1999 Lippincott Williams & Wilkins, Inc. Volume 1(369) December 1999 pp

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1 1999 Lippincott Williams & Wilkins, Inc. Volume 1(369) December 1999 pp Symptomatic Multifocal Osteonecrosis: A Multicenter Study [Section II: Original Articles: Miscellaneous] Collaborative Osteonecrosis Group (A complete list of coinvestigators is listed alphabetically at the end of the article.) Reprint requests to Michael A. Mont, MD, Department of Orthopaedic Surgery, The Johns Hopkins Medical Institutions, Good Samaritan Professional Building, 5601 Loch Raven Boulevard, Baltimore, MD Received: May 26, Revised: January 21, 1999; May 12, Accepted: May 19, Outline Abstract PATIENTS AND METHODS RESULTS Clinical Evaluation Radiographic Evaluation Surgical Management DISCUSSION Coinvestigators Acknowledgments References Graphics Table 1 Table 2 Fig 1 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table. No caption av... Abstract

2 Osteonecrosis of the femoral head frequently occurs in a young population (mean age, approximately 35 years) and may lead to disabling arthritis requiring hip arthroplasty surgery. This disease is compounded when it has concurrent involvement of other joints. Multifocal osteonecrosis is defined as disease involving three or more anatomic sites. The purpose of this study was to review the demographic, clinical, radiographic staging patterns, and treatment options in patients with multifocal osteonecrosis to facilitate earlier diagnosis and optimize treatment. Twenty-one centers participated by submitting completed data forms on patients under their care after review of their databases. One hundred one patients were identified. Patient demographics, associated diseases, corticosteroids and other medications used, presenting joints, and symptomatology were evaluated. Radiographs and magnetic resonance imaging scans or both were used to diagnose and stage osteonecrotic lesions. Ninety-two of the 101 (91%) patients had a history of corticosteroid therapy. Twelve patients (of 14 tested) were found to have a coagulation disorder. All 101 patients had femoral head involvement. Osteonecrosis also was seen in the knee (96%), shoulder (80%), ankle (44%), and seven other sites. Overall, 631 joints were involved (6.2 lesions per patient). Bilaterality was common: hips, 98%; knees, 86%; and shoulders, 83%. Most lesions (69%) were in a precollapse stage at the time the patients presented for treatment. In eleven patients, the knee was the sole presenting symptomatic joint, and the shoulder and ankle were the sole presenting symptomatic joints in five and four patients, respectively. An improved understanding of the epidemiology, pathogenesis, and etiology of multifocal osteonecrosis will facilitate the diagnosis and treatment of this disease. In patients with osteonecrosis of the hip, all symptomatic joints should be evaluated with radiographs. In patients with osteonecrosis presumably not involving the femoral head, the patient's femoral heads should be evaluated radiographically, regardless of whether the hips are symptomatic. Osteonecrosis is a disease primarily affecting patients in the third through fifth decades of life.36 It affects the hip most commonly and often leads to a disabling arthritis, necessitating total hip arthroplasty. The disease also may affect other sites, thus magnifying its adverse clinical effects on patients. These other sites include the knee, shoulder, ankle, and less commonly, the elbow and wrist. Multifocal osteonecrosis is defined as disease involving three or more separate anatomic sites. A review of the literature revealed numerous case reports concerning this entity,2,5-7,9,13,23,24,26,33,40,47 all of which had a limited number of patients. Some of the case reports described this process as systemic, and one purpose of this study was to analyze whether multifocal disease was different in patients with more limited musculoskeletal osteonecrosis (one or a few joints). Because no one center has sufficient numbers of patients to conduct a thorough examination of the problem, it is necessary to conduct a metaanalysis of published results or to conduct multicenter studies. In multiple meetings of leaders in the field of osteonecrosis (Association Research Circulation Osseous. October 1996, Fukuoka, Japan; American Orthopaedic Association Symposium. November, 1996, Durham, NC; The Johns Hopkins University Center for Osteonecrosis Research and Education Symposium. August, 1995, Baltimore, MD), it was concluded that a comprehensive collaborative effort was needed to address many of the questions concerning this entity. The purpose of this study was to review the clinical, demographic, radiographic staging patterns, and treatment options observed in this group of patients with multifocal osteonecrosis.

