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Osteonecrosis

 

Introduction

  • Osteonecrosis (ON) is an infarction of an area of bone secondary to a microvascular insult which may ultimately lead to bone resorption and structural collapse
  • The disease typically affects epiphyseal bone on the convex side of a joint, likely due to the lack of collateral circulation
  • It most commonly affects the femoral head, followed by the distal femur, proximal humerus and talus 

Pathogenesis

  • ON is certainly a multifactorial process that is not clearly defined as of yet
  • Most would argue that it is caused by a combination of
    • Metabolic factors
    • Local factors that affect blood supply (e.g., vascular damage)
    • Increased intraosseous pressure
    • Mechanical stresses
  • Majority of osteonecrosis cases are related to
    • Idiopathic disease
    • High dose of corticosteroid
      • Up to 38% of patients with ON have a history of high dose corticosteroid use (~2 grams of prednisone within 2-3 months)
      • However, only 5% of patients with a history of high dose corticosteroid use develop osteonecrosis

         

    • Alcohol abuse
      • Up to 29% of patients with ON have a history of alcohol abuse
      • However, only 5% of patients with a history of alcohol abuse develop ON

         

  • The pathophysiolgy of corticosteroid and alcohol-related ON has been studied extensively and the strongest evidence is in support of increased adipogenesis as a major underlying mechanism
    • It has been shown that corticosteroids and ethanol can induce the pluripotent bone marrow cell line to preferentially differentiate into adipocytes in vitro
    • Increased adipogenesis causes venous sinusoidal compression which leads to venous congestion, intraosseous hypertension, impaired arterial flow and ultimately infarction

    • However, as stated earlier, only 5% of patients with a history of high-dose corticosteroid use or alcohol abuse develop ON
    • Corticosteroid use and excessive alcohol intake have been speculated to contribute to vascular compromise through
      • Elevations in lipid levels resulting in microemboli
      • Increased bone marrow fat cell size that leads to venous flow obstruction
      • Alterations in venous endothelial cells causing stasis and increased intraosseous pressure
  • Many groups are researching genetic traits that may predispose to the development of ON
  • There is increasing evidence for the role of clotting disorders in the development of this disease
    • One study reported 82% of patients with osteonecrosis had at least one clotting disorder vs. 30% of controls

    • Some of the more common abnormalities seen include
      • IgG anti-cardiolipin antibodies
      • Stimulated plasminogen activator
      • Plasminogen activator inhibitor-1
    • Similar results have been reported in other studies

       

  • Other predisposing factors may include
    • Mutations in a multidrug resistance gene
    • Genetic variation in alcohol-metabolizing enzymes
    • Abnormal type II collagen

The table below lists many of the conditions associated with osteonecrosis (Mont et al. 2006)

Direct Causes

Indirect Causes

Less Common

Trauma

Corticosteroids

Polyarteritis

Irradiation

Alcohol abuse

Thalassemia

Hematologic disorders

Idiopathic

Carbontetrachloride poisoning

Cytotoxins

Thrombophilia

Hyperlipidemia

Dysbaric

Hypofibrinolysis

Cushing's disease

Gaucher's disease

Lupus

Pregnancy

Sickle cell diseas/trait

Renal failure

 

 

Organ transplant

 

 

Hemophilia

 

 

Pathology

  • The pathologic characteristics of bone necrosis are the same regardless of aetiology
  • Ischemia causes bone and marrow cell death
  • The necrosis is geographic and involves cancellous bone and marrow in medullary infarcts
  • The cortex is not typically affected, due to its collateral blood supply
  • In subchondral infarcts, necrosis involves a wedge-shaped segment of tissue that has the subchondral bone plate as its base and the center of the epiphysis as its apex
  • In the femur, this is most commonly at the lateral and anterior femoral head
  • Since the overlying articular cartilage receives nutrition from the synovial fluid, it remains viable
  • The dead bone has empty lacunae and is surrounded by necrotic adipocytes that often rupture and release their fatty acids
  • These fatty acids can bind calcium and form insoluble calcium soaps
  • Histologic findings of osteonecrosis
    • Indistinct cellular outlines
    • Smudged nuclei surrounded by amorphous eosinophilic material
  • An ineffective healing process usually follows, with bone resorption outweighing bone formation
  • The dead bone is replaced with fibrous granulation tissue
  • Thickened trabeculae form as living bone is deposited directly onto dead bone
  • Edema, hemorrhage, fibrilloreticulosis and hypocellularity may be present in bone marrow lesions
  • During the healing process, osteoclasts resorb the necrotic trabeculae, while the remaining ones serve as scaffolding for the deposition of new bone (i.e., creeping substitution)
  • Nevertheless, the pace of creeping substitution is not fast enough to be effective, and as a result, the necrotic cancellous bone collapses
  • The unsupported cartilage soon collapses and joint destruction follows

