Osteonecrosis, also known as avascular necrosis or ischemic necrosis of
the femoral head, is a pathologic process that results from interruption of
blood supply to the bone. The accurate prevalence of disease is unknown, but
10,000 to 20,000 new cases are diagnosed in the United States per
year.1,2 An estimated 5% to 18% of the more than 500,000 total hip
arthroplasties (THAs) performed annually are for osteonecrosis of the femoral
The etiology of osteonecrosis is believed to be multifactorial and
associated in some cases with both a genetic predilection and exposure to
certain risk factors (Table 1).3-6
Trauma is a potential cause due to disruption of the blood supply from
the superior retinacular vessels and the nutrient artery as well as the
increases of intracapsular pressure due to intracapsular hematoma following a
femoral neck fracture. In cases of hip dislocation the artery of the ligamentum
teres is damaged. Extracapsular lesions, as intertrochanteric fractures, rarely
result in avascular necrosis.3-6
The use of corticosteroids7-9 is the most common risk factor
accounting for almost 10% to 30% of osteonecrosis cases. However, only 8% to
10% of patients exposed to corticosteroid therapy may develop
osteonecrosis.9 Dosages typically considered to be associated with
the disease are >2 g of prednisone, or its equivalent, within a 2- to
3-month period.8 Koo et al9 found that the total dose of
corticosteroids used until osteonecrosis was detected with magnetic resonance
imaging (MRI) ranged from 1800 to 15500 mg (mean, 5928 mg) of prednisolone or
The period from the start of corticosteroid treatment to the diagnosis
of osteonecrosis ranges from 1 to 16 months (mean, 5.3 months), and the
majority of patients are diagnosed within 12 months.9 In an animal
model, Korompilias et al10 reported that corticosteroids may act as
a trigger, potentiating the effects of a pre-existing condition and increasing
the risk of osteonecrosis. These authors also found evidence supporting that
the immunologic reaction was important in the pathogenesis of the disease.
Excessive alcohol intake has been identified as an etiologic factor in
osteonecrosis. The relative risk increases from 2.7 for <4000 drink-years
(with drink-years defined as weekly alcohol consumption multiplied by the
number of years of drinking) to 9.0 for 10,000 drink-years.11 One
prospective study12 suggested that an intake of >400 mL of
alcohol per week increased the relative risk of osteonecrosis 9.8-fold.
Occasional drinkers (<8 mL of alcohol once a week, but not daily) (relative
odds=3.2) and regular drinkers (8 mL of alcohol daily) (relative odds=13.1) are
found to have a higher risk to develop osteonecrosis than controls. A
significant dose-response relationship (P<.001) was found,
with the relative odds for current drinkers being 2.8, 9.4, and 14.8 in
association with ethanol intakes of <320, 320 to 799, and 800 g/wk,
Smoking has been implicated as a risk factor for osteonecrosis of the
femoral head.12-14 Hirota et al13 showed that there is an
increased risk for current smokers (relative odds=4.7); however, a cumulative
effect of smoking was evident only in association with >20
pack-years. Matsuo et al12 also found an increased risk for current
smokers (relative risk=3.9). Various studies have demonstrated that smoking
inhibits osteogenesis or fracture healing.14-16
Osteonecrosis has been associated with several hemoglobinopathies
including hemoglobin SS (sickle cell disease), hemoglobin SC, and sickle
thalassemia. The reported prevalence of osteonecrosis in these populations has
been 4% to 20%.11,17,18 Studies have shown an association with
thrombophilia and hypofibrinolysis.11,17 At least 1 coagulation
factor abnormality was found in 82% of patients with osteonecrosis of the
femoral head compared with 30% of controls (P<.0001).11
Two or more abnormalities were identified in 21 patients (47%) compared with
2.5% of controls (P<.0001). Glueck et al17 found a
high prevalence of plasminogen activator inhibitor-1 coagulation abnormalities
in patients with osteonecrosis. The same author showed that heritable
hypofibrinolysis and thrombophilia, often augmented in women by
hyperestrogenemia, are major pathoetiologies of osteonecrosis, and proposed
anticoagulation therapy with Enoxaparin.18
Patients infected with human immunodeficiency virus (HIV) are also at
increased risk.19,20 It is unclear whether the virus or the
medications used are the pathogenic agents. Several studies have implicated
antiretroviral therapy as the most important pathogenic agent.19,20
Ries et al21 found 4 patients with HIV and osteonecrosis of the
femoral head that were not treated with retroviral drugs, a finding that
suggests that HIV infection may be a unique risk factor.
