oosteo2

Pathogenesis and Natural History of Osteonecrosis Yehudith Assouline-Dayan, Christopher Chang, Adam Greenspan, Yehuda Shoenfeld, and M. Eric Gershwin Background and Objectives: Osteonecrosis (avascular necrosis) is a relatively common disorder seen by both rheumatologists and orthopedic surgeons. The vast majority of cases are secondary to trauma. However, for non-traumatic cases, there often remains a diagnostic challenge in defining the cause of bone death. The goal of this article is to review data extensively in the medical literature with respect to the pathogenesis of osteonecrosis, its natural history, and treatment.

Methods: A review of 524 studies on osteonecrosis was performed, of which 213 were selected and cited.

Results: Non-traumatic osteonecrosis has been associated with corticosteroid usage, alcoholism, infections, hyperbaric events, storage disorders, marrow infiltrating diseases, coagulation defects, and some autoimmune diseases.

However, a large number of idiopathic cases of osteonecrosis have been described without an obvious etiologic factor. Although corticosteroids can produce osteonecrosis, careful history is always warranted to identify other risk factors. The pathogenesis of non-traumatic osteonecrosis appears to involve vascular compromise, bone and cell death, or defective bone repair as the primary event. Our understanding of the pathogenesis of osteonecrosis is now much better defined and skeletal scintigraphy and magnetic resonance imaging have enhanced diagnosis greatly. Early detection is important because the prognosis depends on the stage and location of the lesion, although the treatment of femoral head osteonecrosis remains primarily a surgical one.

Conclusions: Osteonecrosis has been associated with a wide range of conditions. Many theories have been proposed to decipher the mechanism behind the development of osteonecrosis but none have been proven. Because osteonecrosis may affect patients with a variety of risk factors, it is important that caregivers have a heightened index of suspicion. Early detection may affect prognosis because prognosis is dependent on the stage and location of the disease. In particular, the disease should be suspected in patients with a history of steroid usage, especially in conjunction with other illnesses that predispose the patient to osteonecrosis.

From the Division of Rheumatology, Allergy and Clinical Immunology, Department of Radiology, University of California at Davis, Davis, CA; and Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Yehudith Assouline-Dayan, MD: Postdoctoral Fellow, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA; Christopher Chang, MD: Associate Professor of Medicine, University of California at Davis, Davis, CA; Adam Greenspan, MD: Professor of Radiology, Department of Radiology, University of California at Davis Medical Center, Sacramento, CA; Yehuda Shoenfeld, MD: Professor and Chief of Medicine, Chaim Sheba Medical 94

Center, Tel-Hashomer, Israel; M. Eric Gershwin, MD: Professor of Medicine and Chief of the Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA Address reprint requests to M. Eric Gershwin, MD, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, TB 192, One Shields Avenue, Davis, CA 95616. E-mail: megershwin@ucdavis.edu Copyright 2002, Elsevier Science (USA). All rights reserved.

0049-0172/02/3202-0002$35.00/0 doi:10.1053/sarh.2002.33724

Seminars in Arthritis and Rheumatism, Vol 32, No 2 (October), 2002: pp 94-124

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

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Relevance: A better understanding of the pathophysiology, diagnosis and treatment of osteonecrosis will help the physician determine which patients are at risk for osteonecrosis, facilitating early diagnosis and better treatment options.

Semin Arthritis Rheum 32:94-124. Copyright 2002, Elsevier Science (USA). All rights reserved.

INDEX WORDS: Avascular necrosis; magnetic resonance imaging; osteonecrosis; scintigraphy.

O

STEONECROSIS is the death of bone that results in the collapse of the architectural bony structure, leading to joint pain, bone destruction, and loss of function. Synonyms of osteonecrosis are avascular necrosis (AVN), ischemic necrosis, subchondral avascular necrosis, aseptic necrosis of bone, and osteochondritis dissecans.

Destruction of the bone and articular cartilage frequently is severe enough to require joint replacement surgery. Osteonecrosis is a common disorder and accounts for 10% or more of the 500,000 total joint replacement procedures performed annually in the United States (1). Approximately 75% of patients with osteonecrosis are between 30 and 60 years of age (2). With the exception of systemic lupus erythematosus (SLE) patients, the disease is seen predominantly in males (7:3 male-female ratio).

The causes of osteonecrosis include interruption of the vascular supply as a result of local trauma or non-traumatic systemic conditions (Table 1). Conditions associated with osteonecrosis include corticosteroid administration, hemoglobinopathies (eg, sickle cell anemia), fat emboli, alcoholism, and SLE. In symptomatic patients, the diagnosis of osteonecrosis traditionally has been made by conventional radiography and radionuclide bone scan.

During the past decade, however, magnetic resonance imaging (MRI) has proven to be a more sensitive tool for detecting osteonecrosis at earlier stages and in asymptomatic locations (3,4). Nevertheless, the difficulty of identifying the asymptomatic patient with osteonecrosis remains a significant hurdle in our efforts to achieve early detection.

By the time a patient progresses to end-stage osteonecrosis, hemiarthroplasty or total hip replacement (THR) may be the only therapeutic option. Despite advances in total hip arthroplasty, the 5-year survival of the prosthesis in patients

with osteonecrosis is much lower than that of the older osteoarthritis population (5). Indeed, most patients diagnosed with osteonecrosis will need more than one procedure during their lifetime.

Because osteonecrosis occurs mainly in young patients who are generally very active, and because there are limited treatment options for advanced disease, the importance of early diagnosis and assessment of population at risk should be emphasized.

CLINICAL FEATURES OF OSTEONECROSIS

The natural history of osteonecrosis is variable, but dependent primarily on the size of the infarcted segment and the site of occurrence. Pain is almost always the presenting symptom. The pain may be mild initially or vague in cases of insidious onset, when the diagnosis is not suspected. Conversely, severe pain can develop rapidly in cases in which trauma is the obvious cause (6-8). Rarely, pain can be very intense, particularly when caused by large infarcts such as those that occur in Gaucher disease, dysbarism, or hemoglobinopathy (9). In osteonecrosis of the femoral head, pain is located most frequently in the groin or anterior thigh, and is almost always unilateral to begin with; however, in approximately 55% of cases, the opposite hip becomes involved within 2 years. Usually, pain increases with use of the joint, ultimately appears even at rest, and frequently requires analgesics for relief.

Range of motion is well preserved at the beginning of the disease but gradually deteriorates. Motion can be limited by accompanying pain. In osteonecrosis of the lower extremities, a limp may be present and is sometimes the presenting finding of a patient with a normal radiograph.

Medullar bone infarcts are mostly silent. Osteonecrosis of the small bones of the hand or foot may present with pain, but not a high degree of disability (10-12). Osteonecrosis of the medial femoral

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ASSOULINE-DAYAN ET AL

Table 1: Conditions Leading to or Associated with Osteonecrosis Trauma Burns Fractures Dislocations Vascular Trauma Kienbo¨ck Disease Non-Traumatic Conditions Hematologic Hemoglobinopathies Sickle-Cell Anemia Thalassemias Disseminated Intravascular Coagulation Polycythemia Hemophilia Metabolic/Endocrinologic Hypercholesterolemia Gout Hyperparathyroidism Hyperlipidemia Pregnancy Cushing Disease Chronic Renal Failure Gaucher Disease Diabetes (in association with obesity) Fabry Disease Gastrointestinal Pancreatitis Inflammatory Bowel Disease Neoplastic Marrow Infiltrative Disorders Infectious Osteomyelitis Human Immunodeficiency Virus Meningococcemia Vascular/Rheumatologic/Connective Tissue Disorders Systemic Lupus Erythematosus Polymyositis Polymyalgia Rheumatica Raynaud Disease Rheumatoid Arthritis Ankylosing Spondylitis Sjo¨gren Syndrome Giant Cell Arteritis Thrombophlebitis Lipid Emboli Ehler-Danlos Syndrome Orthopedic Problems Slipped Capital Femoral Epiphysis Congenital Hip Dislocation Hereditary Dysostosis Legg-Calve´-Perthes Disease Extrinsic Dietary or Environmental Factors Dysbaric Conditions (Caisson Disease) Alcohol Consumption Cigarette Smoking Iatrogenic Corticosteroids Radiation Exposure Hemodialysis Organ Transplantation Laser Surgery Idiopathic NOTE. These conditions have been reported to be associated with osteonecrosis, whether or not the association has been established definitively.

condyle in elderly women (“spontaneous osteonecrosis”) is a distressing but uncommon problem (13). Although disease involving the shoulder joint is disabling, especially if bilateral, it fails to match the debilitating morbidity of osteonecrosis of the femoral head (14). Table 2 shows the most common sites involved in osteonecrosis, with the femoral heads being the most commonly affected, as shown by the data from one series of 101 patients that were reviewed. Other reports of affected sites include the femoral and humeral head (15); knees (femoral condyles, proximal tibia) (16); small bones of the foot and ankle (17,18), wrist and hand (including scaphoid and lunate bones) (10); vertebra (19); and, less commonly, facial bones (20,21).

METHODS

A Medline search of published studies with key words “osteonecrosis and avascular necrosis from 1961 to 2001” was conducted. From these studies and their accompanying references, a total of 524 studies dating from 1948 to the present were reviewed and 213 were determined to be pertinent to our discussion. These manuscripts included a variety of subjects, including disease pathogenesis and treatment. The manuscripts were reviewed with particular reference to the potential mechanisms involved in the generation of osteonecrosis.

In addition, data describing the associations of osteonecrosis with corticosteroid usage, alcoholism, clotting disorders, trauma, orthopedic conditions, genetic factors, and a variety of other features were reviewed. The clinical characteristics of these associations, as well as diagnostic technological advances, also were compiled. Finally, the treatment of osteonecrosis, from both conservative and surgical standpoints, was studied and is presented herein.