3 PATIENTS AND METHODS A multicenter study of osteonecrosis was initiated by sending questionnaires to 30 investigators across the United States. A list of questions initially was compiled by six of the coauthors and sent for review by all of the investigators. The questionnaire included clinical and radiographic queries. The demographic data included age of the patient at initial presentation, gender, weight, disease associations, corticosteroid use, alcohol use, tobacco use, presenting symptom(s), and presenting joint(s). Twenty-one centers participated by submitting completed data forms on patients under their care. Forms were reviewed by the writing committee to verify that the patients fulfilled the inclusion criteria and that the forms were completed. Multifocal disease was defined as involvement of three separate anatomic sites. For example, a patient with osteonecrosis of the hip, knee, and shoulder or the hip, knee, and ankle would meet the inclusion criteria. A patient who had three joints involved, but not three separate anatomic sites involved, such as two hips and one knee, would not be included. Osteonecrosis of the knee, which could include the distal femur and the proximal tibia, was considered one site. The centers also were asked to identify the total number of patients seen in the same period who had any evidence of osteonecrosis in any joint as confirmed by magnetic resonance imaging (MRI). Based on these results, an approximation of the incidence of multifocal disease was made. Corticosteroid use was analyzed by peak dose, duration of therapy, and by route of administration of prednisone or its equivalent dose. The study cohort was divided into three groups based on corticosteroid dose and treatment history (none, low corticosteroid, high corticosteroid). Patients receiving 2 mg or less per day of prednisone and treated for 2 years or less were included in the low corticosteroid group. Patients with a history of corticosteroid doses greater than 20 mg per day and/or treatment for greater than 2 years comprised the high corticosteroid group. This system was based on groupings used by Petri et al 44 and others 10,34,35 to simplify reporting because it is difficult to categorize corticosteroid use because of the variability of parameters, such as time of use, peak dose, and route of administration. Intraarticular injections and other local treatments of corticosteroid were excluded from this analysis because they were regarded as different from systemic administration. Alcohol use also was quantitated to determine which patients had a history of consuming greater than 400 ml of absolute 100% ethanol per week (the threshold reported to be associated with osteonecrosis by the Japanese Orthopaedic Association).29,42 Although this work has been done in a Japanese population, it represents the best effort to date at establishing a threshold for alcohol as a relevant associated risk factor. Cigarette consumption was evaluated to indicate which patients had a greater than 10 pack year smoking history (equivalent to one pack per day for 10 or more years) or smoking greater than or equal to one pack per day at the time of presentation.16,29 The temporal relationship of each patient's multiple symptomatic joints was recorded to identify which joint(s) was affected first and afterward to characterize the onset of symptoms. Symptomatology was categorized by presence or absence for each affected joint. The radiographic review included analysis by plain radiographs, MRI, or computed tomographic (CT) scans of involved joints to determine presenting stage, size, and

