The Open Orthopaedics Journal




ISSN: 1874-3250 ― Volume 13, 2019

Glucocorticoid-Induced Avascular Bone Necrosis: Diagnosis and Management



KL Chan, CC Mok*
Department of Medicine, Tuen Mun Hospital, Hong Kong, China

Abstract

Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty.

Keywords: : Avascular, osteonecrosis, aseptic necrosis, corticosteroid, glucocorticoid.


Article Information


Identifiers and Pagination:

Year: 2012
Volume: 6
First Page: 449
Last Page: 457
Publisher Id: TOORTHJ-6-449
DOI: 10.2174/1874325001206010449

Article History:

Received Date: 13/7/2012
Revision Received Date: 09/9/2012
Acceptance Date: 13/9/2012
Electronic publication date: 5/10/2012
Collection year: 2012

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open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, SAR China; Tel: (852) 2468 5386; Fax: (852) 2456 9100; E-mail: ccmok2005@yahoo.com




INTRODUCTION

Avascular bone necrosis (AVN), also known as osteonecrosis, aseptic necrosis of bone, ischemic bone necrosis and osteochondritis desiccans, is a condition that causes significant morbidity and impairment of daily function to patients. AVN involves progressive destruction of bone as a result of compromise of bone vasculature, death of osteocytes and fat cells and alteration of bone architecture. The most common cause of AVN is trauma, which causes direct disruption of blood supply [1 Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002; 32(2 ): 94-124.]. Non-traumatic causes or associations include the use of glucocorticoids [2 Weinstein RS. Glucocorticoid-induced osteonecrosis Endocrine 2012; 41(2 ): 183-90.], alcoholism [3 Wang Y, Li Y, Mao K, Li J, Cui Q, Wang GY. Alcohol-induced adipogenesis in bone and marrow: a possible mechanism for osteonecrosis Clin Orthop Relat Res 2003; 410: 213-4.,4 Shigemura T, Nakamura J, Kishida S, et al. The incidence of alcohol-associated osteonecrosis of the knee is lower than the incidence of steroid-associated osteonecrosis of the knee: an MRI study Rheumatology (Oxford) 2012; 51(4 ): 701-6.], hematological diseases (sickle cell anemia, thalassemia, polycythemia, hemophilia, myeloproliferative disorder) [5 MacNicol MF, Ludlam CA. Does avascular necrosis cause collapse of the dome of the talus in severe hemophilia? Haemophilia 1999; 5(2 ): 139-42.,6 Poignard A, Flouzat-Lachaniette CH, Amzallag J, Galacteros F, Hernigou P. The natural progression of symptomatic humeral head osteonecrosis in adults with sickle cell disease J Bone Joint Surg Am 2012; 94(2 ): 156-62.], metabolic diseases (Gaucher disease), hypercholesterolemia [7 Moskal JT, Topping RE, Franklin LL. Hypercholesterolemia: an association with osteonecrosis of the femoral head Am J Orthop 1997; 26(9 ): 609-12.], pregnancy, chronic renal failure, hyperparathyroidism, Cushing’s disease, autoimmune diseases [8 Mok CC, Lau CS, Wong RW. Risk factors for avascular bone necrosis in systemic lupus erythematosus Br J Rheumatol 1998; 37(8 ): 895-900.], chronic pancreatitis, caisson disease, radiation, congenital hip dislocation [9 Gregosiewicz A, Wosko I. Risk factors of avascular necrosis in the treatment of congenital dislocation of the hip J Pediatr Orthop 1988; 8(1 ): 17-9.], and use of potent intravenous bisphosphonates (Table 1). Glucocorticoid use and alcoholism comprise 90% of all non-traumatic causes of AVN [10 Michael AM, David H. Non-traumatic avascular necrosis of the femoral head J Bone Joint Surg Am 1995; 77(3 ): 459-74.].

