Radiology

James Francis Griffith, FRCR Gregory Ernest Antonio, FRCR Shekhar Madhukar Kumta, MD David Shu-Cheong Hui, MD Jeffrey Ka Tak Wong, FRCR Gavin Matthew Joynt, MRCP Alan Ka Lun Wu, MD Albert Yu Kiu Cheung, MSc Kwok Hing Chiu, FRCS Kai Ming Chan, FRCS Ping Chung Leung, FRCS Anil Tejbhan Ahuja, FRCR Published online before print 10.1148/radiol.2351040100 Radiology 2005; 235:168 –175 Abbreviations: ALT ⫽ alanine transaminase LDH ⫽ lactate dehydrogenase SARS ⫽ severe acute respiratory syndrome SPIR ⫽ spectral presaturation and inversion recovery 1

From the Departments of Diagnostic Radiology and Organ Imaging (J.F.G., G.E.A., J.K.T.W., A.T.A.), Orthopaedics and Traumatology (S.M.K., K.H.C., K.M.C., P.C.L.,), Medicine (D.S.C.H., A.K.L.W.), Anaesthesia and Intensive Care (G.M.J.), and Centre for Epidemiology and Biostatistics (A.Y.K.C.), Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Received January 19, 2004; revision requested March 19; final revision received June 30; accepted July 26. Address correspondence to J.F.G. (email: [email protected]).

Authors stated no financial relationship to disclose. Author contributions: Guarantor of integrity of entire study, J.F.G.; study concepts and design, J.F.G., G.E.A., S.M.K., D.S.C.H., G.M.J., A.K.L.W., K.H.C., K.M.C., P.C.L., A.T.A.; literature research, J.F.G., G.E.A.; clinical studies, S.M.K., D.S.C.H., G.M.J., A.K.L.W., K.H.C., K.M.C., P.C.L.; data acquisition, J.F.G., G.E.A., J.K.T.W., D.S.C.H., G.M.J., A.K.L.W., K.H.C.; data analysis/interpretation, J.F.G., G.E.A., A.Y.K.C.; statistical analysis, all authors; manuscript preparation and revision/review, A.Y.K.C., J.F.G.; manuscript editing, J.F.G., G.E.A.; manuscript definition of intellectual content and final version approval, all authors ©

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Osteonecrosis of Hip and Knee in Patients with Severe Acute Respiratory Syndrome Treated with Steroids1 PURPOSE: To evaluate whether there is a relationship between steroid treatment and risk for osteonecrosis of the hip and knee in patients with severe acute respiratory syndrome (SARS). MATERIALS AND METHODS: The hospital ethics committee approved the study, and all patients provided written informed consent. A total of 254 patients with confirmed SARS treated with steroids underwent evaluation with magnetic resonance (MR) imaging for osteonecrosis. Clinical profiles, joint symptoms, relevant past medical and drug history, steroid dose, and radiographic and MR imaging evidence of osteonecrosis and other bone abnormalities were evaluated. MannWhitney, Kruskal-Wallis, and Pearson exact ␹2 tests were performed, and univariate and multivariate logistic regression analyses were applied. RESULTS: One hundred thirty-four (53%) of 254 patients had recent onset of large joint pain, but 211 (80%) of 264 painful joints were not associated with abnormality on MR images. MR images in 12 (5%) of 254 patients showed evidence of subchondral osteonecrosis in the proximal femur (n ⫽ 9), distal femur (n ⫽ 2), and proximal and distal femora and proximal tibiae (n ⫽ 1). Additional nonspecific subchondral and intramedullary bone marrow abnormalities were present in 77 (30%) of 254 patients. Results of multiple logistic regression analysis confirmed cumulative prednisolone-equivalent dose to be the most important risk factor for osteonecrosis. The risk of osteonecrosis was 0.6% for patients receiving less than 3 g and 13% for patients receiving more than 3 g prednisolone-equivalent dose. No relationship was found between additional nonspecific bone marrow abnormalities and steroid dose. CONCLUSION: An appreciable dose-related risk was found for osteonecrosis in patients receiving steroid therapy for SARS. Additional nonspecific bone marrow abnormalities were frequent. Joint pain was common after SARS infection and was not a useful clinical indicator of osteonecrosis. ©