PATHOGENESIS OF OSTEONECROSIS

It commonly is accepted that the final common pathway for the development of osteonecrosis involves a compromise in blood flow to the bone. In trauma, it is the disruption of the normal vascular supply to the bone that leads to necrosis. On the other hand, in non-traumatic osteonecrosis, the underlying pathology is not always clear. The events leading to the destruction of the bone in non-traumatic osteonecrosis may vary depending on the underlying cause and may involve either extraosseous or intraosseous abnormalities. Sev-

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

97

Table 2: Sites of Involvement in Osteonecrosis Percentage of Patients Site Hip (Femoral Head) Knee (Femoral Condyles) Shoulder (Humeral Head) Ankle (Talus)

With Involvement of this Site (%)

Frequency of Bilateral Involvement (%)

References

100

98

15

96

86

16

80

83

15

44

Not reported

17,18

*The percents reflect the incidence of involvement of the particular site in 101 patients for whom data was submitted. The percentages for bilateral involvement reflect the proportion of patients with bilateral involvement of the affected site.

eral theories have been proposed as the underlying etiologic event that leads to disruption of the vascular supply to the affected bone. For the purpose of this discussion, we will address the pathogenesis of osteonecrosis primarily as it pertains to the femoral head.

Vascular Occlusion or Ischemia Anatomy of the femoral head. Trueta and Harrison (22) gave the first description of the intracortical vascular anatomy of the femoral head in 1953.

The lateral epiphyseal arteries branch off from the medial circumflex arteries and penetrate the posterosuperior aspect of the femoral head. Once within the cortex, these arteries run medially and anteriorly as they course just over the scarred growth plate toward the anterosuperior quadrant of the femoral head. These arteries supply 80% of the femoral epiphysis and are usually 2 to 6 in number (22,23). Intracortical blockage of these arteries could account for the anatomic predisposition of osteonecrosis to affect the anterosuperior quadrant of the femoral head (24). Chandler compared osteonecrosis of the femoral head to coronary artery occlusion (25), suggesting that blockage of the posterolateral retinacular artery can result in infarction of the superolateral segment of the femoral head.

In Legg-Calve´-Perthes disease (LCPD), the femoral head has been studied by Kikkawa et al (26) using a rat model with osteonecrosis of the femoral epiphysis that resembles the disease in children.

They found that the rats exhibited altered expres-

sion of insulin-like growth factor-I (IGF-I), which led to delayed expression of type X collagen during epiphyseal ossification and to secondary mechanical instability of the femoral epiphyseal plate.

They believe that the collapse of this unstable segment physically interrupts blood supply in a way similar to trauma-induced osteonecrosis.

Altered Fat Metabolism and Fat Emboli Jaffe et al (27) first suggested steroid-induced hyperlipidemia increases the amount of fat within the femoral head, elevates the intracortical pressure, and leads to sinusoidal collapse. Since 1977, Wang et al (28) have undertaken studies to show how altered lipid metabolism may lead to osteonecrosis. The adipocytes within the femoral head of steroid treated rabbits had a 25% increase in fat content compared with those of untreated rabbits (10-12,15,28,29). In subsequent studies, fat cell size correlated with both increased femoral head pressure and decreased blood supply. Surgical decompression in steroid treated rabbits reduced the elevated femoral pressure and gradually increased blood flow (30,31). Clofibrate, a lipid lowering agent, was administered to steroid treated rabbits and led to decreased fat cell size and intracortical pressure, and improved blood flow (32). Osteonecrosis was induced in rabbits by arterial injection of lipids (33). Steroids administered to growing and adults rabbits caused fat emboli that were visible in the histopathologic sections of the femoral and humeral heads (28). This led to the hypothesis that fat emboli lodged in the microvascu-

98

lature activate the complement pathway, leading to secondary immune complex deposition and ultimately to arteriolar hemorrhage and osteonecrosis.

This theory, although intriguing, remains unproven (34). The work of Wang et al (28) suggests that hypercholesterolemia may play a role: their steroid-treated animals developed increased serum cholesterol levels with fatty metamorphosis of the liver and fat emboli that partially obliterated the microcirculation of their femoral and humeral heads.

Jones proposed fat embolism as a cause of steroid-induced osteonecrosis (33). Hungerford and Lennox (35) suggested that osteonecrosis may result in increased intraosseous pressure as a result of the increase in fat content in the marrow. The common denominator in cases of osteonecrosis is a compromise in blood flow to the affected area; an increase in pressure can conceivably lead to this compromise.

Intravascular Coagulation Thrombophilia and hypofibrinolysis have both been implicated as causative factors for osteonecrosis (36,37). Intravascular coagulation of the intraosseous microcirculation (capillaries and venous sinusoids), progressing to generalized venous thrombosis, and less commonly to retrograde arterial occlusion, appears to be one of the causes of nontraumatic osteonecrosis (38). However, coagulopathy is usually a secondary event, which occurs as a result of some other underlying etiologic risk factor(s) or chemical substance(s). Conditions capable of triggering intravascular coagulation include familial thrombophilia, hyperlipidemia and fat emboli, hypersensitivity reactions, allograft organ rejection, and other prothrombotic and hypofibrinolytic conditions. Biologic and chemical substances that can lead to disseminated intravascular coagulation include bacterial endotoxins, proteolytic enzymes, tissue factors such as tumor necrosis factor, antiphospholipid antibodies, and immune complexes. These may be present in various conditions including infection, pancreatitis, malignancies, collagen vascular diseases, and pregnancy.

Healing Process Although primary occlusion of the lateral epiphyseal arteries can lead to osteonecrosis, it is also conceivable that osteonecrosis may be secondary to the healing process occurring within the femoral

ASSOULINE-DAYAN ET AL

head in response to the development of necrotic bone (39,40). Necrotic bone tissue initiates recruitment of osteocytes, histiocytes, and vascular elements to the affected area. Osteoclasts are stimulated to degrade dead bone, whereas osteoblasts are stimulated to lay down new bone. This osteoblastic activity creates a new layer of bone on top of the old necrotic bone. In addition, other marrow elements (primarily fibroadipose tissue) are stimulated to help repair the necrotic lesion. Generally, this repair is counter productive, forming a thick scar of fibrous tissue at the base of the necrotic bone, separating it from viable tissue, and preventing the penetration of revascularization into the necrotic lesion.

Recently, the reparative process after vascular deprivation-induced necrosis of the femoral head was studied histologically in rats (41). Granulation tissue and well-vascularized fibrous tissue originating from the joint capsule invaded the necrotic marrow spaces. With progressive resorption of the necrotic tissue and osteoneogenesis, the remodeling process led to a shift of the normal spongy architecture of the femoral head to a “compactlike” one. Remodeling was associated with flattening of the femoral heads as well as with degenerative, regenerative, and reparative alterations of the articular cartilage. These findings were consistent with the hypothesis that collapse of the femoral head may result from ineffective attempts of the body to replace necrotic bone with viable tissue (41).

Atsumi et al (42) and Atsumi and Kuroki (43) performed microangiographic studies on 31 femoral heads with osteonecrosis and showed interruption of the superior retinacular arteries in the extraosseous area and blockage of revascularization at the weight-bearing region. These impressive arteriographic studies provide additional support to the hypothesis that arterial occlusion is secondary to the healing process.

Elevated Intracortical Pressure As discussed previously, interruption of blood flow also can be the result of elevated pressure within the femoral head. The femoral head is essentially a sphere of cancellous bone, marrow, and fat surrounded by a cortical shell. An increase in the space occupied by any element within the femoral head, whether it is related to the healing

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

process or not, may elevate the intracortical pressure and compromise blood flow (35,39,44).

Inhibition of Angiogenesis Osteonecrosis may result from compromise of normal angiogenesis that occurs regularly in bone tissue. This new hypothesis for the inhibition of angiogenesis was introduced by Smith et al (45).

This theory is supported by the fact that a number of drugs and mediators, including glucocorticoids, interferons, constituents of cartilage, and other endogenously produced cytokines, inhibit angiogenesis. In addition, inhibition of vascularization, as a result of steroid administration, has been observed in angiography studies of the femoral head.

Intramedullary Hemorrhage For many years investigators have observed zones of intramedullary hemorrhage in the vicinity of osteonecrotic lesions (7), but its presence either was not commented on, was attributed to secondary changes occurring in response to osteonecrosis, or was described as an artifact of preparation. Saito et al (46) investigated whether or not primary hemorrhage could be a possible cause of osteonecrosis. In 16 femoral heads, old and new hemorrhage in the marrow of osteonecrosis patients was the most common and characteristic feature and correlated with necrosis. Examination of fresh hemorrhage zones revealed damage to the internal elastic membrane, the tunica media, and the smooth muscle of the arteriolar walls (47). These findings were absent in the femoral heads of patients with osteonecrosis. They concluded that silent, recurrent intramedullary hemorrhage secondary to arteriopathy is an important event in the pathogenesis of osteonecrosis. Which patients may be more prone to this type of hemorrhage is unknown. Spencer and Brookes (48) found similar pathologic changes in the vascular pattern in the femoral head of steroid-treated renal transplant patients. Matsui et al (49) were later able to induce osteonecrosis secondary to hypersensitivity vasculitis and high-dose steroids in 14 of 20 steroidtreated rabbits. Intramedullary hemorrhage was detected in 8 of the 14 rabbits with osteonecrosis. All specimens that showed osteonecrosis or marrow necrosis revealed arteriopathy. Unfortunately, this relationship could be established only as an association because hemorrhage always accompanies necrosis in any tissue, including bone.

