Version May 2024
INTRODUCTION — Osteonecrosis, also known as aseptic necrosis, avascular necrosis (AVN), atraumatic necrosis, and ischemic necrosis, is a pathologic process that is associated with numerous conditions and therapeutic interventions. The cause is clearly identifiable in patients who have direct damage to bone vasculature (eg, femoral neck fracture) or direct injury of bone or marrow elements (eg, radiation injury, dysbarism, or decompression disease). However, in many patients, the mechanisms by which this disorder develops are not fully understood.
Reduced perfusion leading to ischemia and eventual death of bone and marrow cells (bone marrow infarction) and ultimate mechanical failure appears to be common to most proposed etiologies. The process is most often progressive, resulting in joint destruction within a few months to several years in the majority of patients [1,2]. The femoral head is the most commonly affected site, but osteonecrosis can develop in other locations including the distal femur, humeral head, and small bones of the wrist and foot.
Two types of osteonecrosis are limited to children: idiopathic osteonecrosis of the femoral head (Legg-Calvé-Perthes disease) and osteonecrosis occurring in children, usually adolescents, with a slipped capital femoral epiphysis. The differences in the natural history of adult osteonecrosis and the juvenile forms may reflect differences in the pathogenesis and natural history of these diseases. These diseases are discussed in detail separately. (See "Approach to hip pain in childhood", section on 'Legg-Calvé-Perthes and secondary avascular necrosis' and "Evaluation and management of slipped capital femoral epiphysis (SCFE)", section on 'Osteonecrosis'.)
The clinical manifestations and diagnosis of osteonecrosis in adults will be reviewed here. The treatment of this disorder is discussed separately. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)
EPIDEMIOLOGY — The exact prevalence of osteonecrosis is unknown. In the United States, there are an estimated 10,000 to 20,000 patients newly diagnosed each year [3], with even larger numbers worldwide, and it is the underlying diagnosis in approximately 10 percent of all total hip replacements (THR) in the United States [4]. The male-to-female ratio varies depending upon the associated comorbidities. For example, alcohol-associated osteonecrosis is more common in men, while osteonecrosis associated with systemic lupus erythematosus (SLE) is more common in females. The mean age at diagnosis also depends upon comorbidities but is typically less than 50 years [5-7].
PATHOGENESIS — The pathogenesis of osteonecrosis is an area of controversy. Most experts believe that it is the result of the combined effects of genetic predisposition, metabolic factors, and local factors affecting blood supply, such as vascular injury, increased intraosseous pressure, and mechanical stresses [4,8,9]. The early stages of the natural history are unclear, as these stages are largely asymptomatic and patients often do not present until later. It is generally agreed that there is an interruption of the blood circulation within the bone; subsequently, the adjacent area becomes hyperemic. During the natural history of osteonecrosis, it is often possible to identify a reparative zone enveloping the sequestrum (ie, a necrotic zone). The reparative zone has been characterized in early stages by sinusoidal congestion and hemorrhage [10]. This is followed by "reactive angiogenesis," a process in which vasodilators released from the tissue surrounding the infarct, such as nitric oxide and vascular endothelial growth factor (VEGF), promote angiogenesis [11,12]. However, the angiogenesis is often impaired, resulting in demineralization, followed by trabecular thinning, and, later, by collapse [13].
The histopathologic finding of bone marrow infarction has been noted in marrow samples from patients with some of the same disorders that cause clinically apparent osteonecrosis [14]. However, other etiologies for bone marrow infarction include neoplastic disorders, particularly hematologic and lymphoid malignancies and metastatic cancer with associated coagulopathy. The causes of bone marrow infarction (bone marrow necrosis) are discussed elsewhere. (See "Evaluation of bone marrow aspirate smears", section on 'Bone marrow necrosis'.)
RISK FACTORS — A variety of traumatic and atraumatic factors contribute to the etiology of osteonecrosis. A definitive etiologic role has been established for some of these factors, based upon longitudinal cohort studies or meta-analyses, but not for the majority, which are considered associated risk factors [15]. The use of glucocorticoids and excessive alcohol intake are associated with more than 80 percent of atraumatic cases [8].
Medications and drugs — Both prescribed medications and alcohol have been implicated as causes of osteonecrosis.
Glucocorticoids — Numerous studies relate the use of systemic glucocorticoids to the development of osteonecrosis. In one study of 1199 joints in 302 patients, the incidence of developing osteonecrosis as a consequence of systemic glucocorticoids ranged from 21 to 37 percent [16]; the frequency varied, depending, in part, upon the associated comorbidities, duration, and dose [16-18].