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Severe acute respiratory syndrome (SARS) first emerged in southern China during the final quarter of 2002. International air travel facilitated rapid global spread of the infection, and cases were confirmed in 29 countries (1). By the close of this outbreak in July 2003, the cumulative number of persons affected by the disease worldwide was 8098, and 774 had died (1). Many patients with SARS received high-dose steroid therapy, which was administered for a variable period. A serious side effect of steroid therapy is osteonecrosis. Unlike many other side effects (such as immunosuppression, myopathy, and reduced bone density), osteonecrosis, once established, does not regress after discontinuation of steroid therapy. High doses of steroids administered over a short period to patients who are not predisposed to osteonecrosis seem to confer little or no risk of osteonecrosis (2). On the other hand, high doses of steroids administered over a longer period to osteonecrosis-predisposed patients (such as patients with systemic lupus erythematosus, rheumatoid arthritis,

Radiology

malignancy, or organ transplant) are associated with a dose-related risk of osteonecrosis of between 4% and 52% (3,4). The majority of patients treated for SARS in our hospital were not predisposed to osteonecrosis. They received variable doses of steroid therapy for a variable period. Thus, the purpose of our study was to evaluate whether there is a relationship between steroid treatment and risk for osteonecrosis of the hip and knee in patients with SARS.

MATERIALS AND METHODS Patients Between March 5 and May 27, 2003, 342 patients with SARS were admitted to the Prince of Wales Hospital, Hong Kong. The diagnosis of SARS was confirmed in all these patients by using established World Health Organization diagnostic criteria (5). Thirty-three patients died of the disease. Thus, 309 patients remained who were eligible for osteonecrosis evaluation with magnetic resonance (MR) imaging. Five patients, who were younger than 10 years old, were not screened, as sedation prior to MR imaging may have been required. The remaining 304 patients were contacted by telephone. Of these 304 patients, 48 were unavailable to undergo MR imaging for various reasons. MR imaging was contraindicated in two patients because of metallic implants. Therefore, of 304 eligible patients, 254 patients underwent evaluation with MR imaging for osteonecrosis. This group of 254 study participants comprised 99 (39%) male patients (mean age, 38 years; range, 16 – 89 years) and 155 (61%) female patients (mean age, 36 years; range, 20 –77 years). Median time from admission for SARS treatment to MR imaging was 6.7 months (range, 3.3–9.7 months). The hospital ethics committee approved the study, and all patients provided written informed consent. The 50 patients who recovered from SARS infection and who were not evaluated with MR imaging were classified as nonparticipants. To ensure uniformity between participants (n ⫽ 254) and nonparticipants (n ⫽ 50), the variables of age, sex, maximum radiographic score, days in hospital, and intensive care unit admission were analyzed.

Questionnaire and Steroid Dose Prior to MR imaging, the patient’s height and weight were measured and a four-page questionnaire was completed to determine whether there were any preexVolume 235

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isting factors that predisposed the patient to osteonecrosis. The patient was questioned about the presence and duration of joint symptoms, past medical and trauma history, past and current medications (including topical steroids, Chinese herbal medicines, oral contraceptives, and nonsteroidal antiinflammatory agents), past and present smoking habits, and alcohol consumption. All patients who showed no response to antibiotic therapy within 48 hours of initial administration received intravenous ribavirin at a dosage of 24 mg/kg/d and hydrocortisone at a dosage of 10 mg/ kg/d. Pulsed intravenous methylprednisolone (500 –1000 g/d) was administered to patients who were affected by progressive deterioration (6). Hospital databases were accessed for steroid dosage information. Prednisolone-equivalent doses were calculated by adjusting the hydrocortisone or methylprednisolone dose to the prednisolone-equivalent dose on the basis of antiinflammatory potency. Conversion factors of 0.20 and 1.25 were used to calculate prednisolone-equivalent doses of hydrocortisone and methylprednisolone, respectively. Osteonecrosis risk was compared with patient age, sex, weight, body mass index, smoking, alcohol intake, preexisting comorbidity, intake of other medications, maximum radiographic score (7), intensive care unit admission, days in the intensive care unit, days in hospital, alanine transaminase (ALT) level at admission, lactate dehydrogenase (LDH) level at admission, maximum LDH level, cumulative prednisolone-equivalent dose, cumulative prednisolone-equivalent dose adjusted for weight and body mass index, and average daily prednisolone-equivalent dose to determine whether there was a correlation. The relationship between hip or knee pain and the presence of osteonecrosis or other bone abnormalities was analyzed, as was the relationship between the severity of SARS infection (determined with reference to radiographic score, ALT level at admission, and LDH level at admission or maximum LDH level) and osteonecrosis (6).

