eMedicine Specialties > Radiology > Musculoskeletal

Avascular Necrosis, Femoral Head

Author: Michael R Aiello, MD, Radiologist, St Elizabeth Medical Center, Utica, NY
Contributor Information and Disclosures

Updated: Oct 6, 2009

Introduction

Background

Avascular necrosis of the femoral head (AVN) is an increasingly common cause of musculoskeletal disability, and it poses a major diagnostic and therapeutic challenge. Although patients are initially asymptomatic, AVN usually progresses to joint destruction, requiring total hip replacement (THR), usually before the fifth decade. It is estimated that almost 10% of the nearly 500,000 THRs performed each year in the United States are intended to treat AVN; at a cost of more than 1 billion dollars, THRs performed to treat AVN constitute approximately 25% of the total national costs for THR.

Treatment of AVN has been facilitated by the adoption of an international classification system, by effective early diagnosis using MRI, and by more aggressive surgical management; nevertheless, no universally satisfactory therapy has been developed, even for early disease.

Because measures to preserve the joint are associated with better prognoses when the diagnosis of AVN is made early in the course of the disease and because the results of joint replacement therapy are poorer in younger age groups than in older patients, it is critical to diagnose AVN as early as possible to prevent or delay progression of the disease.

AVN is characterized by areas of dead trabecular bone and marrow extending to involve the subchondral plate. The anterolateral aspect of the femoral head, the principal weightbearing region, typically is involved, but any region of the femoral head may be involved. In the adult, the involved segment usually never fully revascularizes, and collapse of the femoral head usually occurs sometime after AVN is detected radiographically.

Konig first described the condition, then termed osteochondritis dissecans, in 1888. In 1925, Haenish described the first case of idiopathic ischemic necrosis of the femoral head in an adult. In 1940, arterial occlusion was postulated as the cause of the necrosis. AVN following steroid therapy was described first by Pietrograndi in 1957.¹

AVN represents a failure to supply adequate oxygen to underlying bone. AVN is extremely rare in healthy individuals.

AVN only occurs in fatty marrow, which contains a sparse vascular supply. In contrast, hematopoietic marrow has a rich blood supply.

The femoral head is the most vulnerable site for the development of AVN. The site of necrosis is usually immediately below the weightbearing articular surface of the bone (ie, the anterolateral aspect of the femoral head). This is the site of greatest mechanical stress.

Elderly persons are at decreased risk for developing AVN. Fat cells become smaller in elderly persons. The space between fat cells fills with a loose reticulum and mucoid fluid, which are resistant to AVN. This condition is termed gelatinous marrow. Even in the presence of increased intramedullary pressure, interstitial fluid is able to escape into the blood vessels, leaving the spaces free to absorb additional fluid.

Nontraumatic AVN is commonly bilateral and occurs in younger persons.

Nontraumatic bilateral AVN usually occurs at different times and progresses at different rates in different hips.

The incidence of AVN is increasing. The causes include greater use of exogenous steroids and an increase in trauma.^{2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17}

Recent studies

Yeh et al conducted a prospective study of 28 hips in 25 patients to determine the accuracy of routine MRI in identifying subchondral fracture in AVN without apparent focal collapse. CT was used as the standard of reference in diagnosing the subchondral fractures. The MR images were reviewed by a musculoskeletal radiologist and a general radiologist in blinded fashion, and the reviewers were in agreement in only 16 of the 28 diagnoses (57.5%). Only 17 of the 28 MR imaging readings (60.7%) made by the musculoskeletal radiologist and only 15 of the 28 (53.5%) made by the general radiologist agreed with those of the CT standard. False-positive diagnoses (ie, diagnosis of fracture by MRI when no fracture was seen on CT) was more common than false-negative diagnoses. The authors concluded that MRI was therefore not satisfactory when compared with CT in identifying subchondral fracture in AVN.¹⁸

Tiderius et al performed a retrospective analysis of the predictive ability of contrast-enhanced MRI for AVN after closed reduction for developmental dysplasia of the hip (DDH) in 28 hips of 27 infants and suggested from their findings that gadolinium-enhanced MRI provides information about femoral head perfusion that may be predictive for future AVN. Presence of AVN was determined by the presence of 1 of 5 Salter criteria, and MRI was graded as normal, asymmetric enhancement, focal decreased enhancement, or global decreased enhancement. Six (21%) hips showed evidence of clinically significant AVN on follow-up radiographs. Fifty percent of the hips with AVN, but only 2 of 22 hips without AVN, showed a global decreased MRI enhancement. Multivariate logistic regression indicated that a global decreased enhancement was associated with a significantly higher risk of developing AVN.¹⁹

Etiology

Pathologic changes leading to avascular necrosis of the femoral head (AVN) are initiated in 2 broad categories of anatomic regions, intravascular and extravascular factors.²⁰

Intravascular factors

Extraosseous vascular factors — arterial factors

Arterial factors are believed to be the most important mechanism for the development of avascular necrosis of the femoral head (AVN). The femoral head is at increased risk for developing AVN, partly because the blood supply is an end-organ system with poor collateral development. Trauma to the hip may lead to contusion or mechanical interruption to the lateral retinacular vessels, the main blood supply of the femoral head and neck. In a study involving a large group of patients, arteriography demonstrated stenosing arteritis and atherosclerotic disease of the lateral retinacular vessels; these conditions may be an important consideration in older patients.

Vasculitis, as seen in Raynaud disease, or vasospasm, as seen in decompression sickness, may interfere with extraosseous circulation. Extraosseous interruption of the lateral epiphyseal and medial femoral circumflex arteries has been demonstrated in early adult AVN and in Perthes disease by superselective angiography.

Intraosseous vascular factors - arterial factors

The primary etiology of avascular necrosis of the femoral head (AVN) appears to be circulating microemboli that block the microcirculation of the femoral head. Such conditions can occur in sickle cell disease (SCD), fat embolization, or air embolization from dysbaric phenomena. Vascular obstruction of the microcirculation may be caused by fat emboli, related to hyperlipidemia associated with alcoholism, steroid therapy, SCD, and nitrogen bubbles in decompression sickness.