Although the pathogenesis of glucocorticoid-associated osteonecrosis has not been established, there are several mechanisms that have been proposed [15,19]. One possible mechanism involves alterations in circulating lipids with resultant microemboli in the arteries supplying bone [20]. Another potential mechanism is that an increase in bone marrow adipocyte size and number within the bone marrow compartment of convex joints contributes to blocking venous outflow resulting in increased intraosseous pressure [21]. Yet another theory proposes that glucocorticoids induce changes in venous endothelial cells, leading to stasis, increased intraosseous pressure, and eventual necrosis [22].
Patients treated with prolonged high doses of systemic glucocorticoids appear to be at the greatest risk of developing osteonecrosis, but these patients often have multiple other risk factors [23,24]. Patients receiving chronic physiologic glucocorticoid replacement for adrenal insufficiency may develop osteonecrosis (2.4 percent in one report) [25]. However, osteonecrosis generally does not result from short-term use of these medications. In previous anecdotal reports suggesting an association, multiple additional risk factors were also present, suggesting that it was highly unlikely that these low doses led to the disease [26].
Most studies have found that the risk is low (less than 3 percent) in patients treated with doses of prednisone less than 15 to 20 mg/day. A population-based study identified 98,390 patients who had received a single short-term, low-dose methylprednisolone taper pack (MTP) prescription and found that the incidence of osteonecrosis among this group of patients was only 0.13 percent [27]. However, compared with patients who had not received an MTP, the relative risk was 1.60 (95% CI 1.34-1.84). In a small series of systemic lupus erythematosus (SLE) patients exposed to higher doses of glucocorticoids, the prednisone dose in the highest month of therapy exceeded 40 mg/day in 93 percent and 20 mg/day in 100 percent of patients with osteonecrosis [28]. The only clinical finding that distinguished patients with osteonecrosis from those without this complication was a Cushingoid appearance (86 versus 15 percent).
The initial glucocorticoid dose may be more important than the total dose or duration of therapy [26,29]. A meta-analysis of seven studies including 1515 patients taking systemic glucocorticoids found a dose-dependent association between glucocorticoid use and the risk of developing osteonecrosis [26]. Each 10 mg/day increase in glucocorticoid dose was associated with a 3.6 percent increase in the risk of osteonecrosis, and doses >20 mg/day resulted in a higher incidence. Another report evaluated 17 patients with SLE who developed osteonecrosis [30]. The glucocorticoid dose during the initial period of therapy was compared with that of 25 control patients with SLE. The patients with osteonecrosis had received a substantially higher dose of glucocorticoid in the first one, three, and six months of therapy. By comparison, the duration of therapy did not correlate with osteonecrosis, and total glucocorticoid exposure was virtually identical in both groups.
Osteonecrosis has been described as a rare complication of intraarticular glucocorticoid injections and is discussed in more detail separately. (See "Joint aspiration or injection in adults: Complications", section on 'Osteonecrosis'.)
Bisphosphonates and other antiresorptive agents — The use of bisphosphonates, particularly in patients with malignant diseases such as multiple myeloma and metastatic breast cancer, is a risk factor for osteonecrosis of the jaw. This disorder has been likened to radiation-induced osteonecrosis of the jaw and presents with nonhealing of the socket following tooth extraction or exposure of the jaw bone. Osteonecrosis of the jaw associated with bisphosphonate use, as well as use of other antiresorptive agents (eg, denosumab), is discussed in detail separately. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)
Alcohol — Excessive alcohol use and the development of osteonecrosis have long been linked; fat emboli, adipocyte hypertrophy, venous stasis, and increased cortisol levels have all been implicated as etiologic factors. While only a small percentage of patients with alcohol use disorder develop osteonecrosis, excessive alcohol intake has been considered an associated risk factor in up to 31 percent of the osteonecrosis patients evaluated [5,31-33]. One epidemiologic study compared 112 patients who had idiopathic osteonecrosis of the femoral head and no history of systemic glucocorticoid use with 168 hospital controls [31]. An elevated risk for regular drinkers and a clear dose-response relationship were noted; the relative risk was 3.3, 9.8, and 17.9 for current consumers of less than 400 mL/week, 400 to 1000 mL/week, and more than 1000 mL/week of alcohol, respectively, compared with controls.
Cigarette smoking — Cigarette smoking has been implicated as a risk factor for osteonecrosis of the femoral head in a dose-dependent manner [34]. However, it is difficult to assess the true risk of tobacco use due to its close association with, and the potential confounding effect of, alcohol intake.