A recent study22 demonstrated a potential for autosomal
dominant inheritance, for osteonecrosis of the femoral head, mapping the
chromosomal position of a collagen type-II gene (COL2A1 gene) mutation. It has
also been associated with certain genetic polymorphisms such as
alcohol-metabolizing enzymes and the drug-transport protein
P-glycoprotein.23-25 Glueck et al26 recently found that
eNOS polymorphisms may be associated with a risk of development of idiopathic
osteonecrosis. The T-786C eNOS mutation was associated with idiopathic
osteonecrosis but was not associated with secondary osteonecrosis
(P=.52, P=.19). Moreover, in the current study, the
smoking-eNOS genotype interaction was associated with idiopathic osteonecrosis
(P<.0001). The importance of their findings is that genetic
screening of families with osteonecrosis of the femoral head could be used to
identify carriers before the onset of clinical symptoms, allowing for
initiation of measures that could delay disease progression.
The pathogenesis of osteonecrosis was recently reviewed and a unifying
theory that focuses on the role of ischemia was presented.27
Ischemia can be produced by vascular interruption (fractures or dislocations),
by thrombotic occlusion (intravascular coagulation), or by extravascular
compression (marrow fat enlargement).27
Current evidence suggests that intravascular coagulation and
microcirculatory thrombotic occlusion likely provide a final common pathway for
nontraumatic osteonecrosis. Arteriolar and other intravascular thromboses have
been found in large numbers of osteonecrotic femoral heads.28
Microcirculatory thrombosis associated with fat emboli has been described.
Elevated levels of fibrinopeptides and fibrin degradation products have been
measured in some cases of osteonecrosis providing indirect evidence of ongoing
Several studies have demonstrated the presence of hypofibrinolysis and
thrombophilia in patients with osteonecrosis.18,29 Hypofibrinolysis
is usually associated with a low level of tissue plasminogen activator,
elevated levels of plasminogen activator inhibitor, and high levels of
lipoprotein A. Thrombophilia is characterized by decreased levels of the
antithrombotic proteins C or S, and resistance to activated protein C. Both
hypofibrinolysis and thrombophilia are accompanied by an increased incidence of
clinical thrombotic events contributing to the pathogenesis of osteonecrosis.
However, other studies have suggested that these coagulopathies may not be
specific for osteonecrosis and are present in other diseases including
osteoarthritis,30 and bone marrow edema syndrome.31
Corticosteroid administration has been associated with osteonecrosis as
a sequence of fat cell proliferation and hypertrophy. It produces a significant
amount of fat accumulation in marrow due to both adipocyte hypertrophy and
hyperplasia, which results in intraosseous hypertension and diminished blood
Classification & Staging
It is generally agreed that successful treatment of patients with
osteonecrosis is related directly to the stage of disease at diagnosis, which
stresses the importance of a reliable classification system.32-34 A
number of different classification systems, presented in Table 2, have been
developed to evaluate patients with osteonecrosis, but there is no standard
unified classification system for determining the extent and location of the
necrotic area in the femoral head.
|Table 2: Click the table to view it in a
The study by Plakseychuk et al,38 which was designed to
assess the reliability of a commonly used classification systems, showed an
unacceptably high intraobserver and interobserver error rate. In light of the
need for an accurate standard classification system, the authors proposed a
3-stage Pittsburgh classification system based on MRI, structure of the femoral
head, and contour of the femoral head as seen on plain radiographs (Table 2).
Each staging system has limitations, and no single system has been
universally accepted for use alone as a guide to treatment. The different
classification systems could be equally applicable based on the comparison of
different studies according to Mont et al.39 These authors found
several similarities and concluded that if specific MRI and radiographic data
are collected, comparison of studies using different systems of classification
could be allowed.
