Arthritis & Allied Conditions
15th Edition

Chapter 107
Chris T. Derk
Raphael J. DeHoratius
Osteonecrosis comes from the Greek words for bone (osteo) and death (necrosis), a concept first put forward by Hippocrates in antiquity (1). This term is used to describe cellular death in bone tissue most commonly related to an interruption of its blood supply and the subsequent destruction of its architectural structure. Many different terms have been coined to describe this disorder, such as avascular necrosis, aseptic necrosis, ischemic necrosis, and osteochondritis dissecans, all of which are commonly used in the medical literature.
In 1794, the first modern-day description of this disorder was made by James Russell (2). At that time, infectious etiologies were the primary pathogenic agent. It was only in 1888 that the term aseptic necrosis of the bone was first used to describe what we now know as osteonecrosis (3).
Most osteonecrosis cases are related to traumatic interruption of the blood supply to the bone; however, nontraumatic cases related to systemic disorders remain a diagnostic challenge, especially in defining the precise cause of bone death (Table 107.1).
TABLE 107.1. Other selected conditions potentially related to the pathogenesis of osteonecrosis

Hematologic Metastatic carcinoma
Thalassemias Acute leukemia
Polycythemia Hodgkin’s disease
Hemophilia Marrow infiltrative disorders
Clotting disorders Embolism
Myeloproliferative disorders  
  Fat necrosis
Crohn’s disease Pregnancy
Ulcerative colitis  
Pancreatitis Endocrinologic
  Fabry’s disease
Infectious Cushing’s disease
Septic arthritis Hyperparathyroidism
Osteomyelitis Gout
Congenital hip dislocation Hypersensitivity reaction
Hereditary dysostosis Solid organ rejection
  Anaphylactic shock
Connective tissue disorders Serum sickness
Systemic lupus erythematosus  
Raynaud’s phenomenon Iatrogenic
Systemic sclerosis Solid organ transplantation
Polymyalgia rheumatica Radiation therapy
Sjögren’s syndrome Hemodialysis
Rheumatoid arthritis Corticosteroids
Ankylosing spondylitis Alcohol
  Cytotoxic agents
  Radiation therapy

There seem to be two distinct forms of this condition: (a) a secondary form, caused by a number of well-recognized risk factors, working alone or in concert, and (b) an idiopathic, or primary form, for which no identifiable risk factors have been identified (4).
Even though significant advances have been made with early radiologic recognition, the mainstay of therapy continues to be surgical. This is possibly related to difficulties with early detection because of the lack of early clinical symptoms as well as the heterogeneity of its pathogenesis, which limits any focused medical approach as a therapeutic option. Better delineation of the pathogenic processes that lead to osteonecrosis and better understanding of the pathogenic mechanism in each patient may bring a long sought after medical therapeutic option for these patients.
Osteonecrosis affects individuals of both genders and all age groups with the exception of systemic lupus erythematosus (SLE), for which a higher prevalence is seen in female patients. It is estimated that osteonecrosis accounts for 10% of the 500,000 total joint replacements performed each year in the United States (5).
In large series of total hip replacements (THRs), 5% to 12% of the procedures were performed for osteonecrosis (6,7,8). It usually affects patients between the ages of 20 and 50 years (mean age, 38 years), with a slight male prevalence, especially in idiopathic cases. It most commonly involves the femoral head, with the femoral condyles, humeral head, and small bones of the hands and feet affected less frequently. It may potentially involve any bone in the body, although cases of symptomatic multifocal osteonecrosis are more common in patients with SLE, renal disease, inflammatory bowel disease, and coagulation disorders (9). For the purpose of this chapter, we discuss osteonecrosis as it pertains to the femoral head, which is the most commonly involved site.
Within 4 years from the diagnosis of femoral head osteonecrosis, collapse of the head and joint destruction occur in at least 80% of the patients (10), with pronounced clinical symptoms observed in 68% to 83% of patients (11,12,13). Within 3 years of diagnosis of osteonecrosis, more than 50% of patients undergo THR (14).
When osteonecrosis of the femoral head follows a fracture or a dislocation of the hip, there is a clear association between the mechanical interruption of the blood supply and the subsequent development of osteonecrosis. The pathogenesis of osteonecrosis is even somewhat understood when related to such disorders as sickle cell disease, hypercoagulable