Table 1

Conditions Associated with Avascular Necrosis




Glucocorticoid-induced AVN most commonly affects the femoral head [1 Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002; 32(2 ): 94-124.], but it can occur in any skeletal sites such as the knee, shoulder, ankle and the hand [11 Kelman GJ, Williams GW, Colwell CW Jr. Steroid-related osteonecrosis of the knee Two case reports and a literature review Clin Orthop Relat Res 1990; 257: 171-6.]. The most common symptom is pain, which is usually insidious in onset, and exacerbated by activity and exercise. With time, the pain may occur at rest and affects function and range of motion of the involved joints. It is crucial for early identification of this condition, especially in susceptible individuals because treatment options for advanced disease are limited and many sufferers of glucocortoicoid-induced AVN are young and active individuals.

EPIDEMIOLOGY OF GLUCOCORTIOID-INDUCED AVN

Glucocorticoid-induced AVN causes significant morbidity and accounts for around 10% of all cases of total hip replacement in the United States [12 Mankin HJ. Non traumatic necrosis of bone N Engl J Med 1992; 326: 1473-9.]. The prevalence of glucocorticoid-induced AVN is between 3% and 38% [1 Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002; 32(2 ): 94-124.], depending on the underlying diseases, glucocorticoid dosage and route of administration. Two medical conditions commonly associated with glucocortioid-induced AVN are post-renal transplantation and systemic lupus erythematosus (SLE). The incidence of renal transplant recipients receiving glucocorticoids is between 3% and 41% [13 Drescher W, Schlieper G, Floege J, Eitner F. Steroid-related osteonecrosis-an update Nephrol Dial Transplant 2011; 26(9 ): 2728-31.], while the incidence of AVN among glucocorticoid-treated SLE patients is 4% to 40% [1 Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002; 32(2 ): 94-124.].

PATHOGENESIS

Up till now the mechanisms by which glucocortoicoid induces AVN are not fully understood. Hypotheses include fat cell hypertrophy, fat embolisation, intravascular coagulation and osteocyte apoptosis, with a similar final common pathway of compromise of vasculature of bone and bone marrow, leading to ischemic necrosis of the bony tissues and subsequent mechanical failure and finally collapse of the bone.

Fat cell hypertrophy and fat emboli were demonstrated in rabbits which were given high-dose cortisone [14 Wang GJ, Sweet DE, Reger SI, Thompson RC. Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits J Bone Joint Surg Am 1977; 59: 729-35.]. These emboli caused obliteration of vasculature in the subchondral bone of femur and humeral heads. Increase in the number of marrow fat cells were also noted in these rabbits. Similar finding of fat cell hypertrophy was also demonstrated in pluripotent cell line obtained from mice bone marrow in vitro after dexamethasone was added [15 Cui Q, Wang GJ, Balian G. Steroid induced adipogenesis in a pluripotential cell line from bone marrow J Bone Joint Surg Am 1977; 59(6 ): 729-35.]. It is postulated that fat cell hypertrophy would cause expansion of cell volume within a restricted volume of the femoral head, thus a decrease in blood perfusion and leads to AVN. On the other hand, fat emboli deposits within the subchondral vessels and sinusoids appear to activate the complement pathway and cause deposition of immune complex and subsequent activation of the thrombotic process such as intravascular coagulation, leading to AVN [16 Jones JP Jr. Fat embolism and osteonecrosis Orthop Clin North Am 1985; 16(4 ): 595-633.]. A role of the lipid lowering agents in the treatment of AVN has been demonstrated in animals [17 Wang GJ, Cui Q, Balian G. The pathogenesis and prevention of steroid-induced ostseonecrosis Clin Orthop Relat Res 2000; 370: 295-310., 18 Iwakiri K, Oda Y, Kaneshiro Y, et al. Effect of simvastatin on steroid inudced osteonecrosis evidenced by the seum lipid level and hepatic cytochrome P4503A in a rabbit model J Orthop Sci 2008; 13(5 ): 463-8.]. When rabbits receiving corticosteroid treatment were given clofibrate, fat cell size was reduced and so was the intra-cortical pressure, leading to the improvement of blood flow [19 Wang GJ, Rawles JG, Hubbard SL, Stamp WG. Steroid induced femoral head pressure changes and their response to lipid clearing agents Clin Orthop 1983; 174: 298-302.]. However, the efficacy of the lipid lowering agents in the treatment and prevention of AVN in human is still unproven.

