I) Definitions

Bone infarction denotes necrosis of the metaphysis or diaphysis of a long bone, commonly referred to as osteonecrosis. The term may also be applied to some cases involving the epiphysis, but the term avascular necrosis is preferred to describe subchondral osteonecrosis. Other terms used to describe bone infarction are avascular necrosis of bone, ischemic necrosis, or aseptic necrosis.

Necrosis is unprogrammed disordered cell death involving large groups of cells. This is in contrast to apoptosis or programmed cell death, which is more organized and involves a single cell or small groups of cells. In necrosis, lack of signaling renders the process of phagocytosis difficult, because the immune system cannot identify the location of the dying cells. This causes inflammation as cellular membrane breakdown releases intracellular content. Apoptosis is not followed by inflammation.

II) Pathogenesis

Bone infarcts result from a circulatory disturbance interrupting blood supply to a section of bone, ultimately leading to ischemia of bone trabeculae. Osteonecrosis involves more frequently convex articular surfaces of bones because in this region, the diameter of the terminal vessels is narrower. Moreover, the absence of collateral vascularization contributes to the process. For example, the femoral head is often affected. The metaphysis of long bones and flat bones can also be affected. In osteonecrosis, the medullary portion of the bone is always involved first. The cortex, with its collateral blood supply, may be spared. The articular cartilage is avascular but received nutrients through diffusion from the synovial fluid and can sustain itself. Other factors that play a role in the development of osteonecrosis are the reduced vascularity of the stromal marrow (involved in the production of fat, cartilage, and bone) in comparison with the hemopoietic marrow, which contains hematopoietic stem cells (giving rise to leukocytes, erythrocytes, and thrombocytes).

III) Etiology

Interruption of blood flow can result from a variety of etiologies such as arterial disease, embolism, or obstruction of venous return. Mechanisms include fractures during traumatic events (discussed in detail below). Traumatic osteonecrosis is typically unilateral, in contrast to nontraumatic osteonecrosis, which is commonly bilateral. The underlying processes when necrosis of bone is due to non-traumatic mechanisms remains unclear and several theories have been postulated, depending on the cause. Endogenous or exogenous corticosteroids excess is a recognized source of bone necrosis. Patients treated with prolonged high doses of glucocorticoids appear to be at the greatest risk of developing osteonecrosis. One proposed mechanism for glucocorticoid-associated osteonecrosis involves alterations in circulating lipids with resultant microemboli in the arteries supplying the bone [11]. Red blood cell sickling and bone marrow hyperplasia may cause impairment of the blood flow during vaso-occlusive crisis in sickle cell disease. Nitrogen bubbles occluding vessels in decompression sickness (Caisson disease) is yet another well recognized cause of osteonecrosis. Excessive alcohol intake is linked to bone necrosis, possibly as a result of fat emboli, adipocyte hypertrophy, venous stasis, and increased cortisol levels. Patient suffering from Gaucher disease experience osteonecrosis due to buildup of cerebroside-filled cells within the bone marrow, constricting the blood vessels.

IV) Osteonecrosis of the femoral head secondary to fracture of the femoral neck

Fracture can damage the extra-osseous blood vessels supplying the affected region. Fractures of the femoral neck (subcapital fracture) are most often encountered in elderly following minor trauma (slip). Underlying osteoporosis or osteomalacia along with neuromuscular deterioration are contributing factors. These fractures are occasionally seen in the younger population after major trauma. Fractures in the subcapital region of the femoral neck results in interruption of the major blood supply to the femoral head of the femur and therefore ischemia with more or less complete ischemic necrosis.

Based on morphology, there are four identified stages in the development of subchondral avascular necrosis that were identified by Catto. Those stages can similarly be applied to other forms of osteonecrosis. Of note, these stages correlate with the observed radiographic appearance and form the basis for radiological staging of osteonecrosis.