states, and myeloproliferative disorders, in which an intravascular obstruction of the blood supply to a distal artery is thought to be the cause of a bony infarction, comparable to a myocardial infarction. To the contrary, it still remains a challenge for most researchers to describe the exact pathogenesis of osteonecrosis when it is related to risk factors such as SLE, corticosteroid use, renal transplants, or radiation therapy. Furthermore, an idiopathic or primary category has also been postulated for cases in which there is no clearly identifiable risk factor, and the pathogenesis for these cases remains an enigma.
Vascular Occlusion
Trauma is the most common cause of vascular occlusion with subsequent osteonecrosis, and the likelihood of developing this is directly proportional to the following:
  • Extent of fracture displacement
  • Impingement on the vascular supply of the bone
  • Available collateral circulation of the affected site (15)
To better understand this pathogenic process, a description of the vascular anatomy of the femoral head is required (Fig. 107.1). The arterial supply to the femoral head is both rich and diverse; the metaphyseal and epiphyseal arterial systems coexist in close proximity in this region. The epiphyseal plate is the boundary separating these two systems during bone growth, although the two systems are widely interconnected.
FIG. 107.1. Diagrammatic representation of the vascular supply to the femoral head.
The extracapsular arterial ring lies at the base of the femoral neck, formed anteriorly by a branch from the lateral femoral circumflex artery and posteriorly by a branch from the medial femoral circumflex. From this ring, cervical and retinacular branches ascend the surface of the femoral neck in lateral, medial, posterior, and anterior groups. At the articular margin of the femoral head, these ascending vessels form another ring called the subsynovial intraarticular arterial ring. From this ring, epiphyseal arteries branch out and penetrate the femoral head (16,17). The lateral group of these arteries supplies 80% of the femoral epiphysis and the anterosuperior quadrant of the femoral head (18), thus making this area of the femoral head the most vulnerable for the development of osteonecrosis (19) (Fig. 107.1).
An intracapsular fracture of the hip interrupts the ascending cervical and retinacular vessels, and more importantly

the lateral epiphyseal arteries. This explains why 80% of femoral head specimens in these postfracture patients show some form of osteonecrosis (20). Similar pathogenic mechanisms predisposing to osteonecrosis are also seen in fractures of the femoral condyles, the humeral head, and the talus.
Posttraumatic osteonecrosis on rare occasions is also seen in the small bones of the hands and feet, this being related to the poor blood supply to these bones, with the lunate and scaphoid being the most commonly involved. Osteonecrosis has been reported in 20% of lunate fractures, where this is called Kienbock’s disease (21), whereas 3% of scaphoid fractures also develop osteonecrosis (22).
Other, less common causes of vascular occlusion are embolic phenomena related to sickle cell disease, nitrogen bubbles in dysbaric trauma, and caisson disease, as well as damage to the vasculature from radiation or the development of systemic vasculitis.
Intravascular Coagulation
The intraosseous microcirculation is as susceptible to a prothrombotic state as any other part of the circulation. Taking Virchow’s triad as an example, this may be the result of one or a combination of factors, including endothelial damage, circulatory stasis, or a hypercoagulable state. Endothelial damage may be related to trauma, atherosclerotic lesions, or autoimmune inflammatory connective tissue disorders that may affect the endothelial lining. For example, in scleroderma, a potent vasoconstrictor, endothelin, is secreted from endothelial cells, causing vasoocclusion of vessels that are already compromised by endothelial hyperplasia (23). In patients with SLE and rheumatoid arthritis, early vessel wall atherosclerosis is postulated to be related to the inflammatory nature of these disorders and to contribute to ischemic events such as osteonecrosis (24). Circulatory stasis is also facilitated in the microcirculation of the femoral head and especially in the subchondral areas where the blood supply is that of terminal arterioles with very few collaterals. Compromise in this vulnerable circulatory system promotes stasis, which leads to intravascular thrombosis and subsequent osteonecrotic lesions. In turn, the compromised blood flow causes elevated intramedullary pressures, which lead to further compromise in the blood flow (25,26). Hypercoagulable states also manifest themselves with intravascular coagulation, which at times may lead to osteonecrosis. Examples of these disorders are (a) protein C and S deficiency, (b) antithrombin III deficiency, (c) factor V Leiden mutation, (d) polycythemia rubra vera, (e) SLE, (f) antiphospholipid antibody syndrome, (g) pregnancy, (h) pancreatitis, and (i) the development of a malignancy.