99

Mechanical Stress Mechanical stress may be important in the pathogenesis of non-traumatic osteonecrosis. The weight-bearing region of the femoral head is the anterior-superior quadrant, and therefore, is under a large mechanical strain. Occlusion of vessels in the lateral part of the femoral head might be the result of cartilage breakdown secondary to excessive mechanical stress. Support for this hypothesis stems from experiments by Iwasaki et al (50), in which rabbits with vascular occlusion to the femoral head developed osteonecrosis, but rabbits with vascular occlusion to the femoral head who had the sciatic nerve cut, thus preventing weight bearing, had a lower incidence of osteonecrosis. Suehiro et al (51) studied osteonecrosis of the femoral head in rats. One group of animals was kept in high cages and had to stand on their hind limbs to feed. The high prevalence (33%) of osteonecrosis in that group suggested that excessive mechanical stress on the femoral heads was responsible, at least in part, for the development of osteonecrosis.

Primary Cell Death Rather than osteocyte death being secondary to vascular compromise, several authors have presented evidence of direct cell death being the primary event. Spencer et al (52) were the first to describe the presence of empty osteocyte lacunae in the subchondral bone of renal transplant patients who had no other findings of osteonecrosis. Other investigators (53) have found nonviable osteocytes in the central region of many trabeculae in patients with osteonecrosis. This has led to the conclusion that osteocyte death may precede other histologic changes found within the femoral head. Therefore, inflammatory cell infiltration, osteoblast recruitment, vascular hemorrhage, and avascularity would all be secondary changes in response to the necrotic osteocyte. Further studies focused on mechanisms by which steroids and alcohol can directly cause osteocyte death. The accumulation of lipid in the osteocytes of the femoral head in rabbits was studied after the administration of high-dose steroids (54). Electron microscopy showed lipid droplets within the osteocytes that gradually enlarged, compressed the cell nucleus, and led to loss of cell membrane integrity and death. Similar findings also were noticed in the femoral heads of patients treated with steroids or in

100

ASSOULINE-DAYAN ET AL

patients who consumed large amounts of alcohol (55).

ROLE OF GLUCOCORTICOSTEROIDS IN PATHOGENESIS OF OSTEONECROSIS

Steroid use has been associated with osteonecrosis, but a causal relationship is not always directly found. The influence of steroids on the kinetics of osteocytes has been studied by Weinstein et al (56). When mice were given high doses of prednisolone for 27 days, the investigators found that they had an increase in both osteoblast apoptosis and osteoclast apoptosis in metaphyseal corticol bone. Associated changes included a decrease in bone density, formation, and turnover. Serum osteocalcin levels were diminished and histologic sections showed increased formation of cancellous bone and decreased trabecular width. Increases in osteoblast and osteocyte apoptosis also were documented in patients with glucocorticoid-induced osteoporosis. Decreased production of osteoclasts explains the reduction in bone turnover, whereas decreased production and apoptosis of osteoblasts would account for the decline in bone formation and trabecular width. Furthermore, accumulation of apoptotic osteocytes may contribute to osteonecrosis. These findings provide evidence that steroid induced bone disease arises from changes in the numbers of bone cells.

The effect of pulsed doses of methylprednisolone acetate on bone and bone marrow tissue has been investigated by Yamamoto et al (57).

Rabbits were treated with methylprednisolone injections and observed for the formation of osteonecrosis at 4, 6, 8, and 10 weeks. Forty-three percent of the rabbits developed osteonecrosis in multiple sites by the fourth week after injection with 20 mg/kg of methylprednisolone. Other factors related to altered lipid metabolism also were found to be present, including fatty liver, hyperlipidemia, and intraosseous fat embolism. However, in a prospective study in humans with spinal cord injury, no cases of osteonecrosis were found after short-term megadose methylprednisolone (58).

MULTIFACTORIAL ETIOLOGY

The epidemiology of osteonecrosis suggests that the pathogenesis is multifactorial. In 1983, Kenzora (59) introduced the concept of accumulative cell stress theory. He postulated that, when multi-

ple stress factors are present, the osteocytes are unable to recover from chronic damage, become overwhelmed, and die. This theory stems from epidemiologic data that show a higher rate of steroid-induced osteonecrosis in systemically ill patients.

The incidence of osteonecrosis when steroids are the only triggering factor present is low. More than 6000 patients were treated at the Maryland Institute for head injuries with prolonged highdose corticosteroids without occurrence of osteonecrosis (59). However, in patients with systemic illnesses, primarily those involving immune complex deposition, steroid use dramatically increases the incidence of osteonecrosis. In patients with vasculitides, the incidence of steroid-induced osteonecrosis is higher during disease flare-ups (59,60). As described below, the duration of steroid usage also is important. In patients with asthma and inflammatory arthritis on corticosteroids, the incidence of osteonecrosis is low. Colwell et al (61) performed a 10-year prospective study on patients with the above conditions who received corticosteroids; none of the 142 patients developed osteonecrosis. We do not know why these data are different from studies. It may be a reflection of the degree of vascular compromise in bone tissue.

Renal transplant patients, who have had years of systemic chronic renal failure and renal osteodystrophy, have a high incidence of steroid-induced osteonecrosis. With improvements in renal dialysis, the systemic effects of chronic renal failure have been minimized, and the incidence of steroidinduced osteonecrosis also has been reduced. Alcohol abuse, which damages cells of many organ systems, also is a factor influencing the accumulated stress of the osteocyte within the femoral head. At each stage of the systemic illness, the osteocytes become more distressed. Frequently, it appears to be steroid administration that produces the overwhelming stress leading to irreversible damage and cell death. The exact mechanism of cell stress in chronic renal patients may involve direct toxic effects of “poisons” in the body, such as alcohol or uremia, in addition to indirect stresses, such as steroids, that affect the osteocytes by altering lipid metabolism or by causing bone cell death. A list of proposed mechanisms for the development of osteonecrosis is shown in Table 3.

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

Table 3: Proposed Mechanisms for the Development of Osteonecrosis Vascular Occlusion Altered Lipid Metabolism/Fat Emboli Intravascular Coagulation Healing Processes Primary Cell Death Mechanical Stress Elevated Apolipoprotein B/Apolipoprotein A1

CLINICAL ASSOCIATIONS

Trauma Trauma is the most common cause of osteonecrosis, and the site most frequently affected is the femoral head. The cause of ischemia in trauma-related osteonecrosis is interruption of the blood supply to the affected segment of the bone. Osteonecrosis is associated with approximately 16% of nondisplaced subcapital fractures and 27% of displaced subcapital fractures. Osteonecrosis also occurs in conjunction with approximately 3% of anterior hip dislocations and in more than 13% of posterior hip dislocations.

Transcervical fractures and compression fractures of the femoral head also may lead to osteonecrosis. Osteonecrosis is increasingly recognized as a postoperative complication (62,63).

Corticosteroids When first described, the association between osteonecrosis and steroids was observed in renal transplant patients who were treated with steroids as part of the immunosuppressive regimen (64). At the time, establishing a clear association between steroids and osteonecrosis was not an easy task because these patients also suffered from bone disease secondary to renal insufficiency and dialysis treatment. However, there have been many reports linking the use of steroids and the development of osteonecrosis since then, and the association is now well established. Steroids are now the second most common cause of osteonecrosis after trauma and the prevalence in studies of AVN varies between 3-38% (Table 4). In retrospective studies, the interval between steroid administration and the onset of symptoms is rarely less than 6 months and may be more than 3 years. However, in prospective studies, this interval may be shorter.

101

Sakamoto et al (65) recently performed a prospective study using MRI to evaluate early necrosis of the femoral head. Initial changes were seen as early as 3.6 months (mean interval), although approximately half of the lesions spontaneous decreased in size about 1 year after treatment had started, and had not changed further with a longer follow-up (mean follow-up, 31 months). In addition to osteonecrosis of the hips, which often is bilateral, corticosteroid usage may be associated with involvement of the humeral heads and other bones (15).

Most of the cases that were first described involved patients who had undergone immunosuppressive therapy after renal transplantation (64).

Since then, there have been many reports of steroid-induced osteonecrosis in patients treated for other conditions (Table 5). In a multicenter study of symptomatic multifocal osteonecrosis (defined as disease involving 3 or more anatomic sites), 92 of the 101 (91%) patients had a history of steroid therapy (15).

Establishing an association between osteonecrosis and steroids is difficult because many of the underlying conditions for which steroids were administered can lead to osteonecrosis.

There is an increased incidence of osteonecrosis in patients with renal insufficiency, whether or not they are on steroids. These patients also suffer from renal osteodystrophy; therefore, the role of corticosteroids in the cause of osteonecrosis is unclear.

It has been observed that osteonecrosis occurs more commonly in patients who have received long-term courses of steroids, especially those patients who received long-acting steroids. Nonetheless, osteonecrosis also has developed in patients treated with short-term courses of high-dose steroids. Good (66) reported a case of osteonecrosis following a 16 day course of adrenocorticotropic hormones. Fisher and Bickel (67) reported osteonecrosis complicating a 30-day course of 16 mg/ day of prednisolone. Osteonecrosis also has been associated with intra-articular injection of steroids (68) and steroid enemas (69). Nonetheless, just because a patient has been treated with steroids does not mean that the steroids produced the osteonecrosis. All risk factors need to be considered.

