Osteonecrosis

Hiba K. Anis, MD

Nipun Sodhi, MD

Joseph O. Ehiorobo, MD

Michael A. Mont, MD

Dr. Mont or an immediate family member has received royalties from Microport and Stryker; serves as a paid consultant to or is an employee of Cymedica, DJ Orthopaedics, Flexion Therapeutics, Johnson & Johnson, Ongoing Care Solutions, Orthosensor, Pacira, Peerwell, Performance Dynamics, Pfizer, Skye Biologics, Stryker, and Tissue Gene; has stock or stock options held in Peerwell and USMI; has received research or institutional support from DJ Orthopaedics, Johnson & Johnson, National Institutes of Health (NIAMS & NICHD), Ongoing Care Solutions, Orthosensor, Stryker, and TissueGene; and serves as a board member, owner, officer, or committee member of the American Academy of Orthopaedic Surgeons, the American Association of Hip and Knee Surgeons, and the Knee Society. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Anis, Dr. Sodhi, and Dr. Ehiorobo.

INTRODUCTION

Osteonecrosis (ON) is a debilitating condition that can result in joint pain and progressive joint destruction most commonly in relatively young and active patients. In the United States, the disease is estimated to affect 10,000 to 30,000 new patients per year, who are primarily between the ages of 30 and 50 years. The prevalence of ON is increasing, and many associated risk factors have been identified. Corticosteroid use and alcohol abuse are notable modifiable risk factors associated in approximately 80% of cases.¹ Recently, alongside these acquired risk factors, there has also been interest in identifying potential genetic predispositions for this disease. Although the etiology of this condition is considered multifactorial, the fundamental cause is thought to potentially be a prolonged interruption of blood flow to the femoral head that leads to ischemia and ultimately infarction and resorption of the subchondral trabeculae followed by subchondral fracture. Subchondral fracture usually progresses to collapse and joint incongruity. The characteristic radiographic appearance of advanced ON is mixed zones of sclerosis and radiolucency, reflecting dead or repaired bone and areas of resorption, respectively.

Given the progressive nature of the disease, prompt diagnosis is critical for optimal head preservation outcomes. Detailed histories with thorough physical examinations are crucial as early stages of osteonecrosis can be difficult to detect clinically. The most common site for ON is the hip with the knee and shoulder following in prevalence. ON of the hip will be referenced here for pathophysiology and treatment. Advanced stages of hip ON are characterized by femoral head collapse often with painful arthritis, joint space narrowing, and acetabular involvement. Varying staging systems have been developed and largely rely on abnormalities seen on imaging. The importance of these staging systems lies in their guidance for treatment. According to the disease severity, several medical and surgical treatments are available to delay progression or reverse the damage. Surgical management options are further categorized depending on whether they preserve the native femoral head. Joint preservation procedures are largely reserved for patients with precollapse disease, whereas, femoral head replacement is often the only feasible option for postcollapse patients.

In this chapter, we review the current knowledge on osteonecrosis and its management. First, to get an understanding of the disease process, the associated risk factors and pathophysiology will be discussed. Next, the clinical and diagnostic
features of osteonecrosis will be described including the current staging systems. In the latter part of the chapter, we will review available treatment options.

EPIDEMIOLOGY AND ETIOLOGY

Every year, approximately 20,000 to 30,000 patients are newly diagnosed with osteonecrosis of the femoral head in the United States.² It is the underlying condition for which approximately 10% of total hip arthroplasties (THAs) are performed and therefore places a substantial burden on healthcare cost and utilization. The disease affects people of all ages but is most common in those aged between 30 and 50 years. As the disease primarily affects young, active patients, the resulting changes and limitations to their daily and leisure activities can be drastic. The extent of disability and effect on quality of life is compounded when the contralateral hip is involved as is the case in 50% to 80% of the patients.

Associated risk factors for this disease are varied and are now believed to be multifactorial. However, associated risk factors can be broadly classified as traumatic or nontraumatic.

TRAUMATIC OSTEONECROSIS

Trauma is one broad classification of risk factors that can result in osteonecrosis due to the direct impact on the vascular supply. The vasculature of the femoral head and its compromise with trauma have been described in a recent review on skeletal circulation.³ The femoral head is primarily supplied by three arterial systems: retinacular, foveolar, and intraosseous. The superior and inferior retinacular arteries branch off the medial circumflex artery (MCFA), and in adults, these arteries are the dominant arterial supply to the femoral head. Fractures of the femoral neck and dislocation of the hip can compromise this blood supply since the terminal branches are located in the posterior aspect of the femoral head-neck junction. Ischemia and infarction of the femoral head may be caused directly by disruption to these terminal vessels or indirectly by tamponade by intra-articular fracture hematomas.