The above-mentioned theories concerning the initial event in the development of osteonecrosis are primarily mutually supportive and not exclusive. Osteonecrosis may be better considered as a multifactorial disorder initiated by different pathogenic mechanisms that leads to a final common pathway of mechanical failure of the femoral head. As part of the early ischemic injury, oxygen free radicals cause increased capillary permeability, which in turn causes local edema and intramedullary hemorrhage in the region of the osteonecrotic lesion, which has been postulated by some investigators to be an important event in the propagation and pathogenesis of osteonecrosis (27,28). After irreversible bone ischemia occurs, osteocytes are recruited to the region to differentiate into osteoclasts, which will degrade the dead bone, and osteoblasts, which will create a new layer of bone. Some studies have shown that this remodeling of the bone is ineffective and may be directly related to the subsequent collapse of the femoral head (29).
Intraosseous Hypertension
A cortical shell surrounds the femoral head, limiting the expandability of this structure and leading to an elevated intracortical pressure whenever there is an expansion of the space occupied by the underlying elements of the femoral head. For example, if hemorrhage occurs within the femoral head, the intracortical pressure rises as a result of the inability of the femoral head to expand under the increased pressure, thus leading to the compromise of the blood flow because of a tamponade-like physiology on the intracortical vessels, the end result being osteonecrosis (1,26).
Of final note is the intriguing evidence presented by some researchers investigating the pathogenesis of osteonecrosis in patients receiving glucocorticoids. In these patients, it has been shown that in femoral head osteonecrotic specimens, the cause of injury was not one of ischemia secondary to vascular compromise, but instead was one of direct osteocyte apoptosis (30,31). Similar findings were also seen in osteonecrosis specimens taken from patients consuming large amounts of alcohol (32).
The most common cause of femoral head osteonecrosis is that related to a vascular compromise after a displaced or nondisplaced fracture of the proximal femur (33), and the underlying pathogenesis is directly related to the extent of compromise to the distal arterioles supplying the femoral head. Trauma-related osteonecrosis can also occur in any bone of the body that derives its blood supply from a group of terminal arterioles or has a poor collateral circulation. In some rare cases, osteonecrosis may also be related to a posterior dislocation of the hip, and less commonly an anterior dislocation (34,35). Osteonecrosis has also more recently been recognized as a postoperative complication after orthopedic surgery for the fixation of bone fractures, in which the patient reports persistent pain even after successful surgery and adequate rehabilitation. At times, it has also been described as a complication of arthroscopic procedures for the repair of meniscal tears of the knee (36).
About 25% of patients receiving corticosteroids develop osteonecrosis (5), whereas the prevalence of glucocorticoid use in patients with osteonecrosis ranges from 3% to 38% (37). After trauma, corticosteroid use is thought to be the second most common cause of osteonecrosis. It is thought to be directly proportional to the dose and duration of corticosteroid therapy (38,39). More recent studies have contradicted this and have shown magnetic resonance imaging (MRI) changes as early as 3.6 months after initiation of corticosteroid therapy (40), whereas in case reports, courses of corticosteroids as short as 16 days have been implicated in the development of osteonecrosis (41). It is difficult to predict which patients will develop osteonecrosis as a consequence of glucocorticoid use, but comorbidities that increase the risk for osteonecrosis may play a role. The most commonly involved site is the femoral head, often in a bilateral distribution.
Different hypotheses have been described to play a pivotal role in the pathogenesis of osteonecrosis in these patients, although a unifying pathogenic mechanism is as of yet unclear. Hypotheses include fat emboli causing occlusion of the distal vessels supplying the femoral head (42), tamponade of these same vessels by increased marrow fat or water (43), and the most intriguing one, corticosteroid-induced osteocyte apoptosis (30).
Systemic Lupus Erythematosus
An association between osteonecrosis and SLE was first made by Dubois in 1960 (44). The prevalence of osteonecrosis in patients with SLE ranges from 5% to 37.5% in large case series (45,46,47,48,49). Osteonecrosis commonly affects these patients in a bilateral fashion, and SLE has the highest prevalence of multifocal osteonecrosis as compared with other risk factors (9) (Figs. 107.2, 107.3, 107.4, 107.5 and 107.6). In contrast to other patients with osteonecrosis, there is a preponderance of female patients in this group, a reflection of the gender prevalence in SLE patients.
FIG. 107.2. An anteroposterior view of the hips in a 23-year-olf female patient with osteonecrosis of both femoral heads (arrows), associated with systemic lupus erythematosus.
FIG. 107.3. A lateral frog leg view of the hip in a patient with osteonecrosis (arrow) associated with systemic lupus erythematosus.
FIG. 107.4. Gross sagittal section of right femoral head showing a stage III postcollapse lesion with an extensive subchondral fracture (radiolucent crescent) with incomplete detachment of the overlying cartilage, and a dark zone of revascularization, especially in the region of the lateral epiphyseal vessels. This patient had morbid obesity, diabetes, fatty liver, arterial fat embolism, increased free fatty acids, and intravascular coagulation.
FIG. 107.5. An anteroposterior view of the knee in a 23-year-old female patient with osteonecrosis of the femoral condyle (arrow) associated with systemic lupus erythematosus.
FIG. 107.6. A lateral view of the knee in a 23-year-old female patient with osteonecrosis of the femoral condyle (arrow), associated with systemic lupus erythematosus.
Clinical findings related to which patients with SLE will develop osteonecrosis have been extensively evaluated in many studies, with conflicting results. Some studies have shown an increased prevalence of Raynaud’s phenomenon, vasculitis, thrombophlebitis, antiphospholipid antibodies, and cushingoid habitus in patients with SLE and osteonecrosis (38,50,51), whereas other studies did not confirm these results (47,48,52,53). It is hypothesized that multiple factors

predispose these patients to osteonecrosis other than corticosteroids. The possibilities include the hypercoagulable state and vascular endothelial damage seen in these patients, the prevalence of circulating anticardiolipin antibodies, the abnormal fat distribution related to long-term corticosteroid use, the vasospastic effects of Raynaud phenomenon, and the vasoocclusive effects of vasculitis.
Ficat initially reported a potential relationship between heavy alcohol consumption and osteonecrosis (54). A number of reports have considered this association because there is a high prevalence of habitual drinkers among patients who have osteonecrosis, although this may be as a result of the chronic pain that these patients endure (55,56) (Fig. 107.7). A more recent epidemiologic study from Japan