In most cases, it appears that the effect of steroids is cumulative and that the risk of osteonecrosis decreases after they are stopped. Fink et al (70) found that for post–marrow transplant patients the

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ASSOULINE-DAYAN ET AL

Table 4: Studies of Corticosteroid-Induced Osteonecrosis

Reference

Condition or Disease

Type of Study

193

ALL

Prospective

194

Kidney Transplant

Retrospective

Patients Prevalence (n) (%)

Mean Interval Between Treatment and Glucocorticosteroid Osteonecrosis (mo) Dose

24

38

NA

374

11

34 mg/day

376

5

17 mg/day Total dose 189 mg/kg (range 13-555 mg/ kg) Total prednisone 2725-5250 mg

195

Post-allogenic Retrospective BMT

272

6

196

Hodgkin Disease

Retrospective

784

1

197

ALL

Retrospective

850

0.6

NA

Post-BMT

Case control

1939

5

NA

198

Pediatric, ALL

Prospective

28

32

199

Post-BMT

Multicenter Retrospective

4388

4

70

High-dose Dexamethasone

NA

Conclusions/ Shortfalls

Within a few Corticosteroids may months cause osteonecrosis in cancer patients.

26 Steroids may cause osteonecrosis in post-transplant 21 patients.

13 MRI can help detect asymptomatic osteonecrosis.

35 Osteonecrosis rare in corticosteroidtreated patients with Hodgkin disease.

29 Radiography and bone scans were performed on symptomatic patients only.

26 Corticosteroids are a high risk factor for developing osteonecrosis in ALL. NA

22

56% were asymptomatic at time of diagnosis.

A significant risk of developing osteonecrosis exists in patients on intensive corticosteroid treatment for ALL. Steroids are a significant risk factor for developing osteonecrosis in post-BMT patients.

Abbreviations: ALL, acute lymphoblastic leukemia; BMT, bone marrow transplantation; NA, not available.

greatest risk was for those receiving steroids at the time of diagnosis with osteonecrosis. Although the risk appears to increase with both the dose of steroids and the duration of treatment, it is difficult to predict which patients will develop osteonecrosis. It also is difficult to characterize steroid use because of the variability of prescription parameters, such as duration of use and route of administration.

Weinstein et al (71) further studied a group of patients who had undergone prosthetic hip replacement because of osteonecrosis. The underlying cause for the osteonecrosis was nontraumatic in the majority of cases. There was increased apoptosis in those patients who were on glucocorticoids but not in patients with trauma, sickle cell disease, or alcoholism. They concluded that glucocorticoid use interferes with the mechanosensory function of

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

Table 5: Conditions that Are Associated with Osteonecrosis Treated with Corticosteroids Connective Tissue Diseases SLE Rheumatoid Arthritis (200) Scleroderma (201) Polymyositis/Dermatomyositis (202) Hematologic Disorders/Malignancies ALL Promyelocytic Leukemia (203) Lymphoma Aplastic Anemia (204) Post Bone Marrow Transplantation Solid Malignancies Testicular Carcinoma (205) Bronchogenic Carcinoma (148) Ovarian Carcinoma (206) Organ Transplant Kidney Heart (207) Lung (208) Inflammatory Bowel Disease (IBD) Crohn Disease (209) Ulcerative Colitis Miscellaneous Premature Ovarian Failure (210) Refractory Celiac Disease (211) Spinal Cord Injury (212) Topical Steroid Use (213)

osteocytes, resulting in collapse of the femoral head.

Alcohol Alcohol abuse is a possible etiologic factor in osteonecrosis of the femoral head, and this association was first described in 1922. In one study of 57 patients, the incidence of alcohol-associated osteonecrosis of the femoral head and of idiopathic osteonecrosis were 29% and 12%, respectively.

Nine patients in the alcohol group were heavy drinkers, 4 were alcoholics, and 2 were moderate drinkers at the time of onset of symptoms (72). A different study compared 112 patients with nontraumatic osteonecrosis of the femoral head who had no history of systemic steroid use with 168 controls (73). An elevated risk for regular drinkers and a clear dose-response relationship was noted for ongoing consumers of less than 400, 400-1000,

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and greater than or equal to 1000 mL/week of alcohol. The relative risk was 3-, 10-, and 18-fold, respectively.

Orlic et al (74) attempted to determine risk factors for the development and progression of osteonecrosis in patients who consumed alcohol and in idiopathic osteonecrosis patients (a total of 172 patients). Patients with alcohol-induced osteonecrosis were significantly older than patients with idiopathic osteonecrosis (average age, 49 years v 40 years), were men (97%), and presented with collapsed femoral heads (90%). In patients with idiopathic osteonecrosis, 35% had bilateral disease and 55% presented with a collapsed femoral head.

Another group of 164 patients with alcohol-induced osteonecrosis was analyzed for different factors. The average duration of alcohol abuse was 9.5 years, 28% of patients were younger than 40 years of age, and 76% were younger than 50 years.

Bilateral necrosis of femoral heads was present in 45% of patients, and, within 3 years of the diagnosis, multifocal osteonecrosis became evident in 23 cases at distant sites (shoulders and knees).

Elevated cholesterol and triglyceride levels were found in 38% of cases. Serum amylase was elevated in 33 (20%) patients, liver dysfunction was present in 50 (30%), hepatomegaly was found in 32 (20%), and biopsy confirmed cirrhosis was present in 22 (13%) cases. Disabling hip pain was the first manifestation of disability related to alcohol-induced osteonecrosis in 158 patients, most of whom required total hip joint replacement (75).

Many studies have been designed to elucidate the mechanism of alteration of bone metabolism by alcohol. Rico et al (72) studied serum cortisol and urinary free cortisol levels in 8 patients with osteonecrosis of the femoral head caused by alcoholism. They found significantly higher serum cortisol levels and urinary free cortisol levels in the alcoholic group than in a similar group with idiopathic osteonecrosis. The results of pathologic studies of 68 osteonecrotic femoral heads (45 patients) caused by steroids were found to be similar to those taken from alcoholic patients (76). In a different study (55), the cholesterol content was elevated in both the affected and unaffected regions of alcohol-induced osteonecrotic bones when compared with the cholesterol content of control bones.

In an alcoholic rabbit model, there was a significantly higher serum cholesterol level and greater bone marrow pressure compared with controls.

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There was no significant difference in serum triglyceride levels. The effect of alcohol on the trabecular bone volume in rabbit was not significant but the average fat cell size of the femoral head was significantly larger than in normal controls (77). Alcohol appears to compromise blood flow through fat embolization or fat hypertrophy, and can cause cell death by its direct toxic effect on osteocytes and other marrow elements.

SLE SLE is a multisystem autoimmune disease characterized by fluctuating disease activity. Steroids are an essential part of the treatment programs, with the route of administration and dosage schedule dependent primarily on the severity of the disease and organ involvement. One of the complications of steroid treatment of SLE is osteonecrosis, which is clinically apparent in 4%-15% of patients but reaches 40% prevalence when asymptomatic patients also are included (78-83).

Osteonecrosis in SLE was first documented by Dubois and Cosen in 1960 (84) and there have been frequent reports of the association thereafter (85-88). Patients with SLE commonly have multiple joint involvement, including unilateral or bilateral osteonecrosis of the hip. In a prospective study, osteonecrosis was present in 93 sites in 28 SLE patients, and all but 2 of them had more than 1 site involved. The hips were most frequently involved, followed by the knees and shoulders (83).

Most investigators have found steroid use to be the major risk factor for osteonecrosis in SLE patients. However, the association between the potential risk and parameters such as the threshold for cumulative steroid dosage, maximum steroid dose, route of administration, and the duration of treatment have yet to be established (86-88). In a recent retrospective study of 38 SLE patients with osteonecrosis, the highest steroid dose given within 4 months of diagnosis of osteonecrosis correlated with an increased risk for osteonecrosis. There was no relationship between risk of osteonecrosis and the total dose of steroids, the duration of steroid therapy and disease activity (81). There also is conflicting evidence regarding pulse steroid therapy and the risk of osteonecrosis. One study showed that pulse methylprednisolone increases the risk of osteonecrosis in SLE (89), whereas others have failed to document such an association

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(81,90,91). Although most reported cases of osteonecrosis in SLE patients were associated with steroid use, there have been cases of osteonecrosis in SLE in which steroids could not be implicated.

Vasospasm, as seen in Raynaud phenomenon and Cushingoid features, are possible risk factors for osteonecrosis (83). Kalla et al (92) documented Raynaud phenomenon in 6 of 13 SLE patients with osteonecrosis. All patients had been on corticosteroids, 10 patients had severe multisystem involvement, and 1 had digital vasculitis.

A recent study (93) showed that patients with osteonecrosis had significantly higher rates of Cushingoid body habitus, thrombophlebitis, vasculitis, cigarette smoking, and preeclampsia. Mok et al (81) found that patients who required an initial high-dose steroid for disease control were at risk of osteonecrosis, especially if they were positive for the lupus anticoagulant or developed Cushingoid habitus after steroid treatment. However, not all investigators documented the relationship between these reported risk factors and osteonecrosis (81,94,95).

Another potential cause for osteonecrosis is the presence of antiphospholipid antibodies that are known to cause intravascular coagulation and vasculitis (93,94,96). Asherson et al (96) detected antiphospholipid antibodies in 73% of the SLE patients with osteonecrosis, whereas the average prevalence of these antibodies among all SLE patients is 44%. Mok et al (81) found the presence of lupus anticoagulant to be associated with increased risk for osteonecrosis. However, as with other potential risk factors, conflicting results have been reported regarding the antiphospholipid antibodies issue. Migliaresi et al (91) found abnormal IgG and/or IgM anticardiolipin serum levels in only 2 of 7 osteonecrosis-SLE patients and in 24 of 62 nonosteonecrosis SLE patients; therefore, they were unable to show a statistically significant difference between the groups. Other studies (79,80,82) have found similar prevalence of antiphospholipid antibody titers among SLE patients with or without osteonecrosis.