Four essential radiographic findings have been routinely used by most
authors when formulating a treatment plan. These findings, which have been
corroborated in peer-reviewed studies of outcomes of various treatment methods,
include (1) evidence that the lesion is either precollapse or postcollapse, (2)
the size of the necrotic segment, (3) the amount of femoral head depression,
and (4) acetabular involvement with signs of osteoarthritis.
Steinberg et al34 described a method for assessing the amount
of femoral head involvement by these lesions with MRI. Volumetric measurements
are calculated from coronal and axial images. Lesions that occupy <15% of
the femoral head are defined as mild, 15% to 30% as moderate or medium, and
>30% of the femoral head as severe lesions. Cherian et al40
showed that various methods for measuring the sizes of lesions (calculation of
an index of necrotic extent and estimation of the percent involvement) could be
used with confidence as they were highly reliable and reproducible.
The importance of the extent of the lesion and its exact localization is
highlighted by Theodorou et al41 who related it to successful
treatment. Because the ideal location for the fibular graft depends on the
size, location, and configuration of an individual lesion, patient-specific
modeling with computerized optimization offers the potential to enhance
structural contributions to the healing process. The authors observed a wide
range of lesion sizes for each stage, and progression according to lesion size
frequently was observed without an increase in the stage of the disease,
according to one of the major classification systems. Moreover, although the
lesion size varied between MRI and radiographs, measurements of the necrotic
area on radiographs correlated with measures on MRI according to the level of
the MR slice, with lesion sizes measured on radiographs proportionate to MRI
taken posterior to the midcoronal plane of the femoral head.
Arthroscopic evaluation has been also used.42-44 Sekiya et
al44 reported on the difficulties that surround decision making in
middle grade osteonecrosis of the hip. By showing poor correlation
between plain radiography, MRI, and hip arthroscopy, the authors made a
convincing argument for direct inspection of the femoral head when MRI shows
stage IV disease. Patients in the MRI stage IV subgroup were found at
arthroscopy to have articular surfaces that were variously salvageable or
severely delaminated (ie, stages III to V).
Magnetic resonance imaging has been shown to be inadequate at assessing
the articular cartilage. Therefore, either arthroscopy or direct visualization
is required for accurate evaluation and staging, especially in stage IV
disease. In another study, Ruch et al43 used arthroscopy to study 52
hips with osteonecrosis in 18 hips in which loss of integrity of the femoral
head had been noted on plain radiographs, arthroscopy of the hip revealed
osteochondral degeneration not detected by MRI. McCarthy et al42
used arthroscopy to study 7 patients and concluded that this procedure could
enhance the accuracy of staging.
Nonoperative treatment usually results in a poor prognosis.
Most methods of nonoperative treatment have involved restricted weight bearing,
pharmacologic agents, and various external, biophysical, nonoperative
modalities (Table 3).
Restricted weight bearing (with various modalities such as canes,
crutches, or walkers) is believed to slow the progression of the disease. The
rates for preservation of the femoral head as reported by Mont and
Hungerford45 are 35% for stage 1 hips, 31% for stage 2 hips, and 13%
for stage 3 hips. Femoral head collapse is seen in >85% of cases. However,
protected weight bearing may be effective for small lesions located within the
medial portion of the femoral head.38
The use of pharmacological agents has received considerable attention in
recent years. Pritchett46 reported that at a mean of 7.5 years
osteonecrosis of the femoral head had been developed in only 1% of patients who
were taking high doses of corticosteroids as well as various statin drugs
(lipid-clearing agents that dramatically reduce lipid levels). That prevalence
is much lower than the 3% to 20% prevalence reported for patients receiving
high-dose corticosteroids without statins.4,47
Glueck et al48 used the anabolic steroid stanozolol (6
mg/day) to treat 4 patients who had hypofibrinolysis associated with a high
level of plasminogen activator activity and 1 patient who had a high level of
lipoprotein in the serum. In another study49 enoxaparin, a
low-molecular-weight heparin (60 mg/day for 12 weeks), was used to treat
patients who had thrombophilic or hypofibrinolytic disorders and early stages
of osteonecrosis with a 89% success rate.