by Matsuo and colleagues has shown a statistically significant excess alcohol intake in patients with osteonecrosis who had no history of previous corticosteroid use as compared with hospital controls (57). Mechanisms concerning the pathogenesis of alcohol-related osteonecrosis are not well understood. The possibilities range from fat emboli, to elevated levels of endogenous cortisol, abnormalities in lipid metabolism, and increased size of fat cells that may cause increased intraosseous pressure and subsequent vascular occlusion (58,59,60,61,62).
FIG. 107.7. MRI (T1-weighted) of femoral head in axial plane showing a classic, reparative lesion without collapse (stage II) that is surrounded by a dark band (black arrows), the revascularization front. Heterogeneous signal intensity in the necrotic segment results from residual, dead, unsaponified adipocytes in the anterior third of the lesion (white arrows). This patient was an alcoholic with pancreatitis and diabetes.
Dysbaric Phenomenon
Early reports of osteonecrosis in laborers working in compressed air environments, in the building of underwater tunnels and bridges, were seen as early as 1913—hence the initial name for this disorder, caisson disease (63). This entity was later also described in underwater divers (64), especially sponge divers who dove at large depths. Osteonecrosis is seen in up to 13% of compressed-air workers in recent studies (65,66), and it has been shown that, if the working conditions expose the worker to less than 11 pounds per square inch gauge, the likelihood of developing osteonecrosis is minimal (67). It is hypothesized that the pathogenesis of osteonecrosis in these patients is similar to the one that causes decompression sickness (the bends) in divers. It is believed that either intravascular nitrogen bubbles cause intravascular coagulation and subsequent occlusion of the distal vessels supplying the femoral head, or that nitrogen bubbles in the fat cells cause extravascular compression, which leads to vascular occlusion, secondary to increased intraosseous pressures (68,69). A final hypothesis is that of the pressure itself causing venous stasis in the intramedullary region and thus initiating a hypercoagulable state that leads to ischemia of the bone (70) (Fig. 107.8).
FIG. 107.8. A: T1-weighted (TR/TE, 600/20) MRI of the lumbosacral spine demonstrating transverse single-banded revascularization fronts involving the inferior L5 and superior S1 vertebral bodies. B: T2-weighted (TR/TE, 2000/20) MRI reveals an obvious double-banded (resorption-formation) front (arrows) within the superior aspect of S1. This vertebral end-plate necrosis perhaps caused degenerative disk disease at L5-S1 by creating diffusion barriers to hydration of the nucleus pulposus. This former U. S. Navy diver also had a focal stage II lesion in his left femoral head and stage IV postcollapse osteonecrosis involving his right hip. (Courtesy of Paul Swenson, M.D.)
Risk factors potentially activating intravascular coagulation are many, and anecdotal reports in the development of osteonecrosis exist for most of these causes. It is not the purpose of this chapter to report exhaustively on all coagulopathic states related to the development of osteonecrosis but rather to touch on a selected few examples.
The antiphospholipid antibody syndrome, with or without SLE, can cause pronounced coagulopathy, both in the venous and arterial circulation, and, at times, can lead to osteonecrosis

(71,72). Other hypercoagulable states reported as related to osteonecrosis include deficiencies in proteins C and S, factor V Leiden, or antithrombin III, and a state of homocystinemia (73,74,75). Another less known hypercoagulable state that has been extensively studied as a potential cause of osteonecrosis is the combination of hypofibrinolysis related to a familial increase of plasminogen activator inhibitor and an associated thrombophilia (76). Glueck and associates have postulated that treating the hypercoagulable state with either warfarin or enoxaparin may bring relief to the symptoms of these patients, and in small pilot studies, they showed some benefit, although large double-blind placebo studies are lacking (77,78).
Sickle Cell Disease
Intravascular sickling causes many untoward side effects secondary to the ischemia related to intravascular blockade, which can lead to thrombosis and progressive ischemia that, when affecting the circulation to the bone, can cause osteonecrosis. Dactylitis in sickle cell patients is a manifestation of this pathogenic process commonly seen in the younger population. In a large study by Milner and colleagues, 2,590 patients with sickle cell disease were followed over 5.6 years, and radiographs of both hips were obtained at 6-month intervals (79). Osteonecrosis of the femoral head was seen in about 2 to 4.5 cases per 100 patient-years of follow-up, with a prevalence of about 10%. Although the pathogenic mechanism is thought to be primarily related to sickling, other reports have suggested that disseminated intravascular coagulation, which has been described during the acute crisis episodes, may also be related to the development of osteonecrosis (80).
Patients with hemoglobin SS genotype and a thalassemia are at the greatest risk for developing osteonecrosis, whereas patients with hemoglobin SC develop osteonecrosis later in life. The frequency of acute crisis episodes appears to be the most highly correlated prognostic indicator for the development of osteonecrosis in these patients. Many patients present with bilateral hip involvement, whereas younger patients have a higher potential for healing their osteonecrotic lesions as compared with older patients. In patients who eventually require total joint arthroplasty, 59% require a revision at 5.5 years after the initial procedure (81); thus, conservative management is promoted for early bone lesions.
Because the frequency of sickle cell crisis correlates with the potential development of osteonecrosis, methods to decrease this may be beneficial. The patient needs to be well hydrated at all times, and the use of hydroxyurea in patients with frequent crisis and those with a high hemoglobin S level in the blood should be undertaken to decrease the relative amount of hemoglobin S.
Legg-Calvé-Perthes Disease
Legg-Calvé-Perthes disease is a disorder affecting children between the ages of 2 and 12 years (mean, 7 years), in which there is osteonecrosis of the capital femoral epiphysis. Arthur T. Legg, Jacques Calvé, and George Perthes were the first to describe this condition in the early 1900s. It more often affects boys, and in 10% of cases, it is bilateral. It is estimated to affect 5.7 patients per 100,000 patient-years of follow-up in the general pediatric population of the United States (82). It has been described that a proportion of these patients have a thrombophilic tendency (83,84,85), whereas recent reports have also described it in association with human immunodeficiency virus (HIV) infection (82). For early cases of Legg-Calvé-Perthes disease, containment and preservation of the range of motion is the mainstay of

