Osteonecrosis of the femoral head: Part 1 Aetiology, pathogenesis, investigation, classification

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1 Current Orthopaedics (2007) 21, Available at journal homepage: HIP Osteonecrosis of the femoral head: Part 1 Aetiology, pathogenesis, investigation, classification Samuel J. Parsons a,, Niall Steele b a Robert Jones and Agnes Hunt Hospital, Gobowen, Oswestry, Shropshire SY10 7AG, UK b Department of Arthroplasty, Robert Jones and Agnes Hunt Hospital, Gobowen, Oswestry, Shropshire SY10 7AG, UK KEYWORDS Osteonecrosis; Hip; Classification; Pathogenesis Summary Changing understanding of the pathology and aetiology of osteonecrosis of the femoral head is leading to a greater insight into potential treatments. This review of idiopathic osteonecrosis looks at causes, classification and treatments options, including more novel approaches. & 2007 Elsevier Ltd. All rights reserved. Introduction Epidemiology Osteonecrosis is a disease arising from impaired osseous blood flow which can follow traumatic or non-traumatic conditions. Originally it was thought to be secondary to infection, but negative bacteriological studies led to the use of the term aseptic necrosis. Further studies showed that the necrotic bone was not only sterile but also avascular, hence the terms ischaemic necrosis, avascular necrosis, and bone infarction. The cessation of blood flow may arise in any part of the vascular network: arterial, capillary, sinusoidal, or venous. If secondary to a mechanical interruption it is termed traumatic osteonecrosis, whereas atraumatic osteonecrosis results from a range of direct and indirect insults. It is most common in the second to fifth decades of life. The typical patient is a male, in his mid 30s. As such patients have a longer life span, and are economically active, this can be costly to society; while joint replacement is the definitive treatment, it has a much higher failure rate in this group of patients, possibly reflecting continued steroid use and younger age. Without treatment more than 70% of femoral heads with osteonecrosis will proceed to collapse, requiring prosthetic joint replacement within 3 4 years of diagnosis. 1 Merle d Aubigne et al. showed 20% collapse at 1 year, and 75% by 3 years. 2 Osteonecrosis accounts for 5 12% of all primary total hip replacements varying geographically from around 10% in the US, up to 45% in Taiwan. Corresponding author. Tel.: ; fax: addresses: samuelparsons@hotmail.co.uk (S.J. Parsons), niallsteele@rjah.nhs.uk (N. Steele). Aetiology/risk factors Causation of atraumatic osteonecrosis of the femoral head is believed to be multifactorial, in some cases associated with /$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi: /j.cuor

2 458 S.J. Parsons, N. Steele Table 1 Indirect cause Steroids Alcohol Coagulation disorders Smoking Hyperlipidaemia Connective tissue disorders/ SLE Sarcoidosis Cushing disease Other endocrine disorders Gout Pregnancy OCP use Pancreatitis Inflammatory bowel disease Shwartzmann reaction HIV (virus/drugs) Haemophilia Renal failure Organ transplant Thermal injuries Thalassaemia Direct cause Trauma Radiation Sickle cell disease/trait Caissons disease Gaucher s disease Chemotherapy/cytotoxics Myeloproliferative disorders both a genetic predisposition and exposure to certain risk factors. There are many factors associated with osteonecrosis of the hip. There are anatomical factors. In a study of the vascular anatomy of 99 hips undergoing vascularised fibular grafting, 93 had abnormal vascular patterns. In contrast, in a control group only 31% had abnormal vascular patterns. Absence or hypoplasia of the superior capsular artery was the most common abnormality. 3 These findings suggest that there is a population of patients at risk for osteonecrosis as a result of anomalies of the microvascular circulation of the femoral head. The lateral epiphyseal vessels supply the superolateral aspect of the femoral head with little collateral circulation. Therefore, this region is sensitive to circulatory impairment and is in fact the most frequent site for osteonecrosis. Additional factors give rise to direct impairment of the circulation, e.g. trauma, radiation, caisson disease, myeloproliferative disorders, etc. For most the pathophysiology is uncertain, with no direct correlation between risk factors and development of the condition. The majority are idiopathic, but alcohol and steroids account for the majority of cases with an identifiable cause (Table 1). While a minimal dose and duration of either steroid and alcohol is necessary to cause osteonecrosis, the amount has not been determined and there is marked patient variability. Fewer than 5% of those with heavy alcohol consumption and between 5% and 10% of those receiving high dose steroids go on to develop osteonecrosis of the hip. What distinguishes those patients that do develop osteonecrosis from those that do not, has yet to be determined. Steroids Conditions such as systemic lupus erythematosus, organ transplant, etc. are regularly treated with significant doses of steroids, often