Intraosseous vascular factors - venous factors

Conditions such as Caisson disease and SCD have a strong tendency to involve the venous circulation by reducing venous outflow and causing stasis. Enlargement of intramedullary fat cells or fat-loading osteocytes causes the cells to expand; this may be the most significant factor leading to obstruction of venous drainage. Intraosseous venography in patients with avascular necrosis of the femoral head (AVN) demonstrated widespread abnormalities in the venous drainage system, indicating that venous circulation is a factor in and contributes to progression of this disorder.

The ability to decompress the marrow space depends on regional anatomic structures, especially vascular outflow and bony architecture. The femoral head is at an anatomic disadvantage for decompression because it is a large sphere perched on a narrow metaphyseal neck. Relatively few of the venous channels that permeate the bony cortex are directly available for decompression. An increase in pressure within this large area must be funneled through the narrow metaphyseal neck for decompression, which is a situation analogous to rush-hour traffic feeding onto a single-lane bridge.

Extravascular factors

Intraosseous factors

The bone system within the subchondral region of the femoral head is enclosed within a rigid shell of cortical bone. Such a system is particularly sensitive to increases in pressure, which result in a compartment syndrome. Ficat et al demonstrated increased bone marrow pressure in the femoral necks of a large number of patients with avascular necrosis of the femoral head (AVN).²¹ The first effects of raised pressure are on the sinusoids and the small marrow capillaries, then on the venous outflow. Reflex spasm can even block nutrient vessels before they enter the cortex.

Fat cells, through hypertrophy resulting from steroid administration, and abnormal cells, such as Gaucher cells and inflammatory cells, may encroach on intraosseous capillaries, reducing intramedullary circulation and contributing to compartment syndrome. Blood flow normally is poorer in fatty marrow. The risk of AVN is increased when the volume of fatty marrow increases at the expense of hematopoietic marrow. This situation is present in normal marrow conversion in the adult and in settings in which the size and volume of the marrow are increased, such as occurs in steroid administration. Transmitted pressure in the weightbearing region of the femur causes compression of the capillary circulation, which is already compromised by increased intraosseous pressure.

Repeated microfractures in the weightbearing segment of the femur may cause multiple vascular lesions, resulting in ischemia within fragile and poorly repaired bone.

Cellular cytotoxic factors, such as alcoholism and steroid-related AVN, may have a direct toxic metabolic effect on osteogenic cells.

Decompression of the subchondral weightbearing area of the femoral head is difficult. Greater amounts of more tightly packed cancellous bone are present in this region, owing to the mechanical requirements of weightbearing; this creates a baffle effect and further restricts the ability to decompress the marrow space, as compared with the more open adjacent subchondral areas.

Trabecular deformation, which normally occurs during weightbearing, also causes some degree of compression of the marrow space and usually results in a temporary, localized increase in intraosseous pressure. This situation may be aggravated further by the morphologic profile of reduced trabecular bone, thickened osteoid seams, and indolent calcification dynamics noted in specimens from iliac bone biopsies performed in patients with abnormal renal function and AVN.

In some instances of idiopathic osteonecrosis, these changes have been accompanied by decreased concentrations of 1,25 dihydroxyvitamin D3. Such findings suggest a possible quantitative or qualitative deficiency in the bone architecture, which undoubtedly potentiates the altered pressure effects of deformation. In either event, increased intraosseous pressure tends to remain concentrated in this area because of the tightly structured architecture. This, coupled with a situation in which the intraosseous pressure already is elevated, may transform an area of bone that is ischemic and marginally perfused into an area of functional anoxia with resulting infarction

Capsular factors

The lateral epiphyseal vessels (LEVs), which are located within the synovial membrane, constitute the primary blood supply to the epiphysis. Disease processes within the hip joint that produce effusions, such as trauma, infection, and arthritis, may result in tamponade of the LEVs through increased intracapsular pressure.

Pathophysiology

Summary of pathophysiologic factors

Some authors feel that avascular necrosis is most likely the result of thrombosis or embolization of smaller arteries of the femoral head by lipid droplets, abnormal red blood cells (as in sickle cell disease, or SCD), or nitrogen bubbles from Caisson disease. Others feel that vasculopathy with structural damage to the arterial or venous walls from vasculitis, radiation necrosis, or the release of vasoactive substances (as in Gaucher disease) is the cause. Still others feel that increased intraosseous pressure from enlargement of intramedullary fat cells or osteocytes is a factor.

The consensus is that the cause is multifactorial and that it is better to deal with the disease as the end result of a number of different factors, the final common pathway of which results in bone death and collapse of the femoral head.

The final common pathway may represent intravascular coagulation with fibrin-platelet thrombosis, beginning in the vulnerable subchondral microcirculation (capillary and sinusoidal beds). This leads to vasoconstriction, impaired fibrinolysis (reperfusion of necrotic vessels with intramedullary hemorrhages), and infarction.

Intravascular thrombosis occurs throughout the body on a smaller scale, but lysis occurs through the fibrinolytic system. A thrombotic process of short duration may be lysed rapidly with preservation of the original thrombosed vessel. Conversely, a thrombotic process of prolonged duration or a recurrent thrombotic process may damage the vessel significantly, resulting in fibrosis and obliteration of the vessel lumen. In such cases, the vascular supply must be restored, either through the process of recanalization or through neovascularization. Recanalization may occur within minutes, or it may take days and involve little morbidity; recanalization may be halted by further thrombotic episodes or by subsequent trauma. Neovascularization requires months to years to complete.^{22,23,24,25,26,27,28,29,30}

Sequelae of avascular necrosis (AVN)

Minimal avascular necrosis: If the vascular area is small and is not adjacent to an articular surface, the patient may be asymptomatic; healing may occur spontaneously, or the disease may remain undetected or be discovered incidentally during workup for other conditions.

More severe avascular necrosis: Once AVN develops, repair begins at the interface between viable bone and necrotic bone. Ineffective resorption of dead bone within the necrotic focus is the rule. Dead bone is reabsorbed only partially. Reactive and reparative bone is laid down on dead trabeculae, resulting in a sclerotic margin of thickened trabeculae within an advancing front of hyperemia, inflammation, bone resorption, and fibrosis. The incomplete resorption of dead bone has a mixed sclerotic and cystic appearance on radiographs. Necrosis and repair are ongoing in various stages of evolution within a single lesion.