MR Imaging Protocol A modified MR imaging protocol was used that was designed specifically for osteonecrosis evaluation (8). Both hips were examined simultaneously, and then both knees were examined. MR imaging was performed with a 1.5-T unit (Magnetom; Siemens, Erlan-

gen, Germany). For imaging of the hips, a coronal T1-weighted spin-echo sequence (590/20 [repetition time msec/echo time msec]) was applied, with a section thickness of 3 mm, intersection gap of 0.3 mm, field of view of 350 mm, and matrix of 256 ⫻ 512. A coronal T2-weighted fat-suppressed short inversion time inversion-recovery sequence (5170/56/160 [repetition time msec/echo time msec/ inversion time msec]), with a section thickness of 3 mm, intersection gap of 0.3 mm, field of view of 300 mm, and matrix of 384 ⫻ 512, also was applied in patients with reported hip pain. For imaging of the knees, a coronal T1weighted spin-echo sequence (520/20) was applied with a section thickness of 3 mm, intersection gap of 0.3 mm, field of view of 300 mm, and matrix of 256 ⫻ 512. A coronal T2-weighted fat-suppressed short inversion time inversion-recovery sequence (4050/56/160), with a section thickness of 3 mm, intersection gap of 0.3 mm, field of view of 280 mm, and matrix of 384 ⫻ 512, also was applied in patients with reported knee pain. For both examinations, a phased-array spinal coil was used in conjunction with a phased-array body coil. Total examination time was 15 minutes for the T1weighted sequences and 25 minutes if two additional T2-weighted fat-suppressed sequences were applied.

MR Image Interpretation MR images were interpreted with consensus by two musculoskeletal radiologists (J.F.G. and G.E.A., with 9 and 5 years of experience in musculoskeletal imaging, respectively). Findings were classified as (a) no osteonecrosis, (b) nonspecific bone marrow abnormality, or (c) osteonecrosis. Nonspecific bone abnormalities were categorized as either subchondral or intramedullary in location (9 –12). Subchondral abnormalities were defined as those located immediately beneath the articular surface. Intramedullary abnormalities were defined as those located within the medullary canal, removed from the articular surface. The location and size of intramedullary and subchondral abnormalities were recorded on a predesigned template. For calculating the size of abnormalities, the major and minor axis lengths were measured directly on the hard-copy images. Osteonecrosis was defined as an area, either subchondral or intramedullary in location, demarcated by a distinct marginal rim with low signal intensity that encompassed medullary fat on T1-

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used for all statistical analyses. A 5% significance level was applied for all tests (P ⬍ .05).

TABLE 1 Synopsis of Patient Questionnaire and Responses

Radiology

Patient Response Abbreviated Question

Yes

No

Joint symptoms prior to SARS? Previous pelvic or hip trauma? Previous chronic medical condition? Cigarette (or other) smoking intake? Alcohol intake? Previous heavy alcohol ingestion? Previous steroid medication? Other medications taken since SARS infection?

6 (2.4) 1 (0.4) 28 (11.0)* 8 (3.1)† 8 (3.1)‡ 0 4 (1.6) 136 (53.5)§

248 (97.6) 253 (99.6) 226 (88.9) 246 (96.9) 246 (96.9) 254 (100) 250 (98.4) 118 (46.4)

Note.—Data are numbers of patients; numbers in parentheses are percentages. Each of 254 patients evaluated for osteonecrosis completed the questionnaire. * Previous chronic medical conditions reported were thyroid disease (n ⫽ 5), hepatitis B (n ⫽ 5), hypertension (n ⫽ 4), diabetes (n ⫽ 3), chronic obstructive airway disease (n ⫽ 4), asthma (n ⫽ 2), renal calculi (n ⫽ 2), ischemic heart disease (n ⫽ 1), systemic lupus erythematosus (n ⫽ 1), and chronic renal failure (n ⫽ 1). † Mean reported intake per patient was eight cigarettes per day. ‡ Mean reported intake per patient was 2.8 units per week. § Other medications taken since SARS infection were Chinese herbs (n ⫽ 106), naproxen (n ⫽ 1), oral contraceptive (n ⫽ 6), and various other nonsteroidal antiinflammatory medications (n ⫽ 14).