for prolonged periods, and there is a clear association with osteonecrosis. In particular, the risk of steroid associated osteonecrosis is especially high in patients undergoing renal transplant, possibly due to underlying mineralisation defects and structural weakening of the cancellous bone. Hence, the difficulty in determining whether the osteonecrosis is related to the disease process or its treatment. Multivariate analysis has suggested that high dose steroid use is an independent variable despite such confounding factors. The dose of steroid necessary to cause osteonecrosis is not known, but the mean daily or peak dose rather than cumulative or duration of therapy appears has been implicated; higher doses, even of short duration, present greater risks. Specifically doses of 420 mg/day appear to be associated with a higher risk of osteonecrosis or total doses of 42 g of prednisolone within 2 3 months. Lower doses seem not to be typically related to osteonecrosis of the femoral head. A meta-analysis of 22 studies of steroid associated osteonecrosis revealed a 4.6-fold increase in the rate of osteonecrosis for every 10 mg/day increase in mean daily dose. 4 The level of activity and the number of mesenchymal cells in both the haemopoietic and the stromal compartments of the bone marrow have been shown to be depressed in patients with steroid related osteonecrosis of the femoral head. Steroid treatment produces a hyperlipidaemic state that often leads to osteoporosis but not usually osteonecrosis and it is not possible to predict which patients of the many treated with steroids will develop osteonecrosis. Prolonged steroid treatment also stimulates the differentiation of pluripotent bone marrow stromal cells into adipocytes. 5 Steroid induced adipogenesis in bone stem cells and the systemic changes in lipid metabolism are major contributors to steroid induced osteoporosis and osteonecrosis 5,6 and fat cell hypertrophy can result in elevated intraosseous pressure producing an intraosseous compartment syndrome that may result in ischaemia and osteonecrosis. 7 As well as enhancing the expression of adipocytes specific genes, steroids decrease the expression of type 1 collagen and osteocalcin mrna. 6,7 The marrow becomes lipid infiltrated with less collagen and osteocalcin and there are fewer osteoprogenitor cells available to repair damage. MRI based studies on patients on steroids have shown that the risk period is more easily defined. The initial necrotic changes, seen as well demarcated bands on MRI, appear between 3 and 5 months after starting steroid treatment, with virtually all appearing before 12 months. Alcohol There is a higher risk of osteonecrosis in occasional and regular drinkers when compared to non-drinking controls, both in the volume of alcohol consumed and the duration of consumption. Although the true incidence of osteonecrosis is low, in alcoholics figures of 5 12% have been reported.

3 Osteonecrosis of the femoral head 459 Matsuo et al. found an elevated risk in regular drinkers (48 ml alcohol daily) compared to non-drinking controls, relative risk of 7.8. They also demonstrated a significant dose response relationship, with relative risks of 3.3, 9.8, and 17.9, for current drinkers imbibing o400, , and ml/wk of alcohol, respectively. 8 The relative risk increased from 2.7 for o4000 drink years to 9.0 for 10,000 drink years. (Drink years defined as weekly alcohol consumption multiplied by the number of years of drinking.) Coagulation/embolic abnormalities The most likely common pathophysiologic event in nontraumatic osteonecrosis is intravascular coagulation and microcirculatory thrombosis. Thrombotic emboli have been found in both arterioles and venules in specimens of osteonecrotic tissue and have been associated with osteocyte necrosis in some animal models. Those with an inherited coagulation disorder may be at risk for the development of osteonecrosis of the femoral head, indeed thrombotic occlusion of the microcirculation in the femoral head has been associated with hypofibrinolysis (a reduced ability to lyse intravascular thrombi) and thrombophilia often caused by reduced levels of the liver derived anticoagulants: Protein C Protein S (protein S potentiates the effect of APC) Antithrombin III Hypofibrinolysis may be due to elevated levels of plasminogen activator inhibitor 1 (PAI-1), and/or decreases in tissue plasminogen activator (tpa). The presence of lipoprotein associated antigen Lp(a) also leads to impaired fibrinolysis. Hypofibrinolysis can also occur be due to a resistance to activated protein C (RAP-C). Activated protein-c is a serine protease that degrades factor Va and VIIIa. It also promotes fibrinolysis by inactivating PAI-I. Factor V leiden results from arginine to glutamine substitution in the factor V peptide chain; as this occurs at the point of cleavage of factor V by its regulatory protein (protein C) it makes factor V resistant to inactivation. This is measured clinically as resistance to activated protein C. Altered anti-phospholipid antibody levels, such as lupus anticoagulant, and anticardiolipin