therapy, by improving pain control and hip joint mechanics (86,87,88). Different abduction casts and orthoses are used to contain the femoral head in the acetabulum because the acetabulum can act as a mold for the reossification of the capital femoral epiphysis. If the disorder has progressed to the point that the femoral head cannot be contained in the acetabulum, then a surgical intervention may need to be considered (89,90). Up to 50% of patients do well without treatment, whereas 25% of patients require arthroplasty in their fifth or sixth decade of life.
Slipped Capital Femoral Epiphysis
Slipped capital femoral epiphysis is the most commonly described adolescent hip disorder. The etiology is unknown, although osteonecrosis may occur as a result of injury to the retinacular vessels by compression from a hematoma or as a result of forced or surgical reduction. The incidence of osteonecrosis appears to be related to the extent of slippage and the time from the initial presentation to the reduction of the slipped epiphysis. Early reduction usually decreases the risk for osteonecrosis (91,92,93).
Gaucher’s Disease
Gaucher’s disease, a deficiency of the enzyme β-glucosidase, is the most common genetic lysosomal storage disorder. The enzyme deficiency leads to the accumulation of glucocerebrosidase, especially in children of Jewish descent. Gaucher disease is classified into three different types, with type I disease being the one most commonly associated with osteonecrosis. This is a form of the disease commonly seen in adults, with chronic visceral and osseous involvement and a relative sparing of the nervous system, which is usually involved in other types of Gaucher disease (94). Bone crisis episodes, similar to the ones seen in sickle cell disease, are seen in 25% to 37% of patients (95). A group of these patients develop osteonecrosis, often multifocal in nature. The pathogenesis behind this manifestation is thought to be related to increased intraosseous pressure from expanding histiocytes due to increased glucocerebrosidase, although other hypotheses also exist (96). Enzyme replacement therapy is now available for this disease (97).
Human Immunodeficiency Virus
Since the initial report of osteonecrosis in HIV in 1990 (98), many more case reports and case series have been described in the literature (99,100,101,102,103), and more recently, a large study was performed in a group of asymptomatic HIV patients (104). Three hundred thirty-nine asymptomatic HIV-positive patients and 118 age- and sex-matched HIV-negative controls were evaluated for osteonecrosis of the hip by MRI; 15 (4.4%) of the HIV-positive patients had osteonecrotic lesions as compared with 0 patients in the control group. Risk factors evaluated in the group of HIV-positive patients with osteonecrosis versus the HIV-positive patients without osteonecrosis showed an increased prevalence of corticosteroid use, use of lipid-lowering agents, testosterone use, an increased prevalence of bodybuilding exercises, and an increase in anticardiolipin antibody levels. The use of protease inhibitors, which has also been studied in the past, again showed no relationship with the development of osteonecrosis (104,105). The exact pathogenesis is not clear, but the increased prevalence needs to be kept in mind when evaluating patients with HIV who have symptoms suggestive of osteonecrosis.
Osteonecrosis of the femoral head is a rare manifestation of pregnancy, especially in healthy women who have no known risk factors for the development of this disorder (106,107). The cause of osteonecrosis in these patients is unknown, but different hypotheses have postulated the possibility of amniotic fluid emboli, a relative hypercoagulable state, excessive mechanical strain, and an increase in endogenous steroid production. To date, the largest case series was described by Montell and associates (106). In this case series, 13 women developed hip pain late in the second or in the third trimester of their pregnancy. In general, these women tended to have a small body habitus, and during their pregnancy, they had gained excessive weight, indicating that this may have a pathogenic role in the development of osteonecrosis. All the affected women had involvement of their left hip, and 4 of them had bilateral involvement. As a rule, a high index of suspicion is required by the clinician to prevent the misdiagnosis or the delayed diagnosis of osteonecrosis in these patients.
Hyperlipemia has already been linked to intravascular coagulation, which could potentially lead to osteonecrosis in some patients (108). In a study by Moskal and colleagues of 19 patients who had 33 hips involved with osteonecrosis, and in whom common risk factors were ruled out, it was shown that there was a statistically significant elevated serum cholesterol level. These results suggest that the systemic effect of hypercholesterolemia may be involved in the pathogenesis of osteonecrosis (109) (Fig. 107.9). The hypercholesterolemia, although not proved by currently available data, may have just been an epiphenomenon as a result of an increased endogenous steroid state.
FIG. 107.9. The double-line sign (arrows) is obvious on the T2-weighted (TR/TE, 2400/20) MRI appearing as a transverse double band across the dome of the body of the right talus, immediately beneath the ankle mortise. This patient had morbid obesity, diabetes, and hyperlipemia.
In another study, Palmer and associates evaluated a family with familial hyperlipoproteinemia, and from 16 family members available for evaluation, 8 were found to have both hyperlipoproteinemia and osteonecrosis (110). Finally, of interest is a report by Pritchett and co-workers, in which, on retrospective chart review of 284 patients who were taking statin drugs at the time they began steroid use, only 3 patients (1%) developed osteonecrosis as compared with

