clark and Umbreit reported similar findings in vitro.16 Synthesis increased, however, when hydrocortisone an d its acetate salt were administered to normaladult male rats. Thomas reported similar findings in1964.17

Intramuscular injection of cortisone in rabbits delayed the recovery of papain-treated ear cartilage,causing the ears to remain collapsed.18 In this study,cortisone was found to inhibit and delay synthesisand deposition of chondroitin sulfate, an importantmatrix constituent that imparts major morphologicaland functional characteristics to hyaline cartilage.Thomas et al showed that pretreatment of rabbitswith prednisolone completely blocked the lytic effectsof hypervitaminosis A,19 whose action is indistinguishable from that of papain.20 These findings indicate that cortisone (and its derivatives) has the effectof stabilizing lysosomes to prevent cartilage breakdown.21-23

Whitehouse's 1961 study on the somites of three-day-old chick embryos treated in vitro with cortisoneand hydrocortisone showed depression of cartilagegrowth and reduced radiosulfate uptake into chondroitin sulfate; D N A content was not inhibited.24 Thisshows that cortisone's primary effect is to inhibitsulfation rather than simply inhibiting cell reproduction or reducing c ell vitality. In a similar study, Lashand Whitehouse made similar observations.25 Structural analogues were also tested. Prednisone andprednisolone severely depressed radiosulfate uptakewhile 6 -methylprednisolone did not. In 1972, Man-kin et al arrived at essentially the same conclusionafter treating rabbits with daily intramuscular injections of cortisone acetate for up to nine weeks.26Similar findings were also reported by Shaw andLacey using daily intra-articular or intramuscularmethylprednisolone.27 In the same experiment, rabbits given papain to induce arthritis showed no signsof repair when pretreated with corticosteroids.

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PRACTICECollin's and Aniline's 1959 investigation of costalcartilage of hypophysectomized rats treated with hydrocortisone snowed inhibition of sulfate fixation. 28The same investigation by Denko and Bergenstalperfor med two years later produced similar findings. 29An inhibition of the stimulatory effect of growthhormone and weight loss were additionally reported

in the latter study.Using tritiated glycine (glycine 3H) as an indicatorof amino acid incorporation in protein synthesis incartilage matrices, M ankin and Conger injected hydrocortisone acetate in rabbit knees. 30 Their datashowed a rapid and profound decrease in glycineincorporation that appeared to depend on dosage.With smaller doses, recovery occurred within threedays while with larger doses, recovery took about twoweeks. M aximum decline occurred about six hoursafter injection. A similar experiment, using glycine14 C, as the amino acid indicator, showed a definitedecrease in the rate of protein synthesis within twohours.31 The rate of the effect of intra-articular injection on synthesis was about twice that of the observedrate for corticosteroids given by intramuscular route.Others have reported changes in the ultrastructure ofcartilage matrix within four hours of subcutaneousinjection of cortisone acetate in three-week-oldmice. 32 Changes included alteration of the rough endoplasmic reticulum and the Golgi apparatus, whichappears consistent with inhibition of the synthesis ofprotein polysaccharides. Changes in membranepermeability may explain this occurrence. Behrens etal made the same obser vations in similar experimentsin 1975.33

BIOMECHA NICAL A ND HISTOLOGICA LC H A N G E S

In 1969, Kopta and Blosser investigated the effectsof intra-articular methylprednisolone acetate on theknee joints of adult rabbits that had undergone ar-throtomy and meniscectomy. 34 After surger y, the kneejoints were injected monthly for six months. (M echanical and histological analyses of the articularcartilage were performed at the end of the experiment. ) Finding s showed that the elasticity of the tibialarticular cartilage was m arkedly reduced. M icroscopic degenerative changes were progressively moreevident including loss of protein polysaccharide inthe matrix; decreased number of chondrocytes; multiple Assuring of the matrix; clumping of collagenstain; and finally, by the sixth month, appearance oflarge cysts containing amorphous debris and degenerated chondrocytes and m ucoprotein. These findingsindicated a breakdown in protein synthesis. Systemiceffects included nystagmus, vertigo, and marked adrenal atrophy. M ore r ecently, investigators (Roach etal35 and Lutfi and Kosel36) r eported the same findings

when comparing the effects of corticosteroids andsalicylates on the ar ticular cartilage of r abbits.DISCUSSION