Fractures of the femoral neck are often associated with osteonecrosis, and the risk is often determined by the fracture location and displacement, as well as patient age and the quality and timing of reduction. The retinacular arteries supplying the femoral head are most susceptible to mechanical damage in femoral head fractures, which are therefore associated with the highest incidence of osteonecrosis of up to 40%.⁴^,⁵^,⁶ Due to the proximity to the MCFA and its terminal branches, medial neck fractures are more likely to interrupt the blood flow and lead to subchondral bone infarction compared with lateral neck fractures. The incidence of osteonecrosis can be 50% higher in displaced femoral neck fractures compared with nondisplaced fractures.⁷^,⁸ Similarly, patients with fractures that are malreduced with severe residual varus or valgus deformities are at an increased risk. In comparison to femoral head and neck fractures, osteonecrosis is rarely seen following intertrochanteric or femoral shaft fractures due to their distance from the MCFA.

The incidence of osteonecrosis following hip dislocation varies between 10% and 25% depending on various contributing factors.⁹ The risk is far higher among those with concomitant femoral head or acetabulum fractures as there is an increased likelihood of damage to the blood vessels. Patients with posterior hip dislocations are also at a higher risk for osteonecrosis compared with those with anterior dislocations (29% vs 9%). Delays in treatment of the dislocation have also been associated with an increased incidence of osteonecrosis.

NONTRAUMATIC OSTEONECROSIS

Several nontraumatic risk factors for ON have been identified (Table 1). These can be broadly classified according to their contributions to the circulatory pathophysiology of ON. In addition to the vascular disruption described in traumatic ON, the blood supply to the femoral head is vulnerable to extravascular compression and intravascular occlusion.¹⁰ There is presently no consensus regarding the relative contributions of several putative etiological risk factors for ON, most likely due to the varying methodologies, prospective and retrospective, used to determine associations in current literature.

TABLE 1 Traumatic and Nontraumatic Risk Factors for Osteonecrosis

Traumatic Risk Factors

Fracture

Hip dislocation

Nontraumatic Risk Factors

Intraosseous Extravascular Compression

Corticosteroid use

Alcohol

Gaucher disease

Intravascular Occlusion

Sickle cell disease

Coagulation disorders

Smoking

Other Etiologies

Caisson disease

Radiation

Chemotherapy

Genetic predisposition

INTRAOSSEOUS EXTRAVASCULAR COMPRESSION

Microcirculatory blood flow in the femoral head is susceptible to compression by increases in extravascular pressure as the bone is thought to function as a rigid-walled chamber surrounding the vasculature.¹⁰ When the pressure in the intraosseous extravascular compartment exceeds capillary pressure, the small vessels in the femoral head are compressed and the resulting reduction in arterial flow leads to regional ischemia. Corticosteroid use, excessive alcohol intake, and Gaucher disease are all examples of conditions that have been associated with reduced arterial supply secondary to increased intraosseous extravascular pressures.

Corticosteroid use is thought to be one of the most commonly associated risk factors of nontraumatic osteonecrosis.⁹^,¹¹^,¹²^,¹³^,¹⁴ Although this association has long been established, the exact mechanism is poorly understood. Corticosteroids can result in an increase in the number and size of adipocytes in the bone marrow resulting in venous congestion, raised intraosseous pressure, and ultimately inadequate arterial blood flow. Chronic corticosteroid use may result in further vascular dysregulation by their inhibition of vasodilatation. Additionally, corticosteroids have shown to impair bone repair processes by inducing osteoblast and osteocyte apoptosis as well as suppressing osteoblast production in the bone marrow. It is also thought that the antiangiogenic and prothrombotic effects of corticosteroids contribute to the risk of osteonecrosis through the impairment of bone repair and the interruption of intraosseous blood flow.

Excessive alcohol intake is also a major risk factor for nontraumatic osteonecrosis and is estimated to be a risk factor in 20% to 40% of all osteonecrosis cases.¹⁵ It has been suggested that alcohol consumption leads to induced adipogenesis and decreased osteogenesis in the bone marrow which might contribute to the development of raised intraosseous extravascular pressures and subsequent reductions in arterial flow. Studies have found that the increased risk in osteonecrosis with excessive alcohol use is dose-dependent. Compared with nondrinkers, the odds of developing osteonecrosis have been found to be 2.8, 9.4, and 14.8 times higher for those drinking <320, 320 to 799, and >800 g of alcohol/week, respectively.¹⁶ Smoking has also been implicated as a major risk factor for this disease.¹⁶

Raised intraosseous extravascular pressure is suggested to be the underlying mechanism for the development of osteonecrosis in patients with Gaucher disease as well. In these patients, the deficiency of beta-glucocerebrosidase leads to the accumulation of glucocerebrosides in the lysosomes of histiocytes, known as “Gaucher cells.” The large collections over time of Gaucher cells in the extravascular space raises intraosseous pressures and compress the small vessels supplying the femoral head resulting in ischemia.