Nutritional factors

  • Nutrition does play an important role in this condition
  • Alcohol abuse should be avoided
  • A healthy, balanced diet (with low lipids) should be adopted
  • The patient should have normal intake of calcium and vitamin D to maintain normal bone density

Prevention

  • To prevent osteonecrosis, the minimum effective dose of systemic corticosteroids should be used and if possible, steroid-sparing agents should be used
  • Statins may reduce osteonecrosis incidence with long-term corticosteroid use
  • Patients at high risk of osteonecrosis (e.g., prolonged corticosteroid use, hemoglobinopathies, renal transplant) should be educated about osteonecrosis and advised to report symptoms as soon as possible to facilitate treatment
  • Patient education and minimizing corticosteroid dose are both very cost-effective ways to reduce the incidence of osteonecrosis and even though they may not always prevent osteonecrosis, they would allow patients to be treated earlier in the course of disease
  • Early detection of osteonecrosis allows the treatment to be initiated when less invasive options are still available
  • Two uncontrolled studies showed that bisphosphonates may delay collapse of the femoral head and delay the need for surgical intervention, but further studies are required

Natural History

  • Osteonecrosis has been estimated to affect 20,000 new patients per year in the US
  • 75% of patients are between the ages of 30-60 years old
  • 25% of patients with the condition are < 25 years of age
  • The disease is more common in males 
    • 7:3 males-females
    • An important exception to this male-to-female ratio is SLE
  • It may be bilateral in up to 72% of the cases
  • The condition accounts for 5-12% of total hip replacements

Clinical Presentation

  • Osteonecrosis can be asymptomatic and found incidentally on imaging
  • A high index of suspicion is necessary for patients with risk factors
  • Pertinent patient history includes history of steroid use, alcohol abuse and clotting abnormalities
  • Pain in the affected joint (although non-specific) is usually the presenting symptom
  • Patients with osteonecrosis of the femoral head often complain of groin pain and less commonly thigh and buttock pain
  • Pain worsens with weight-bearing and motion
  • Rest pain occurs in about two-thirds of patients
  • Night pain occurs in about one-third of patients
  • The initial physical exam findings may not be useful and are often non-specific
  • After osteonecrosis progresses, joint function deteriorates and the patient may
    • Walk with a limp
    • Have tenderness around the affected bone
    • Have painful, restricted active and passive joint movements, esp. IR and abduction
    • Have joint deformity and muscle wasting
    • May even have a neurologic deficit if a nerve is compressed due to necrosis and deformity of the affected bones
  • Mechanical symptoms may be present once collapse of the femoral head has occurred
Late Presentation
  • Unfortunately, most patients present late in the course of disease
  • In the late stages, you may see highly deteriorated joint function and a significant limp
  • Without treatment, the patient would be more likely to present with severe pain at rest and at night and would have more restriction and pain with joint movements
  • Joint deformity, muscle wasting and non union of fracture are also more common with advanced osteonecrosis
  • Medullary infarcts usually remain stable over time, while subchondral infarcts often collapse and may predispose to severe secondary osteoarthritis

Differential Diagnosis

  • Diseases with a similar presentation include
    • Transient regional osteoporosis
    • Subchondral fracture : usually in patients with pre-existing osteopenia
  • Other diseases on the differential
  • Conditions associated with osteonecrosis
    • Sickle-cell anemia / other hemoglobinopathies
    • SLE
    • Cushing disease
    • Decompression disease
    • Gaucher disease
    • Myeloproliferative disorders
    • Organ transplantation
    • Inherited thrombophilias
    • HIV infection
    • Trauma
      • Femoral neck fracture
      • Hip dislocation
    • Chronic pancreatitis
    • Pregnancy
    • Hyperlipidemia
    • Smoking
    • Hyperuricemia
    • Radiation

Psychosocial Impact of Disease

  • Given the high morbidity rates and the significant prevalence of long-term disability with osteonecrosis, psychosocial factors are a key consideration in this patient population
  • The pain and difficulty with weight bearing can prevent these patients from working and from socializing to the extent that they usually do
  • This can certainly lead to depression and anxiety
  • In addition, the psychological distress can affect these patients' relationships with their partners and families because they are less independent
  • Another important issue to consider is that many patients with advanced osteonecrosis require more than one hemiarthroplasty or total hip replacement during their lifetime. These patients may become more apathetic and may feel as though they are a burden to their friends and families