It is likely that multiple factors may contribute to the development of osteonecrosis in SLE patients. Further prospective studies are needed to clarify this matter because patients with antiphospholipid antibodies at risk for osteonecrosis may benefit from anticoagulation therapy. Moreover, defining the exact risk factors in SLE patients will

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

Table 6: Risk Factors in SLE Patients Associated with Development of Osteonecrosis Cushingoid Body Habitus Presence of Antiphospholipid Antibodies Thrombophlebitis Vasculitis Raynaud Phenomenon Cigarette Smoking Preeclampsia Hypertension Pleural Effusion* Interstitial Pneumonitis* Cerebritis* Nephritis* Anemia Thrombocytopenia Purpura Early Age of Disease Onset Afro-American Origin Migraine Headache *These are severe complications, and such patients may have been treated with higher doses of steroids for longer duration; such data is not always available.

enable closer monitoring of high-risk populations and facilitate earlier diagnosis (Table 6).

Asymptomatic osteonecrosis of the femoral head is not an uncommon finding in steroid-treated

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SLE patients. In a recent prospective study, 60 patients with SLE and normal hip radiography were followed up for a mean period of 5 years by using MRI. Patients who had no MRI finding typical of osteonecrosis (Table 7), had a very low risk of femoral head collapse by the end of the first year of steroid treatment (98). Similarly, in a different study that included 23 asymptomatic SLE patients with normal radiography, disease progression over 3 years of follow-up was documented in only 25% (2/8) of patients who initially had abnormal MRI (99).

Treatment of SLE patients with osteonecrosis is directed toward joint preservation. Total hip arthroplasty (THA) is the most common solution for advanced disease. For a long time, surgeons were reluctant to perform THA in this group of patients because of poor surgical outcome. Alcoholism or trauma may have had a contributing effect on the outcome of THA surgery in young patients with osteonecrosis (100,101). However, Zangger et al (102) recently conducted a study in which they compared the long-term results of 26 THA performed in SLE patients with 29 THA performed in non-SLE patients. The average follow-up was longer than 4.5 years and they found good shortand medium-term results in the SLE group that were no different from the non-SLE group. Moreover, not all investigators have documented the

Table 7: Correlation of MRI Findings with Histologic Changes Class

Appearance

MRI Findings

Histology

A

Fatlike

Normal fat signal except at the sclerotic margin surrounding the lesion

B

Bloodlike

C

Fluidlike

D

Fibrous

High signal intensity of inner border and low signal of surrounding rim Decreased T1-weighted and increased T2-weighted signal changes, extending from the osteonecrotic segment down the femoral neck* Circumscribed signal abnormality with decreased signal on T1- and T2weighted images

Premature conversion to fatty marrow within the femoral neck and intertrochanteric region Bone resorption and replacement by vascular granulation tissue Bone marrow edema

Sclerosis from reinforcement of existing trabeculae at the margin of live bone (ie, repair tissue interface)†

*The latter finding usually occurs following subchondral collapse and suggests a poor prognosis. †It is speculated that this appearance is due to reactive bone (dark line) and vascular tissue (bright line) at the ischemic-viable bone interface.

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relationship between these reported risk factors and osteonecrosis. There were no significant differences between patients with osteonecrosis and controls in prevalence of specific organ system involvement, Raynaud phenomenon, or abnormal serologic or hematologic variables; the conclusion was that glucocorticosteroid intake is the major factor predisposing to aseptic necrosis in patients with SLE (92). Rascu et al (95) found no increased frequency of Raynaud phenomenon, leukopenia, antiphospholipid antibodies, or a flare of SLE activity in their patients with osteonecrosis. Nagasawa et al (94) found no association between osteonecrosis and Raynaud phenomenon, hyperlipidemia, nephrotic syndrome, hypertension, or disease activity.

Coagulopathies Intravascular coagulation and increased thrombotic tendency appears to be a potential risk factor for osteonecrosis in adults and children. Patients with osteonecrosis may exhibit coagulation disorders, including thrombophilia mediated by Factor V Leiden, deficiency of protein C, S or antithrombin III, homocysteinemia, or the presence of anticardiolipin antibodies. Hypofibrinolytic disorders, mediated by increased levels of plasminogen activator inhibitor, also may be associated with osteonecrosis. Wermes et al (103) reported a 4-year-old boy with severe protein C deficiency who was treated with coumadin after experiencing an episode of purpura fulminans, and who was diagnosed with osteonecrosis of the femoral head after complaining of hip pain.

In addition to these anecdotal reports, a number of investigations have studied the correlation between osteonecrosis and coagulation disorders.

Glueck et al (104) tested 59 patients with osteonecrosis for the presence of increased thrombotic tendency. They found no difference in the frequency of mutations for Factor V Leiden, prothrombin, or methylene tetrahydrofolate reductase (MTHFR) between osteonecrosis patients and controls, but they documented increased hypofibrinolysis in the osteonecrosis group. High plasminogen activator inhibitor activity (PAI-Fx) was found in 61% of osteonecrosis patients versus 5% of controls. In another study, an evaluation of the fibrinolysis system of 4 patients with osteonecrosis and 1 patient with transient osteoporosis showed abnormal fibrinolysis in all 5 patients. Four pa-

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tients had increased levels of PAI-Fx and 1 patient had an abnormal tissue plasminogen activator (tPA) response to venous occlusion (37).

Some investigators have treated osteonecrosis by treating of the underlying coagulation disorder (105). Twenty-six patients with coagulation disorders and osteonecrosis of the jaw who suffered from chronic facial pain were given an oral anticoagulant or an anabolic steroid. After an average of 22 months, approximately 60% of patients reported improvement of pain while the remaining 40% reported no change or enhanced pain. Unfortunately, no objective tests or imaging modalities were used to document the disease reversal or the prevention of progression. The investigators concluded that many patients with facial pain secondary to osteonecrosis of the jaw may benefit from treating the underlying coagulation defect. However, further studies are needed to determine whether anticoagulant treatment can halt the progression of osteonecrosis.

Legg-Calve´-Perthes Disease (LCPD) Legg-Calve´-Perthes disease is a disorder affecting children between the ages of 4 and 12 years.

One feature of LCPD is osteonecrosis of the capital femoral epiphysis. The prevalence of this condition varies between 1:1200-1:12000. The early ischemic changes in LCPD may be asymptomatic.

Advanced disease involves secondary osteoarthritis of the hip joint and/or shortening of the affected leg by an average of 1 to 1.5 cm. Even with this deformity, patients can function quite well. Unfortunately, by the sixth or seventh decade of life, osteoarthritis develops and THR may be required (106).

Thrombophilia has been postulated to be the underlying pathology in LCPD. Glueck found increased thrombophilic tendency in up to 75% of 46 children with LCPD. Conversely, in a different group of children, Gallistl et al (107) found this abnormality to be only 9%. Thomas et al (108) found coagulation abnormalities in only 8 (12%) of 64 children with LCPD, and only 5 exhibited clinical signs of thrombophilic tendency. Of the 8 children with coagulation abnormalities, 1 had a low protein S level, 4 had resistance to activated protein C (RPCA), and the other 3 had slightly low levels of antithrombin III (108).

Another possible cause of LCPD involves synovitis of the hip joint, which is an important feature

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

in LCPD (109). Synovitis is ďŹ rst characterized by cartilage edema and subsequently by cartilage hypertrophy, which increases intracapsular pressure and compromises blood ow. It also is possible that the hypertrophied cartilage increases mechanical strain within the femoral head and leads to lateral subluxation and femoral head deformity.

Whether synovitis results from ischemia or is the primary pathology remains unclear.

Hemophilia and Hemorrhage Arthropathy of the ankle joint is commonly observed in people with severe hemophilia. A review of the radiological appearance of ankle arthropathy suggests evidence that the changes in the talar bone are due to osteonecrosis. This may arise because of impairment to the arterial supply, as it enters the talar neck, secondary to the increased pressure at the times of hemarthroses (110).

Rodgers described a child who developed massive subperiosteal hemorrhage and subsequent osteonecrosis of her right femur after treatment with tissue plasminogen activator for post-varicella streptococcal purpura fulminans. Radiographs showed posteromedial translation of the capital femoral epiphysis on the necrotic shaft, and the hip was immobilized. One-year follow-up showed remodeling and growth of the femur. The child developed a 2.1-cm leg length discrepancy, a varus deformity of the hip, and a valgus distal femur (111), but was able to ambulate without assistance.

Most cases of osteonecrosis associated with hemophilia appear to be the result of recurrent hemarthroses, and like other forms of osteonecrosis, may be insidious. Therefore, awareness of the association may facilitate early diagnosis and decrease the frequency of long-term complications.

Hemoglobinopathy Osteonecrosis of the femoral and humeral heads is one of the complications of vaso-occlusive episodes in patients with sickle cell hemoglobinopathies and is often bilateral (112,113). Individuals who are homozygous for the sickle cell gene (hemoglobin SS) appear to have a high propensity to develop sickle cell related osteonecrosis. Osteonecrosis also occurs in patients with sickle-C (hemoglobin SC), sickle-beta, and alpha thalassemia (114). The prevalence of symptomatic osteonecrosis in sickle cell patients is estimated to be 3%-5%,

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whereas asymptomatic osteonecrosis is more common (10%-41%) (114-117). The increased risk of osteonecrosis is correlated with increasing frequency of painful episodes, higher hematocrit levels, and low mean corpuscular volume (114). Osteonecrosis may be the result of occlusion of small blood vessels by rigid sickled erythrocytes, but also may be the result of marrow hyperplasia that compresses the draining veins and causes a secondary decrease of arterial blood ow (112,114).

In sickle cell patients with osteonecrosis, the size of the necrotic segment is usually very large. Treatment with core decompression or osteotomy is therefore not an option. Moreover, other surgical options like THR are complicated in this population by postoperative vaso-occlusive episodes, excessive intraoperative blood loss, and postoperative congestive heart failure (9). In addition to the high morbidity, THR has a high failure rate with 30% of patients undergoing a second surgery within 4.5 years (114).