Iloprost, a prostacyclin derivative used as a vasodilator, has been
studied in patients with osteonecrosis and bone marrow edema50,51
promising clinical and radiographic improvements at 1 year of treatment.
Use of bisphosphonates is associated with reduction in the prevalence of
femoral head collapse.52,53 Recent clinical reports have suggested
that alendronate can be potentially beneficial in patients with nontraumatic
osteonecrosis52,53 and IV biphosphonates in adolescents with
traumatic femoral osteonecrosis.
Zaidi et al54 reported lately that adrenocorticotropic
hormone (ACTH) protects against osteonecrosis of the femoral head induced by
depot methylprednisolone acetate (depomedrol). The authors attributed this
therapeutic outcome to enhanced osteoblastic support and stimulation of VEGF by
ACTH; the latter is largely responsible for maintaining the fine vascular
network that surrounds highly remodeling bone.
Electromagnetic stimulation, extracorporeal shock-wave
therapy55 and hyperbaric oxygen56,57 have also been used
with controversial results.
Core decompression. Core decompression is currently the most
common procedure in the early stages of osteonecrosis of the femoral
head.58 The goal is to decompress the femoral head and thereby
reduce the intraosseous pressure in the femoral head, restore normal vascular
flow, and subsequently reduce the hip pain.58
We are aware of only a few randomized trials in which the efficacy of
core decompression alone was assessed, as it is usually combined with other
treatment options. Stulberg et al59 compared core decompression
alone with conservative treatment in a prospective, randomized study of 55
hips. Based on Harris hip scores, operative treatment was successful in
approximately 70% of hips with Ficat Stage-I, II, or III osteonecrosis
comparing to 20% of nonoperative management of early osteonecrosis.
Core decompression is usually combined with nonvascularized grafts
(allograft bone or demineralized bone matrix),60 vascularized bone
grafts (fibula or iliac crest),61,62 electrical
stimulation,63 or electromagnetic fields.64
There is also interest in using growth factors that can enhance
osteogenesis (bone morphogenetic protein) or angiogenesis (fibroblast growth
factor or vascular endothelial growth factor). In a recent study, Cui et
al65 demonstrated that cloned bone marrow stem cells can directly
form bone after transplantation into bone defects and at ectopic sites,
indicating that the in vitro expanded bone marrow stem cells can serve as a
graft material to enhance bone repair and to treat osteonecrosis.
Early results from the treatment of osteonecrotic lesions with
autologous bone graft that included bone marrow cells, with or without growth
factors, have shown favorable outcomes.65-68 Hernigou and
Beaujean69 had a 94% success rate (avoidance of THA) on hips that
had been operated before collapse. Clonal stem-cell lines can be pivotal tools
to define the characteristics of marrow stem cells in fracture-healing and bone
repair, but information on this topic is limited. With use of gene-labeling
techniques, Cui et al65 demonstrated that the cloned bone-marrow
stem cell can directly form bone after transplantation into bone defects or
into ectopic sites, indicating that the in vitro expanded bone marrow stem
cells can serve as a grafting material to enhance healing of femoral defects.