4 location of lesions. All of the lesions were staged using one of three staging systems (Ficat and Arlet,11 Steinberg et al,51 ARCO 36). Because most centers used the Ficat and Arlet system, all lesions were converted to this staging system for the purpose of reporting results (Table 1). Although the Ficat and Arlet system may be an oversimplification, 100% of the lesions could be characterized to one of the four stages in all patients, regardless of the system used by the responding center. The authors acknowledge that variability may have been introduced because several physicians from different centers reviewed the radiographs. TABLE 1. Ficat and Arlet Classification of Osteonecrosis The treatment of each patient's involved joints was reviewed. Surgical treatment was identified by joint involved and correlated with the presence of symptoms. Outcome of treatment was not analyzed. The data were compiled from each center and tabulated using an Access 7.0 database (Microsoft Corporation, Redmond, WA). Descriptive statistics were calculated. Trends concerning the relationship of various demographic variables to corticosteroid use, radiographic staging, and other variables were evaluated. Parametric and nonparametric statistical analyses of the results were conducted using the Computer Programs for Epidemiologic Analysis (PEPI) Software Package Version 2.03 (USD, Incorporated, Stone Mountain, GA). Frequencies were analyzed using a chi square distribution with a Yates correction. Nonparametric data were evaluated using the Mann Whitney two-tailed test, whereas parametric data were analyzed with analysis of variance (ANOVA). RESULTS One hundred one patients with multifocal osteonecrosis were included in this multicenter study from 21 centers throughout the United States between the years of 1980 and There were 75 female (74%) and 26 male (26%) patients, with a mean age at presentation of 36 years (range, years). Data were available from 12 centers concerning their total number of patients with osteonecrosis. From these centers, 81 patients had multifocal disease of 2484 patients (3.3%) with a diagnosis of osteonecrosis. The most common associated factors, diseases, or comorbidities are listed in Table 2. Twenty (20%) patients had a history of smoking at least one pack per day of tobacco or had a greater than 10 pack year smoking history (one pack per day for 10 years). Ten (10%) patients consumed more than 400 ml per week of alcohol, equivalent to 12 cans of beer.32 Ninety-two of the 101 (91%) patients had a history of corticosteroid therapy. Of the nine patients with no history of corticosteroid therapy, four had thrombophilia and hypofibrinolysis or both,14,15,17,45 one with familial Protein S

5 deficiency, two with high tissue plasminogen activator inhibitor, and one with Factor V Leiden deficiency or resistance to activated Protein C. The other five patients were not tested for a possible coagulation disorder. Twelve of 14 patients tested were found to have a coagulation disorder. Thirty-two (32%) patients had more than one risk factor for osteonecrosis, with the most common combination being corticosteroid use and a smoking history (16 patients, 16%). When these patients were compared with the 61 patients who had corticosteroid history as their only risk factor for osteonecrosis, there was no significant difference with respect to radiographic stage at presentation (p = 0.7). TABLE 2. Comorbidities Clinical Evaluation Six hundred thirty-one bony lesions were identified (6.2 per patient) (Fig 1). All patients had femoral head involvement. The most common other sites involved included the distal femur (96 patients), proximal humerus (80 patients), and talus (44

6 patients). Other joints or bones involved included the elbow (capitellum, trochlea), wrist (distal radius, various carpal bones), calcaneus, tarsal navicular, cuneiform, cuboid, and metacarpal head; the distributions are shown in Figure 1. Bilaterality (as confirmed by radiographs or MRI) was common, including 98% of the hips, 87% of the knees, and 83% of the shoulders. The joints that were less often bilateral included the ankles (61%) and elbows (42%), as shown in Table 3.

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8 Fig 1. Location of 631 osteonecrotic lesions in 101 patients. TABLE 3. Distribution of 632 Osteonecrotic Lesions in 201 Patients Hip symptoms, with or without multiple other joint pain, was the most common presentation (81 patients, 80%). Forty-four patients presented initially with reports of hip pain only, whereas 37 patients presented initially with multiple symptomatic joints. In 11 patients, the knee was the sole presenting symptomatic joint. The shoulder and the ankle were the only presenting symptomatic joints in five and four patients, respectively. Of the 287 joints in which symptoms initially presented, there were 130 hips (45% of presenting joints), 70 knees (24% of presenting joints), 49 shoulders (17% of presenting joints), 29 ankles (10% of presenting joints), and nine wrists or elbows (3% of presenting joints). When the patients were divided into high and low dose corticosteroid and noncorticosteroid groups, the data were not significantly different in terms of gender, number of sites involved, bilaterality, and presentation (Table 4). Age in the low corticosteroid group was significantly greater than in the other two groups (p <.005). When the patients with systemic lupus erythematosus were analyzed separately and compared with the remaining patients in the study group, the data were not significantly different with respect to age (mean, 34 years; range, years), number of sites involved (mean, 6.1 sites; range, 4-10 sites), bilaterality, and mode of presentation. However, there was a trend toward a greater proportion of women versus men in the systemic lupus erythematosus group (32 women, six men) as compared with the remaining study group (43 women, 20 men) (p = 0.076).