Congenital Dysplasia of the Hip Untreated congenital dysplasia of the hip (CDH) often leads to coxarthrosis and therefore treatment is mandatory. However, one of the serious complications of all treatment modalities of CDH is osteonecrosis. The incidence of osteonecrosis in this group of patients is 3%-13% and is higher when the child is younger than 6 months or when there is severe acetabular dysplasia (118). Osteonecrosis may be the result of increased intraarticular pressure caused by forced reduction or by the use of casts and devices that prevent mobilization and hold the joint in an extreme position. The frequency of this complication can be reduced by casting in a less extreme position and by using devices that enables movement in the hip joint (119).

Pregnancy There are about 30 reported cases of osteonecrosis occurring during pregnancy in otherwise healthy women, none of whom had any of the known risk factors for the disease (120-122). The cause of pregnancy associated osteonecrosis is unknown and several mechanisms have been postulated. These include excess endogenous steroids secondary to increased adrenocortical activity, enhanced bone turnover secondary to parathyroid gland hyperplasia, and excessive mechanical strain

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secondary to weight gain or difficult delivery (123). Factors such as large weight gain in a relatively small body and varicose veins in the legs also were associated with osteonecrosis (121). Osteonecrosis often develops late in the first pregnancy or soon after delivery, and is first manifested by hip pain. In the largest series reported, 11 women (15 hips) were treated surgically with freevascularized fibular grafts, 9 of whom experienced significant or complete pain relief (121). The rarity of the disease during pregnancy, and the tendency to attribute the hip pain to other conditions that occur during pregnancy, are responsible for the delay in diagnosis that averages 10 months from the onset of pain. A high index of suspicion is needed to prevent delayed diagnosis and to improve treatment and long-term outcomes.

Gaucher Disease Gaucher disease is a storage disease caused by a deficiency of the enzyme beta-glucosidase, which is responsible for degradation of glucocerebrosidase, resulting in the accumulation of glucocerebrosidase in liver, spleen, and bone. Clinically, patients present with hepatosplenomegaly, bone pain, and osteoporosis (124).

Osteonecrosis in patients with Gaucher disease commonly develops in the long bones and in the vertebrae, and male gender and splenectomy have been found to be independent risk factors for this complication (125). Traditionally, the assumption was that glucocerbrosidase-engorged histiocytes pack the bone marrow, causing elevated intracortical pressure that eventually diminishes blood flow. Gaucher cells previously have been found to infiltrate the hepatic vasculature but bone marrow infiltration has not been observed. However, the size of Gaucher cells makes it possible for individual cells to act as emboli, which may lead to vascular occlusion. The T lymphocyte-induced impaired function of osteoblasts and osteoclasts is the major underlying pathology (126), and increased cytokine levels correlate with disease severity.

The treatment of osteonecrosis in this population is difficult because of the multifocal involvement and the patients’ young age. Enzyme replacement therapy may halt the progression of disease and reduce the number of pathologic fractures (127,128). THR is performed in advanced disease, but frequently is complicated by aseptic loosening of the prosthesis (129). Conservative treatment

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with crutch support does not favorably influence radiographic results, but with non–weight bearing and the use of analgesics, function may improve temporarily (130).

Slipped Capital Femoral Epiphysis Slipped capital femoral epiphysis (SCFE) is the most common hip abnormality of adolescence, presenting with sudden onset of severe hip pain.

SCFE also may be the consequence of delayed treatment of septic arthritis of the hip (131). Osteonecrosis is a serious complication of SCFE and is the result of diminished blood supply to the femoral head. The incidence of osteonecrosis increases with delayed diagnosis and treatment and correlates with the degree of slippage. In a study of 91 patients with SCFE, osteonecrosis developed in 7% (3/42) of hips reduced ⬍24 h from presentation, whereas in hips reduced in ⬎24 h from presentation, the incidence was 20% (10/49).

Treatment of SCFE is associated with a risk of osteonecrosis; therefore, forced reduction should be avoided. Sometimes, positioning for radiographic procedures may be sufficient to precipitate the development of osteonecrosis. When treating SCFE, fixation devices must be applied properly, or the risk of osteonecrosis is increased. The presence of ischemia on bone scans also increases the frequency of subsequent osteonecrosis (132).

Complications of treatment of SCFE include secondary osteoarthritis, hardware-related problems, and progression of slippage. Therefore, close radiologic follow-up is essential.

Hyperlipidemia Mielants et al (133) found a significant increase in serum triglyceride levels, cholesterol, pre-Blipoprotein, and uric acid in 35 patients with osteonecrosis compared with a control group. However, patients with other known risk factors, such as alcohol abuse and steroid use, were not excluded. Moskal et al (134) measured serum cholesterol levels in patients with idiopathic avascular necrosis (not treated with steroids) and found that the mean serum cholesterol level was elevated significantly in comparison with age-matched controls.

Dysbaric Osteonecrosis Exposure to large or rapid changes in the surrounding atmosphere pressure is associated with a

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

risk of decompression sickness and with dysbaric osteonecrosis (135). Dysbaric osteonecrosis mainly affects the femoral and humeral heads, although the shafts of long bones also may be affected (135,136). The risk of dysbaric osteonecrosis directly correlates with increasing frequency of exposures to decompression and by the magnitude of pressure increase at the time of exposure. It is assumed that the mechanism of dysbaric osteonecrosis involves the formation of nitrogen bubbles at the time of the decompression, but that it is not the only mechanism as decompression is not implicated in 25% of patients. It is hypothesized is that nitrogen bubbles that are formed in the fatty bone marrow eventually pack the microvasculature and elevate the pressure in the draining veins.

Others researchers have suggested that, by packing the blood vessels, nitrogen bubbles trigger a secondary intravascular coagulation that is responsible for the occlusion of the microvasculature within the damaged bone segment (137,138). In some cases, it is possible that compression itself is another cause (136,139,140). Rapid compression can lead to intramedullary venous stasis. In the presence of intramedullary gas bubbles, this may progress to thrombosis, ischemia, and bone necrosis. Others postulate that rapid compression delays venous drainage within the bone and may initiate venous stasis that causes the bone to be more susceptible to decompression injury.

Infections Osteonecrosis is a rare complication of human immunodeficiency virus (HIV) infection (141).

The pathogenesis of osteonecrosis in HIV infection is unclear; approximately 30 cases have been reported in the literature. Because a number of these cases had no other risk factors, and had osteonecrosis at multiple sites, it is assumed that HIV infection itself is the causative agent. The occurrence of osteonecrosis early in the course of HIV suggests that it could be the consequence of metabolic or immunologic changes occurring in the setting of HIV, rather than the consequence of infectious complications of HIV or acquired immune deficiency syndrome (AIDS). In other patients, anticardiolipin antibodies or elevated serum lipid levels are found. Furthermore, an association of osteonecrosis with proteinase inhibitor-induced metabolic lipid disorders has been reported.

Case reports of osteonecrosis as a complication

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of meningococcemia and disseminated intravascular coagulation have been reported (142). This association was observed in adults as well as in children.

Malignant Fibrous Histiocytoma Malignant fibrous histiocytoma is a neoplasm with a poor prognosis. It occurs in patients with long standing bone infarcts, particularly in men. In patients with dysbaric osteonecrosis (143), it has been postulated to be caused by the repair process at the site of the original infarct. It also has been found in patients with bone infarcts secondary to sickle cell trait and alcoholism (144). Although malignant fibrous histiocytoma is the most common tumor which arises at the site of pre-existing bone infarcts, other tumors have been reported, including fibrosarcoma, and more rarely, angiosarcoma (145).

Radiation Induced Osteonecrosis Osteonecrosis after radiation therapy for neoplasms is a well-documented occurrence with a plethora of anecdotal reports. It may involve the femoral head (146), bones of the jaw (147), and other sites (148). The incidence of osteonecrosis in postradiation therapy of the femoral head has been reported to be 4 in 763 patients (157). Chemotherapy may increase the risk of osteonecrosis in patients who received radiation therapy. Elderly women may be more prone to develop femoral head osteonecrosis after chemoradiation therapy.

The development of osteonecrosis after radiation is dose dependent, so certain types of hyperfractionated radiotherapy, which led to higher dose exposure, were discontinued in 1992 (149).

DIAGNOSIS, STAGING, AND CLASSIFICATION OF OSTEONECROSIS OF THE FEMORAL HEAD

The clinical features and imaging studies are the primary tools used to diagnose and stage osteonecrosis. Several different staging systems have been developed based on the severity of symptoms and radiographic findings (7,150). The introduction of new imaging techniques can help with early diagnosis and improve treatment outcomes. In femoral head osteonecrosis, determining the degree of involvement helps select the optimal treatment and also correlates with the size of the necrotic seg-

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Table 8: Staging Systems of Osteonecrosis of the Femoral Head Steinberg Stage

Criteria

0

Normal or equivocal radiography, bone scan, and MRI

I

Normal radiography, abnormal bone scan and/or MRI A. Mild (⬍15% of femoral head affected) B. Moderate (15%-30%) C. Severe (⬎30%) Cystic and sclerotic changes in femoral head A. Mild (⬍15% of head affected) B. Moderate (15%-30%) C. Severe (⬎30%) Subchondral collapse (crescent sign) without flattening A. Mild (⬍15% of articular surface) B. Moderate (15%-30%) C. Severe (⬎30%)

II

III

Marcus Stage

Ficat

Criteria

Stage 0

Criteria

I

Normal or equivocal radiography

I

II

Cystic and sclerotic changes in femoral head

IIA

Cystic and sclerotic Patients are changes in asymptomatic femoral head

III

Crescent sign

IIB

Crescent sign

IV

Flattening of the femoral head A. Mild (⬍15% of surface and ⬍2 mm depression) B. Moderate (15%-30% of surface or 2-4 mm depression) C. Severe (⬎30% of surface or ⬎4 mm depression)

IV

Step-off in outline of subchondral bone

III

Broken contour of femoral head

V

Joint space narrowing and/or acetabular involvement A. Mild B. Moderate C. Severe Average of femoral head involvement as determined in stage IV and estimated acetabular involvement.