weighted images. The severity of osteonecrosis in the femoral head was graded by using the University of Pennsylvania system (13). According to this system, grades IA, IB, and IC reflect osteonecrotic involvement of less than 15%, 15% to 30%, and more than 30% of the volume of the femoral head, respectively, on MR images obtained in patients with normal plain radiographs (13). Forty-four patients either with nonspecific subchondral bone marrow abnormalities not obviously related to degenerative change or with osteonecrosis were asked to return for a more detailed MR imaging examination, as well as a radiographic examination. At the detailed MR imaging examination, the affected hip or knee joint was evaluated individually by using standard coils and orthogonal sequences, depending on the site of the initial abnormality. For lesions of the femoral condyles, T1weighted (518/14), T2-weighted (3970/74), and T2-weighted spectral presaturation and inversion recovery (SPIR) (3970/74/ 160) sagittal images and intermediateweighted (3500/43) coronal images were obtained. For lesions of the patella, a smallfield-of-view surface coil was used, and T1weighted (518/14), intermediate-weighted fat-suppressed (2480/31), and T2-weighted SPIR (4080/67/160) transverse images were obtained. For lesions of the proximal femora (nearly all intramedullary lesions), T1weighted (599/20) and T2-weighted SPIR (5170/66/160) oblique coronal images were obtained. The duration of each detailed imaging examination of a joint was approximately 30 minutes. Radiographic examination comprised anteroposterior 170

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and lateral views of the affected hip or knee joint. Radiographs were interpreted by two authors (J.F.G., G.E.A.) in consensus, who compared radiographs with both initial and detailed MR images specifically to identify early radiographic signs of osteonecrosis (subchondral osteopenia, osteosclerosis, or early subchondral collapse). Similar criteria were used for interpretation of both the detailed MR images and the initial MR images. Incidental unrelated pathologic entities depicted on radiographs and MR images also were noted. Irrespective of the imaging findings, all cases were reviewed at a special orthopedic clinic, and patients were informed of the results.

Statistical Analysis Median and range were calculated to characterize continuous variables, and percentages were calculated for discrete variables. Mann-Whitney and Kruskal-Wallis tests were applied to analyze group distribution, and the Pearson exact ␹2 test was applied to compare proportions among groups. Univariate logistic regression models were applied to identify significant risk factors that were predictive of osteonecrosis or of a negative result at MR imaging. A stepwise multivariate logistic regression model was developed to identify important risk factors. The adjusted odds ratio for prediction of osteonecrosis was determined for each risk factor, while controlling for the effects of other covariates, by using the multivariate logistic regression model. Statistical software (SPSS version 11.5 for Windows; SPSS, Chicago, Ill) was

RESULTS Participants versus Nonparticipants For participants, there was no difference in age distribution according to sex (P ⫽ .51). When compared with nonparticipants (n ⫽ 50), participants (n ⫽ 254) were younger (median age, 33 vs 34 years) and less likely to be male (35% vs 47%) than were nonparticipants (P ⬍ .05). In other respects (steroid dosage, maximum radiographic score, days in hospital, intensive care unit admission), no differences between participants and nonparticipants were apparent (P ⬎ .05).

Predisposition to Osteonecrosis One patient (with normal findings at MR imaging) had a history of systemic lupus erythematosus. None of the other patients evaluated had a recognizable predisposition to osteonecrosis (Table 1).

MR Imaging Findings No osteonecrosis present.—One hundred sixty-five (65%) of 254 patients (64 men, 101 women; median age, 29 years; range, 20 – 83 years) had no evidence of osteonecrosis. This group included six patients with unrelated incidental pathologic conditions. The incidental findings in these patients were nonossifying fibroma (n ⫽ 4), endochondromatosis (n ⫽ 1), and hypoplastic medial tibial plateau (n ⫽ 1). Nonspecific bone marrow abnormality.— Nonspecific subchondral and intramedullary bone marrow abnormalities were present on MR images in 77 (30%) of 254 patients (29 male, 48 female; median age, 42 years; range, 16 – 89 years). Patients with nonspecific bone marrow abnormalities were older, on average, than patients with no osteonecrosis and no bone marrow abnormalities (P ⬍ .001). Subchondral bone marrow abnormality.— One hundred sixty-one subchondral bone marrow abnormalities (Figs 1–3) were present in 64 (25%) of the 254 patients evaluated. The locations of these abnormalities are diagrammed in Figure 4. Maximum length ranged from 3–26 mm (mean, 6.5 mm). Twelve (19%) of the 64 patients had appreciable associated degenerative change. Intramedullary bone marrow abnormality.—Fifty-four intramedullary bone marrow abnormalities (Fig 5) were present in 38 (15%) of 254 patients evaluated. Of Griffith et al