9 TABLE 4. Clinical Findings by Corticosteroid Grouping Radiographic Evaluation Plain radiography or MRI revealed that most (69%) joints presented in a precollapse stage (Ficat and Arlet Stage I or II) (Table 5). Eighty-five of 200 (43%) hips had Stage III (59 hips) or Stage IV (26 hips) disease. Only 17% of 179 knees, 38% of 146 shoulders, and 24% of 71 ankles had Stage III or IV disease. Approximately 30% of the lesions were diagnosed solely by MRI (Stage I disease). There was a higher incidence of these Stage I lesions in the knee (38%), shoulder (30%), and ankle (44%) than in the the hip (18%). TABLE 5. Ficat and Arlet Staging at Presentation When the three corticosteroid groups were analyzed, the staging pattern and distribution were significantly different in the low dose corticosteroid group, with a greater incidence of presentation with postcollapse disease (Table 6) (p values ranging from to 0.014). When the patients with systemic lupus erythematosus were evaluated separately and compared with the remaining patients in the study group, the staging pattern and distribution were not significantly different (p values ranging from to 0.956).

10 TABLE 6. Ficat and Arlet Staging by Corticosteroid Grouping Surgical Management The 180 painful hips were treated most commonly with core decompressions, various grafting procedures, and eventually 77 total hip arthroplasties. The distribution of procedures is listed in Table 7. The 162 symptomatic knees were managed most commonly with core decompressions, arthroscopies, and total knee arthroplasties. The distribution of management methods for the 138 painful shoulders and 78 painful ankles is listed in Table 7. TABLE 7. Methods of Treatment DISCUSSION Previous journal articles concerning multifocal osteonecrosis have been limited to case reports.2,5-7,9,13,23,24,26,33,40,47 For this reason, the use of multiple centers to garner information about this entity was used. Of 13 patients from 13 published case reports in the English literature concerning this entity, 11 had a corticosteroid association.2,5,7,9,23,26,33,40,47 The other two patients had the human immunodeficiency virus and an antiphospholipid antibody syndrome.6,13 Of the patients with a history of corticosteroid therapy, four had systemic lupus erythematosus,5,12,26,47 one had a renal transplant,7 one had idiopathic thrombocytopenic purpura,33 three had malignancy,7,23,40 and one had a head injury secondary to a motor vehicle accident.2 Although these numbers are small, the incidence of systemic lupus erythematosus (four of 13; 31%) in these reports is similar to the incidence seen in the current study group (38 of 101; 38%). In the current study, patients had a mean of 6.2 osteonecrotic lesions. The hips were involved in all patients with disease, and there was a bilateral predominance at all