antibodies, cause hypercoagulability. They react against a b-2 glycoprotein in endothelial cell membranes and promote the activation of soluble clotting factors. Jones and Hungerford 9 looking at nine different coagulation factors found at least one clotting factor abnormality in 82% of patients with osteonecrosis compared to 30% of controls, two or more were found in 47% of patients compared with 2.5% of controls. Hypercoagulability associated with any one of these conditions represent an underlying predisposition for microvascular thrombosis and osteonecrosis. Some of these disorders have a known inheritance pattern so it may be possible to screen people at risk. Smoking Smoking has been shown to inhibit osteogenesis and fracture healing, so it is not surprising that it is risk factor for osteonecrosis. There is an increased risk for current smokers (relative odds 4.7), and a cumulative effect of smoking was evident only in association with twenty pack years or more. The exact pathophysiology is uncertain, but vascular compromise and decreased marrow activity have been proposed as possible mechanisms. Other factors Dysbaric osteonecrosis or Caisson disease is associated with working in pressurised environments (as in tunnelling) using compressed air or diving with poorly controlled decompression. The risk of osteonecrosis under dysbaric conditions appears to be related directly to the depth and number of dives, uncontrolled decompression, and low partial pressures of oxygen. The circulatory nitrogen bubbles formed cause osteonecrosis directly via cryogenic insults resulting in cell death. Additionally, the bubbles act as space occupying lesions that kill osteocytes. In certain Asian populations (Taiwan, etc.), while steroid use may explain the increased rates, recent genetic linkage studies have identified mutations in the type II collagen gene (COL2A1 gene) on chromosome 12q13 in a Taiwanese pedigree that strongly predisposes to osteonecrosis. 10 Radiation causes a direct injury leading to osteocyte death and the development of osteonecrosis. The dead cells cause further damage by acting as a space-occupying lesion. Radiation may also compromise the microvasculature and disturb bone repair. Lipid disorders such as Gaucher s disease cause external vascular occlusion of the affected bone due to abnormal cell mass. Pregnancy can be complicated by osteonecrosis. Such patients typically have no other risk factors. In a series of 13 pregnancies 11 patients became symptomatic in the last 4 months of pregnancy, and 11 of the 13 were pregnant for the first time and had small body frames and large weight gains during the pregnancy. Many were initially misdiagnosed as having transient osteoporosis. Pathogenesis/pathology While the vascular insult that leads to osteonecrosis may be a single event, it must be remembered that the development of osteonecrosis is a multifactorial process. Failure of perfusion occurs by three mechanisms: Vascular interruption Vascular occlusion Extravascular compression Any of these leads to a decreased blood supply/ischaemia to the femoral head. Cell death from anoxia is not immediate, but rather occurs in progressive stages of ischaemic injury. After about 2 3 h of ischaemia, osteocyte necrosis occurs, though histological evidence of osteocyte death is only

4 460 S.J. Parsons, N. Steele apparent after h, when they are seen to be absent from their lacunae. Adipocyte and haemopoietic marrow necrosis occur before osteocyte necrosis. There then follows a sequence of reactions to the injury and variable attempts at repair. There will be adjacent areas of bone with an intact blood supply and viable cells, and the remodelling cycle continues there, but unfortunately bone resorption predominates, causing further weakening of the subchondral bone, and ultimately progressive collapse of the subchondral trabeculae. This gives rise to the radiolucent crescent sign, before flattening of the articular surface. Eventually this process involves the cartilage and subchondral endplate causing gross collapse of the articular surface of the femoral head. Once established, these changes are irreversible and lead to progressive joint damage with increasing symptoms. Local oedema develops and, seen on MRI, may extend a considerable distance beyond the necrotic lesion. Areas without circulation may remain stable for some time, but with mechanical stress transmitted to subchondral trabeculae, microfractures occur that now cannot be repaired weakening the subchondral bone. Osteoclasts resorb necrotic bone, which weakens the structure of the cancellous bone between viable and necrotic areas leading to multiple microfractures and eventual collapse. A unifying concept has been suggested by Aaron 12 which emphasises the central role of vascular occlusion and ischaemia leading to both marrow cell and osteocyte necrosis (Fig. 1). Presentation and investigation Prompt diagnosis allows earlier treatment ideally before femoral head collapse and should alter prognosis. Risk factors should be sought. Figure 1 Possible pathogenesis of osteonecrosis.