Imaging and Diagnostic Studies

  • MRI is the modality of choice for diagnosing and monitoring stage I disease (99% sensitivity and specificity)

  • Once the disease has progressed to stage II, plain films are typically the preferred imaging modality
X-Ray
  • X-Rays may not show abnormalities for months after the disease process begins
  • The first X-Ray findings are mild density changes, followed by the development of alternating areas of cysts and sclerosis
  • The crescent sign is pathognomonic for subchondral bone collapse and appears as a strip of subchondral radiolucency
  • In later stages, X-Rays reveal a collapsed femoral head that has lost its spherical shape
  • End-stage disease is characterized by narrowed joint spaces and degenerative changes of the acetabulum
  • X-rays have moderate sensitivity and specificity, with the highest levels in the 45°, flexed knee, anterior-posterior film
  • The Kerboul Angle, also known as the "Combined Necrotic Angle" is a system used to quantify size of the lesion
    • To calculate, first the center of the femoral head is identified
    • Two lines are then drawn from this point to the borders of the lesion on both AP and Lateral radiographs
    • The sum of the angles on the AP and Lateral radiographs is the Kerboul angle
    • Lesions are classified as small, medium, or large:
      • Small: 160º or less
      • Medium: 161º - 199º
      • Large: 200º or more
Bone scan
  • Technetium-99m bone scans can be used, if patients have negative X-Rays
  • Increased uptake occurs at areas between dead and reactive bone, because of increased bone turnover (doughnut sign)
  • Less sensitive than MRI, especially in early-stage disease
  • Low overall specificity with a large number of false positives
  • No advantage over MRI
CT scan
  • The best modality for estimating the extent of bone death
  • It is not as sensitive as MRI
MRI
  • MRI has a overall sensitivity of 91%, much higher than X-Rays and bone scans
  • It can detect early-stage disease when other studies are negative
  • T1 shows a single low-intensity line early on, representing the transition from normal to ischemic bone
  • T2 shows a second high intensity line that represents hypervascular granulation tissue. This double-line sign on MRI is pathognomonic for osteonecrosis
  • Conversely, MRI has a lower specificity, especially in asymptomatic patients
Laboratory Evidence
  • No laboratory test findings specifically suggest or confirm the presence of osteonecrosis

Classification

  • At least 17 classification systems have been used
  • The majority are branches of the Ficat and Arlet System outlined below
  • Ficat and Arlet classification system outlines the natural progression of the disease

     

Stage

Imaging Findings

I

Evidence seen on MRI only

II

Diffuse sclerosis, subchondral cysts. No femoral head collapse

III

Subchondral fracture ("Crescent sign") with or without collapse

IV

Collapse of the femoral head and secondary degenerative joint disease

Treatment

Conservative Management
  • Bed rest, crutches and non-steroidal analgesics
    • Retrospective studies and meta-analyses have proven these to be ineffective at slowing disease progression, particularly in lower-limb joints
    • Some studies suggest that conservative management of shoulder osteonecrosis consisting of limited overhead use, gentle stretches and strengthening exercises and analgesics may be as successful as surgical therapies
  • Bisphosphonates : shown to delay disease progression
  • Newer pharmacologic options
    • Still largely unproven for treatment of osteonecrosis
    • Potential promising therapies include
      • Growth factors
      • Cytokines
      • Angiogenic agents
      • Bone morphogenetic proteins
Surgery

Although there is no consensus on the best surgical procedure for osteonecrosis, core decompression with or without bone graft is appropriate in early stages of osteonecrosis and total hip arthroplasty is appropriate in the late stages

  • Joint preserving procedures
    • These procedures attempt to preserve the femoral head and slow disease progression
    • Core decompression
      • Provides pain relief
      • Increases range of motion in early stage disease
    • Vascularized fibular graft
      • Provides structural support, stem cells and a vascular supply to the necrotic tissue
      • Results with this technique have been highly variable {ref: 12690862}. Complications include donor site morbidity (~24% rate){ref:  9692940} and proximal femur fracture (~2.5% rate) 20 . Conversion to total hip arthroplasty in patients who have undergone this procedure requires burring laterally to prevent the prosthesis from being placed in varus.
    • Bone marrow grafting
      • Currently experimental
      • Favorable early reports
    • Osteotomy
      • Creates a new weight bearing area away from the necrotic area
      • Has varying clinical results with the best results seen in early stage disease.
  • Joint replacement
    • Used for end-stage osteonecrosis when severe degenerative changes are present
    • Options
      • Hemiarthroplasty
        • Hemiarthroplasty has poor long-term results. The high activity level in this patient population results in increased polyethylene wear and osteolysis. This technique should not be used in these patients.