11 sites. In the study group, 89% of knees, 73% of shoulders, and 35% of ankles were involved. This is a similar distribution but much higher prevalence than was seen by Zizic et al 57 in 28 patients with systemic lupus erythematosus, who had 41 hips (73%), 36 knees (64%), and 16 shoulders (29%) affected. In that study, some patients had two areas involved, but none had multifocal disease defined by three separate areas. The joint distribution in the current study group is significantly different from that reported by McCallum and Walder 30 in patients who worked with compressed air. Disease involvement in the patients included 34% of the knees (16 of 47 knees), 32% of the shoulders (15 of 47 shoulders), and 17% of the hips (8 of 47 hips). However, this difference possibly could be explained by the study being performed in 1966, before the advent of MRI. Multifocal disease was found to occur in at least 3% of patients diagnosed as having osteonecrosis. This is likely to be an underestimation of patients with asymptomatic multifocal disease because some patients with multifocal disease have silent lesions that otherwise would not be identified. Patients with this disease often have fragmented care, being seen by multiple practitioners (shoulder, hip, knee, foot specialists), which is another reason for the potential underestimation of the disease incidence. This is especially true because all joints do not become symptomatic at the same time. The current study does not answer the question of whether all hips, knees, and shoulders should be evaluated if more than one site is involved. The authors do not know how many patients were not identified who had two sites involved with multiple other asymptomatic lesions. It has been suggested by various authors 51,52,58 that total body scintigraphic bone scans may be the most cost effective means of screening for multifocal involvement. However, not enough information is available to determine if this is the best approach. It has been found that bone scans may miss lesions 10% to 20% of the time and may not be the best diagnostic modality in these patients.37 Thus, a separate study is needed to determine the accuracy of this modality. In this cost conscious climate, it is not possible to perform MRI on every patient with an asymptomatic joint. An additional clinical research study is needed to justify the effectiveness of these various diagnostic approaches. The incidence might be overestimated because the participating centers have a special interest in this disease and may be more likely to evaluate patients with this degree of affliction. However, the type of center reporting and its patient population are crucial because centers that specialize in treatment of patients with systemic lupus erythematosus or patients who have had transplants may skew the prevalence of this disease. This study may not reflect centers that have populations of various high risk patient groups that did not contribute to this study, including patients with Gaucher disease, sickle cell disease, and other hemoglobinopathies, those with dysbarism (especially native diving fishermen), and patients from various leukemia and cancer treatment centers. In addition, this study was compiled from patients from selected centers in the United States and may not reflect the experience in other countries. Ninety-eight percent of the hips were involved bilaterally in patients in the study group, as were 87% of the knees and 83% of the shoulders. This finding is consistent with a case study by Egan and Munn 6 that described a patient with antiphospholipid syndrome and multifocal lesions affecting bilateral hips, knees, shoulders, ankles, elbows, wrists, and feet. Similarly, Gerster et al 13 described a patient with human immunodeficiency virus and osteonecrosis of bilateral hips, knees, and shoulders. In

12 contrast to the findings of the current study, Darlington 5 reported on a case of multifocal osteonecrosis in a patient with systemic lupus erythematosus with no hip involvement, and Murphy and Greenberg 40 described a patient with acute lymphocytic leukemia and multifocal osteonecrosis involving only one hip. In the general literature regarding osteonecrosis, bilaterality of hip lesions ranges from 34% to 80%.3,4,18,31,36,46 The difference in the current study might be accounted for by all hips in this study undergoing MRI, so asymptomatic lesions were identified. The finding of 98% bilaterality of hip lesions in the current study emphasizes the importance of examining the contralateral hip in a patient with multifocal osteonecrosis, regardless of the presence or absence of symptoms. This observation is particularly relevant in the evaluation of a patient with osteonecrosis of joints other than the hip. It is important that such patients have their hips evaluated, regardless of whether the joints are symptomatic. Although outcomes were not analyzed in the current study, most authors believe such patients should have their hips evaluated, regardless of whether these joints are symptomatic. The high incidence of bilateral hip involvement in patients with multifocal disease may be a reflection of the severity or intensity of risk from an undiagnosed comorbidity, such as a coagulation disorder. In one report concerning osteonecrosis of the hip, the knee and shoulder were involved 5% to 15% of the time, with other joints less commonly involved.37 Based on the current study, multifocal osteonecrosis will be found slightly greater than 3% of the time in patients with osteonecrosis. However, it has been found that patients with osteonecrosis of other joints have a much higher incidence of multifocal disease.37 From one institution with 1056 patients with osteonecrosis of the hip, 40% (n = 32) of patients with osteonecrosis of the knee had multifocal disease. In addition, 60% (n = 28) of patients with osteonecrosis of the shoulder had multifocal involvement, and 57% (n = 8) of patients with osteonecrosis of the ankle had multifocal lesions. This study emphasizes the possible need to screen other joints in patients with osteonecrosis of the knee, shoulder, or ankle because such patients may have multifocal disease approximately 50% of the time. The association between osteonecrosis of the hip and multifocal disease is much lower (3%), so asymptomatic joints in patients presenting only with hip disease do not need to be evaluated routinely. Radiographic evaluation revealed that most sites present in early stages, when treatment methods aimed at saving the joints may be more successful. Sixty percent of joints in this study were Ficat and Arlet Stage I or II (precollapse) at the time the patients presented initially, when nonoperative or operative methods aimed at preserving the joint are most effective. It is extremely important to diagnose these lesions as early as possible to initiate treatment because the results of joint replacement in the knee or hip have been poorer in patients with osteonecrosis than for other diagnoses.36,39 The incidence of negative radiographic findings but positive MRI scans (Stage I) was highest in the ankle (44%) and knee (38%) and lower for the shoulder (30%) and hip (18%). These percentages are similar to those cited in reports in the literature (Table 8).