the reported incidence of up to 25 % of patients receiving corticosteroids (5,111).
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation (DIC) is characterized by excessive and unregulated generation of thrombin, which induces platelet activation and aggregation, with subsequent intravascular coagulation and the potential to cause osteonecrosis (112,113). A multitude of disorders are associated with DIC, including infection with encapsulated gram-positive bacteria, gram-negative bacterial infections, and viral infections such as varicella virus, cytomegalovirus, and HIV. Other potential causes are amniotic fluid embolism, burns, heat stroke, malignancies, dead fetus syndrome, and fatty liver of pregnancy.
Many of the clinical manifestations of DIC are thought to be related to the initial hypovolemia, which predates intravascular coagulation, although for osteonecrosis, it appears that the main pathogenic mechanism is a combination of both intravascular coagulation and hypovolemic ischemia (114) (Fig. 107.10).
FIG. 107.10. Coronal section of left humeral head in a patient who expired 18 hours after developing anaphylactic shock. Disseminated intravascular coagulation (DIC) had resulted in fibrin thromboses of vessels, with infarction of adipocytic marrow tissue (nonviable light areas) and secondary fibrinolysis and interadipocytic hemorrhage of adjacent marrow (viable dark areas). This classic distribution of osteonecrosis was also seen in this patient’s right humeral head and both femoral heads.
Osteonecrosis following a hip fracture is described as prolonged pain even after the successful surgical treatment of the orthopedic injury. The pain is described as a deep aching or boring pain localized to the groin and at times radiating down the thigh and into the knee region. Radiographs often are normal early, and a high suspicion is required to make the diagnosis by the use of a bone scan or MRI. In patients with atraumatic osteonecrosis of the hip, the earliest stages of the disease process are often asymptomatic. Patients usually present with insidious onset of deep aching groin pain, which subsequently is exacerbated by weight-bearing and physical activity. The gait may become antalgic, and on physical examination, the range of motion of the affected joint is limited and painful. A noninflammatory joint effusion may also be present in the affected joint. In non-weight-bearing joints, and specifically the hand joints, osteonecrosis may remain silent even when it reaches an advanced stage.
Initial radiographs of the hip should include both an anteroposterior view and a lateral frog-leg view (Figs. 107.2 and 107.3). If the standard radiographs are nondiagnostic and there is still a high suspicion for osteonecrosis, an MRI study or a three-phase bone scintigraphy using technetium 99m medronate methylene diphosphonate may be helpful in early diagnosis (115,116,117). Early lesions are seen on bone scan as nonspecific cold spots due to decreased uptake of the radiotracer, whereas with time, an increased uptake of radiotracer is observed as a result of the increased bone metabolism related to the reparative mechanisms in the region. This is nonspecific and may be seen in other disorders such as bone fractures or tumors. The only pathognomic finding seen on bone scan is the “cold in hot spot” seen in about 25% to 50% of patients with osteonecrosis, and this is related to the central bone necrosis and the surrounding reparative process (118).
On MRI studies, osteonecrosis is seen as a focal subchondral defect with or without surrounding bone marrow edema (119). This area of edema is postulated to be a region of transient ischemia with still viable bone tissue. Bone edema

related to osteonecrosis needs to be differentiated from a condition called transient osteoporosis. The cause of transient osteoporosis is unknown, but it usually affects young men and pregnant women who have no risk factors for osteonecrosis, and although the clinical symptoms are similar to those of osteonecrosis, this disorder is usually self-limited. Early, the two disorders are indistinguishable on MRI, but subsequent studies, after the disease progresses, show a subchondral defect in the osteonecrosis patients as compared with patients with transient osteoporosis (120,121,122).
There is no single staging system for osteonecrosis that is universally accepted, although two systems, one derived by Ficat (123) and another by Steinberg (124), are commonly used in the medical literature and for research purposes. Both staging systems are based on roentgenologic abnormalities, taking into consideration radiograph, bone scan, and MRI results. We favor the Steinberg classification (Table 107.2) because the extent of the disease is subdivided at each level according to the percentage of the femoral head affected, which has been shown in some studies to have a clinical correlation (125).
TABLE 107.2. Staging systems for femoral head osteonecrosis