Since Thorn, in 1951, first injected hydrocortisoneinto the knee joint of a patient with rheumatoidarthritis, the anti-inflammatory effects of intra-ar ticular corticosteroid compounds have been established. 4 Corticosteroids have not only offered reliefbut partial or complete remission of symptoms associated with this and other conditions. Because theiraction 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,1weight loss,29 gross radiographic abnormalities,7-13loss of elasticity of articular cartilage,34 biochemicalalterations,15,18-33 degeneration of tissue, microscopic34 and ultrastructural changes of chondrocytesand matrix.33 Because of these sometimes serious sideeffects, clinicians attempt to balance the treatmentprogram of patients suffering from joint dysfunctionand other related problems by using judiciously administered chemical treatments combined with physical therapeutic treatments including exercise andmanipulation. At times, medications and exercise areused concurrently to maintain joint flexibility, softtissue continuity, and strength and to preserve function.

Exercise has been sh own to affect ar ticular cartilagepositively by maintaining its structure and physiologic status.37-39 Conversely, the lack of exercise (eg,immob ilization) secondary to acute inflammation andpain 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 eventualdeath of chondrocytes and reduced production ofmatrix components when immobilization is sufficiently pr olonged.40-42

Abundant information appears in the literature onthe effects of corticosteroids

1-14 ,17 ,22 ,24-27 ,30-36and exercise 37-39 used separately. Little investigation hasbeen reported on the inter-relationship between thesetwo treatments. Few investigators have studied theeffects of different types of exercise o n articular struc

tures. Clinicians, such as physical therapists, recognize the importance of choosing appropriate exercises(eg, active, passive, or resistive) to promote recoveryfrom illness, but the effects of specific exercises onhyaline cartilage that is simultaneously treated withcorticosteroids have received little study; the advisability of exercising while receiving intra-articularsteroids has not yet been clearly established in clinicalor laboratory studies. One situation that requiresstudy is that of the athlete who is given cor ticosteroidsfor an acute or chronic injury to r educe inflammation.

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Athletes receive intra-articular injections and returnto full intensity participation within days or evenhours of injection. One possible outcome is that thedeleterious effects of corticosteroids on articular cartilage may be exacerbated by exercise or manipulation. M oreover , responses to exer cises may differwhen the exercises are performed in weight-bearingpositions as compared to nonweight-bearing positions. (In the former, joint compression forces produced by muscular contraction may be augmented byground reaction forces, while in the latter, groundreaction forces are not a factor.) Increases in both theintra-articular forces and the diffusion pressure in thecartilage matrix may drive steroid-laden synovialfluid in an accelerated fashion, which would hastenthe negative effects of steroids. Conver sely, joint m otion may ha ve an ameliorating effect o n intrasynovialsteroid concentrations by permitting the compoundto be flushed from the joint capsule into generalcirculation before deleterious effects o n chondrocytesand other matrix components occur. In the absenceof clear evidence to demonstrate either theory iscorrect, physical therapists and others treating jointdysfunction should question their patients concer ning

past and present use of corticosteroids and closelymonitor the effects of adjunctive procedures, such asexer cise or manipu lation, until sufficient data is available.S U MMA R Y

A review of the literature has been presented concerning the effects of corticosteroid compounds onarticular cartilage. Substantial evidence demonstratesthat significant adver se histostructural, histochemical,and ultrastructural changes occur in articular cartilage leading to a decrease in synthesis of matrixcomponents, disorganization of various strata, andimpairm ent or loss of function. Because corticosteroidtherapy is often a component of a total therapeuticmanagement program that may also include variousforms of exercise or manipulative procedures, thepotential relationship between these treatments wasdiscussed. Data on this relationship are currentlyunavailable; therefore, physical therapists should beaware of the effects of corticosteroids on articularcartilage and closely monitor patient performance sothat treatment programs m ay be modified as r equired.