Lieberman et al66 reported on the use of bone morphogenetic
proteins for the treatment of osteonecrosis of the femoral head with clinically
successful result in 14 out of 17 hips and no patient requiring conversion to a
THA. Some investigators have reported good results in patients with a collapsed
femoral head, but only small numbers of patients have been
Free vascularized fibular grafts. The use of vascularized bone
grafts to treat osteonecrosis of the femoral head was developed to prevent
collapse of the femoral head and to enhance vascularization of the bone in this
region.72 The use of free vascularized fibular grafts is a
reasonable option for patients younger than 50 years without collapse of the
femoral head. The procedure is more controversial in patients with collapse of
the femoral head, and whether it is used should be determined by the diagnosis,
patient age, and the extent of disease progression. However, a vascularized
fibular graft may be considered as a treatment option to avoid performing
arthroplasty in patients younger than 20 years with 2 or 3 mm of collapse and
The Ioannina technique73 uses serial computed tomography (CT)
scans of the proximal femur to identify the configuration of the femur, and the
size, location, and configuration of the lesion. Optimal graft placement is
determined and translated into a patient-specific aiming device with a
predrilled guide wire canal. The authors report that the arbitrary placement of
the graft during conventional fibular graft surgery leads to accurate graft
placement in only 55% of the patients, whereas the use of the patient-specific
Ioannina Aiming Device resulted in optimal graft placement in 89% of the
Successful results with free vascularized fibular graft technique have
been reported at a number of centers.62,72 The expected 10-year
survivorship ranges from 74% to 82%. Patients with preoperative collapse of the
femoral head had a worse prognosis. Conversion to THA was needed in 13% to 28%
Nonvascularized bone grafts. Nonvascularized bone grafts have
numerous theoretical advantages for the treatment of pre-collapse and early
post-collapse osteonecrosis of the femoral head when the articular cartilage is
relatively undamaged.75 No consensus exists regarding the
indications for nonvascularized bone grafting. Most authors recommend them for
hips with <2 mm of femoral head depression or those in which a core
decompression has failed and there is no acetabular involvement. Some
investigators have reported good results in patients with a collapsed femoral
head, but only small numbers of patients have been studied.71,75
However, the indications for nonvascularized bone grafting may increase
in the future as the primary results from addition of growth factors and
various bone-graft substitutes are promising.71,75
Cortical strut-grafting has shown a wide range of success rates.
Boettcher et al76 reported clinical and radiographic success in 71%
of hips after 6 years of follow-up. However, in a long-term evaluation by Smith
et al77 that included the original 38 patients evaluated by
Boettcher et al, 40 (71%) of 56 hips had a poor clinical result at a mean
follow-up of 14 years (range, 4-27 years).76 However, Dunn and
Grow78 reported only 4 good results in 23 patients so treated.
Buckley et al79 reported excellent clinical result at a mean
follow-up of 8 years (range, 2-19 years) in 18 (90%) of 20 hips that had Ficat
Stage I or II disease.
Osteotomies. Osteotomies are used to move the segment of necrotic
bone away from the weight-bearing region. A report on 474 patients treated with
rotational osteotomy revealed a success rate of 78%, with higher success rates
seen in cases in earlier stages (stage II had an 89% success rate, stage III
73%, and stage IV 70%), and in cases involving smaller lesions. In those
involving less than one third of the articular surface procedures were
successful in 93% of cases compared with only 64% success in those involving
more than one third. The outcome was also related to the ratio of the
transposed posterior articular surface to the weight-bearing area of the
Inao et al,81 in a 10-year follow-up study of 14 rotational
osteotomies, noted excellent results with minimal degenerative changes after 15
years in all patients with <2 mm of collapse and no acetabular changes.
Overall, success rate was 78%.
The results of angular osteotomies82,83 are variable, with
success rates ranging from 40% to 96% at 3- to 26-years postoperatively. The
angular osteotomies offered better results in young active patients who were
not taking corticosteroids, had unilateral involvement with a good preoperative
range of hip motion, and had a small lesion without femoral head collapse.
Canadell et al84 supported the relevance of lesion size in a
series of 102 intertrochanteric osteotomies. At an average follow-up of 4.2
years, the best results were in patients with necrotic angles <200° (69%
satisfactory outcome) compared with those with more extensive involvement (48%
unsatisfactory). Poorer results were found in cases with more advanced lesions,
with satisfactory results seen in 91% of cases in stage II, 56% in stage III,
and 32% in stage IV.84
Tantalum rod. Porous tantalum is a biomaterial with a unique set
of physical and mechanical properties. It has a high porosity (>80% of
volume) with fully interconnected pores to allow secure and rapid bone
ingrowth.85 The addition of bone marrow, growth factors, or
bisphosphonates can augment bone formation around and within porous
tantalum.86 Recently, Tsao et al87 reported favorable