Mechanical failure: Mechanical failure of trabecular bone at the interface between dead and viable bone may exacerbate AVN. In the subchondral region, such microfractures do not heal because they occur within an area of dead bone. Progression of the microfractures results in a diffuse subchondral fracture, seen radiographically as the crescent sign (see image below and Image 9 in Multimedia). Following subchondral fracture and progressive weightbearing, collapse of the articular cartilage occurs (see images below and Image 8, Image 20, Images 25-26 in Multimedia). Continued fracture, necrosis, and further weightbearing may progress to degenerative joint disease (DJD) and joint dissolution.

Conditions associated with avascular necrosis

Trauma

Trauma is the most common cause of avascular necrosis. AVN may occur within 8 hours after traumatic disruption of the blood supply. The superior retinacular vessels and the nutrient artery may be damaged as they enter the femur. The artery of the ligamentum teres (ALT) also may be damaged. Intracapsular hematoma increases intracapsular pressure, which may cause tamponade of the vessels within the joint capsule.

Intertrochanteric and extracapsular fractures of the femur rarely result in AVN. Following hip dislocation, circulation is interrupted because of tearing of the ligamentum teres and the ALT. Tearing of the joint capsule compromises the vessels within the capsular reflections. AVN may develop as late as 10 years after subcapital fracture of the femur.

Alcoholism

Alcohol may have a toxic effect on osteogenic cells. The direct toxic effect of alcohol results in fat deposition in the liver. Livers with fat deposits are a constant source of low-grade asymptomatic fat emboli. Intraosseous fat emboli become hydrolyzed to free fatty acids, which cause endothelial damage. In persons whose alcohol consumption exceeds 40 mL per week, the risk of AVN is increased more than 11 times, as compared with the risk in nondrinkers. A clear dose-response relationship exists.

Steroid use

Six possible mechanisms may be present.

• Occlusion of small vessels occurs in relation with fat emboli from the liver.
• Increased intraosseous pressure results from a steroid-related increase in the size of the intramedullary fat cells without an equivalent compensatory loss of trabecular and cortical bone.
• Fat emboli become hydrolyzed to free fatty acids, which are toxic to vascular endothelium, causing intravascular coagulation.
• Angiogenesis is inhibited by a reduction of proteolytic activity by the synthesis of polyclonal antithyroid hormone receptor alpha-1 antibody.
• A direct toxic effect occurs on osteogenic cells.
• Steroid use causes conversion of hematopoietic marrow to fatty marrow, a prerequisite for the development of AVN. The conversion may be related to steroid-induced reduced blood flow.

The steroid exposure threshold is approximately 2000 mg of prednisone administered continuously. However, avascular necrosis has been known to occur after use of lower doses. The risk of AVN is greater risk in patients treated for a short duration (6 wk) with high doses (³20 mg). The risk of AVN in association with low-dose steroid therapy is controversial. Some studies link such therapy to the disease, whereas others indicate no such link. High doses of steroids administered within a relatively short period are more of a causative factor than the cumulative dose or the duration of therapy.

AVN may occur up to 3 years following cessation of therapy. Steroid-induced AVN is more severe than AVN caused by other conditions because underlying demineralization and accelerated osteolysis place the weightbearing surface of the femoral head at increased risk for collapse.

The incidence of AVN is highest in individuals with systemic lupus erythematosus (SLE) and in renal allograft recipients who are treated with steroids. In cases of renal transplantation, a high association exists between AVN and the use of prednisone at doses greater than 100 mg/d within the first month following transplantation. AVN is an uncommon occurrence in transplant recipients who receive prednisone at a dosage of less than 100 mg/d. In patients with chronic renal disease, there is an increased risk of underlying bone changes, such as hypophosphatemia.

The incidence of AVN may be reduced in patients with renal disease who are undergoing dialysis by reducing the risk of bone disease with better dialysis therapy (ie, increasing the level of ionized calcium in the dialysate) and by careful medical management. A delay in diagnosis may occur because of pain reduction provided by concurrent administration of steroids.

AVN is the dominant orthopedic problem in patients with SLE. Patients with SLE with vasculitis and Raynaud syndrome are at higher risk for AVN. Patients usually are younger and have more active disease with multiple organ involvement.

In general, the risk for AVN is considered low for patients who are on oral steroid therapy, with no data having yet established a direct relationship. A large controlled, prospective, long-term study is needed to refine any association between dose, duration of treatment, and other risk factors.

Dermatologists should be aware of the risk of AVN in patients receiving oral steroids, and patients should always be informed about the possibility of severe related complications. Most published studies agree that there is some association between steroids and AVN. One study, by Morris et al, included 72 patients treated with either high-dose or low-dose steroids and found a positive association for those treated with high doses of oral steroids. They could not, however, define an exact dose-time relationship but suggested that femoral head necrosis is related to the cumulative dose.¹¹⁴

Therefore, because of the need for and common use of steroids in dermatology, often with few alternative treatments, they should be prescribed carefully; and the dose and duration of therapy should be checked and rechecked regularly. Patients on oral steroid therapy should be examined on a regular basis and asked about pain and other risk factors associated with AVN.

Numerous case reports have been described of AVN developing after steroid therapy, without any other risk factors present for AVN, but the findings were statistically insignificant. In the literature, patients have been described who developed AVN after being treated with steroids for dermatologic conditions, especially autoimmune disorders such as systemic lupus erythematosus, pemphigus, and dermatomyositis.

The problem of establishing an association between AVN and steroid therapy may lie in the unknown role of patient habits and personal predispositions; it is possible that another, currently unknown pathologic mechanism may be responsible for the onset of AVN.

Decompression sickness (Caisson disease)

People who work in underwater enclosures that require compressed air to prevent water seepage are at risk. AVN occurs as a result of exposure to pressure greater than 17 lb per square inch. These infarcts tend to be large. Undersea divers are at risk. Key risk factors are the depth of the dive, the number of dives, uncontrolled decompression, and low oxygen concentrations. Intravascular bubbles of nitrogen obstruct capillaries. Extravascular nitrogen within the fatty marrow, encased within the bone, compresses intramedullary vessels. Arteriolar spasm also may occur. Fat cells have a 5-fold ability to absorb dissolved nitrogen. Such absorption increases their volume within the nonexpandable confines of the bony trabeculae and cortex, increasing intraosseous marrow pressure and causing venous stasis.