Radiology

those 38 patients, 24 had coexistent subchondral abnormalities. The locations of these abnormalities are shown in Figure 4. Maximum length ranged from 3–20 mm (mean, 5.9 mm). Osteonecrosis present.—Twelve (5%) of the 254 patients (six men, six women; median age, 39 years; range, 28 –52 years) had osteonecrosis of the femoral head (n ⫽ 9), the femoral head and femoral and tibial condyles (n ⫽ 1), or the femoral condyles (n ⫽ 2) (Figs 6, 7). Four (33%) of these 12 patients had no symptoms related to the affected joint. Femoral head involvement was unilateral in six patients and bilateral in four patients (ie, 14 femoral heads were affected). The percentage of femoral articular surface affected ranged from 10% to 60% (median, 32%). Radiographs were negative for osteonecrosis in all cases. According to the University of Pennsylvania system (13), the severity of osteonecrosis was stage IA in two femoral heads, stage IB in two femoral heads, and stage IC in 10 femoral heads. The 12 affected patients received cumulative prednisolone-equivalent doses of 8.74, 7.71, 7.29, 5.53, 5.15, 4.96, 4.15, 4.02, 3.52, 3.67, 3.01, and 0.76 g, respectively (mean, 4.57 g) (Fig 8). The patient with the most severe osteonecrosis (in both hips and knees) received a 5.53-g cumulative prednisolone-equivalent dose and, in addition, a nonsteroidal antiinflammatory drug (naproxen). The patient who received only a 0.76-g prednisoloneequivalent dose, at 18 years of age, was the youngest of the cohort with osteonecrosis. Other than steroid treatment, this patient had no past or current risk factor for osteonecrosis. Patients with osteonecrosis received a higher cumulative prednisolone-equivalent dose (median, 4.50 g; range, 0.76 – 8.74 g) than did those with no finding of osteonecrosis on MR images (median, 2.22 g; range, 0.05–10.02 g) or with a finding of nonspecific bone marrow abnormality (median, 2.58 g; range, 0.06 – 9.91 g) (P ⫽ .002) (Fig 6). Patients with osteonecrosis also received a higher cumulative prednisolone-equivalent dose adjusted for weight (P ⫽ .002) and body mass index (P ⫽ .025). Patients with osteonecrosis were no more likely to smoke, have a high alcohol intake, have a comorbid condition, or take other medications than were patients without osteonecrosis (P ⬎ .05) (Table 1). Fifteen potential risk factors were assessed, namely age, sex, weight, body mass index, maximum radiographic score, adVolume 235

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Figure 1. Subchondral abnormality. (a) Coronal T1-weighted (590/20) image of both knees shows foci of low signal intensity (arrows) in the inferior aspects of both lateral patellar facets. Transverse (b) T1-weighted (518/15) and (c) intermediate-weighted fat-suppressed (2480/21) images of left patella show area of ill-defined subchondral edema (arrow) in lateral patellar facet and mild lateral patellar subluxation. Although cartilage overlying this area is thin, this level is at the inferior aspect of patella, where articular cartilage is normally thinned. Cartilage located immediately cephalad (not shown) was of normal thickness. Radiographs were normal.

mission to the intensive care unit, days in the intensive care unit, days in hospital, ALT level at admission, LDH level at admission, maximum LDH level, cumulative prednisolone-equivalent dose, cumulative prednisolone-equivalent dose adjusted for weight and body mass index, and average daily prednisolone-equivalent dose. Intensive care unit admission, days in hospital, cumulative prednisolone-equivalent dose, cumulative prednisolone-equivalent dose adjusted for weight, cumulative prednisolone-equivalent dose adjusted for body

Figure 2. Subchondral abnormality related to chondral defect. (a) Coronal T1-weighted (590/20) image of both knees shows small focus of low signal intensity (arrow) in intercondylar region of right knee. Localized sagittal (b) intermediate-weighted (3500/43) and (c) T2-weighted fat-suppressed (3970/74) images of right knee show small focus of subchondral edema (arrow in b and arrowhead in c) in intercondylar region and overlying focal cartilage defect (arrow in c). Radiographs were normal.

mass index, and average daily prednisolone-equivalent dose were found to be significant predictors of osteonecrosis (Table 2). The results of analysis with a stepwise multivariate logistic regression model based on these six significant indicators, which were individually identified in univariate logistic regression analysis, revealed that cumulative prednisolone-equivalent dose was the only significant predictor of

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Radiology

Figure 4. Diagram shows sites in knee for 161 subchondral abnormalities (dark gray) in 64 patients and for 54 intramedullary abnormalities (light gray) in 38 patients. The relative frequency of abnormalities in each site is represented as a percentage.