5 Osteonecrosis of the femoral head 461 The commonest presenting symptom is deep groin pain. Physical examination can be unremarkable, or demonstrate pain on internal rotation, a reduced range of movement, and an antalgic gait. Due to the high risk of bilateral disease, both hips should be thoroughly examined. Radiographic studies are essential. Plain radiographs are still the first investigation necessary, good quality AP and lateral films are mandatory, and enable measurement of the combined necrotic angle. Prior to the advent of MRI, lesion size was estimated with the use of outlines of the lesion on AP and lateral radiographs as described by Kerboul et al. 13 where the arc of the surface involved by the necrotic process is measured. These two angles are added together to give the combined necrotic angle. Kerboul reported that when the combined angle is greater than 2001 it is predictive of a poorer clinical outcome. Bone scans which rely on the uptake of a labelled tracer onto the surface of hydroxyapatite crystals during osteogenesis can detect osteonecrosis before radiographic evaluation. Bone scans were formerly used for high risk patients who had normal plain films, but recent studies have shown they can mislead, due to a 25 45% false negative rate when compared with cases subsequently diagnosed by MRI or histology. Additionally, bone scanning is also less sensitive in the presence of bilateral disease as interpretation of scans is often based on asymmetric findings. MRI has become the standard for diagnosing osteonecrosis. It is 99% specific and sensitive. A single density line on T1-weighted images demarcates the normal/ischaemic bone interface and double density lines ( double line sign ) on the T2-weighted images represents the hyper-vascular granulation tissue. Using MRI it is also possible to differentiate between transient osteoporosis and osteonecrosis, as MRI shows oedema into the femoral neck and metaphysis in transient osteoporosis, which is not common with osteonecrosis. CT and tomograms can identify collapse, but are rarely used due the dose of radiation involved, and the accuracy of MRI. Functional evaluation of bone, an invasive procedure, in which marrow pressure was measured directly, intramedullary venography, and biopsy are now rarely undertaken since the advent of MRI. Staging/classification The classification of osteonecrosis has undergone many changes. A disease classification should guide treatment and prognosis. Not all classifications enable this but may be better suited to allow comparisons of treatments. Of the many classifications, the most widely used are Ficat and Arlet, Steinberg, Association Research classification Osseous (ARCO), and the Ohzono classification. Ficat and Arlet The Ficat and Arlet classification system for osteonecrosis of the femoral head is still the most widely used. Their original system described three stages. 14 A fourth stage was added later 15 : I Normal X-ray Diffuse sclerosis of femoral head Normal joint space Subchondral fracture, crescent sign +/ Head collapse Femoral head collapse Acetabular involvement Joint destruction (OA) In stage 0 was added, giving the current five stage classification: Stage 0 I Preclinical Pre-radiographic (+ve MRI/bone scan) Pre-collapse (reparative stage before flattening occurs) Collapse Osteoarthritis Steinberg/University of Pennsylvania The Ficat and Arlet system predated the routine use of MRI and has a number of drawbacks; it depended upon invasive techniques, such as core decompression and functional exploration of bone and did not quantify the size of the osteonecrotic segment, so restricting the measurement of progression. This failing was addressed by the Steinberg classification which uses MRI to define seven distinct stages. 17 Whilst similar to Ficat and Arlet it has the addition of stages V and VI. For each stage from I to V, there is further subdivision depending on the size of lesion, or degree of collapse. No attempt is made to quantify the extent of involvement in stage 0 or VI. Steinberg suggested that once the stage was determined then the extent of involvement should be measured as lesion size is directly related the probability of collapse. Clinically this was determined visually as mild moderate or severe. More precise measurement for research purposes calculated the percentage of head involvement and the collapse in millimetres, then placing in group A, B, or C (Table 2). Stage 0 I Stage V Stage VI Normal or non-diagnostic imaging. FEB positive Normal X-ray, abnormal bone scan and/ or MRI Abnormal X-ray showing cysts and sclerotic change in femoral head Subchondral collapse without flattening Crescent sign Flattening of the femoral head (normal acetabulum) Joint narrowing with or without acetabular involvement Advanced degenerative changes

6 462 S.J. Parsons, N. Steele Table 2 Stage Grade I and II A, mild o15% of head involved as seen on MR or X-ray B, moderate 15 30% C, severe 430% III A, mild Subchondral collapse beneath (crescent) o15% of articular surface B, moderate Crescent beneath 15 30% C, severe Crescent beneath 430% IV A, mild o15% of surface has collapsed and depression is o2 mm B, moderate 15 30% collapsed or 2 4 mm depression C, severe 430% collapsed or 44 mm depression V A, mild Average of femoral head involvement, as in and estimated acetabular involvement B, moderate C, severe Figure 2 Ohzono classification. ARCO This is a five stage system based on the Steinberg system proposed by Association Research classification Osseous (ARCO). 18 I Sclerosis, osteolysis (sub-classified) Crescent sign, +/ flattening of articular surface (sub-classified) Osteoarthritis, acetabular changes, joint destruction Stage 0 Normal radiography, histology only Normal X-ray/CT. Positive bone scan/mri (subclassified) Stages I, II, and III are subclassified, as minimal (A), moderate (B), and extensive (C), depending on extent of involvement as previously described in the Steinberg system (see Table 2).