early clinical results indicating similar or better survival rates (92% at 48
months) than hips treated with core decompression and vascularized fibular
grafting. Tanzer et al88 presented the results of a retrieval
analysis of 15 clinically failed porous tantalum implants that were associated
with little bone ingrowth and insufficient mechanical support of subchondral
bone. Factors including the surgical technique, its application, and the
clinical characteristics of candidates for this procedure should continue to be
Total joint replacement. Total hip arthroplasty is a predictably
effective treatment of avascular necrosis of the femoral head when the disease
is progressed to Ficat and Arlets32 stages III and IV. The
underlying diagnosis associated with osteonecrosis of the femoral head appears
to have an impact on implant durability. Use of corticosteroids, ethanol abuse,
systemic lupus erythematosus, or organ transplants negatively affect the
Cemented and cementless THAs have shown variable success rates related
to demographic features of the patients in each cohort. Despite the difficulty
of comparing different series, several generalizations can be made. Cemented
components have shown increased loosening rates whereas cementless components
have been associated with polyethylene wear and periprosthetic
Development of modified polyethylene and alternative articulating
surfaces (ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal)
diminish or eliminate the generation of polyethylene particles, however,
ceramic and metal particles are produced. Additional investigation is needed to
identify the potential beneficial or harmful effects of these
Limited femoral resurfacing arthroplasty. Patients with Ficat and
Arlet Stage-III disease, a combined necrotic angle of >200° or >30%
involvement, femoral head collapse of >2 mm, and no evidence of damage to
the acetabular cartilage are the main candidates for limited femoral
Generally, limited femoral resurfacing arthroplasty has shown
satisfactory results for up to 10 years.92-94 Recently, a few
studies showed less predictable outcomes of these procedures with overall hip
survivorship reaching 75.9% at 3 years.95 In a study of 59 hips
followed for a mean of 4.5 years, Cuckler et al93 reported 18
Bipolar hemiarthroplasty. Variable success rates in the treatment
of osteonecrosis of the femoral head have been reported.96,97
Femoral loosening, acetabular protrusio, osteolysis, and polyethylene
wear98,99 are the main reported drawbacks of this reconstructive
option, showing high complication rates98 and radiographic failure
rates that reach 42%.99
Treatment Algorithm/Patient-specific Factors
Several considerations should be given when planning treatment of
patients with osteonecrosis of the femoral head. Patient age, activity level,
general health, comorbidities, and life expectancy are major contributing
factors guiding the decision-making process. Treatment options will also be
influenced by the surgeons familiarity with various procedures. Different
treatment modalities offer better clinical outcome for each stage of disease.
Physical examination assessing the amount of pain, limp, and limitation
of hip motion may also be used to determine the severity of joint involvement.
Systemic disease or a short life expectancy may preclude a major surgical
procedure. Patients with a severe medical background may be more appropriately
treated with one definitive procedure (THA) rather than with procedures that
may be only temporizing.
The duration of symptoms has been found to influence the outcomes of
preservative treatment. In a previous study of 45 Ficat and Arlet Stage I and
II hips in which core decompression was done by drilling multiple times with a
percutaneous small diameter pin, a mean preoperative duration of symptoms of 6
months for patients who had a successful outcome compared with 11 months for
those who had a poor outcome was reported.100 Beaulé et
al101 observed a better prognosis for patients who had experienced
symptoms for <12 months before treatment with limited femoral head
resurfacing than for patients who had had symptoms for >12 months before
Generally, nonoperative pharmacologic or biophysical treatment
modalities should be preferred in asymptomatic hips with precollapse lesions.
For later stage lesions, without distraction of the articular cartilage,
osteotomies as well as bone grafting procedures, vascularized and
nonvascularized, could be considered supplemented by bone marrow stem cells
that can serve as a grafting material to enhance healing of femoral defects. An
alternative option for this stage could be the use of tantalum rod. In
situations where there is a limited defect of the femoral head cartilage
without acetabular involvement, limited femoral head resurfacing could be
considered. Finally, when acetabular involvement occurs, the only viable option
is THA. Ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal
bearings should be considered for active young patients.
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Drs Babis, Sakellariou, and Soucacos are from 1st Orthopaedic
Department, University of Athens, School of Medicine, Attikon University
Hospital, Athens, Greece; and Dr Parvizi is from the Rothman Institute of
Orthopaedics at Thomas Jefferson University, Philadelphia, Pennsylvania.
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Correspondence should be addressed to: George C. Babis, MD, PhD, 1st
Orthopaedic Department, University of Athens, Attikon University General
Hospital, 1 Rimini Str, Chaidari, Greece, 12462 (firstname.lastname@example.org,