1) Necrosis of both bone and bone marrow without evidence of reparative processes

2) Reparative process is evident at the periphery of the necrotic region

3) Segmental collapse of the articular surface

4) Evidence of secondary osteoarthritis have developed

a. Stage 1

The gross specimen of the external femoral head may be normal or show an articular cartilage with an ill-defined focal yellow discoloration. However, if the femoral head is cut in cross section, it will reveal a wedge-shaped subarticular area (necrotic zone) with a chalky white bone marrow. A pale elongated area (the necrotic core) encircled by a sharply demarcated hyperemic ischemic rim is seen on gross specimens.

On histology, the overlying articular cartilage is viable. The dead bone beneath is characterized by necrotic bone marrow, which is eosinophilic and mostly acellular. Ghosts of necrotic adipocytes can sometimes be identified. In the focal area of necrosis, the bone trabeculae contain empty lacunae with no viable osteocytes. However, it is essential to recognize that loss of osteocytes is not complete until fifteen days after the onset of ischemia and therefore, identification of osteonecrosis may be delayed if based on histological features alone.

The central necrotic core is circumscribed by an area increased osteoclastic activity and osteoblastic reparative function. At the border of the necrotic bone, the walls of the surrounding adipocytes break down, releasing their fatty acids. These fatty acids bind calcium, forming insoluble calcium soaps. This process in the bone marrow is accompanied by proliferation of the capillaries and fibroblasts. This corresponds to the hyperemic border seen on the gross specimen.

b. Stage 2

Although the articular surface still appears intact, a cross section of the femoral head reveals a rim of sclerosis separating dead bone from healthy bone due to the ongoing healing process.

On histology, granulation tissue, composed of foamy histiocytes and proliferating fibroblasts and capillaries, deposits around the necrotic area. During the healing process, the necrotic trabeculae undergo osteoclastic resorption. At the same time, creeping substitution takes place in the trabecular bone, where osteoblasts slowly deposit a layer of newly formed woven bone on the framework of dead trabeculae. However if creeping substitution is not efficient, the necrotic cancellous bone collapses.

c. Stage 3

At this point in the process, there is a change in the convex outline of the articular bone secondary to a pathologic fracture, causing collapse of the articular surface. The fracture can be located in the necrotic part of the bone or at the confluence of necrotic bone and healed tissue.

The gross specimen can show a linear dimpling of the articular cartilage overlying the fracture site. Cross sections of the femoral head will usually show a linear fracture superficially below the articular bone end plate or more deeply within the necrotic side of the advancing sclerosis on the reparative front. The subchondral infarct is demarcated from the healthy tissue by a hyperemic zone.

Histologically, the fracture area is composed of a combination of fragmented bony trabeculae and cartilage along with reparative tissues, including reactive woven bone, cartilage and granulation tissue, similarly to an unstable fracture anywhere else in the body.

d. Stage 4

The articular cartilage is markedly deformed secondary to collapse due to separation of the bone and cartilage from the infarcted portion. The femoral head may still possess residual cartilage and dense fibrous connective tissue in the area of infarction. This is accompanied by the development of signs of osteoarthritis. For example, at the margin of the infarct, the articular surface will become densely sclerotic and show eburnation of the bone around the infarct. When the changes of secondary osteoarthritis are advanced, it may be difficult to identify that the initial event might have been subchondral avascular necrosis. The only indication is that the femoral head may have a saddle-shaped deformity.

V) Radiographic findings of a bone infarct

Bone infarctions have distinctive imaging features on conventional radiography, CT and MRI.

a. Early stages

MRI has a high sensitivity for detecting the early stages of infarction in bones. On T-1 weighted MRI, a single line of hyper-intensity marks the sharp demarcation between healthy and necrotic bone. Areas of low intensities represent edema. The double-line sign can be identified on T-2 weighted MRI (pathognomonic). It represents a second line of high intensity between normal and ischemic marrow that suggests hypervascular granulation tissue. During stage I, radiological imaging is unremarkable.

b. Late stages

Plain radiograph may be normal for months after the onset of symptoms of osteonecrosis. At the later stages, the infarcted portion of the bone can finally be seen on radiographs. Demarcation between the normal bone marrow, the necrotic core, and the surrounding ischemic zone accounts for many of the radiographic appearances of bone infarcts. There is a direct relationship between the radiographic findings and the pathophysiology because the lesions seen on imaging reflect the joint surface damage and bone collapse that ultimately result from ischemia.