7 Osteonecrosis of the femoral head 463 Ohzono Developed in 1991, Ohzono 19 described a classification based on the radiographic characteristics of the necrotic lesion in the femoral head and was able to show that this could be used to predict the fate of the hip. Type 1 is characterised by the presence of a demarcation line in the femoral head and is divided into three subtypes, by its relationship to weight bearing area (1 A, B, and C). Type 2, shows early flattening of the weight-bearing surface but has no demarcation line around the necrotic area. Type 3, demonstrate cystic lesions and is divided into two subtypes according to their site within the femoral head (3A medial, 3B lateral). They showed that types 1A, 1B, and 3A had little tendency to collapse whereas types 1C, 2, and 3B had a high incidence of collapse and hence a poor prognosis (Fig. 2). Collapse by stage/percentage: 1A/0% 2/100% 1B/19% 3A/12% 1C/94% 3B/100% References 1. Steinberg ME. Recent advances in the management of osteonecrosis of the hip. Introduction. Semin Arthroplasty 1998;9: Merle d Aubigne R, Postel M, Mazabraud A, Massias P, Gueguen J. Idiopathic necrosis of the femoral head in adults. J Bone Joint Surg 1965;47-B: Wheeless CR, Lins RE, Knelson MH, Urbaniak JR. Digital subtraction angiography in patients with osteonecrosis of the femoral head. In: Osteonecrosis: aetiology, diagnosis and treatment. Rosemont, IL: American Academy of Orthopedic Surgeons; p Felson DT, Anderson JJ. A cross study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet 1987;1: Cui Q, Wang GJ, Balain G. Steroid induced adipogenesis in a pluripotential cell line from bone marrow. J Bone Joint Surg 1997;79-A: Cui Q, Wang GJ, Su CC, et al. The Otto Aufranc Award: Lovastatin prevents steroid induced adipogenesis and osteonecrosis. Clin Orthop 1997;344: Wang GJ, Cui Q, Balain G. The Nicolas Andry Award: the pathogenesis and prevention of steroid induced osteonecrosis. Clin Orthop 2000;370: Matsuo K, HIrohata T, Sugioka Y, Ikeda M, Fukuda A. influence of alcohol intake, cigarette smoking and occupational status on idiopathic osteonecrosis of the femoral head. Clin Orthop 1988;234: Jones LC, Hungerford DS. Osteonecrosis: etiology, diagnosis and treatment. Curr Opin Rheumatol 2004;16: Liu YF, et al. Type-II collagen variants and inherited osteonecrosis of the femoral head. N Eng J Med 2005;352: Montella BJ, Nunley JA, Urbaniak JR. Osteonecrosis of the femoral head associated with pregnancy. A preliminary report. J Bone Joint Surg 1999;81-A: Aaron RK. Osteonecrosis: etiology, pathophysiology and diagnosis. In: Callaghan JJ, Rosenberg AG, Rubash HE, editors. The adult hip. Philadelphia: Lippincott-Ravin; p Kerboul M, Thomine J, Postel M, Merle D Aubigné R. The conservative surgical treatment of idiopathic aseptic necrosis of the femoral head. J Bone Joint Surg 1974;56-B: Arlet J, Ficat RP. Forage-biopsie de la tete femorale dans l 0 osteonecrose primative. Observations histo-pathologiques portant sur huit forages. Rev Rhumat 1964;31: Ficat RP, Arlet J. In: Hungerford DS, editor. Ischaemia and necrosis of bone. Baltimore: Williams and Wilkins; Ficat RP. Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment. J Bone Joint Surg 1985;67-B: Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis. J Bone Joint Surg 1995;77-B: Gardeniers JWM. Report of the committee of staging and nomenclature. ARCO News Lett 1993;5: Ohzono K, Saito M, Takaoka K, Ono K, Saito S, Nishina T, et al. Natural history of non-traumatic avascular necrosis of the femoral head. J Bone Joint Surg 1991;73-B:68 72.