Figure 3. Subchondral abnormality not related to chondral defect. Localized sagittal (a) T1-weighted (518/14) and (b) T2-weighted fat-suppressed (3970/74) MR images of knee show area of subchondral bone marrow edema (large arrow) situated posteriorly in medial femoral condyle. No osteonecrosis is present, as is evidenced by the lack of any demarcation line on any of the MR images. Overlying articular cartilage (small arrows) is normal. Radiographs were normal.

osteonecrosis (P ⫽ .001). In addition, it was the most important risk factor: The adjusted odds ratio and 95% confidence interval, with control for the effects of age, sex, and intensive care unit admission, was 1.589 (1.143–2.208) (P ⫽ .006) (Table 3). Only one of 168 patients evaluated who received a cumulative prednisolone-equivalent dose of less than 3 g developed osteonecrosis, while 11 of 86 patients evaluated who received a prednisolone-equivalent dose of more than 3 g developed osteonecrosis (Fig 8). In other words, the risk of osteonecrosis was 0.6% for patients who received less than 3 g and 13% for patients who received more than 3 g. 172

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No relationship between the severity of SARS infection (as judged from radiographic score, ALT level at admission, and LDH level at admission or maximum LDH level) and the development of osteonecrosis was observed (P ⬎ .05).

Joint Pain One hundred thirty-four (53%) of 254 patients had new onset of joint pain after admission for SARS treatment. The pain involved only one joint in 18 (7%) of 254 patients and more than one joint in 116 (46%). The joints affected were the hip in 51 (20%), the knee in 104 (41%), the shoulder in 86 (34%), and the ankle in 46 (18%) of 254 patients. Details such as time of onset and site of hip and knee pain are shown in Table 4. Among 264 painful hip or knee joints in the 254 patients screened, findings on MR images in 210 (80%) joints were normal. Patients with osteonecrosis of the hip were more likely to have pain (P ⬍ .001), yet the majority of patients with hip pain did not have osteonecrosis. Patients with osteonecrosis of the knee were no more likely to have knee pain than were other patients evaluated (P ⫽ .93).

DISCUSSION Steroids were widely used in the treatment of SARS, usually to counteract con-

tinued clinically or radiologically evident deterioration in the patient’s condition. While they appear to have been beneficial in at least a subset of SARS patients (14,15), there are also strong opponents to the use of steroids (16). Steroid treatment is a well-recognized major risk factor for nontraumatic osteonecrosis (2– 4). Steroids are postulated to induce osteonecrosis by causing a decrease in local blood flow by means of either (a) marrow fat hypertrophy, which leads to increased intraosseous pressure and impairment of venous flow, or (b) lipid emboli and lipidloaded fibrin-platelet thrombi, which occlude subchondral arterioles and capillaries (17). Core decompression, the main surgical treatment for early osteonecrosis, is aimed at reversing this process by reducing intraosseous pressure and providing a conduit for angiogenesis to revascularize subchondral bone (18). The clinical symptoms of osteonecrosis are nonspecific, and patients may be asymptomatic, as were four of the 12 patients with osteonecrosis in this study (19). Radiography does not depict osteonecrosis until a relatively late stage of disease (19,20). MR imaging is a sensitive test for detection of early osteonecrosis, especially in the femoral head (20,21). In this study, T1-weighted coronal imaging in the hips and knees was found useful in the evaluation of patients for osteonecrosis (8). While steroids administered over a prolonged period increase osteonecrosis risk in otherwise predisposed patients (3,4,19), short-duration steroid therapy appears to be safe in nonpredisposed patients, even if administered in very high doses. Wing et al (2) reported the results of a study of 59 patients with acute spinal cord injury, most of whom received 11–15 g methylprednisolone (equivalent to 13.75–18.75 g prednisolone) over a period of 24 hours. No osteonecrosis was apparent on MR images obtained 6 months after initiation of steroid therapy (2). Little is known regarding the osteonecrosis risk with high-dose steroids administered to nonpredisposed patients over a more prolonged period. Patients in this study were generally healthy prior to infection with SARS; thus, we had the opportunity to study the relationship between steroid dosage and osteonecrosis in a population without known predisposition. We analyzed as many variables as possible in an effort to establish factors predictive of osteonecrosis. Twelve (5%) of 254 patients evaluated had osteonecrosis. Cumulative predGriffith et al

Radiology Figure 5. Coronal T1-weighted (590/20) MR image of both hips shows discrete intramedullary bone marrow abnormalities, 12–14 mm in length, in the right greater trochanter and left femoral neck (arrows). Radiographs were normal.