Metastatic disease

Metastatic cells can pack the marrow, resulting in increased intramedullary pressure obstructing the intramedullary vessels. Patients are at higher risk if they are receiving steroid therapy and/or are undergoing local radiation therapy to the hip.

Pancreatic disease

The release of lipolytic enzymes into the bloodstream results in the breakdown of the fat within the marrow cells into free fatty acids, which are toxic to endothelium and that cause intravascular coagulation. Upon entering the portal venous radicals in patients with pancreatitis, pancreatic enzymes may cause the release of intracellular fat from fat-laden hepatic cells.

Hemoglobinopathies (SCD, thalassemia, hemoglobin C disease, hemoglobin D disease, hemoglobin E disease)

Hemoglobinopathies are the principal cause of AVN in African countries such as the Democratic Republic of the Congo (formerly Zaire). Infarcts associated with hemoglobinopathies tend to be large. AVN only occurs when a sickle gene causes the sickling phenomena. Sickling of abnormal red blood cells occurs in intramedullary capillaries and venules, causing hyperviscosity and vascular occlusion.

Bone marrow hyperplasia resulting from chronic anemia may pack the marrow, placing it at increased risk for developing AVN through elevations in intramedullary pressure. Sites of AVN are susceptible to osteomyelitis caused by Salmonella infection. See US frequency. AVN may be more common in patients with the sickle trait and sickle-thalassemia than in patients who are homozygous for the sickle gene, because the latter do not live long enough to demonstrate the changes.

Gaucher disease

Gaucher disease is a metabolic disorder consisting of a deficiency of the enzyme β-glucosidase, which normally catalyzes the removal of glucose from glucocerebroside. Glucocerebroside accumulates in the reticuloendothelial cells within the bone marrow, resulting in packing of marrow, compression of interosseous sinusoids, and elevation of interosseous pressure. Infarcts tend to be large.

Dialysis

Elevation in parathormone levels may cause an increase in subchondral bone turnover, with replacement by disorganized bone matrix that is unable to support normal weightbearing. This results in microfractures and increased intramedullary pressure.

Irradiation

Fibrosis and endothelial proliferation resulting from radiation-induced arteritis cause underlying vascular compromise. Patients with metastatic lymphoma or carcinoma of the femoral head who are treated with steroids and chemotherapy are at increased risk for AVN. AVN occurs with doses exceeding 30 Gy.

Hemophilia

Repeated microhemorrhages within the confines of the marrow result in increased intramedullary pressure. Capsular distention from hemorrhage may compress the retinacular vessels within the synovial capsule.

Hypercoagulable states — inherited disorders

There are deficiencies of specific protein inhibitors of the coagulation cascade (protein C,³¹ protein S, and structural abnormalities of factor V [resistance to activated protein C]). Protein S is a vitamin K–dependent antithrombin plasma protein that serves as a cofactor for another antithrombotic plasma protein, protein C. Once activated, protein C inhibits the coagulation cascade by enzymatic cleavage of the activated forms of clotting factors V and VII.

Disorders of the fibrinolytic system occur; such disorders include impairment of the release of tissue plasminogen activator activity and increases in the level of lipoprotein A.

Hyperfibrinogenemia produces a hypercoagulable state associated with enhanced erythrocyte aggregation and hyperviscosity resulting in a reduction of blood flow and ischemia. Hyperfibrinogenemia is seen in patients with hyperlipoproteinemia (types II and IV), in those who smoke, in patients with diabetes, and in persons who use oral contraceptives. As with hereditary thrombophilia, hyperfibrinogenemia may decrease the threshold for developing AVN in persons with alcoholism and in persons receiving steroid therapy.

Hypercoagulable states - Acquired disorders

When superimposed on underlying hereditable disorders, acquired disorders increase the likelihood of vascular thrombosis synergistically.

• Legg-Calvé-Perthes (LCP) disease is the most common cause of AVN in children.
  • The time of onset ranges from 3-10 years of age, with the highest incidence occurring from age 6-8 years. The greatest incidence is in Japanese, Mongolian, Eskimo, and Central European children; the incidence in blacks and Native Americans is low.
  • The vascular anatomy of the proximal femur is in a transitional stage of development in children 4-7 years of age, making the blood supply to the femoral head especially vulnerable. The artery of the ligamentum teres does not penetrate the epiphysis of the femoral head until age 9 or 10 years. The epiphyseal growth plate prevents communication between the blood supply of the epiphysis and metaphysis; thus, the femoral head is at increased risk for developing AVN, even from innocuous events such as minor trauma.
  • Venous tamponade may contribute to the development of AVN. Nonspecific synovitis may result in elevations of intracapsular pressure to a degree sufficient to obstruct venous outflow. In adults, epiphyseal venous drainage may go into the metaphysis and may protect the femoral head.
• Slipped capital femoral epiphysis³²
  • Epiphyseal dislocation results in superolateral displacement and external rotation of the femoral metaphysis; the twisting and kinking of the lateral epiphyseal vessels result in compromise of the blood flow to the epiphysis. Dislocation tends to occur late in the terminal stage of renal failure.
  • Epiphyseal dislocation may occur in association with hypothyroidism, obesity, growth hormone administration, and radiation therapy.
  • When related to HIV infection, multifactorial etiologies probably are involved. Hypertriglyceridemia, which occurs in AIDS wasting, may be potentiated by steroid use, either on a long-term basis through megestrol therapy for wasting or transiently, in association with burst-and-taper hydrocortisone therapy for Pneumocystis carinii infection.
  • Caloric deprivation, as occurs in AIDS wasting, may cause irreversible deposition of acid mucopolysaccharides in the marrow space. This less vascular ground substance may predispose patients to ischemia in the interosseous space.
• Congenital dislocation of the hip¹⁹ : Strangulation of the afferent blood vessels occurs by forced abduction and internal rotation of the femur. The iliopsoas muscle compresses the medial circumflex vessels at the acetabular rim. Dislocation may result from splinting of the hip in association with abduction. The incidence has been reduced by abandonment of forced reduction of the hip and through the introduction of modern abduction devices. Dislocation occurs with every form of hip splintage.
• Fatty liver: Both clinical and experimental studies have shown that a fatty liver is capable of spontaneously releasing large numbers of embolism-sized fat globules into hepatic venous channels after rupture of fatty cysts into adjacent sinusoids and central veins. In vitro studies of hepatic perfusion indicate that the magnitude of fat embolism is directly related to the degree of intracellular fat present in hepatic cells at the beginning of the study.
• Femoral head fracture: The ligamentum teres usually is ruptured, which causes a disruption in the arterial supply to the femoral head. The superior retinacular vessels may be compromised (see images below and Images 6-7 in Multimedia).