Post-transplantation — Osteonecrosis has been reported to occur in approximately 5 to 20 percent of renal transplantation patients [35,36]. Osteonecrosis is usually multifocal when it occurs following renal transplantation [37], with 50 to 70 percent of affected patients having more than one joint involved [38]. However, a decreased risk of osteonecrosis in renal transplant patients has been shown to occur following the introduction of cyclosporine and tacrolimus (with consequent decreases in glucocorticoid dosing) [39,40]. (See 'Glucocorticoids' above and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)
It is unclear whether osteopenia and preexisting hyperparathyroidism are independent risk factors in the renal transplantation population [41]. (See "Prevention and treatment of osteoporosis after solid organ or stem cell transplantation".)
Osteonecrosis may also occur with other types of transplantation, such as hematopoietic cell transplantation (HCT). Osteonecrosis has been reported to occur in 4 to 19 percent of HCT survivors [42], with a mean time from HCT transplantation to diagnosis of osteonecrosis of 15 months (range 5 to 48) [43]. As an example, one study surveyed the prevalence of osteonecrosis among 207 patients undergoing HCT for lymphoproliferative or myeloproliferative diseases [44]. Patients receiving allogeneic HCT were more often affected than those receiving autologous HCT (10 versus 2 percent). The duration and cumulative dose of glucocorticoids, as well as the presence of graft-versus-host disease, were risk factors for the development of this complication [45]. (See 'Glucocorticoids' above.)
Among allogeneic HCT recipients, the risk of osteonecrosis may also depend upon the sex of the donor and the recipient, as well as the disease for which HCT is being performed. This was illustrated in a study of 255 patients who underwent allogeneic HCT for one of a variety of hematologic disorders and were evaluated for osteonecrosis of the hip [46]. The following risk factors were noted in addition to glucocorticoid exposure:
●The overall incidence of osteonecrosis of the hip was 6 percent during four years of post-transplant observation, but there were no cases among the 152 patients transplanted for chronic myeloid leukemia. The incidence in the remaining patients was 20 percent (13 percent of 70 patients with acute myeloid leukemia, 28 percent of 13 patients with myelodysplastic disorders, and 37 percent of 20 patients with acute lymphoblastic leukemia).
●Female donor to female recipient transplantation carried the highest risk of osteonecrosis, with more than 40 percent of such patients underwent subsequent hip replacement for osteonecrosis.
Systemic lupus erythematosus — Osteonecrosis has been reported in 3 to 44 percent of patients with SLE [30,47-49]. This wide range reflects the use of different techniques in defining this disorder (from the less sensitive plain film radiograph to the quite sensitive magnetic resonance imaging [MRI]), variations in glucocorticoid dosing, and different durations of follow-up. One report followed 228 patients with SLE for a mean period of 31 months. Nine percent had osteonecrosis, and it was estimated that the frequency would rise to 30 percent at 10 to 15 years [47].
Patients with SLE who have taken glucocorticoids are at greatest risk, although occasional cases have been noted in the absence of this therapy [30,47,50]. Osteonecrosis often develops in patients with SLE a relatively short time after the onset of glucocorticoid therapy. One prospective study, for example, evaluated 60 patients with SLE over a period of five years [50]. Those who had no MRI abnormalities in the femoral head during the first year of follow-up were unlikely to develop osteonecrosis at a later date. (See 'Glucocorticoids' above.)
Other risk factors for osteonecrosis have also been identified in SLE. These include regular doses of prednisone greater than 20 mg/day, evidence of glucocorticoid-associated end organ effect, Raynaud phenomenon, and hyperlipidemia [51]. Additional associations have been suggested [51,52], including the presence of antiphospholipid antibodies, African-American origin, Cushingoid habitus, vasculitis, pleuritis, and central nervous system (CNS) involvement.
There are conflicting data on the role of antiphospholipid antibodies in SLE; some data support an association [52,53], while other data do not [54]. As an example, in a study of 45 patients who had osteonecrosis, only nine of whom had SLE [55], the prevalence of antiphospholipid antibodies was more than threefold greater among the 45 patients with osteonecrosis compared with 40 healthy controls (34 versus 10 percent). In a study of multifocal osteonecrosis patients, antiphospholipid antibody positivity was detected in 20 percent of cases [56]. However, as with patients with SLE, not all data regarding the risk of osteonecrosis in patients with primary antiphospholipid syndrome are concordant, suggesting, at best, a weak association [57]. (See "Clinical manifestations of antiphospholipid syndrome".)