nisolone-equivalent dose was the most important risk factor predictive of osteonecrosis. The risk of osteonecrosis was 0.6% for patients receiving less than 3 g and 13% for patients receiving more than 3 g. No additional unrelated variable was found to be predictive of osteonecrosis risk. This finding does emphasize the individual susceptibility to osteonecrosis even in patients not known to be predisposed to the condition. Subchondral bone marrow abnormalities were present in a greater number of patients than expected. Two recent MR imaging– based studies, performed in 100 (mean subject age, 42.7 years) and 115 asymptomatic knees (mean subject age, 47.5 years), reported 3% and 11.3% prevalence of subchondral bone marrow abnormalities, respectively (18,19). All abnormalities occurred on the medial side of the joint and in patients older than 40 years (18,19). Mean subject age in the current study was only 35.5 years, yet the prevalence of subchondral bone marrow abnormalities (24 [25%] of the 254 patients examined) was more than twice that previously reported. Patients with nonspecific bone marrow abnormalities were analyzed as a separate group, in case the abnormality in some patients eventually would be found to represent a mild form of osteonecrosis. Subchondral bone marrow abnormalities mainly comprised areas of low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, findings that are compatible with a “bone marrow edema” pattern (9,10). The MR imaging appearance of these subchondral marrow abnormalities was comparable with that observed in severe Volume 235

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Figure 6. Coronal T1-weighted (590/20) MR image of both hips shows well-demarcated areas of osteonecrosis (arrows) in the anterosuperior aspect of both femoral heads. Radiographs were normal. Other MR images in this patient also depicted established osteonecrosis in the distal femora and proximal tibiae.

TABLE 2 Results of Univariate Logistic Regression Analyses of Risk Factors for Osteonecrosis Variable

Crude Odds Ratio and 95% Confidence Interval

P Value

Age Male sex Weight Body mass index Maximum radiographic score Intensive care unit admission Days in intensive care unit Days in hospital ALT at admission LDH at admission Maximum LDH Prednisolone-equivalent dose Adjusted for weight Adjusted for BMI Daily average

1.025; 0.984, 1.068 1.603; 0.495, 5.189 1.036; 0.985, 1.089 1.096; 0.996, 1.205 1.021; 0.988, 1.055 5.240; 1.412, 19.446 1.011; 0.977, 1.046 1.049; 1.004, 1.096 0.999; 0.989, 1.009 0.998; 0.992, 1.004 1.002; 0.999, 1.004 1.610; 1.244, 2.084 1.030; 1.013, 1.047 1.009; 1.003, 1.015 1.012; 1.004, 1.020

.228 .431 .165 .060 .217 .013* .540 .032* .869 .578 .158 ⬍.001† ⬍.001† .003† .003†

* P ⬍ .05. † P ⬍ .01.

TABLE 3 Results of Multivariate Logistic Regression Analysis of Risk Factors for Osteonecrosis Variable

Adjusted Odds Ratio and 95% Confidence Interval*

P Value

Age Male sex Intensive care unit admission Prednisolone-equivalent dose

0.997; 0.933, 1.065 1.694; 0.415, 6.915 1.626; 0.326, 8.108 1.589; 1.143, 2.208

.923 .463 .553 .006†

* Adjusted odds ratio was determined after controlling for the effect of other covariates in the model. † P ⬍ .01.

degenerative disease (10), and the abnormalities did tend to occur in patients who were older than those with normal

findings or osteonecrosis at MR imaging. However, cartilage thinning (as a manifestation of degenerative disease) was not

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TABLE 4 Hip and Knee Pain after SARS Infection in 254 Patients

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Site of Pain Painful Joint

No. of Patients

Onset of Pain*

Unilateral

Bilateral

Abnormal Findings on MR Images†

Hip Knee

51 (20) 104 (41)

6 (1–20) 8 (1–18)

17 (32) 26 (22)

34 (68) 77 (75)

4 (8) 50 (48)

Note.—Unless otherwise indicated, data are numbers of patients, and numbers in parentheses are percentages. * Data are median interval after diagnosis of SARS, given in weeks, with range in parentheses. † Abnormal findings on MR images were presence of either osteonecrosis or nonspecific bone marrow abnormality of the painful joint.

Figure 8. Histogram shows spectrum of cumulative prednisoloneequivalent doses for patients with no osteonecrosis, patients with nonspecific bone marrow abnormality, and patients with osteonecrosis.