Stage Steinberg criteria Stage Ficat criteria

0 Normal x-ray, bone scan, and MRI 0  
I Normal x-ray, abnormal bone scan or MRI I Normal x-ray, equivocal bone scan
  A. Mild (<15% of femoral head)    
  B. Moderate (15%–30% of femoral head)    
  C. Severe (>30% of femoral head)    
II Cystic and sclerotic changes IIA Cystic and sclerotic changes
  A. Mild (<15% of femoral head)    
  B. Moderate (15%–30% of femoral head)    
  C. Severe (>30% of femoral head)    
III Subchondral collapse without flattening IIB Crescent sign
  A. Mild (<15% of femoral head)    
  B. Moderate (15%–30% of femoral head)    
  C. Severe (>30% of femoral head)    
IV Flattening of femoral head III Broken contour of femoral head
  A. Mild (<15% of femoral head)    
  B. Moderate (15%–30% of femoral head)    
  C. Severe (>30% of femoral head)    
V Joint space narrowing/ acetabular involvement IV Joint space narrowing, flattened
  A. Mild (<15% of femoral head)   contour, collapse of femoral head
  B. Moderate (15%–30% of femoral head)    
  C. Severe (>30% of femoral head)    
VI Advanced degenerative changes    

With conventional radiography, early lesions are usually missed, and MRI studies will reveal them only when a high suspicion is entertained, usually as bone marrow edema and early subchondral lesions. In both staging systems, stage I is exactly that, patients in whom the diagnosis of osteonecrosis is entertained from their clinical symptoms with negative conventional radiographs, whereas MRI studies or bone scans show distinct abnormalities. In stage II of the Steinberg classification, lucent and sclerotic changes, and stage IIA of the Ficat classification, cystic and sclerotic changes of the femoral head are the main radiographic findings for both staging systems. In Steinberg stage III, subchondral fracture (crescent sign) without flattening is noted, and in Ficat stage IIB, subchondral collapse is viewed as a crescent sign on conventional x-rays for both classification systems (Fig. 107.4). In stage IV of the Steinberg classification, there is subchondral fracture with flattening or segmental depression, whereas in Ficat stage III, there is a broken contour of the femoral head. In stage V of the Steinberg classification, joint space narrowing is present, and acetabular involvement is taken into consideration. Ficat stage IV is collapse of the femoral head. Finally, stage VI of the Steinberg classification takes into consideration all the patients who have advanced degenerative changes beyond those described previously (Table 107.2).
Therapy for osteonecrosis is based on the stage of the disease as well as the age of the patient. In patients who have, according to the Steinberg classification system, stage I lesions, conservative measures may be undertaken early, such as pain control and limited weight bearing, although the disease itself continues to progress if the lesion is in the weight-bearing portion of the femoral head (126,127). In children, and especially patients with Legg-Calvé-Perthes disease, early lesions may be treated conservatively by containment of the femoral head in the acetabulum by the use of an abduction

splint or brace, as opposed to an operative osteotomy of the femur or pelvis. Physical therapy is also very important to preserve the range of motion of the joint. In many of these patients, the disease does not progress because bone remodeling in this young population is much more efficient than in adults (86,87,88).
Based on the same premise, some studies have looked at the use of bisphosphonates for early lesions, and at the possibility of preventing collapse of the femoral head by inhibiting osteoclastic activity in the area of the necrotic bone during revascularization (128). It is thought that structural failure results from the early reparative changes to the necrotic bone, before there is enough time for new bone formation to sustain load bearing and thus the subsequent collapse of the femoral head. In one study, 16 patients with early osteonecrotic lesions of the hip were treated with alendronate and were found to have a decrease in pain symptoms, less disability than expected by the natural course of the disease, and stability of MRI findings (129). This study was limited by the lack of a control group, although further studies may shed light on the potential use of bisphosphonates in osteonecrosis.
Statins have also been studied as a preventive measure in patients who are thought to be at risk for developing osteonecrosis by a hyperlipemic state and more specifically in patients who take corticosteroids. A single retrospective study revealed that patients who were on statins before the initiation of corticosteroids and remained on these agents during the course of steroid exposure were less likely to develop osteonecrosis (111).
Warfarin and enoxaparin have been studied in small pilot studies for their potential benefit in patients who have developed osteonecrotic lesions secondary to a hypercoagulable state. In these patients, it was observed that there was some benefit in pain management as well as improved function (77,78). Appropriate controlled studies are lacking, and we are thus unable to draw any conclusions about the potential benefit of these agents in patients with osteonecrosis.
Electrical stimulation has also been used on the premise that it enhances osteogenesis and vascularization, causing an increase in bone production by altering the balance between the function of the osteoblasts and osteoclasts in the osteonecrotic lesion. It has been used both as a primary modality on its own and in combination with core decompression and bone grafting procedures. Three different modalities of electrical stimulation have been used:
  • Pulsed electromagnetic fields are generated by the placement of a coil from a generator on the skin over the femoral head. In a study comparing core decompression with or without this electrical field, improved hip survival was seen with the use of this field (130).
  • Capacitance coupled current is generated by an electrode placed on the skin over the femoral head. Comparison of core decompression and bone grafting with or without this modality showed no increased benefit (131).
  • Direct current stimulation is achieved by placing an electrode directly into the femoral head after core decompression. Although it has shown an improvement in clinical function and a decrease in radiographic progression, there has been no increase in hip survival (132).
Core Decompression
Core decompression of hip osteonecrosis is one of the most popular and controversial procedures for treating osteonecrosis. With this procedure, a biopsy tract, which begins below the greater trochanter and is directed along the femoral neck and into the osteonecrotic lesion, stops short of the subchondral bone and removes a part of the osteonecrotic lesion. It is believed that this procedure provides pain relief as well as an increased chance for revascularization in the area of the osteonecrosis by relieving the increased intraosseous pressure. Complications related to this procedure are related to the potential of collapse of the necrotic lesion if the procedure is not performed correctly. The controversy in regard to the efficacy of this procedure is possibly related to the nonuniform use of a single staging system for the performance of research studies. In a metaanalysis evaluating a single surgical core decompression procedure for femoral head osteonecrosis, success rates of 84%, 63%, and 29% were seen, respectively, for Steinberg stages I, II, and III lesions (133). A further study analyzing the survival of a femoral head after core decompression for osteonecrosis has shown that at 2 years follow-up, there was no need for further surgery in 85% of hips that were classified by the Steinberg classification as stages 0, I, and II, in contrast to 66% of hips that were classified as stages III, IV, and V (134). Survival studies, which followed patients for an average of 10 years, showed that the higher the preoperative stage of osteonecrosis, the more likely it was that the core decompression would fail (135). Two studies evaluating a prospective randomized protocol between core decompression and conservative nonoperative therapy and subsequent femoral head collapse showed contradictory results. Although one study showed that core decompression produced better results than conservative therapy in early stages of osteonecrosis (136), the other study showed there was no difference between core decompression and conservative therapy in early stages of osteonecrosis. At 24 months of follow-up, there was collapse in 78% of core decompression patients and in 79% of conservatively treated patients (137).
Core Decompression with Bone Grafting
Bone grafting with autogenous or allogenous bone grafts may be done either with or without a core decompression. When combined with a core decompression procedure, a bone graft is inserted through the core decompression tract