Trauma — Fracture or dislocation may cause damage to the extraosseous blood vessels supplying the affected region. Anatomic sites that predispose adjacent bone to avascular necrosis (AVN) after fracture include the femoral neck, proximal humerus, talar neck, and scaphoid [58]. Dislocation of the proximal femur or humerus can also result in osteonecrosis if reduction is delayed.
●The blood supply to the femoral neck is complex, with the dominant supply from the ascending branch of the medial femoral circumflex artery (figure 1). Fractures in the subcapital region of the femoral neck frequently interrupt the blood supply to the head of the femur due to fracture displacement or intracapsular hematoma [58]. This can result in ischemia and bone necrosis. In a meta-analysis including 1558 femoral neck fractures in patients 60 years or younger, the pooled incidence of osteonecrosis was 14.3 percent [59]. The incidence was higher for displaced versus nondisplaced fractures (14.7 versus 6.4 percent). Symptoms develop six months to two years after injury, but the presentation can be delayed even longer. (See "Overview of common hip fractures in adults", section on 'Femoral neck fractures'.)
●Damage to the anterior and/or posterior humeral circumflex artery (figure 2) can occur with typical fracture patterns of the proximal humerus (figure 3). Osteonecrosis occurs in 1 to 10 percent of such fractures [58]. In a systematic review, the rate of osteonecrosis was similar for surgically and nonsurgically managed proximal humerus fractures [60]. (See "Proximal humeral fractures in adults" and "Proximal humeral fractures in children".)
●Perforator vessels enter the talus in three locations with contributions from each of the tibial arteries (anterior tibial, posterior tibial, peroneal) (figure 4). The majority of cases of osteonecrosis occur after talar neck fractures (90 percent), although it has been reported after talar body fractures as well. The incidence of osteonecrosis correlates with the fracture severity (Hawkins type (figure 5)) ranging from 0 to 10 percent for low-grade (type I/II) and 33 to 48 percent for type IV fractures, depending on the version of the classification used [58,61,62]. (See "Talus fractures".)
●At the wrist (figure 6), fractures of the scaphoid and lunate are also associated with an increased risk of osteonecrosis. The dorsal carpal branch of the radial artery can be disrupted with scaphoid waist and proximal pole fractures. (See "Scaphoid fractures".)
Genetic disorders
Sickle cell hemoglobinopathies — Osteonecrosis is common in patients with homozygous sickle cell disease due to various mechanisms, including red blood cell sickling, and bone marrow hyperplasia. The reported prevalence of osteonecrosis of the femoral head in patients with sickle cell disease ranges from 10 to 50 percent [63-65]. Patients with more severe sickle cell disease have a higher incidence compared with patients with less severe sickle cell disease (1.06 per 100 person-years) [63]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Skeletal complications' and "Acute and chronic bone complications of sickle cell disease".)
Gaucher disease — Gaucher disease (GD) is a hereditary (autosomal recessive) disorder of glucocerebroside metabolism, which results in the accumulation of cerebroside-filled cells within the bone marrow. This process may lead to compression of the vasculature and to subsequent osteonecrosis. Bone pain has been reported to occur in 50 percent and osteonecrosis in 30 percent of type 1 GD patients [66]. However, the introduction of enzyme replacement therapy (ERT) has been shown to decrease the rate of osteonecrosis in these patients [67-69]. In a study using the International Collaborative Gaucher Group (ICGG) Registry, GD patients who initiated ERT within two years of diagnosis had a lower incidence rate (8.1 per 1000 person-years) compared with GD patients who started ERT ≥2 years after diagnosis (16.6 per 1000 person-years) [69]. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)
Heritable osteonecrosis — Rarely, osteonecrosis of the femoral head occurs as a heritable disorder. In one study of three affected Chinese families, mutations were present in the gene for the alpha chain of type II collagen (COL2A1) [70]. However, no mutations in the COL2A1 gene were found in 65 patients who had sporadic osteonecrosis of the femoral head. Substitution of serine for glycine in a portion of the molecule that forms an extended triple helical portion was predicted to result from the observed mutations.
The same COL2A1 mutation described above can be associated with at least three different clinical presentations. This was observed in another Chinese family that included individuals with premature osteoarthritis, osteonecrosis of the femoral head, or idiopathic osteonecrosis of the femoral head (Legg-Calvé-Perthes disease), which were diagnosed, respectively, in young adults, adolescents, or children [71]. Legg-Calvé-Perthes disease has also been reported in members of a Japanese family [72].