Starting at stage II, a thick radioopaque serpentine border (ischemic zone) surrounds an elongated area of central radiolucency (necrotic core). The increased vascularity with osteoblastic activity and new bone formation give rise to a line of bone sclerosis on the radiographic imaging corresponding to the hyperemic zone. Creeping substitution gives rice to increased radiodensity at the healing margin of the infarct. During stage III, the radiolucent crescent sign, best seen in the frog-lateral view, results from collapse of the subchondral bone following a fracture in the zone between the infarct and the underlying viable bone.

Bone scans can show increased uptake of radioactive technetium 99m due to increased bone turnover at the junction of necrotic and reactive bone, but it is significantly less sensitive than MRI in diagnosing osteonecrosis. CT scanning may be used to determine the extent of the disease and calcification, but it is not as sensitive as MRI.

c. Radiology staging (based on Catto’s stages)

VI) Early prediction of femoral head avascular necrosis following neck fracture: a review paper

In light of the aforementioned discussion, the remaining of this paper discusses a review article that examines evaluation of femoral head vascularity following femoral neck fracture and, in particular, assesses the risk of developing osteonecrosis of the femoral head. This paper reviews methods to timely assess femoral head perfusion, in the first couple of hours following femoral neck fracture, as an index of necrosis risk in order to permit optimal management and to avoid iterative surgery.

a. Relevance and goals of treatment

On the one hand, fracture of the femoral neck is a common pathology with an incidence of 1/1000 every year. The complication of interrupted blood supply following a fracture is osteonecrosis, with an estimated risk as high as 10 to 30%. On the other hand, it is a life-threatening lesion in the elderly, who make up the majority of the cases, with a mortality rate of 20 to 30%. Although young individuals are not as affected, when it does occur in the younger population, functional prognosis is poor and depends on whether necrosis follows the fracture. In elderly patients, the goal is speedy reestablishment of the patient’s autonomy. In young patients, osteosynthesis should be performed soon, with anatomic reduction and stable assembly.

b. Blood supply to the femoral head

To better understand how significant the risk of necrosis following neck fracture is, it is important to understand the normal vascularization of the femoral head. In their study, Trueta and Harrison determined that the femoral head was getting most of its blood supply from the extra-osseous retinacular vessels out of the medial circumflex artery branching from the deep femoral artery, conclusions confirmed by Sevitt and Thompson’s work. The superior retinacular vessels have cervical branches in the femoral head. Those are the superior metaphyseal and lateral epiphyseal arteries. The lateral epiphyseal arteries supply 70 to 80% of the femoral head.

The ligament teres artery anastomoses with the terminal branches of lateral epiphyseal artery. Sevitt and Thompson consider the ligament teres artery to vascularize only a small part of the head, making its contribution inconsequential. Catto, Chandler and Kreuscher and Crock consider the anastomosis between the ligament teres and lateral epiphyseal arteries to be of crucial to revascularized the femoral head after neck fracture. The inferior retinacular vessels do not play a significant role in supply the femoral head. Although the lateral circumflex artery supplies some anterior retinacular vessels, they are very few, so that any interruption of blood supply has little influence on the viability of the femoral head.

c. Physiopathology of osteonecrosis following neck fracture

Sevitt reported that up to 84% of femoral heads showed devascularization following neck fractures. The degree of displacement is important to assess the severity of vascular lesions. However, some studies showed reduced vascularization in up to 60% of cases after low-grade displacement. Following trauma, retinacular vessels can detach and intra-osseous vessels are ruptured by the fracture itself. In particular, when the fracture line extends all the way into the margin of the femoral head, the lateral epiphyseal artery and posterior retinacular vessels are damaged. Lateral epiphyseal artery disruption almost consistently induces necrosis and participates in the process leading to collapse of the head. When the superior retinacular vessels are broken, the femoral head relies on the ligament teres and inferior retinacular vessels, which are insufficient for complete revascularization of the femoral head.