• Femoral head dislocation: The subsynovial retinacular vessels, located along the femoral neck, may be disrupted or severely damaged. The only remaining blood supply to the femoral head may be the artery of the ligamentum teres, providing it was functional before the fracture.
• Sickle cell disease: Sickled erythrocytes sludge within the sinusoidal vascular bed, resulting in occlusion. Localized anoxia accentuates the sickling process, extending the area of involvement within the femoral head. AVN frequently is accompanied by osteomyelitis, especially in association with infection by Salmonella organisms.
• Pregnancy: Impaired venous drainage by the gravid uterus places women in the third trimester of pregnancy at increased risk.

Diseases or conditions associated with or leading to avascular necrosis

• Trauma — Fracture of the femoral neck
  • Slipped capital femoral epiphysis
  • Proximal femoral epiphysiolysis
  • Dislocation of the femoral head
  • Epiphyseal compression
  • Vascular trauma
  • Burns
  • Radiation exposure
• Hemoglobinopathies
  • Sickle cell disease
  • Hemoglobin S or hemoglobin C hemoglobinopathy
  • Polycythemia
• Caisson disease — Dysbaric osteonecrosis
• Local infiltrative disease
  • Gaucher disease
  • Infection
  • Neoplasms
• Hypercortisolism
  • Corticosteroid medications
  • Cushing disease
• Alcohol consumption
• Pancreatitis
• Chronic renal failure
• Cigarette smoking
• Collagen vascular diseases
• Congenital and developmental
  • Congenital dislocation of the hip
  • Ehlers-Danlos syndrome
  • Heredity dysostosis
  • Legg-Calvé-Perthes disease
• Fabry disease
• Giant cell arteritis
• Gout and hyperuricemia
• Hemodialysis
• Hypercholesterolemia
• Hypercoagulable states
• Hyperlipidemia
• Hyperparathyroidism
• Intravascular coagulation
• Organ transplantation
• Pregnancy
• Systemic lupus erythematosus
• Thrombophlebitis
• Idiopathic

Pathology

Gross pathology

Avascular necrosis of the femoral head (AVN) almost always is covered by a surface of compact subchondral bone and articular cartilage. Articular cartilage derives its nourishment from synovial fluid. Only the cartilage below the tidemark may die.

Cancellous bone in the femoral head shows irregular areas of yellow necrosis extending to within several millimeters of articular cartilage. Individual trabeculae remain intact. With progression, a patchy zone of softening develops in the necrotic cancellous bone, adjacent to viable bone, representing resorption of the necrotic segment. With further weightbearing and bone resorption, structural support is lost in the subarticular region, with resultant microfractures and subsequent creation of an articular sequestrum.

A line of trabecular fractures extends across the dead bone, which creates and separates an articular sequestrum. Following trabecular fracture, the load-bearing segment of the femoral head collapses. Breaks in the smooth contour of the femoral head become visible, most often at the superior margin of the fovea and beneath the acetabular lip. After collapse of the femoral head, progressive destruction of the articular cartilage and underlying bone occurs; loose bodies appear; and marginal osteophytes develop, heralding the development of degenerative joint disease (DJD) (see image below and Image 8, Image 15 in Multimedia).

Avascular necrosis can be divided into a phase of cell necrosis followed by the repair of cancellous bone.

• Cell necrosis
  • Hematopoietic elements are the first to die (with death occurring within 6-12 h of the insult), followed by bone cells, including osteocytes, osteoclasts, and osteoblasts (with death occurring within 12-48 h), and cells (with death occurring in 48 h to 5 d).
  • Bone infarcts are composed of 4 zones — a central zone of cell death, surrounded by successive zones of ischemia, hyperemia, and normal tissue.
  • Once AVN develops, breakdown products of dead, dying, and damaged cells provide the initial inflammatory response, characterized by vasodilatation, transudation of fluid, fibrin precipitation, and local infiltration by inflammatory cells. This response forms the basis of the development of the hyperemic zone and represents the initial step of repair, removal, and reconstruction of the infarcted area.
  • The complete absence of osteocytes within localized areas of trabecular bone is a reliable indicator of previous or existing AVN. This disappearance of osteocytes occurs approximately 2 weeks after the onset of AVN.
  • Death of marrow cells is reflected by loss of nuclei and disruption of clusters of fat cells (forming lipid cysts).
  • Mineralized bone matrix is not altered directly by AVN because death is a cellular phenomenon. The underlying supporting bony structure is unaltered initially.
• Repair
  • Bone resorption occurs first, followed by new bone formation.
  • Neither the infarcted zone nor the ischemic zone can support bone resorption or deposition. Repair begins along the outer perimeter at the junction between the dead area and the viable area containing an intact circulation (ie, the hyperemic zone). This reparative response results in progressive development of a reactive margin, or interface, between the dead zone and adjacent viable tissues. Here, mesenchymal cells and capillaries proliferate and migrate along with macrophages and fibroblasts into the dead zone.
  • Resorption of dead bone and subsequent revascularization are an indication of osteoporosis.
  • Progressive loss of mechanical support resulting from resorption and disruption of cancellous bone within the reactive interface stimulates compensatory reinforcement of adjacent viable cancellous bone by osteoblastic activity and, less frequently, the formation of new trabeculae within the marrow space.
  • New bone formation fails to keep pace with bone resorption, resulting in significant loss of bone in the subchondral plate. Further weightbearing causes subchondral bone plate fracture and focal articular cartilage collapse (see image below and Image 9, Image 14, Image 20, Images 25-26 in Multimedia).