Recently glucocorticoid-induced osteocyte apoptosis has been suggested to be another pathogenetic mechanism of AVN [20 Kabata T, Kubo T, Matsumoto T. Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits J Rheumatol 2000; 27(9 ): 2166-71., 21 Calder JD, Buttery L, Revell PA, Pearse M, Polak JM. Apoptosis-- a significant cause of bone cell death in osteonecrosis of the femoral head J Bone Joint Surg Br 2004; 86(8 ): 1209-3.]. Apoptotic osteocytes were found in pathologic specimen of femoral head during total hip replacement in patients with glucocorticoid-induced AVN. Similar findings were not reported in those with AVN due to trauma or alcohol related causes [22 Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid induced osteonecrosis of the hip Endocrinology 2000; 85(8 ): 2907-12.]. These apoptotic osteocytes gradually accumulate in the bone causing disruption of osteocyte-lacunar-canalicular system and vascular space and finally collapse of femoral head.

DIAGNOSIS OF AVN

Typical symptom in a patient with AVN is pain, which is usually insidious in onset and aggregates with activity and weight bearing. Conventional radiography is the most convenient and inexpensive first-line investigation for the diagnosis of AVN. Abnormal findings in AVN include ‘crescent sign’ representing subchondral collapse, cystic or sclerotic change in femoral head, abnormal contours of femoral head, collapse or secondary degenerative change. However, plain radiograph is not sensitive in detecting early AVN lesions.

Bone scintigraphy helps to pick up AVN at an earlier stage [23 Hayes CW, Balkissoon AR. Current concepts in imaging of the pelvis and hip.al Orthop Clin North Am 1997; 28(4 ): 617-42.]. In early AVN, there is increased osteoblastic activity and blood flow in the bone which may be picked up by bone scan. In later stage of AVN, the necrotic center of the bone shows decreased radioisotope uptake but there is increased uptake in the surrounding subchondral bone adjacent to the necrotic segment. Bone scan has the advantage of detecting abnormalities at multiple sites. It can be considered when patient complains of pain at multiple bone and joint areas. However, bone scan is less specific for the diagnosis of AVN. Other limitation includes radiation dose, poor spatial resolution and unable to quantify the lesion for prognostic purpose [24 Malizos KN, Karantanas AH, Varitimidis SE, Dailiana ZH, Bargiotas K, Maris T. Osteonecrosis of the femoral head: etiology, imaging and treatment Eur J Radiol 2007; 63(1 ): 16-28.].

MRI is the most sensitive modality in diagnosing AVN (Figs. 1, 2). The early detectable change in T1 image is a single density line that represents the separation of normal and osteonecrotic bone. In T2 image there may be another line seen within this line which represents the increased vascularity of granulation tissue [25 Kokubo T, Takatori Y, Ninomiya S, Nakamura T, Kamogawa M. Magnetic resonance imaging and scintigraphy of avascular necrosis of the femoral head. Prediction of subsequent segmental collapse Clin Orthop Relat Res 1992; 277: 54-60.]. MRI also allows quantification of the area and extent of AVN [26 Karantanas AH, Drakonaki EE. The role of MR imaging in avascular necrosis of the femoral head Semin Musculoskelet Radiol 2011; 15(3 ): 281-300.]. The drawback of MRI scan is cost if multiple sites are involved.