INTRAVASCULAR OCCLUSION

Arterial supply to the femoral head can also be compromised through intravascular obstruction. Examples of potential obstructions are sickle cell aggregates, thrombi, and lipid thrombi.

Almost half of all sickle cell disease patients develop osteonecrosis by the age of 35 years. Low oxygen tension environments are thought to polymerize abnormal hemoglobin, produced as a result of a genetic mutation, and lead to the characteristic sickling of red blood cells. These abnormal red blood cells adhere to each other and lead to intravascular occlusion. The femoral head is particularly susceptible to ischemia from intravascular obstruction by sickled red blood cells as the osseous vasculature tends to have low blood flow.¹⁷

Several medical conditions and hypercoagulable states are also important risk factors for intravascular occlusion and therefore nontraumatic osteonecrosis. Examples include antiphospholipid syndrome, thrombophilias, and hypofibrinolysis. The prevalence of inherited coagulation disorders have been reported to be notably higher among osteonecrosis patients. Factor V Leiden thrombophilia was reported to be almost four times more prevalent in osteonecrosis patients compared with controls (18% vs 4.6%) in a retrospective study,¹⁸ and in another prospective study, hypofibrinolysis secondary to excess plasminogen activator inhibitor was reported to be 10 times more prevalent in osteonecrosis patients compared with controls (31% vs 3%).¹⁹

PATHOPHYSIOLOGY

Although there are many putative etiology associations with osteonecrosis, they are all considered to contribute to a unifying pathophysiology: ischemia and infarction of the bone (Figure 1). Together, compromised circulation is a final common pathway, and is a unifying concept, of many etiologies of ON. Vascular occlusion can be the result of extravascular compression from intraosseous hypertension, microcirculatory thrombi from intravascular coagulation, or mechanical interruption from trauma. In all cases, a reduction in blood flow to the femoral head leads to bone infarction and osteocyte necrosis.²⁰

In the context of prolonged corticosteroid use and alcohol abuse, it is postulated that the following mechanism occurs: bone marrow stem cells convert from an osteoblastic to adipogenic lineage and differentiate into fat cells which subsequently hypertrophy, occupy the intraosseous extravascular space, and result in intraosseous hypertension, venous congestion, microvascular coagulation, and impaired arterial flow to the subchondral bone.²¹^,²² Intramedullary ischemia further stimulates the conversion of bone marrow stem cells to fat cells creating a vicious cycle.²³^,²⁴ A similar process is observed in Gaucher disease, whereby glucocerebrosides accumulate in the bone marrow.²⁵

Several hereditary thrombophilias and hypercoagulable states put patients at risk of osteonecrosis given the particularly vulnerable vasculature of the femoral head. The lateral epiphyseal artery, which is derived from the MCFA, provides the principal blood supply to the femoral head. Vascular occlusion from microthrombi can result in ischemia at the peripheral
zone of the lateral epiphyseal artery in the subchondral bone. When the ischemia is transient, the lesion is less likely to progress to osteonecrosis, as is seen in borderline necrosis or bone marrow edema syndrome. However, prolonged ischemia with osteocyte and bone marrow necrosis leads to progression of the lesion to osteonecrosis.

FIGURE 1 Illustration demonstrating the pathophysiology of osteonecrosis.

An impairment of angiogenesis following bone marrow necrosis puts patients at an increased risk for osteonecrosis. It has been suggested that corticosteroid use and genetic polymorphisms suppress the reactive processes of new vessel formation.¹⁹^,²⁶^,²⁷^,²⁸^,²⁹ Moreover, the natural reparative processes surrounding the lesion are thought to compromise the structural integrity of the femoral head. The necrotic lesion is surrounded by a fibrous capsule formed of histiocytes and giant cells, termed the reactive zone, which in itself is surrounded by bone marrow edema. Finite element modeling has demonstrated that the loss of structural integrity is due to resorption of subchondral trabeculae leading to fracture beneath the subchondral plate.³⁰ Additionally, the necrotic bone marrow undergoes saponification from the released fatty acids thereby losing its mechanical strength and structural integrity. At the macroscopic level, these processes lead to depression of the articular cartilage and ultimately collapse of the femoral head.³¹^,³²^,³³^,³⁴

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