• Fragmentation and compaction of subchondral bone debris leads to the development of a subchondral lucent area along the fracture line, which is the crescent sign seen on plain radiographs (see Image 9).
• Late complications
  • Continued weightbearing results in flattening of the articular cartilage. Capillary invasion results in articular cartilage resorption. Such a loss predisposes patients to osteoarthritis (see Image 8, Image 15).
  • Extensive resorption and fibrous replacement within the reactive interface in the presence of continued weightbearing can cause fragmentation and separation of the osteonecrotic segment from the underlying viable area of the femoral head.

Frequency

United States

The incidence of avascular necrosis is approximately 15,000 cases per year. The incidence has increased, owing to an increase in the use of exogenous steroids, as well as an increase in the incidence of trauma and of alcohol abuse. Patients with diseases associated with AVN, especially patients with systemic lupus erythematosus (SLE) and recipients of renal allograft transplants, are living longer and are at increased risk for AVN. AVN is bilateral in 30-70% of patients at the time of initial presentation. The stage of disease and time of onset is usually different in each hip. The relative frequencies of the most common causes of AVN are alcoholism (20-40%) and steroid treatment (35-40%); many cases are idiopathic (20-40%).

• Frequency of AVN by associated conditions

• Trauma
  • Transcervical and subcapital fractures — 11-45%
  • Displaced femoral head fractures (27-30%) and undisplaced fractures (16%)
  • Reported following intramedullary nailing of a fracture of the femoral head in an adolescent
  • Up to one third of cases of AVN that occur in patients 4-10 years of age result from a fracture
  • Posterior femoral head dislocation — 10-26%
  • Anterior femoral head dislocation — Less frequent, 3-9%
  • The frequency of AVN in hips that remain dislocated for a period longer than 12 hours that developed AVN — 52%; the frequency of AVN in dislocated hips that undergo reduction within 12 hours — 22%
• Excessive alcohol intake — As many as 40% of all cases of AVN; the incidence of bilaterality is as high as 73%
• Renal transplantation
  • As many as 40% of renal transplant recipients develop AVN.
  • AVN is present within the first year in 40% of patients and in 85% by the second year.
  • The interval between time of transplantation and onset of symptoms is 1-126 months, with a mean of 9-19 months.
  • Within the first month following transplantation, patients who take prednisone at doses greater than 100 mg/d are at increased risk of AVN
  • In 54-80% of transplant recipients in whom AVN is detected with plain radiographs, the disease is bilateral.
• Steroid use
  • The risk is 5-25% in patients who use high doses of steroids over a long term.
  • AVN occurs in 1-10% of patients who undergo steroid treatment for acute leukemia and lymphoma.
  • AVN occurs in 10% of long-term survivors of bone marrow transplantation who receive high doses of steroids for the prevention or treatment of graft-versus-host disease.
  • AVN develops in 2% of patients receiving steroid replacement therapy.
• Systemic lupus erythematosus — 5-40%. As many as one third of patients receive high-dose steroids.
• Sickle cell disease — In SS disease, 4-12%; in SC disease, 20-68%
• Hemophilia — Approximately 3%
• Rheumatoid arthritis — Approximately 12% (most cases are associated with steroid treatment)
• Slipped capital femoral epiphysis — Approximately 15% and less than 7% in hips reduced within 24 hours and 17% after 24 hours
• Legg-Calvé-Perthes disease — Bilateral in 15-20%

International

Sickle cell disease and the hemoglobinopathies are the major cause of avascular necrosis in African countries such as the Democratic Republic of the Congo (formerly Zaire). Thalassemia is prevalent in southern Mediterranean European populations and in people from Southeast Asia. The incidence of Legg-Calv é -Perthes disease is increased in Japanese, Mongolian, and Central European children. The incidence is low in blacks and Native Americans.

Mortality/Morbidity

Fifty percent of patients with avascular necrosis experience severe joint destruction as a result of deterioration and undergo a major surgical procedure for treatment within 3 years of diagnosis. Femoral head collapse usually occurs within 2 years after development of hip pain.

Race

Conditions that predispose persons to avascular necrosis, such as sickle cell disease, are concentrated in the African American population. Beta-thalassemia is common in southern Europeans and Southeast Asians.

Sex

Legg-Calvé-Perthes disease affects males 4 times more frequently than it affects females.

Age

Avascular necrosis usually occurs in patients in the third to fifth decades; predisposing conditions, such as Legg-Calvé-Perthes disease and slipped capital femoral epiphysis, increase the risk of avascular necrosis in patients in certain age groups.

Anatomy

Gross anatomy

The hip is a ball-and-socket joint. The acetabulum, which provides bony coverage of 40% of the femoral head, has a horseshoe-shaped lunate surface. The femoral head is round and smooth in all imaging planes. The fovea capitis, a small depression on the medial femoral head, is the site of attachment of the ligamentum teres (see image below and Image 3 in Multimedia).

The LEV enters the femoral head within a 1-cm-wide zone between the cartilage of the femoral head and the cortical bone of the femoral neck. They supply the lateral and central thirds of the femoral head (see Images 6-7). When patent, the artery of the ligamentum teres (ALT) supplies the medial third of the femoral head.

Branches of the LEVs and the ALT anastomose in the junction of the central and medial third of the femoral head. The thickest part of the articular cartilage of the femoral head is located along the posterior-superior aspect and measures 3 mm in diameter. It thins to 0.5 mm along the peripheral and inferior margins.

Blood supply in children

In children 4-7 years of age, the vascular anatomy of the proximal femur is in a transitional stage of development. The ALT does not penetrate the epiphysis of the femoral head until 9 or 10 years of age. The medial circumflex artery, a branch of the profunda femoris artery, penetrates into the femoral proximal metaphysis but is prevented from passing into the femoral epiphysis by the growth plate. The blood supply to the femoral head is especially vulnerable during this time.

CT anatomy

Physiologic thickening of bone trabeculae in the center of the femoral head is present and appears similar to a star, which is termed the asterisk sign. The configuration is related to the stress of weightbearing (see image below and Image 1 in Multimedia).

Sclerotic raylike branches of the star usually extend to the upper surface of the femoral head (see Image 1). A dense line, extending from the lateral to the medial portion of the mid femoral head, represents the fused epiphysis.

MRI anatomy

Fatty marrow is present in the femoral capital epiphysis and the greater trochanter of all individuals older than 2 years. Fatty marrow has high signal intensity on T1-weighted images (T1WIs) and T2-weighted images (T2WIs; see images below and Images 3-5 in Multimedia). Hematopoietic marrow, when present, is found in the femoral neck, the intertrochanteric region, and the acetabulum. It has low signal intensity on T1WIs and high signal intensity on T2WIs (see Images 4-5).