Another factor that plays a role in estimating prognosis is increased intra-articular pressure. In cases of fracture with low-grade displacement, the capsule remains intact causing the hematoma to remain concentrated. This creates increased pressure inside the capsule, giving rise to a tamponade effect (similarly to the phenomenon seen in compartment syndrome). This was demonstrated by Holmberg and Dalen. It engenders a cascade of small vessel thrombosis, inducing reduced blood-flow, and irrevocably ischemic cellular necrosis. Hip positioning also disrupts intra-articular pressure: extension, internal rotation and abduction reduces joint-space volume, increasing intracapsular pressure and aggravating the vascular lesions. Finally, the quality of surgical reduction obviously impacts the risk of osteonecrosis, with anatomic reduction being very successful at decreasing the risk of necrosis. The interval to surgery is another important factor that optimizes quick vascular reperfusion, decreasing the chances of developing ischemia in the head.

d. The 2-stage theory of necrosis of the femoral head

As mentioned previously, the necrotic process culminates in major femoral head deformity caused by pathologic fracture and collapse (Catto stages 3 and 4). This review paper elaborates on the concept that the distortion of the femoral head is due to the healing process and not to direct cell death, and this happens in a 2-stage progression. The 2 stages of necrotic bone repair identified by Glimcher and Kenzora are:

1) Invasion of the femoral head by proliferation of healing tissue

2) Creeping substitution

During the repair process in post-traumatic necrosis, mesenchymatous cell differentiate into osteoblasts. Cells rapidly proliferate past the subcapital fracture line into the femoral head and there, osteogenesis takes place on the surface of dead trabeculae (creeping substitution). Those living cells modify the mechanical properties of the bone. At the junction of the new healthy bone and the necrotic bone, the pathologic fracture occurs, the difference in consistency and elasticity induces head collapse.

e. Perfusion assessment methods

i) Superselective angiography

Superselective angiography (SSA) is able to evaluate extra-osseous arterial vessels, which can be visualized even more effectively by digital subtraction arteriography (DSA). Heuck and Raiser highlighted vascular changes in nearly 97% of cases of necrosis secondary to fracture, showing vascular lesions to be the main etiological factor. Langer et al. applied DSA in nine patients presenting with recent femoral neck fracture and found superior medial circumflex artery branch involvement in 66% of cases. They recommend this technique for assessing necrosis risk. Nonetheless, angiography is an invasive method with a risk of arterial dissection and thrombosis.

ii) Intra-osseous oxygen pressure measurement

Following the hypothesis that subchondral ischemia played a role in the development of avascular necrosis, Watanabe studied another invasive method to assess the risk of avascular necrosis. It involved measuring intra-osseous oxygen pressure in the femoral head following a fracture, using subchondral polarographic electrodes surgically implanted at two points in the femoral head. A 3-mmHg difference in pressure between the two points suggested a risk of necrosis while similar oxygen pressure values between the two points confirmed head viability.

iii) Doppler laser flowmetry

Swiontkowski used this method to compare necrotic bony areas to a healthy reference area in the trochanteric region, in confirmed cases of osteonecrosis. Doppler laser measures blood flow through an introducer implanted in the femoral head and can detect reduced flow in necrotic areas.

iv) Bone scintigraphy

Scintigraphy analyzes vascular perfusion and bone marrow uptake on images taken during and after radiotracer injection. Technetium 99m is the isotope of choice since it is specific to tissue vascularity disturbances in general and of bone in particular, because it is phagocyted by reticulocytes in the bone marrow. It provides early hemodynamic information in the vascular phase as vascular changes can be detected before the necrotic process begins. Scintigraphy in the first 24 hours after a fracture is essential to assess necrosis risk and reveals disturbed hemodynamics, with early histochemical abnormality. In their study, Meyers et al. reported 95% accuracy in the estimation of necrosis risk at the 2 years’ follow-up. Philipps et al. discovered a hypofixation area in the bone before any signs appeared on x-ray imaging. In fact, scintigraphy is positive about fourteen months before any radiological signs appear.