It is important to distinguish between genetic associations found in adult osteonecrosis and secondary osteonecrosis (eg, glucocorticoid-associated) versus genetic association found for Legg-Calvé-Perthes disease. The pathogenetic mechanisms involved may differ between these disorders. (See "Approach to hip pain in childhood", section on 'Legg-Calvé-Perthes and secondary avascular necrosis' and "Evaluation and management of slipped capital femoral epiphysis (SCFE)", section on 'Osteonecrosis'.)
Inherited thrombophilia and hypofibrinolysis — There are some data from small retrospective series regarding the role of mutations in genes for proteins in the coagulation and fibrinolytic pathways in the pathogenesis of osteonecrosis. As an example, four reports suggest an increased prevalence of the factor V Leiden mutation in patients with osteonecrosis of the hip or knee compared with healthy controls [73-76]. However, no significant association was observed between the frequencies of the factor V polymorphisms and haplotypes and the risk of osteonecrosis of the femoral head in a Korean population [77]. As such, it is possible that there are variations in the association between genetic polymorphisms and osteonecrosis based on nationality or ethnicity. In another observational study including 45 patients with osteonecrosis, significantly more patients with osteonecrosis (82 percent) were found to have at least one coagulopathy compared with controls (30 percent) [55]. In addition, 47 percent of patients with osteonecrosis had two or more coagulopathies, compared with 3 percent of controls. While there may be a relationship between inherited thrombophilias and osteonecrosis, there is insufficient evidence to warrant routine testing for such conditions in these patients. (See "Factor V Leiden and activated protein C resistance", section on 'Indications for testing'.)
Decompression disease — The increased pressure associated with decompression disease (also called dysbarism and caisson disease) can lead to the formation of nitrogen bubbles that can occlude arterioles and cause osteonecrosis (see "Complications of SCUBA diving", section on 'Decompression sickness'). Symptomatic osteonecrosis can develop years after the exposure; the number of exposures and the magnitude of depth and pressure are important risk factors. Elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1) are associated with an increased risk of osteonecrosis [78]. The incidence of dysbaric osteonecrosis has decreased over the past several decades with improvements in technology and increased awareness of this disorder [79]. However, there is still a risk if the diagnosis is not timely and medical management is not optimal.
Radiation therapy — Osteonecrosis may result from external beam radiation therapy (osteoradionecrosis). Osteoradionecrosis of the mandible may complicate treatment of head and neck cancer. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis'.)
Other risk factors
●Acute lymphoblastic leukemia – Osteonecrosis is one of the most common adverse effects of antileukemic treatment among children [80]. In a study of 10,729 new-onset acute lymphoblastic leukemia patients (age range, 2.02 to 21.23 years), 242 (2.3 percent) developed osteonecrosis within five years of their acute lymphoblastic leukemia diagnosis [81]. Although the rate of osteonecrosis was lower in a large database study in Finland and Denmark (0.4 percent), there was also an association reported for patients with chronic myeloid leukemia (4.5 percent) and acute myeloid leukemia (2.1 percent) [82]. Glucocorticoid therapy (prednisone and dexamethasone) is commonly used in the treatment of acute lymphoblastic leukemia, and it may increase the risk for osteonecrosis (particularly dexamethasone) [83]. (See 'Glucocorticoids' above and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
●HIV infection – The risk of developing osteonecrosis in patients with human immunodeficiency virus (HIV) infection has been reported to be 45 to 100 times greater than in the general population [84,85]. In one case-control study, the point prevalence of osteonecrosis that was apparent on MRI was 4 percent among 339 HIV-infected patients, while no osteonecrosis was found in 118 sex- and age-matched healthy controls [86]. There has been considerable debate concerning whether highly active antiretroviral therapy (HAART) is a risk factor for osteonecrosis [85,87]. Glucocorticoid therapy is likely a risk factor for osteonecrosis and may be exacerbated by concurrent administration of protease inhibitors [85,88]. Use of antiretroviral therapy (ART) does not appear to be an independent risk factor [89].
Other risk factors for osteonecrosis of the knee include the following:
●Postarthroscopic osteonecrosis of the knee – Osteonecrosis of the knee after arthroscopy is rare but has been described as occurring in up to 4 percent of patients after various arthroscopic procedures [90]. The medial femoral condyle is the most commonly affected site, and typically the affected area coincides with the area of the preexisting pathology and arthroscopic procedure [91]. Patients present with a sudden onset of knee pain approximately six to eight weeks after the procedure.
●Spontaneous osteonecrosis of the knee – Spontaneous osteonecrosis of the knee (SPONK or SONK) is a rare disorder of unknown cause that tends to occur in older adults and typically affects a single condyle (most commonly the medial femoral condyle) [92]. Patients may present with a sudden onset of severe unilateral knee pain that is worse at night or with weight bearing.