A thin line of high signal intensity, which represents the articular cartilage, surrounds the outer margin of the femoral head. A curvilinear low-signal line, representing the physis, crosses the marrow of the femoral neck laterally to medially (see Images 3-5). The medullary cavity of the iliac bone, adjacent to the acetabulum, is of slightly lower and less homogeneous signal intensity than the femoral head (see Images 4-5).

Presentation

Avascular necrosis has no distinguishing clinical features. Patients do not experience pain during the ischemic episode. Occult AVN can be present for more than 5 years before the onset of symptoms. Patients may be asymptomatic or may develop pain gradually and insidiously; they may experience a decrease in range of motion (ROM) and may walk with a limp. Pain may be excruciating and of sudden onset, with the patient able to note the exact time and date it began.

Radiographic findings may appear after a delay of several months to years following the onset of symptoms.

Pain

• Pain may be focal or over the groin or hip, or it may radiate to the buttocks, anteromedial thigh, or knee.
• Pain may be induced mechanically by standing and walking and may be eased by rest.
• Pain may be very intense, especially in the large infarcts often seen in Gaucher disease and dysbarism and in hemoglobinopathies.
• Pain has been described as throbbing, deep, and, often, intermittent.
• Pain may be worsened by coughing and may worsen at night.
• When the disease is chronic, pain may be vague.
• In avascular necrosis, 40% of patients have night pain that may be associated with morning stiffness.
• Patients with pain of several months' duration may notice a sudden increase in pain.
• Following treatment of a traumatic hip fracture, AVN may manifest as worsening pain.
• In elderly patients, pain may be of sudden onset, with no history of trauma.
• Early in the course of the disease, there is frequently a clear dissociation of pain, which may be considerable, and limitation of movement, which may be minimal.

Click

• A click may be heard when the patient rises from a sitting position.
• A click may be elicited by external rotation of an abducted hip.

Range of motion

• ROM may be diminished, especially after collapse of the femoral head.
• ROM may be limited, especially in flexion, abduction, and internal rotation.
• Gait: Patients may walk with a limp. The Trendelenburg sign may be positive.

Clinical summary

For AVN to be diagnosed at an early stage, the physician must have a high index of suspicion, especially regarding patients who have any of the risk factors and whose radiographic findings are negative. This is especially true with unilateral involvement because of the high risk of the development of AVN in the contralateral hip. These patients should be evaluated aggressively.

Preferred Examination

MRI

MRI is the most sensitive means of diagnosing avascular necrosis. MRI provides the criterion standard of noninvasive diagnostic evaluation. It is more sensitive than CT scanning or planar scintigraphy, and it is much more sensitive than plain film radiography for detecting AVN.

Low-field magnets (0.1 T) are not as sensitive for diagnosing AVN. Similar sensitivity and specificity were found between low-field MRI and planar radionuclide bone scanning. At high magnetic field strength, MRI has a higher sensitivity than radionuclide scanning. Using a 1.5-T magnet, Beltran et al reported 88% sensitivity, 100% specificity, and 94% accuracy with MRI and 78% sensitivity, 75% specificity, and 76% accuracy with bone scintigraphy.²² The high sensitivity of MRI has been confirmed by others.

MRI performed at 0.6 T and single-photon emission computed tomography (SPECT) bone imaging using technetium-99m methylene diphosphonate were similarly effective in diagnosing AVN. MRI had a sensitivity of 87% and a specificity of 83%. SPECT had a sensitivity of 91% and a specificity of 78%. Both were more effective than planar bone scintigraphy, which had a sensitivity of 83% and a specificity of 83%.

MRI was more effective than SPECT for diagnosing cases of AVN of the hip in which pain was absent. MRI detected AVN in 10 of 15 patients, but SPECT detected AVN in only 5 of 15 patients.

Using receiver operating characteristic (ROC) curves, MRI was better than CT by more than 2 standard errors and better than radionuclide scanning by more than 3 standard errors in helping diagnose early AVN. MRI has a high sensitivity in the diagnosis of bone marrow abnormalities. The sensitivity of MRI in the diagnosis of AVN is 85-100%. MRI has 97% sensitivity in distinguishing a hip with AVN involvement from a normal hip.

In differentiating AVN from non-AVN disease of the femoral head, MRI demonstrates a sensitivity of 98% and a specificity of 85%. Before femoral head collapse, the specificity is 75-100%. After femoral head collapse, the sensitivity is 100%.

MRI is indispensable for the accurate staging of AVN because images clearly depict the size of the lesion, and gross estimates of the stage of disease can be made. MRI allows sequential evaluation of asymptomatic lesions that are undetectable on plain radiographs. MRI facilitates better response to treatment because, with the use of MRI, AVN is diagnosed at an earlier stage, and therapeutic measures are more successful the earlier they are begun.

MRI does not employ ionizing radiation — a factor that is especially important in the growing skeleton. It is accepted widely and is easy to perform. MRI is capable of imaging in multiple planes (ie, axial, sagittal, coronal, or any variation thereof). MRI demonstrates superior soft tissue resolution and has high spatial and contrast resolution, allowing evaluation of morphologic features.

MRI may help guide interventional procedures such as core decompression. It may demonstrate response of the femoral head to treatment. MRI images may detect the joint effusions and bone edema that often accompany AVN. MRI is a noninvasive means of evaluating articular cartilage congruity, and it allows sequential evaluation of asymptomatic lesions that are undetectable on plain radiographs.^{34,35,36,37,38}

Single-photon emission computed tomography

Initially, SPECT images reflect vascular integrity. Early in the disease, SPECT scans may demonstrate an avascular focus; such findings are missed with MRI unless contrast is used. Collier found a sensitivity of 85% for SPECT.³⁹ With triple-head high-resolution SPECT, Lee et al reported a sensitivity of 97%.⁴⁰

SPECT provides images of the radioactivity within the target organ in 3 dimensions. With SPECT, overlying and underlying areas of radioactivity may be separated into sequential tomographic planes; this provides increased image contrast and improved lesion detection and localization, as compared with planar scintigraphy. SPECT eliminates radioactivity resulting from hyperemia about the hip joint and from the underlying acetabulum and adjacent bladder. SPECT is used as an alternative to MRI when MRI cannot be performed or when the results of MRI are indeterminate.^41,42,43

Planar radionuclide imaging

Collier reported a sensitivity of 55% with planar radionuclide imaging.³⁹ Bone scintigraphy equipped with a pinhole collimator has greater sensitivity for diagnosing AVN than bone scintigraphy using a high-resolution parallel-hole collimator.