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1 5 . L a y t o n L : C o r t i s o n e i n h i b i t i o n o f m u c o p o l y s a c c h a r i d e s y n t h e s i s in t h e i nt a c t r a t. A r c h B i o c h e m B i o p h y s 3 2 : 2 2 4 - 2 2 5 ,1 9 5 11 6 . C l a r k I C , U m b r e i t N W : E f f e c t o f c o r t i s o n e a n d o t h e r s t e r o i d su p o n i n v i t r o s y nt h e s i s o f c h o n d r o i t i n su l f a t e . P r o c S o c E x pB io l M e d 8 6 : 5 5 8 - 6 5 1 , 1 9 5 4

1 7 . T h o m a s L : T h e e f f e c t s o f p a p a i n , v it a m in A , a n d c o r t i s o n e o nc a r t i l a g e m a t r ix in v i v o . Bi o p h y s J 4 ( s u p p l ) : 2 0 7 - 2 1 3 , 1 9 6 41 8 . T h o m a s L : R e v e r s i b le c o l l a p s e o f r a b bi t e a r s a f t e r i nt r a v e n o u s p a p a i n , a n d p r e v e n t i o n o f r e c o v e r y b y c o r t i s o n e . J E x pM e d 1 0 4 : 2 4 5 - 2 5 2 , 1 9 5 61 9 . T h o m a s L , M c C l u s k y R T , W e i s s m a n G : P r e v e n t i o n b y c o r t i s o n e o f t h e c h a n g e s i n c a r t i la g e i n du c e d b y a n e x c e s s o fv i t a mi n A i n r a b b i t s. A m J P a t h o l 4 2 : 2 7 1 - 2 7 9 , 1 9 6 32 0 . F e ll HB , T h o m a s L : C o m p a r i s o n o f t h e e f f e c t s o f p a p a i n a n dv i t a m in A o n ca r t i l a g e . J E x p M e d 1 1 1 : 7 1 9 - 7 4 3 , 1 9 6 02 1 . H o u c k J C , P a t e l YM : P r o p o s e d m o d e o f a c t i o n o f c o r t i c o s t e r o i d s o n t h e c o n n e c t i v e t i s s u e . Na t u r e ( L o n do n ) 2 0 6 : 1 5 8 -1 6 0 , 1 9 6 52 2 . L a c k C H: I n c r e a s e d v a s c u l a r p e r m e a b i l i t y , c h o n d r o l y s i s a n dc o r t i s o n e . P r o c e e d i n g s o f t h e R o y a l S o c i e t y o f M e d i c i n e5 5 : 1 1 3 - 1 1 6 , 1 9 6 22 3 . K a t z W A : R h e u m a t o i d D i s e a s e D i a g n o s i s a n d M a n a g e m e n t ,P h i l a d e l p h i a , P A , J . B . L i p p i n c o t t C o , 1 9 7 7 , p p 8 8 2 - 8 8 32 4 . W h i t e h o u s e M W: E f f e ct o f co r t i s o n e a n d r e l a t e d c o m p o u n d so n b i o g e n e s i s o f ca r t i l a g e . Na t u r e ( L o n do n ) 1 8 9 : 3 7 - 3 9 ,1 9 6 12 5 . L a s h JW , W h i t e h o u s e M W: E f f e c t s o f s t e r o i d h o r m o n e s a n ds o m e a n t i- in f la m m a t o r y a g e n t s u p o n in v i t r o c h o n d r o g e n e s i s .L a b In v e st 1 0 : 3 8 8 - 3 9 6 , 1 9 6 12 6 . M a n ki n HJ , Z a r i n s A , J a f f e e W J : T h e e f f e c t o f s y s t e m i cc o r t i c o s t e r o i d s o n r a b b i t a r t i c u l a r c a r t i l a g e . A r t h r i t i s R h e u m1 5 : 5 9 3 - 5 9 9 , 1 9 7 22 7 . S h a w N E , L a c e y E : T h e i n f l u e n c e o f c o r t i c o s t e r o i d s o n no r m a l a n d p a p a i n - t r e a t e d a r t i c u l a r c a r t i l a g e i n t h e r a b bi t . JB o n e J o i nt Su r g [A m ] 5 5 : 1 9 7 - 2 0 5 , 1 9 7 3

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PRACTICE2 8 . C o l l i n s E J , A n i l i n e J : T h e r e s p o n s e o f c o s t a l c a r t i l a g e t oc h a n g e s i n h o r m o n a l e nv i r o n m e n t . E x pe r i e n t i a 1 5 : 1 1 6 - 1 1 7 ,1 9 5 92 9 . D e n k o C W , B e r g e n s t a l D M: E f f e c t s o f g r o w t h h o r m o n e a n dc o r t i c o s t e r o i d s o n S 3 5 f i xa t i o n i n c a r t i l a g e . E n d o c r i n o l o g y6 9 : 7 6 9 - 7 7 7 , 1 9 6 13 0 . M a n ki n HJ , C o n g e r KA : T h e a c u t e e f f e c t s o f i nt r a - a r t i cu l a rh y d r o c o r t i s o n e o n a r t i c u l a r c a r t i l a g e i n r a b b i t s . J B o n e J o i n tS u r g [A m ] 4 8 : 1 3 8 3 - 1 3 8 8 , 1 9 6 63 1 . Ma n k in HJ, C o n ge r KA: T he ef fe ct o f C o rt iso l o n a r t icula r