to provide structural support to the subchondral bone, in patients with stage I and II osteonecrosis, and at times even in those with Steinberg stage III osteonecrosis (138). At times, the graft will unite with the surrounding bone, although vascularization of the graft is usually incomplete. As described earlier, electrical stimulation may also be employed to try to increase the survival of the hip and to promote vascularization of the bone graft. Even though pain relief is improved and the risk for femoral head collapse is decreased (139), it has been shown that these patients continue to have progression of the osteonecrotic lesions after 2 years of follow-up (140).
To enhance vascularization, vascularized bone grafts have also been used, although the procedure is much more cumbersome because of the need to anastomose the vessels of the graft to a nearby vessel, yet the results are better, with increased survival of the femoral head and better pain control as compared with nonvascularized grafts (141,142).
Osteotomy is a surgical procedure performed to shift the osteonecrotic lesion away from the weight-bearing zone, eliminating direct shearing forces on the necrotic lesion and facilitating healing. The surgical procedure involves a cut at the proximal femur that allows the osteonecrotic lesion to be rotated out of the weight-bearing region of the acetabulum vertical to the longitudinal axis of the femur. Some surgeons have also rotated the osteonecrotic lesion about the longitudinal axis of the femur. Osteotomy is usually recommended for type III and IV osteonecrotic lesions, although the success rate depends on the percentage of the femoral head that is involved. Drawbacks of this procedure are the long period of protected or non–weight bearing as well as the difficulty of the procedure if the osteonecrotic lesion is large. Usually, better results are seen in patients who have less than one third of the femoral head involved (143,144,145), limiting the risk from femoral neck fractures or osteotomy nonunions.
Resurfacing Arthroplasty
In the resurfacing arthroplasty procedure, the necrotic material of the femoral head is débrided, and a ceramic or a metallic shell is cemented over the surface of the femoral head. This type of procedure has been recommended for stage IV lesions, for pain relief and improved mobility in anticipation for a future total hip arthroplasty, usually because of acetabular degeneration (146,147).
Total hip arthroplasty is usually the procedure of choice for stage IV and greater disease, femoral head osteonecrosis lesions when the femoral head has collapsed and acetabular involvement is present. The success rate of this procedure appears to be much lower than in patients who receive a total joint arthroplasty for osteoarthritis. The reasons behind this are postulated to be the young age of the patients with osteonecrosis, placing more functional demands on these prosthetic joints, and the quality of the surrounding bone, which may also be affected by the underlying process that brought on the osteonecrosis in the first place. Even though there is substantial pain relief and increased functional ability, there is a higher rate of surgical revision in these patients as compared with other groups of patients who receive prosthetic joints (5,148,149).
Osteonecrosis remains an insidious bony disorder associated with high morbidity and disability. Although early detection has improved, the therapeutic modalities continue to be predominantly surgical ones. A better understanding of the development of these lesions at the molecular level will help us design specific medical therapy to counteract the additive processes that lead to the vascular and anatomic compromise of the bony regions involved by this disorder.
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