Bone scintigraphy using pinhole collimation

The pinhole collimator is a conical collimator with a small circular aperture (3-5 mm) that produces an inverted image of the object in a manner, analogous to photographic cameras. The image obtained is magnified, allowing better visualization of small structures and improving detection of scintigraphic abnormalities. The pinhole collimator optimizes resolution in the evaluation of circumscribed areas. Acquisition time is only 15 minutes, compared to up to 45 minutes for SPECT. The technique is an alternative to MRI when MRI cannot be performed or when MRI results are not clear-cut.

Planar scintigraphic imaging using quantitative bone scan

This technique provides physiologic data that cannot be obtained with other modalities, including MRI; for example, it allows quantification of uptake in the perfusion and static phases. It requires correct computer programming.^44,45,46,47

CT

The high spatial resolution and contrast resolution of CT allow analysis of morphologic features (see images below and Images 1-2, Images 13-15 in Multimedia). The sensitivity of CT in detecting early AVN is 55%, which is similar to the sensitivity of planar nuclear medicine imaging. CT is more appropriate in evaluating the extent of involvement, such as subchondral lucencies and sclerosis during the reparative stage, before the onset of femoral head collapse and superimposed degenerative disease.

Plain film radiography

Although unable to detect disease of stage 0 or 1, plain film may be helpful in assessing flattening of the femoral head and associated degenerative changes (see image below and Images 8-9, Images 20-21, Images 25-26 in Multimedia).

Limitations of Techniques

MRI

Rarely, bone biopsy analysis was reported to be positive when MRI findings were normal. MRI cannot be performed in patients who have cardiac pacemakers or when intracranial clips are present, nor can MRI be performed in patients who have claustrophobia. Problems related to malpositioning may lead to misrepresentation. In children, slight pelvic obliquity may cause the normal dark-appearing growth plate to appear in the same axial cut as the contralateral bright-appearing epiphysis; in such cases, the normal growth plate may appear to be abnormal on MRI.

Children may require sedation as a result of the long imaging times that MRI requires. It may be difficult to detect avascular necrosis after surgery to repair a hip fracture because of the presence of orthopedic hardware, which creates significant image distortion. Marrow cells are more resistant to ischemia than hematopoietic cells or osteocytes. Because MRI images reflect changes within marrow fat signal intensity, MRI findings of AVN may not be seen for up to 5 days after the ischemic event, until the marrow fat cells have died. In this situation, contrast-enhanced MRI is needed.

Single-photon emission computed tomography

SPECT demonstrates poor spatial resolution. Artifacts from the bladder frequently are encountered; these artifacts may obscure the photon-deficient region of the femoral head. A number of techniques, such as the use of multihead cameras with shorter acquisition times that improve resolution and increase sensitivity, have been advocated, but none has gained universal acceptance.

SPECT imaging requires a cooperative patient who must remain immobile for up to 45 minutes of acquisition time. Diagnosing LCP in small children may be difficult because of the small size of the femoral epiphysis and associated bladder artifacts. SPECT is difficult to use in children because of the necessity to remain motionless for long periods of time. Children may require sedation.

Planar scintigraphy

This technique demonstrates poor spatial resolution (see images below and Image 16, Image 24 in Multimedia). The ring of increased activity reflecting hyperemia in the early stages and bone healing later obscures the photon-deficient necrotic center within the femoral head, which is indicative of AVN. The site may show a uniform high level of activity, making it impossible to distinguish AVN from other causes of increased activity, such as osteoarthritis, fracture, and inflammatory arthritis. A cold spot in the femoral head is highly specific but not sensitive for diagnosing AVN.

Planar scintigraphy using quantitative bone scan

This technique is experimental and is not used widely in the clinical setting.

CT

Although CT may delineate subtle alterations of bone density when plain radiograph findings are normal, MRI and SPECT scintigraphy are much more sensitive for evaluating early manifestations of the disease, such as bone marrow edema. CT scans are insensitive for detecting stage 0 and 1 AVN but are excellent for detecting femoral head collapse, early degenerative joint disease (DJD), and the presence of loose bodies.

CT may improve the accuracy of radiographic staging using thin-slice thicknesses of 1 mm or less and by incorporating multiplanar reconstruction. In one study, 30% of hips with stage 2 (precollapse) AVN, evaluated with plain film radiography, had stage 3 disease when evaluated using CT scans.

Plain film radiography

Using plain film, the sensitivity for detecting early stages of the disease is as low as 41%. Plain film does not detect stage 0 and 1 AVN. A delay of 1-5 years may occur between the onset of symptoms and the appearance of radiographic abnormalities. Normal radiographic findings do not necessarily mean that disease is not present.

Demineralization of the femur may be detected, and the disease may be suggested only after bone resorption has occurred. If early diagnosis is needed for the prompt initiation of therapy, more sensitive imaging methods (ie, MRI) must be used, especially in patients who are at increased risk for AVN.

Differential Diagnoses

Bone Metastases

Other Problems to Be Considered

Clinical

Transient osteoporosis

Plain film radiography

Malignancy
Osteomyelitis
Transient osteoporosis of the hip
Bone sarcoma
Advanced DJD (see Image 9)
Insufficiency fractures
Epiphyseal dysplasia
Bone metastases

Bone scintigraphy

Infection
Plasma cell myeloma
Skeletal metastasis
Hemangioma
Radiation therapy
Arthritis
Sympathetic dystrophy
Bone marrow edema syndrome
Bone metastases

CT

Degenerative disease
Insufficiency fracture
Malignancy
Infection
Plasma cell myeloma
Bone metastases

MRI

Transient osteoporosis of the hip
Transient bone marrow syndrome
Bone bruise
Epiphyseal stress fracture
Infection
Infiltrative neoplasm
Insufficiency fracture
Bone metastases

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