13 TABLE 8. Literature Review of Osteonecrosis Studies Table. No caption available.

14 The prevalence of corticosteroid associated osteonecrosis has been variable, being implicated in 10% to 60% of patients with osteonecrosis in multiple large demographic studies.1,8,20,27,32,49,53,58 For example, Jacobs,20 in a study of 269 patients, found alcoholism to be the highest association, with 104 (39%) patients, and a corticosteroid association in 75 (28%) patients. Zizic et al,58 in a study of 169 patients, reported corticosteroid association in 88 (52%) patients and an association with alcoholism in 19 (11%) patients. The history of corticosteroid therapy found in 11 of 13 (85%) patients in the 13 previous reports of multifocal osteonecrosis 2,5-7,9,12,13,23,24,26,33,40,47 is similar to that found in the current study group (91%). This finding suggests a strong relationship between multifocal disease and corticosteroid therapy. It is difficult to interpret the potential effect of corticosteroid use because of the many variables, including dosage, duration of treatment, and route of administration. In terms of dose and duration relationships, despite that this is a collaborative study with 101 patients, the number of patients available in each group (noncorticosteroid, low corticosteroid, and high corticosteroid) is too small to analyze using statistical models. A finding in the current study was that low dose corticosteroid use was associated with a greater incidence of postcollapse disease. Although this finding remains unexplained, one possible explanation for this observation might have been the suppression of synovitis with higher dose corticosteroid use, leading to suppression of some symptoms that might have led to earlier diagnosis. Regarding other associated factors, there was a low incidence of alcohol ingestion (10%) and cigarette use (20%), which may reflect that lack of voluntary disclosure of information on these habits may lead to an underestimation. Although this was studied, there is an absence of a well documented correlation between cigarette smoking and nontraumatic femoral head osteonecrosis in adult patients who are not Japanese. In addition, the occurrence of thrombophilia or hypofibrinolysis or both seen in patients in this study (12%) is falsely low because testing was performed only in 14 patients (87% positive). This rate of coagulation disorders is similar to rates reported in the literature; between 80% and 90% of patients tested with osteonecrosis had hypofibrinolysis and thrombophilia or both.14,15,17 Because of the high incidence of coagulation disorders in patients with osteonecrosis, it is difficult to analyze differences between patients with multifocal and less musculoskeletal involvement. So far, in a review of the literature,6,14,17,35 patients with single joint involvement are just as likely to have a coagulation disorder as are patients with more joint involvement. The authors think epidemiologic studies are needed to evaluate specific etiologic factors and various combinations of such factors. A comparison of patients with multifocal disease with patients with osteonecrosis of the hips only or osteonecrosis of a few joints was performed (Table 8). In the current study, the high percentage of women (74%) is similar to numbers of women in other studies, which are weighted toward patients with systemic lupus erythematosus and other inflammatory disorders (Zizic et al,57 96% women in lupus population), but dissimilar to incidences reported in studies where there is a preponderance of patients who use alcohol, in which more men are seen (Jacobs,21 80% men). The current study of patients with multifocal disease has a patient population with a higher incidence of steroid use and bilateral hip involvement. The population of patients with multifocal disease was similar in terms of patient age, alcohol use, and percentages of presenting joints reported in 25 large studies. The multitude of treatment methods aimed at preserving osteonecrotic joints used in