c a r t i l a g e o f r a b bi t s : 1. E f f e c t o f a s i n g l e d o s e o f C o r t is o l o ng l y c i n e - C 14 i n co r p o r a t i o n . L a b In v e st 1 5 : 7 9 4 - 8 0 0 , 1 9 6 63 2 . S i lb e r b e r g M , Si l be r b e r g R , H a s l e r M: F i ne s t r u c t u r e o fa r t i c u l a r c a r t i l a g e i n m i c e r e c e i v i n g c o r t i s o n e a c e t a t e . A r c hP a t h o l a n d L a b o r a t o r y M e d i c i n e 8 2 : 5 5 9 - 5 8 2 , 1 9 6 63 3 . B e h r e n s F , S h e p a r d N , M it c h e ll N : A l te r a t i o n o f r a b bi t c a r t i l a g e b y i n t r a - a r t i c u l a r i n j e c t i o n s o f g l u c o c o r t i c o i d s . J B o n eJ o i nt Su r g [ A m ] 5 7 : 7 0 - 7 5 , 1 9 7 53 4 . K o p t a J A , B l o s s e r J A : E l a s t i c i t y o f a r t i c u l a r c a r t i l a g e : E f f e c t so f i n t r a - a r t i c u l a r s t e r o i d a d m i n i s t r a t i o n a n d m e d i c a l m e n i s c e c t o m y . Cli n O r t h o p 6 4 : 2 1 - 3 2 , 1 9 6 9

3 5 . R o a c h J E , To m b li n W, Ey r in g EJ : C o m p a r i s o n o f t h e e f f e c t so f s t e r o i d , a s p i r i n a n d s o d i u m s a l i c y l a t e o n a r t i c u l a r c a r t i l a g e .C li n O r t h o p 1 0 6 : 3 5 0 - 3 5 6 , 1 9 7 53 6 . Lutf i AM, Ko sel K: Effect o f in tra -a rt icula rly a d min isteredc o r t i c o s t e r o i d s a n d s a l i c y l a t e s o n t h e s u r f a c e o f a r t i c u l a rc a r t ila g e . J A n at 1 2 7 : 3 9 3 - 4 0 2 , 1 9 7 83 7 . S a a f J : E f f e c t o f e x e r c i s e o n a r t i c u l a r c a r t i l a g e . A c t a O r t h o pS c a n d 2 0 ( s u p p l 7 ) : 1 - 8 3 , 1 9 5 03 8 . L a n i e r R R : T h e e f f e c t s o f e x e r c i s e o n t h e k n e e j o i nt s o fi nb r e d m i c e . A n a t R e c 9 4 : 3 1 1 - 3 1 9 , 1 9 4 63 9 . E kh o l m R , N o r b c k B: O n t h e r e l a t i o n s h i p b e t w e e n a r t i c u l a rc h a n g e s a n d f u n c t io n . A c t a O r t h o p S ca n d 2 1 : 8 1 - 9 8 , 1 9 5 14 0 . Hall MC: C a r t i l a g e c h a n g e s a f t e r e x p e r i m e n t a l i m m o b i l i z a t i o no f t h e k n e e j o i n t o f t h e y o u n g r a t . J B o n e J o i n t S u r g [ A m ]4 5 : 3 5 - 4 4 , 1 9 6 34 1 . S o o d S C : A st u d y o f t h e e f f e c t s o f e x p e r i m e n t a l i m m o b i li z a t i o n o n r a b bi t a r t ic u la r c a r t i l a g e . J A n a t 1 0 8 : 4 9 7 - 5 0 7 , 1 9 7 14 2 . E n ne k i n g W F, H o r o w i t z M: T h e i n tr a - a r t i c u l a r e f f e c t s o f i m m o b i l i z a t i o n o n t h e h u m a n k n e e . J B o n e J o i n t S u r g [ A m ]5 4 : 9 7 3 - 9 8 5 , 1 9 7 2

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