CLINICAL FEATURES AND DIAGNOSIS — Early diagnosis of osteonecrosis may provide the opportunity to prevent bony collapse and, ultimately, the need for joint replacement or other bone reconstruction. However, most patients present late in the course of the disease. Thus, a high index of suspicion is necessary for those with known or probable risk factors, particularly high-dose glucocorticoid use.
Osteonecrosis usually occurs in the anterolateral femoral head, although it may also affect the femoral condyles, humeral heads, proximal tibia, vertebrae, and small bones of the hand and foot [9]. Many patients have bilateral involvement at the time of diagnosis, including disease of the hips, knees, and shoulders. In patients who present with osteonecrosis of the knee, shoulder, or other non-hip joint, the hip should be evaluated clinically and by imaging. (See 'Imaging studies' below.)
History and physical examination — A thorough history should include questions related to the various risk factors. (See 'Risk factors' above.)
The most common presenting symptom of osteonecrosis is pain [93,94]:
●Groin pain is most common in patients with femoral head disease, followed by thigh and buttock pain.
●Weightbearing or motion-induced pain is found in most cases.
●Pain in the absence of activity (ie, rest pain) occurs in approximately two-thirds of patients, and nocturnal pain occurs in one-third [95]. When an extremity is affected, the position of the limb (eg, elevated, dependent) does not alter the pain.
●Although rare, pain in multiple joints suggests a multifocal process.
A small proportion of patients are initially asymptomatic, particularly in early-stage disease; in these cases, the diagnosis is usually incidental. Asymptomatic involvement contralateral to a symptomatic site is also frequently noted.
Physical findings are largely nonspecific. Patients may have pain and, eventually, limitations of range of motion, the severity of which depends on the affected joint and severity of disease. With hip disease, limitations eventually occur, particularly with internal rotation and abduction. A limp may be present late in the course of lower extremity disease [8]. In the absence of concomitant vascular disease, the pulse examination should be normal.
Diagnosis — A clinical diagnosis can be made in a symptomatic patient when radiographic imaging findings or MRI are compatible with this disease and when other causes of pain and bony abnormalities are either unlikely or have been excluded by appropriate testing. MRI without a contrast agent continues to be the "gold standard" for diagnosis in symptomatic and asymptomatic patients, especially in early-stage disease [96,97].
Imaging studies — The initial evaluation of a patient with suspected osteonecrosis should begin with plain radiographs of the affected anatomic site [98]. For patients with suspected hip osteonecrosis, plain radiography should include anteroposterior and frog-leg lateral plain radiographs. If collapse of the hip is apparent, no further imaging is required for diagnosis. However, if the diagnosis of atraumatic osteonecrosis is suspected at a joint other than the hip, it is recommended that the hip joint also be imaged [94].
MRI of the affected joint should be performed if radiographs are negative and the medical history supports a suspicion of osteonecrosis.
Computed tomography (CT) scans have been used for the identification of subchondral fractures, a pathologic feature which may have prognostic value for joint-preserving procedures [99]. However, improvements in MRI methods, cost, and the amount of radiation exposure deter the more frequent use of this imaging modality.
Plain radiography — The plain radiograph of any site affected by osteonecrosis can remain normal for months after symptoms begin; the earliest findings are mild density changes (image 1A-B and image 2), followed by sclerosis and cysts as the disease progresses.
For osteonecrosis of the femoral head, the pathognomonic crescent sign (subchondral radiolucency (image 3)) is evidence of subchondral collapse. Later stages reveal loss of sphericity or collapse of the femoral head. Ultimately, joint space narrowing and degenerative changes in the acetabulum are visible [100].
Magnetic resonance imaging — MRI has a reported sensitivity of up to 100 percent for the diagnosis of osteonecrosis [9,101-103]. Of particular importance is that changes can be seen early in the course of disease when radiographs or other studies are negative.
●Focal lesions are well demarcated and inhomogeneous on T1-weighted images. The earliest finding is a single-density line (low-intensity signal) that represents the separation of normal and ischemic bone.
●A second high-intensity line appears on T2-weighted images, representing hypervascular granulation tissue; this is the pathognomonic double-line sign (image 4) [104].