Fig. (1)

AVN of the femoral heads in a 19-year-old woman with lupus nephritis treated with long-term glucocorticoid. (a) Coronal T1- weighted MRI scan. (b) Coronal T2-weighted MRI scan. Heterogeneous area bordered by well defined T1W & T2W hypointense rim was observed over the superior left femoral head. T1W & T2W hyperintense lesions bordered by T1W hypointense T2W hyperintense rim was seen at superior right femoral head. Features are suggestive of bilateral AVN, more severe on the left side. (c) X-ray of the hips of the same patient - increased mixed sclerosis/lucency is seen at subchondral region of superior aspect of left femoral head, the configuration of which is still preserved (early AVN). The right hip appears unremarkable.



Fig. (2)

AVN of both knees in a 53-year-old woman with SLE treated with glucocorticoid. (a) Coronal T1-weighted MRI scan. (b) Coronal T2-weighted MRI scan. Multifocal serpiginous areas are present around both knees, from distal femoral shaft to proximal tibial shaft. The areas have inner hypointense outer hyperintense rim on T2W sequences and enhancing outer rim. Similar lesion is also seen in left patella. Overall features are suggestive of AVN which also involves the subarticular region. (c) X-ray left knee of the same woman. Increased sclerosis is noted in subchondral region of lateral condyle, configuration of which is preserved. Serpigenous sclerosis is seen in medullary region of proximal tibia and distal femur, suggesting bone infarct.



STAGING OF AVN

Numerous staging systems have been proposed for femoral head AVN. Proper staging is important to determine the prognosis and to decide for the optimal treatment. Ficat and Arlet [27 Ficat RP. Idiopathic bone necrosis of femoral head. Early diagnosis and treatment J Bone Joint Surg Br 1985; 67(1 ): 3-9.] proposed a classification of four stages of AVN based on radiographic findings. In stage I, the radiograph is normal. In stage II, the femoral head contour is preserved but there are signs of bone remodeling such as cystic and osteosclerotic regions. In stage III, there is subchondral collapse or flattening of femoral head. In stage IV, the joint space is narrowed and secondary degenerative change is shown in acetabulum. Later, Steinberg et al. [28 Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis J Bone and Joint Surg 1995; 77(1 ): 34-41.] put forward a new classification system involving six stages which take into account the quantification of femoral head involvement in both early and late stages from plain radiograph, bone scintigraphy or MRI scan. The newer classification system developed by the Association Research Circulation Osseous (ARCO) consists of stage 0-4 [10 Michael AM, David H. Non-traumatic avascular necrosis of the femoral head J Bone Joint Surg Am 1995; 77(3 ): 459-74.] (Table 2). Stage 0 is the stage when all diagnostic studies normal, diagnosis by histology only. Stage I is the early stage in which osteonecrosis is evident in bone scintigraphy or MRI or both. X-ray finding is normal. Stage II is positive radiographic abnormalities (mottled appearance of the femoral head, osteosclerosis, cyst formation and osteopenia), but no sign of collapse in radiograph or CT scan. Stage III is the presence of crescent sign which signifies the subchrondral plate was separating from the necrotic cancellous bone which is apparent in both radiography and MRI scan. Stage IV is destruction of joint with secondary arthritic change.

Table 2

Association Research Circulation Osseous (ARCO) Classification of Femoral Head Necrosis