Advanced degenerative changes

V

Joint space narrowing and/or acetabular involvement

IV

Joint space narrowing, flattened contour, collapse of femoral head

VI

Advanced degenerative changes

VI

Clinical Syndrome

Preclinical stage that includes patients with hip pain or known risk factors, and those with osteonecrosis of the contralateral femoral head.

Normal radiography Patients are and equivocal asymptomatic bone scan

ment and the outcome (151-153). Staging also provides standards to compare the morbidity and long-term results of different treatment modalities.

Clinically, the most important feature of each staging system is the initial collapse of the femoral head cortex. Before cortical collapse, the necrotic

Patients have mild intermittent pain in the groin that radiates down the inner aspect of the thigh and a normal gait.

Patients have increased pain and crepitus during changes in position particularly when arising from sitting.

Patients have pain with activity.

Patients have pain at rest

lesion can undergo repair and damage may be completely reversible; after collapse, the process is irreversible. Several staging systems have been described in an attempt to differentiate reversible from irreversible disease (Table 8). The staging systems of Steinberg et al (154), Ficat (7), and

PATHOGENESIS AND NATURAL HISTORY OF OSTEONECROSIS

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Imaging

Fig 1. Radiolucent crescent (arrow) is an early radiographic sign of osteonecrosis.

Marcus et al (8) are similar. The Steinberg classification allows the physician to quantify the extent of involvement of the femoral head in both early and late stages. This classification system involves bone scintigraphy or quantitative MRI and consists of 7 stages. The extent of disease is subdivided with each level of involvement recorded as mild, moderate, or severe. Several investigators (151153) have studied the correlation between outcome and size of the necrotic segment and each stage has a clinical correlation.

Fig 2. Conventional radiograph of both hip joints demonstrate osteonecrosis of femoral heads, right more advanced than left. Note increased density of the bone and loss of normal spherical shape of right femoral head.

Conventional radiographs are widely used in the evaluation of osteonecrosis. The specificity of radiography is excellent, but often, early lesions are missed. Radiographs become definitively positive only after the development of a “crescent sign” (Fig 1) or a sclerotic rim of reactive bone at the ischemic-viable bone interface (Fig 2). Newer techniques have been used to evaluate early disease and contralateral involvement in established disease, including MRI, selective angiography, and skeletal scintigraphy.

The use of bone scintigraphy in the early diagnosis of osteonecrosis is dependent on the fact that both osteoblastic activity and blood flow are increased in the early stages of osteonecrosis. Technetium-labeled diphosphonate uptake correlates with these 2 physiologic changes (155) and is much more sensitive than radiography. In advanced osteonecrosis, the appearance may be one of increased activity in a subchondral distribution due to osteoblastic activity at the reactive interface around the necrotic segment. However, the center of the osteonecrotic lesions may show much less radionuclide activity (Fig 3), or even complete lack of activity, reflecting decreased metabolism in the necrotic focus because of interruption of blood supply (156). In addition to bone scintigraphy, pinhole collimation, or single-photon emission computed tomography (SPECT), will maximize sensitivity. Limitations of scintigraphy include low resolution, a difficulty in distinguishing osteonecrosis from fractures, transient osteoporosis or other conditions, and technical limitations. Under

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ideal conditions, scintigraphy appears to be superior to conventional MRI for the detection of early lesions (157), although its specificity is not as high.

Computed tomography (CT) is rarely used to diagnose osteonecrosis but it may show details of the osteonecrotic lesion (Fig 4).

MRI is very sensitive to changes in bone marrow composition and is useful in differentiating fatty marrow from hematopoietic marrow.

Diffuse bone marrow edema produces a lowsignal intensity on T1-weighted images and a high-signal intensity on T2-weighted images and may be an early finding in osteonecrosis (Fig 5).

MRI is highly sensitive and can detect osteonecrosis before the appearance of radiographic abnormalities. A triangular or ovoid area of low signal intensity in the subchondral region at the weight-bearing segment of the femoral head seen on T1-weighted image is characteristic (Fig 6). In addition, a “double-density” sign on T2weighted images is highly specific for osteonecrosis (Fig 7). In more advanced stages of the disease, the osteonecrotic segment shows lowsignal intensity on both T1- and T2-weighted images (Fig 8 and Table 7). Risk factors for osteonecrosis that can be detected with MRI include an increase in fatty marrow content (3,158) and a sealed-off growth plate scar of the femoral head (159). In addition, the specificity of MRI in diagnosing osteonecrosis is very high, and this modality is thus used for identifying patients at risk, differential diagnosis, and the monitoring of therapeutic intervention (3, 160164). Gadolinium-enhanced MRI is particularly useful in the detection of early osteonecrotic lesions (165-168). Intravenous and postintravenous gadolinium, or dynamic gadolinium-enhanced images can be used to assess femoral head ischemia (165-168). MRI changes can be seen in some patients with autoimmune disease who have been on corticosteroids as early as 2 months after the initiation of therapy. Some investigators (65) found that, in the 32% of SLE patients with positive findings, the mean time of detection was 3.6 months after the start of corticosteroid therapy. A “bone marrow edema pattern” associated with increased extracellular marrow content has been described in patients with transient osteoporosis, or the transient bone marrow edema syndrome (169,170). This pattern can be distinguished from osteonecrosis (171)

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(Fig 3) by the presence of focal, subchondral signal abnormalities (155).

TREATMENT

Surgical Versus Pharmacologic Treatment The management of osteonecrosis is primarily palliative and does not necessarily halt or retard the progression of the disease. Treatment options focus on repairing the secondary changes that develop in the femoral head and not on reversing the primary pathology (172). The preferred treatment modality depends on the disease stage, the lesion size and location, the presence of unilateral or bilateral involvement, as well as patient age and general health (153,160,172). Treatment outcome correlates with the stage of the disease, emphasizing the importance of early diagnosis. However, early diagnosis is not always possible, due in part to the variable nature of onset. Nontraumatic cases of osteonecrosis can be limited by minimizing risk factors such as steroid use or alcohol consumption, and with improved management of associated conditions such as renal failure, sickle cell disease, or Gaucher disease.

When the involved segment is smaller than 15% and is far from the weight-bearing region, conservative measures (such as medicating for pain relief and limited weight bearing) may be beneficial but they do not generally prevent disease progression (173,174). In a prospective study of 36 patients (55 hips), Stulberg et al (174) found that surgery was at least 3 times as effective as conservative treatment in Ficat stage I hip disease.

This pattern was even more striking in stage III disease in which conservative treatment had only a 10% success rate (174). Furthermore, in comparing 1206 surgically treated hips with 819 nonsurgically treated hips, treatment success was achieved in about twice as many in the former group. In this retrospective study, success was defined as a decrease in pain and an increase in range of motion (175). Although surgical treatment seems superior to conservative therapy, a large prospective study is needed to clarify this matter.

Core Decompression Ficat (7) first introduced core decompression in 1962. The procedure is performed through a drill hole made in the distal end of the greater trochanter (172) (Fig 9). The goal of this procedure is to

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Fig 3. Skeletal scintigraphy of osteonecrosis of both femoral heads, right greater than left, in a 30-year-old man. In the right hip, note moderate uptake at the site of osteonecrotic segment (open arrow) and markedly increased uptake at the site of bone repair (arrow).

reduce the elevated intramedullary pressure within the femoral head and to interrupt the cycle that results in worsening of the ischemia. The procedure also provides immediate and dramatic pain relief. Being a relatively simple and uncomplicated procedure, core decompression with or without autologous bone graft was once the procedure of choice. The most common complication of this procedure is hip fracture, which is reported in 0%-18% (175). Ficat (7) studied 133 cases of osteonecrosis of the hips who were treated with core decompression, and who were followed up for an average of more than 9 years. Clinical outcomes were evaluated by measuring range of motion and the degree of pain relief and were satisfactory in 94% and 82% of the patients with Ficat stage I and II osteonecrosis, respectively. The radiographic outcome was considered to be good in 87% and 67% of the patients with Ficat stage I and II osteonecrosis, respectively. Others have also reported good long-term results (154,176), but most recent publications conďŹ rm that core decompression yields the best result when performed in early stages of the disease. The results of 300 procedures of core decompression that were performed in

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stages I-IV were evaluated by Steinberg et al (154).

Better outcomes were found for patients treated operatively compared to those treated nonsurgically, with subsequent THR required in 46% and 77%, respectively. Moreover, in hips with small areas of necrosis in stages I and II, only 7% of those treated with core decompression required THR. Similarly, Castro and Barrack (177) performed a meta-analysis of 22 studies that used core decompression and compared them with 8 studies that used conservative treatment. Core decompression was superior to conservative treatment only when used to treat stage I lesions.

Although surgical intervention is at present the only well documented therapy for osteonecrosis, surgery carries risks of anesthesia, postoperative infection, and suboptimal results (Table 9). A number of newer modes of pharmacologic therapeutic agents have theoretical promise in the treatment of this disease, including growth and differentiation factors, cytokines, angiogenic factors, and bone morphogenetic proteins.

Fig 4. Computed tomography of the right hip joint in a 58-year-old man with osteonecrosis of femoral head secondary to steroid treatment for asthma. Note increased bone density posteriorly (arrow) and subchondral bone collapse laterally (open arrows).