      • Hemi-resurfacing arthroplasty of the femoral head 
        • Disadvantages include unpredictable relief of groin pain, which is a complaint in up to 20% of these patients. Also, this is a temporizing measure as failure will eventually occur secondary to acetabular cartilage erosion. Short-mid term results have been relatively encouraging with 5-7 year success rates are approximately 70-90%. At 10-15 years there has been a dramatic decrease in survivorship.
      • Total joint replacement
        • For hip disease, short to mid-term results with newer bearing surfaces and uncemented techniques have been encouraging. Success rates of up to 89% have been reported at 15 years follow-up making THA a reliable, long term option.

Outcome

Conservative Management
  • Bisphoshonates;
    • A prospective, randomized, controlled trial has reported the results of 54 patients with large pre-collapse or early post-collapse lesions randomized either into a group that received observation only or a group treated medically with alendronate for 25 weeks. Seven percent (2/29) of the lesions treated with alendronate had progressed at a minimum 2-year follow-up versus 76% (19/25) of the controls 14 .
Surgical Treatment
  • Core decompression 
    • For hip disease a success rate of 84% for Stage I lesions and 65% for Stage II lesions has been reported {ref:  8595753}. 
    • Efficacy of the procedure drops significantly once the femoral head develops a subchondral fracture.

  • Cortical grafts
    • Success rate as low as 25%
    • Combined with core decompression, it has better outcome in early stages of the disease
  • Vascularized fibular grafting
    • Highly variable results across the literature. A few institutions specializing in this technique have reported acceptable success rates.
  • Total hip replacement
    • Short to mid-term results with newer bearing surfaces and uncemented techniques have been encouraging. Success rates of up to 89% have been reported at 15 years follow-up making THA a reliable, long term option.

Complications

  • The main complication of conservative management is disease progression to subchondral bone collapse and joint destruction
  • The most common complication of core decompression, reported in 0-18% of cases, is hip fracture
  • Vascularized fibular grafting
    • It is a more complicated procedure than other bone grafts, so it has related morbidity consequences; all of which must be considered especially in older patients
    • Disadvantages
      • Longer recovery
      • Less complete analgesia
      • Variable success rate
      • Decreased effectiveness in advanced osteonecrosis
    • Complications
      • Ankle pain
      • Great-toe flexion contracture
      • Foot motor weakness and sensory loss
      • Femoral fracture
      • Deep vein thrombosis
      • Pin migration
      • Hematoma
      • Trochanteric bursitis
    • The overall complication rate for vascularized fibular grafting was found to be 17% at an average of 8 years
    • 4% of total cases required additional surgery or chronic pain management
  • Total hip replacement
    • Deep vein thrombosis (3-5%)
    • Dislocation (1-5%)
    • Infection (1-2%)

References

Jones LC, Hungerford DS, 2007. "The pathogenesis of osteonecrosis." Instr Course Lect56: 179-96 [PubMed]

 Cui Q, Wang GJ, Balian G, 1997. "Steroid-induced adipogenesis in a pluripotential cell line from bone marrow." J Bone Joint Surg Am 79 (7): 1054-63 [PubMed]

 Jones LC, Hungerford DS, 2007. "The pathogenesis of osteonecrosis." Instr Course Lect 56: 179-96 [PubMed]

 Laroche M, 2002. "Intraosseous circulation from physiology to disease." Joint Bone Spine69 (3): 262-9 [PubMed]

 Wang GJ, Sweet DE, Reger SI, Thompson RC, 1977. "Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits." J Bone Joint Surg Am59 (6): 729-35 [PubMed]

 Jones LC, Mont MA, Le TB, Petri M, Hungerford DS, Wang P, Glueck CJ, 2003. "Procoagulants and osteonecrosis." J Rheumatol 30 (4): 783-91 [PubMed]

 Glueck CJ, Freiberg RA, Wang P, 2008. "Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head." Clin Orthop Relat Res 466 (5): 1034-40 [PubMed]

 Lieberman JR, Berry DJ, Mont MA, Aaron RK, Callaghan JJ, Rajadhyaksha AD, Urbaniak JR, 2003. "Osteonecrosis of the hip: management in the 21st century." Instr Course Lect 52: 337-55 [PubMed]

 Mont MA, Marulanda GA, Jones LC, Saleh KJ, Gordon N, Hungerford DS, Steinberg ME, 2006. "Systematic analysis of classification systems for osteonecrosis of the femoral head." J Bone Joint Surg Am 88 Suppl 3: 16-26 [PubMed]

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