v) Magnetic resonance imaging

MRI has 90–100% sensitivity and 100% specificity for detecting necrosis of the femoral head. Various studies tried to assess the minimum interval for conventional MRI to show signs of osteonecrosis but the range found in different studies is inconsistent, varying from 48 hours to several months. Dynamic MRI with contrast has also been used. Kamano et al. used this technique within 24 hours of femoral neck fracture and classified the results according to three levels of head enhancement: type 1 = no enhancement, type 2 = partial enhancement, type 3 = complete enhancement. On follow-up, MRI showed 100% necrosis in type 1, 50% in type 2, and 0% in type 3. Although this method is non-invasive and reliable, there is often poor enhancement in elderly patients. Kubo et al. used color mapping instead and classified the findings according to three types: type A = red or normal perfusion, identical to the healthy side, type B = intermediate, and type C = black or no perfusion.

These dynamic MRI demonstrated that some mildly displaced fractures were associated with impaired blood flow in the femoral head while cases with severe displacement may show normal enhancement. Finally, those MRIs were taken within the first 48 hours following the fracture but they should have been performed in the first 10 hours to allow for early reduction and stabilization and to increase the chances of proper head revascularization.

f. Conclusions on current evaluation of femoral head vascularity and future prospect

Of the perfusion assessment method discussed, SSA and DSA cannot be routinely used because they are invasive and pose iatrogenic risks. Every day application of oxygen pressure measurements and Doppler are not economically and practically feasible. Imaging modalities such as scintigraphy and MRI enable earlier assessment, are more effective, and non-invasive. Although scintigraphy is effective and sensitive, MRI is preferred since the patient is not exposed to radioactive isotope.

In particular, the non-invasive dynamic MRI represents the future for early assessment of femoral head necrosis risk. As discussed previously, several studies have established functional classifications for femoral neck fracture based on residual vascularity, which is a more accurate estimation of the prospective risk of ischemia than fracture morphology, which is commonly used. Functional classifications are more suitable to use to decide the most appropriate treatment.

In patients younger than 65 years old, management should be conservative. In patients 65 years and older, some authors recommend conservative management in case of preserved vascularity and replacement with poor vascular status, whether the fracture is displaced or not. In cases of intermediate vascularity, physiological age is used to decide the most appropriate management. For patients between 65 and 80 years of age, a person can be categorized as “physiologically young” or “physiologically fatigued”, depending on associated comorbidities. Conservative treatment may be recommended in the physiologically fatigued patients while hip replacement would be most appropriate on physiologically young patients, although this is all determined on a case by case basis. Nonetheless, 80-year old is set as the threshold beyond which hip replacement is not recommended.

Lastly, MRI availability is an important limitation, as is expertise of the radiologist. Hence, future studies in necrosis risk assessment should focus on CT perfusion scan as an easier, more readily available technique to evaluate residual head vascularity and risk of necrosis.


Bullough, P. ed., (2003). Osteonecrosis and bone infarction. In: Orthopaedic Pathology, 4th ed. London: Mosby, pp.347-362.

Fondi C, Franchi A. Definition of bone necrosis by the pathologist. Clin Cases Miner Bone Metab. 2007;4(1):21-6.

Murphey MD, Foreman KL, Klassen-fischer MK, Fox MG, Chung EM, Kransdorf MJ. From the radiologic pathology archives imaging of osteonecrosis: radiologic-pathologic correlation. Radiographics. 2014;34(4):1003-28.

Ehlinger M, Moser T, Adam P, et al. Early prediction of femoral head avascular necrosis following neck fracture. Orthop Traumatol Surg Res. 2011;97(1):79-88.

Osteonecrosis. OrthopaedicsOne Articles. In: OrthopaedicsOne – The Orthopaedic Knowledge Network. Created Sep 20, 2009 15:32. Last modified Aug 23, 2014 14:49 ver.32. Retrieved 2018-01-16, from

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