Figure 7. (a) Coronal T1-weighted (590/20) MR image of both knees shows foci of low signal intensity (arrows) in the posterior aspect of both lateral femoral condyles. (b) Sagittal T1-weighted (518/14) MR image of right knee shows area of subchondral osteonecrosis (arrow) in posterior aspect of lateral condyle. Detailed MR images of left knee (not shown) revealed subchondral edema without demarcation line (similar to features depicted in Fig 3). Radiographs were normal.

a feature in many cases, and this fact makes it less likely that degenerative disease or focal chondral injury was the sole cause of the observed abnormalities. One probable cause of subchondral marrow abnormality may be a combination of steroid-induced subchondral bone demineralization and increased physical activity after recovery from SARS, which could lead to subchondral trabecular impaction and edema similar to those described in patients after renal transplantation (11,12,22–25). Another probable cause of subchondral marrow abnormality is early subchondral osteonecrosis (9). The distribution of the marrow abnormalities around the knee was similar to that observed in 174

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osteonecrosis (26 –29). Possibly because of a difference in blood supply, osteonecrosis around the knee tends to affect discrete areas of bone marrow, unlike osteonecrosis in the proximal femur, which nearly always affects the anterosuperior aspect of the femoral head. On detailed MR images obtained in our patients, the deep thin subchondral line, described by Lecouvet et al (9) as one useful discriminatory criterion to distinguish early irreversible subchondral osteonecrosis from transient subchondral bone marrow edema, was not a feature of these lesions. Transient subchondral bone marrow abnormality may represent “reversible” subchondral osteonecrosis (9). A further study is currently under way specifically to investigate the significance of these subchondral bone abnormalities. Small intramedullary abnormalities, occasionally associated with fluid or edema, were present in 15% of patients. The incidence of intramedullary abnormalities in the normal population is not known. Many may simply represent venous lakes or bone islands that were too small to be classified. Although they may potentially represent very small areas of osteonecrosis, they are by virtue of their

small size and location not likely to cause symptoms, structural weakening, or longterm problems. Although no relationship was found between nonspecific bone abnormality and steroid dose, this may be a reflection of our small sample size. New onset of joint pain occurred in 53% of patients after infection with SARS. The majority of painful joints showed no abnormality on MR images. Joint pain in the aftermath of viral infections is not uncommon, and there is a recognized association between joint pain and viruses such as hepatitis C, rubella, and human T-cell lymphotrophic virus type 1 (30). Joint pain, therefore, is not a reliable clinical indicator when evaluating for osteonecrosis after initiation of steroid treatment for SARS. There are three main limitations of this study. First, the time range from initiation of steroid treatment to MR imaging was 3.3–9.7 months, and a small number of patients were examined early (ie, before 6 months). Osteonecrosis, however, is considered to develop soon after the initiation of steroid treatment. In a longitudinal study in which serial MR imaging was performed in 72 patients with systemic lupus erythematosus, all 32 patients who developed osteonecrosis did Griffith et al

Radiology

so within 5 months (mean, 3.1 months) of initiation of steroid treatment. Thereafter, no new case of osteonecrosis was detected with MR imaging up to a period of 12 months (19). The cohort in the current study received high-dose steroids for a short period of about 3 weeks, at the start of the illness, after which the doses were gradually decreased. Second, as all patients were treated with steroids for SARS, no control group was available for study. The possibility that SARS infection itself may have contributed to the development of osteonecrosis has not been refuted. Autopsy in patients with SARS has revealed fibrin thrombi in and intimal swelling of pulmonary vessels (31). The results of the current study, however, revealed no relationship between markers of the severity of SARS infection (radiographic score, ALT level at admission, LDH level at admission, and maximum LDH level) and osteonecrosis. Third, it was assumed that no preexisting osteonecrosis was present, as the cohort studied was healthy prior to infection with SARS. In conclusion, the results of this MR imaging– based study show a dose-related risk of osteonecrosis in patients who receive steroid therapy for SARS, with cumulative prednisolone-equivalent dose being the most important predictor. Nonspecific subchondral and intramedullary bone marrow abnormalities were a frequent observation. Joint pain was common after SARS infection and was not a useful clinical indicator of osteonecrosis. References 1. World Health Organization. Cumulative number of reported probable cases of SARS, 1 Nov 2002 to 31 July 2003. Available at: www.who.int/csr/sars/country/ table2003_09_23/en. Accessed January 9, 2004. 2. Wing PC, Nance P, Connell DG, Gagnon F. Risk of avascular necrosis following short term megadose methylprednisolone treatment. Spinal Cord 1998; 36:633– 636. 3. Cook AM, Dzik-Jurasz AS, Padhani AR, Norman A, Huddart RA. The prevalence of avascular necrosis in patients treated with chemotherapy for testicular tumours. Br J Cancer 2001; 85:1624 –1626. 4. Zizic TM, Marcoux C, Hungerford DS, Dansereau JV, Stevens MB. Corticosteroid

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