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Fig 5. Early osteonecrosis of right femoral head was demonstrated on MRI scan in this 40-yearold woman treated with steroids, whose conventional radiographs were normal. On T1weighted coronal (A) and sagittal (B) MRI scans, the osteonecrotic lesion still demonstrates fatlike signal, surrounded by sclerotic low-signal margin (arrows). (C) On T2-weighted coronal MRI scan, there is increased signal intensity within the lesion, but surrounding margin remains of low signal intensity (arrow). Note high-signal uid in the joint (open arrow).

Bone Grafting Various types of bone-graft procedures have been used to provide mechanical support for the affected joint and delay the need for arthroplasty.

These include autogenous or allogenous cortical bone grafts of ilium, ďŹ bula or tibia alone, or alternatively, these procedures may be combined with core decompression, osteochondral grafts, muscle-

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III). Many of the procedures are technically difficult to perform (181).

Joint Reconstruction

Fig 6. Coronal T1-weighted MRI scan shows an ovoid low-signal segment of osteonecrotic bone (arrow).

pedicle bone grafts, and free vascularized bone grafts (Fig 10). Cortical grafts are simple to perform, but long-term outcomes are not encouraging, with a success rate of only 25%. A combination of cortical bone graft and core decompression is a safe procedure, and the outcomes are better in young patients with Ficat stage II and III disease.

Free vascularized fibular grafting has the additional benefit of enhancing revascularization. This procedure is much more complicated than other types of bone grafts, but the clinical results are much more impressive with more than 80% of patients reporting symptomatic improvement and pain relief (178,179). Although the procedure is appealing for young patients, related morbidity such as pain, motor weakness, and sensory deficit in the foot must be taken into account (180).

Once the femoral head has collapsed or acetabular involvement has occurred, the treatment of choice is reconstructive surgery. The procedure most often performed is THR, but others include resurfacing cup arthroplasty, femoral head replacement, and surface replacement. The decision to select one of these procedures over another depends on the stage and the extent of the disease (182,183). The success rate of cemented THR in patients younger than 40 years of age is not impressive; those who are overweight or physically active have a 5-year failure rate of 15%-20% (1,183). Unfortunately, THR is often the only acceptable option (1,183,184). Despite continued improvement of the technique, it is unlikely that a prosthetic hip will last for the entire life expectancy of these patients. Patients with osteonecrosis have poorer outcomes after THR when compared with age-matched controls with osteoarthritis (182). Among patients with osteonecrosis, those with idiopathic or traumatic osteonecrosis have better postsurgical prognoses compared with patients with steroid-induced osteonecrosis.

Osteotomy Osteotomy shifts the necrotic bone segment away from the weight-bearing zone and reduces mechanical stress. There are different types of osteotomies, although they all share a common goal, and have been performed primarily in young patients with small “post-collapse” lesions (stage

Fig 7. Coronal T2-weighted MRI scan of right humeral head shows characteristic for osteonecrosis “double-line” sign: low-signal line at periphery of the lesion, and more centrally located high-signal band (open arrows).

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Fig 8. Advanced osteonecrosis of the right femoral head and early lesion of the left femoral head. (A) Coronal T1-weighted MRI scan shows sclerotic lowsignal of osteonecrotic lesion of the right femoral head, and early lesion of the left femoral head. (B) On coronal T2-weighted image the right femoral head lesion remains of low signal (class D, fibrous), while the lesion of left femoral head shows still some preservation of high signal (class C, fluidlike).

DISCUSSION

Osteonecrosis is a disease associated with high morbidity and disability. Early detection has the potential to reduce morbidity and to improve the patient’s quality of life. However, despite the technological improvements in diagnostic radiology, detection remains difficult due to the lack of early clinical symptoms. As with many other insidious diseases, anticipation and vigilance can help uncover those patients who may be suffering from the disease but who may not be exhibiting severe symptoms. Although most cases of osteonecrosis result from direct trauma, non-traumatic osteonecrosis should be suspected in patients with predilection for the disease. Osteonecrosis may not be a result of one single factor, but rather a result of additive stresses on the anatomic and vascular integrity of the involved region.

We note that, in this era of molecular biology, significant new data is being developed with reference to not only the inflammatory cascade but also mechanisms of wound healing. Previous work on corticosteroid-induced osteonecrosis initially proposed that alteration of lipid metabolism by steroids may lead to the propagation of fat emboli that occlude the microvasculature, or that packing the marrow with fat compresses the vessels in the femoral head or other sites, and causes vascular insufficiency and then osteonecrosis (33). Wang et al (185) showed that steroids produce fat degeneration, necrosis of osteocytes, and fat embolism in the microvasculature of the femoral head in rabbits. They found that abnormal, hypertrophied fat cells in the bone marrow leads to compression of small veins in the femoral head, resulting in capillary stasis, and inhibition of capillary growth and

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Table 9: Treatment of Osteonecrosis Surgical Bone Grafting Core Decompression Osteotomy Hemiarthroplasty Total Hip Replacement Non-Surgical (Future Directions) Growth and Differentiation Factors Cytokines Angiogenic Factors Bone Morphogenetic Proteins

Fig 9. A 42-year-old woman with bilateral osteonecrosis of femoral heads due to immunosuppressive therapy with corticosteroids after heart transplantation was treated with core decompression procedure (arrows). (Only left hip joint is shown.)

regeneration. Li et al (186) used high-dose steroids to induce osteonecrosis in rabbits. They found that damage to the terminal arterioles was a common pathologic feature. They treated rabbits with steroids alone or steroids and clofibrate. After 6 weeks, they noticed lipid droplets in the osteocytes of the femoral heads of the animals in the steroids group, but almost normal osteocytes in the steroid and clofibrate treated group. They concluded that by decreasing hyperlipidemia and modifying lipid metabolism, clofibrate was able to reduce steroidinduced damage to the osteocytes. Therefore, lipidlowering agents may help to protect against steroid-induced osteonecrosis.

In a related study, Cui et al (187) studied the cholesterol-lowering agent lovastatin in vitro to determine if it would inhibit the effects of steroids on fat specific gene expression in chickens. They were able to show that lovastatin can prevent the development of osteonecrosis in chickens in vivo.

Histologic sections from the group treated with steroids and lovastatin showed less adipogenesis and no bone death in vivo. Both studies showed that lipid-clearing agents might be helpful in preventing the development of steroid induced osteonecrosis. A follow-up study was performed on

bone marrow stroma, in which the cloned pluripotent cells were first transfected with a traceable gene, and then the effects of steroids on adipogenesis studied (188, 189). The cells were treated with increasing concentrations of dexamethasone of increasing duration. This study similarly showed that lovastatin inhibited steroid-induced adipogenesis changes. In addition, in vivo results again showed that lovostatin prevented osteonecrosis in steroid treated chickens. Wang et al (190) observed similar results in chickens. Furthermore, steroids induced up-regulation of the endothelin A receptor (ETRA), and elevated ETRA mRNA levels were

Fig 10. A 48-year-old man with osteonecrosis of the left femoral head associated with Caisson disease was treated with allogenous bone graft (arrows).

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found in bone biopsies of osteonecrosis patients. In addition, higher endothelial cell-derived peptide endothelin 1 (ET1) plasma levels appear to augment the anabolic action of ET1 on the metabolism of osteocytes, suggesting that increased ET1 concentration causes vasoconstriction, thus leading to decreased bone perfusion in active metabolic regions of the bone (191).

Another attempt to probe the pathogenesis of osteonecrosis of the femoral head was performed

by Hirano et al (192). They conducted histologic examinations on autopsy specimens from osteonecrosis patients. Approximately one third of the patients had been on high-dose corticosteroids, whereas the rest were not exposed to steroids. The investigators compared the luminal cross-sections of the superior retinacular veins and found obstruction of these vessels in those patients who had been on steroids. There was no such change seen in the corresponding arteries of the non–steroid-treated group (192). This was particularly interesting because it suggested that downstream obstruction caused by stenotic draining vessels may play a role in the cause of osteonecrosis, perhaps by inducing vascular stasis. Hopefully, further work will identify not only the precise mechanisms but also allow us to extrapolate for predictive studies to identify patients at highest risk for developing corticosteroid-induced osteonecrosis.

Unfortunately, there is no consistent data that enables the quantitative definition of the additional or synergistic risk factors involved in the development of corticosteroid-induced osteonecrosis in specific diseases. Patients with SLE and renal fail-

ure have a higher rate compared with other illnesses, such as rheumatoid arthritis or asthma.

However, corticosteroids play a major role in the treatment of many of these diseases and, as practitioners, we should continue our efforts to minimize the risk and to maximize the benefit. Even with the judicial use of corticosteroids, however, osteonecrosis may develop. Each patient should be individualized in their treatment and attempts made to reduce systemic (oral or parenteral) corticosteroid usage to a minimum. Clearly, a better understanding of the biochemical basis of corticosteroid-induced osteonecrosis may lead to therapeutic intervention, before pathology.

Finally, the emergence of highly sensitive imaging techniques made it possible to intervene before segmental collapse occurs. Various surgical alternatives have been developed to preserve the femoral head, and therefore delay the need for THR. These procedures include core decompression, bone grafting, and osteotomy. None of these procedures is optimal, and the decision to choose any of them over the other depends on the stage and location of the disease and on the skill and experience of the surgeon. Similarly, the role of genetics is still in its infancy as a predictor of rheumatic disease. However, it is likely that there will be genetic factors identified in specific individuals that will allow identification of high-risk patients.

The use of MRI has dramatically improved the diagnosis and we look forward to the day when an earlier diagnosis will lead to better treatment options.

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