15 the United States underlie the importance of studying these methods prospectively. These multiple methods include nonoperative (electrical stimulation, pharmacologic agents aimed at decreasing lipid levels or altering the hypofibrinolysis and/or thrombophilia found) and operative techniques (core decompression with or without bone grafting, nonvascularized and vascularized bone grafting, and osteotomies). Additional multicenter studies are needed to evaluate the outcomes of these various treatment methods. The authors recognize limitations of this study in that it was a retrospective, cross sectional investigation of an uncommon condition. There were differences in categorization, methodology, and screening methods by the different centers with no independent evaluation. Although the authors are all experienced in using the Ficat and Arlet staging system, there is potential variability inherent in trying to stage a disease at multiple centers when there is not universal agreement about the staging. However, despite these limitations, this study has enabled investigation of patients with a condition that no one center has enough patients to evaluate. Using this type of research design, the study: (1) determined the incidence of multifocal osteonecrosis to be approximately 3% of the total population with osteonecrosis; (2) found the distribution of joints with multifocal osteonecrosis to be the hip (91%), knee (87%), shoulder (72%), and ankle (35%); (3) supports examining hips in all patients with multifocal disease because they were found to be involved universally with osteonecrosis; (4) emphasized the need for a high index of suspicion in patients treated with corticosteroids (with an occurrence of 91%); and (5) described an ill defined condition that often is confused with other disorders (infections, tumors) and compared the similarities and differences to more limited disease. The study also underscores the importance of establishing a collaborative national database from multiple centers for the better design of prospective studies for the treatment of osteonecrosis. This could be accomplished by prospective data acquisition to assess the time course of the disease and the outcomes after intervention, which might best be performed using randomized trials. Coinvestigators The data and preparation of this article required major effort on the part of all of the following contributors: Writing team: Michael A. Mont, MD; Lynne C. Jones, PhD; Dawn M. LaPorte, MD; Department of Orthopaedic Surgery, Johns Hopkins Medical Institutions, Baltimore, MD; Co-authors: Roy K. Aaron, MD, Department of Orthopaedics, Brown University, Providence, RI; Michael J. Christie, MD, Vanderbilt Arthritis Joint Replacement Center, Nashville, TN; Charles J. Glueck, MD, Cholesterol Center, The Jewish Hospital of Cincinnati, Cincinnati, OH; Stuart B. Goodman, MD, Division of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA; Steven Haas, MD, Hospital for Special Surgery, New York, NY; William L. Healy, MD, Department of Orthopaedic Surgery, Lahey Hitchcock Medical Center, Burlington, MA; David A. Heck, MD, Indiana University, Indianapolis, IN; Peter A. Holt, MD, The Good Samaritan Hospital, Baltimore, MD; David S. Hungerford, MD, Department of Orthopaedic Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD; Richard Iorio, MD, Department of Orthopaedic Surgery, Lahey Hitchcock Medical Center, Burlington, MA; John Paul Jones, MD, Diagnostic Osteonecrosis Center and Research Foundation, Kelseyville, CA; John Klibanoff, MD, Department of Orthopaedics, Strong Memorial Hospital, Rochester, NY; Carlos J. Lavernia, MD, Department of Orthopaedics and Rehabilitation,