Limited role of radionuclide bone scanning — Bone scans should not be used for the diagnosis of osteonecrosis. There is a high rate of false negatives (up to 25 percent) when using bone scans for the diagnosis of hip osteonecrosis [101]. Moreover, bone scans are even less capable of diagnosing osteonecrosis of the shoulder, knee, and ankle. In selected cases, radionuclide bone scanning may be an alternative for patients in whom other cross-sectional imaging is contraindicated. Increased bone turnover at the junction of dead and reactive bone results in increased uptake surrounding a cold area; this has been called the doughnut sign [105]. However, bone scanning, performed in 48 patients with suspected osteonecrosis of the shoulder, hip, knee, or ankle, was less sensitive than MRI (56 versus 100 percent) in diagnosing histologically confirmed osteonecrosis [101]. Sensitivity was least in patients with early-stage lesions.
Radiologic classification systems — Several different radiologic classification and staging systems, predominantly describing osteonecrosis of the hip, have been developed to provide information on the extent of disease and risk of progression, and thus, help guide treatment decisions [106].
Extent of disease — The updated Association Research Circulation Osseous (ARCO) was developed to bring uniformity to classification of osteonecrosis [107]. In the updated version, stage 0 was eliminated, stage III was subdivided into early (IIIA) and late (IIIB) stages depending on the degree of head depression (≤2 versus >2 mm), and acetabular involvement was incorporated into stage IV:
Precollapse:
●Stage I – Normal radiograph, abnormal MRI findings
●Stage II – No crescent sign, radiographic evidence of sclerosis, osteolysis or focal osteoporosis
Collapse:
●Stage III – Subchondral fracture, fracture in the necrotic portion and/or flattening of the femoral head on radiograph or on radiograph or CT
•IIIA – Femoral head depression ≤ 2 mm
•IIIB – Femoral head depression > 2 mm
●Stage IV – Evidence of osteoarthritis, joint space narrowing, degenerative acetabular change
An earlier and occasionally used system is the Ficat staging system described by Ficat and Arlet [106,108]:
●Stage 0 – No radiographic abnormalities
●Stage I – Slight abnormalities on radiograph
●Stage II – Sclerotic or cystic lesions
•IIA – No crescent sign
•IIB – Crescent sign without flattening
●Stage III – Flattening or subchondral collapse
●Stage IV – Osteoarthritis with articular collapse
Other classification systems have used additional imaging findings (eg, cross-sectional imaging, bone scans) to quantify involvement. As an example, the Steinberg staging system included findings on bone scan and MRI to address the importance of the size and extent of the lesion in the prognosis of various treatments [109]. Other classification systems include the University of Pennsylvania staging system [110,111] and the Japanese Orthopaedic Association System [112].
Risk of progression to collapse — Several morphologic features appear to be associated with a risk of collapse including lesion size and extent and location (eg, lateral pillar involvement) [113]. Various methods using measurements from radiographic images (mainly MRI) have been proposed to help predict the risk of progression of femoral head collapse [113]. The modified Kerboul combined necrotic angle is one method that is relatively easy to obtain. It is calculated by summing the arcs of necrosis on sagittal and coronal MR images (image 5). Combined necrotic angles less than 190 degrees, between 190 and 240 degrees, and greater than 240 degrees are associated with low, moderate, and high risks of femoral collapse, respectively [114,115].
A finite element analysis model to determine the von Mises stress distribution of the femoral head has also been studied, and a patient-specific model may become useful for estimating the risk of collapse; additional study is needed [116].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of pain with characteristics that suggest an osteoarticular origin and with imaging features compatible with osteonecrosis is discussed below.
The general approach to the evaluation of site-specific pain (eg, hip, shoulder) is presented separately. (See "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain" and "Evaluation of the adult with shoulder complaints" and "Approach to the adult with unspecified hip pain" and "Approach to hip pain in childhood" and "Approach to the adult with unspecified knee pain" and "Overview of foot anatomy and biomechanics and assessment of foot pain in adults" and "History and examination of the adult with hand pain".)
Bone pain as a manifestation of primary or metastatic tumor is discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and "Overview of common presenting signs and symptoms of childhood cancer", section on 'Bone and joint pain'.)
Pain with ambulation and nocturnal limb pain or rest pain related to peripheral artery disease (PAD), which is distinguished through history (risk factors) and physical examination (diminished pulses), are reviewed separately. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
There are a few specific variants of osteonecrosis that should also be taken into consideration. These are briefly discussed below and include bone marrow edema syndrome (BMES), subchondral insufficiency fracture, osteonecrosis during pregnancy, and idiopathic transient osteoporosis of the hip.