16 University of Miami School of Medicine, Coral Gables, FL; Tung Le, Department of Orthopaedic Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD; Dennis W. Lennox, MD, Department of Orthopaedic Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD; Roger N. Levy, MD, Department of Orthopaedics, Mount Sinai Medical Center, New York, NY; Michelle Petri, MD, Department of Rheumatology, The Johns Hopkins Medical Institutions, Baltimore, MD; Aiman Rifai, DO, Department of Orthopaedics, The Johns Hopkins Medical Institutions, Baltimore, MD; Aaron G. Rosenberg, MD, Midwest Orthopaedics, Chicago, IL; Melvin P. Rosenwasser, MD, Columbia University Medical Center, New York, NY; Richard N. Stauffer, MD, Department of Orthopaedic Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD; Marvin E. Steinberg, MD, Department of Orthopaedic Surgery, University of Pennsylvania Medical Center, Philadelphia, PA; Bernard N. Stulberg, MD, Cleveland Center for Joint Reconstruction, Cleveland, OH; Audrey Tsao, MD, Department of Orthopaedic Surgery, Jackson, MS; James Urbaniak, MD, Division of Orthopaedic Surgery, Duke University Medical Center, Durham, NC; Thomas Parker Vail, MD, Division of Orthopaedic Surgery, Duke University Medical Center, Durham, NC; Gwo-Jaw Wang, MD, Department of Orthopaedics, University of Virginia Medical Center, Charlottesville, VA; Steven B. Zelicof, MD, PhD, Joint Reconstructive Service, Westchester County Medical Center, Valhalla, NY; and Thomas M. Zizic, MD, The Good Samaritan Hospital, Baltimore, MD. Acknowledgments The authors thank Regina M. Barden, RN, BSN, Midwest Orthopaedics, Chicago, IL; Enrique Barrientos, PAC, Joint Reconstruction Service, New York Medical College, Valhalla, NY; Gail Bunce, RN, Providence, RI; Melanie J. Capps, RN, Vanderbilt Arthritis Joint Replacement Center, Nashville, TN; Eunice Gunneson, PAC, Division of Orthopaedic Surgery, Duke University Medical Center, Durham, NC; Karen M. Hartman, CRC, Department of Orthopaedic Surgery, University of Pennsylvania Medical Center, Philadelphia, PA; Clara Maye-Lewis, Arthritis Division, Good Samaritan Hospital, Baltimore, MD; Cindy Partridge, BS, Indiana University, IN; and Rose Sampson, Arthritis Division, Good Samaritan Hospital, Baltimore, MD. References 1. Aaron RK, Lennox D, Bunce GE, Ebert T: The conservative treatment of osteonecrosis of the femoral head. Clin Orthop 249: , [Context Link] 2. Archer AG, Nelson MC, Abbondanzo SL, Bogumill GP: Case report 554. Skeletal Radiol 18: , Full Text Bibliographic Links Library Holdings [Context Link] 3. Boettcher WG, Bonfiglio M, Hamilton HH: Nontraumatic necrosis of the femoral head. J Bone Joint Surg 52A: , [Context Link] 4. Coventry MB, Beckenbaugh RD, Nolan DR, Ilstrup DM: 2012 total hip arthroplasties: A study of postoperative course and early complications. J Bone Joint Surg 56A: , Bibliographic Links Library Holdings [Context Link] 5. Darlington LG: Osteonecrosis at multiple sites in a patient with systemic lupus erythematosus. Ann Rheum Dis 44:65-66, Bibliographic Links Library Holdings [Context Link] 6. Egan RM, Munn RK: Catastrophic antiphospholipid antibody syndrome presenting with multiple

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20 Arthritis Rheum 29: , Bibliographic Links Library Holdings [Context Link] Accession Number: Copyright (c) Ovid Technologies, Inc. Version: rel9.2.0, SourceID