Bone marrow edema syndrome — BMES, also known as transient osteopenia of the hip (TOH), may occur in isolation or in association with injuries, particularly those that result in neurologic damage. In the latter situation, chronic pain and transient osteopenia are features of complex regional pain syndrome (also known as reflex sympathetic dystrophy, causalgia, and other terms). (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)
When the hip is affected by BMES, MRI findings suggestive of BMES (decreased signal on T1-weighted images and increased intensity on T2-weighted images) may extend from the femoral head into the femoral neck. An effusion may be present. The absence of fever, leukocytosis, or elevation of acute phase reactants (erythrocyte sedimentation rate [ESR] and/or C-reactive protein [CRP]) is characteristic of both osteonecrosis and BMES and helps to exclude an infectious etiology. (See "Imaging evaluation of the painful hip in adults", section on 'Bone marrow edema syndrome'.)
Subchondral insufficiency fracture — A subchondral fracture of the femoral head typically occurs in patients with preexisting osteopenia and is thought, in most cases, to represent an insufficiency fracture. Such fractures may be difficult to visualize with plain radiographs. Subtle flattening is sometimes present with early lesions; collapse is progressive. Linear regions of low signal on both T1- and T2-weighted MRI in the subchondral area that parallel the articular surface are characteristic of these rare fractures [117,118]. There is a growing recognition that most patients diagnosed with spontaneous osteonecrosis of the knee (sometimes called SPONK or SONK) actually have insufficiency fractures as well.
Osteonecrosis during pregnancy — Osteonecrosis of the femoral head during pregnancy is rare but can occur without any of the traditional risk factors for the disease. The clinical presentation and diagnosis of osteonecrosis of the hip during pregnancy is discussed in detail separately (see "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Osteonecrosis of the femoral head'). Osteonecrosis of the hip during pregnancy can be confused with transient osteoporosis of the hip during pregnancy. (See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Transient osteoporosis of the hip'.)
Idiopathic transient osteoporosis of the hip — Transient osteoporosis of the hip is a rare skeletal disorder that can occur in previously healthy young to middle-aged men, and during pregnancy [119,120]. MRI of these patients typically shows edema into the femoral neck and metaphysis, which is not common with osteonecrosis. This disorder has a better prognosis than osteonecrosis during pregnancy and is typically self-limited. (See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain", section on 'Transient osteoporosis of the hip'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteonecrosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Avascular necrosis of the hip (The Basics)")
SUMMARY
●Pathogenesis – Osteonecrosis is associated with numerous conditions and treatments that can cause direct damage to vasculature of the bone or direct and indirect injury to the bone or bone marrow, and ultimately mechanical failure of the bone. Osteonecrosis is also termed aseptic necrosis, avascular necrosis (AVN), atraumatic necrosis, and ischemic necrosis. (See 'Pathogenesis' above.)
●Risk factors – Risk factors for osteonecrosis include traumatic injury that disrupts the arterial supply to the bone, the use of certain medications or conditions that alter perfusion through otherwise normal vessels (eg, glucocorticoids, bisphosphonates, sickle cell disease, systemic lupus erythematosus [SLE], Gaucher disease [GD], thrombophilia, decompression disease), treatments that are toxic to bone marrow (eg, radiation therapy), and others that have multifactorial causes (eg, post-transplantation). (See 'Risk factors' above.)
●Clinical features – Certain anatomic sites are prone to osteonecrosis and include the femoral head, the knee (distal femoral and proximal tibial condyles), humeral head, and certain bones of the foot (talus) and wrist (scaphoid), but any bone can be involved. (See 'Clinical features and diagnosis' above.)
Osteonecrosis can be asymptomatic or symptomatic. Patients with symptomatic osteonecrosis typically complain of pain associated with the affected site with and without activity, which, for the extremities, may limit activities of daily living or ambulation. (See 'History and physical examination' above.)
●Diagnosis – For symptomatic patients, the initial evaluation of a patient with suspected osteonecrosis should begin with plain radiography of the affected site. If the history and physical examination are highly suggestive and plain radiography is not diagnostic, MRI of the affected joint should be performed. MRI is highly sensitive for osteonecrosis, and identifies pathologic changes earlier than other imaging modalities. (See 'Diagnosis' above.)
●Radiologic classification systems – Several different radiologic classification and staging systems, predominantly describing osteonecrosis of the hip, have been developed to provide information on the extent of disease and risk of progression, and, thus, help guide treatment decisions. (See 'Radiologic classification systems' above.)
●Differential diagnosis – The differential diagnosis of osteonecrosis includes a variety of other entities that can cause bone or joint pain. Specific considerations for related but distinct entities that are considered variants of osteonecrosis, including bone marrow edema syndrome (BMES), subchondral insufficiency fracture, osteonecrosis during pregnancy, and idiopathic transient osteoporosis of the hip, are discussed above. (See 'Differential diagnosis' above.)
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