SITE OF INVOLVEMENT IN GLUCOCORTICOID-INDUCED AVN

Glucocorticoid-induced AVN tends to occur at multiple sites, as illustrated by studies of SLE patients receiving long-term glucocorticoid treatment [29 Gladman DD, Chaudhry-Ahluwalia V, Ibanez D, Bogoch E, Urowitz MB. Outcome of symptomatic osteonecrosis in 95 patients with systemic lupus erythematosus J Rheumatol 2001; 28(10 ): 2226-9.-31Collaborative Osteonecrosis Group. Symptomatic multifocal osteonecrosis. A multicenter study Clin Orthop Relat Res 1999; 369: 312-26.]. The reported proportion of SLE patients with AVN involving more than two joint areas varied from 70% to 90% in several case series [29 Gladman DD, Chaudhry-Ahluwalia V, Ibanez D, Bogoch E, Urowitz MB. Outcome of symptomatic osteonecrosis in 95 patients with systemic lupus erythematosus J Rheumatol 2001; 28(10 ): 2226-9.-31Collaborative Osteonecrosis Group. Symptomatic multifocal osteonecrosis. A multicenter study Clin Orthop Relat Res 1999; 369: 312-26.]. In one report [29 Gladman DD, Chaudhry-Ahluwalia V, Ibanez D, Bogoch E, Urowitz MB. Outcome of symptomatic osteonecrosis in 95 patients with systemic lupus erythematosus J Rheumatol 2001; 28(10 ): 2226-9.] evaluating 95 SLE patients with symptomatic AVN, the most commonly affected joints were hip and knee. Among these patients, 52 patients (54.7%) had bilateral hip AVN while 18 patients (18.9%) had bilateral knee AVN. Data from our group [8 Mok CC, Lau CS, Wong RW. Risk factors for avascular bone necrosis in systemic lupus erythematosus Br J Rheumatol 1998; 37(8 ): 895-900.] showed that AVN occurred in 38 out of 320 SLE patients (12%). The AVN patients had received a significantly higher mean daily dose of prednisolone (15.6±2mg) when compared to SLE controls who did not have AVN (9.3±0.5mg). The hip was the most common site of involvement (36 out of 38 patients, 95%), and bilaterality occurred in 72% of patients. This is consistent with another prospective study [32 Sakamoto M. A prospective study of steroid-induced osteonecrosis by MRI screening Nippon Seikeigeka Gakkai Zasshi 1994; 68(5 ): 367-78.] showing that in 120 patients with glucocorticoid-induced AVN, the most common site of involvement was hip (82%) and knee (64%), followed by shoulder (20%) and ankle (25%).

ROUTE, CUMULATIVE DOSE, DURATION OF GLUCOCORTICOID TREATMENT AND AVN

Data on the relationship between glucocorticoid dose, route of administration and duration of treatment leading to AVN are conflicting. Patients exposed to high-dose glucocorticoids with a longer treatment period were considered to be at higher risk of development of AVN [13 Drescher W, Schlieper G, Floege J, Eitner F. Steroid-related osteonecrosis-an update Nephrol Dial Transplant 2011; 26(9 ): 2728-31., 33 McAvoy S, Baker KS, Mulrooney D, Blaes A, Arora M, Burns LJ. Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation Biol Blood Marrow Transplant 2010; 16(9 ): 1231-6., 34 Yildiz N, Ardic F, Deniz S. Very early onset of steroid-induced avascular necrosis of the hip and knee in a patient with idiopathic thrombocytopenic purpura Intern Med 2008; 44(22 ): 1989-92.]. On the other hand, there were reports demonstrating that AVN might develop over a short period of treatment with glucocorticoids [34 Yildiz N, Ardic F, Deniz S. Very early onset of steroid-induced avascular necrosis of the hip and knee in a patient with idiopathic thrombocytopenic purpura Intern Med 2008; 44(22 ): 1989-92.-36 Nagasawa K, Tada Y, Koarada S, et al. Very early development of steroid-associated osteonecrosis of femoral head in systemic lupus erythematosus: prospective study by MRI Lupus 2005; 14(5 ): 385- 90.]. Massardo et al. [35 Massardo L, Jacobelli S, Leissner M, González M, Villarroel L, Rivero S. High dose intravenous methylprednisolone therap associated with osteonecrosis in patients with systemic lupus erythematosus Lupus 1992; 1(6 ): 401-5.] reported that methylprednisolone pulse therapy was a risk factor for AVN. In their study, significantly more SLE patients who received pulse methylprednisolone (7 out of 36 SLE patients i.e. 19%) had AVN compared with those without (10 of 154 patients [6%], p<0.04). However, in another smaller study of 69 SLE patients by Migliaresi et al. [37 Migliaresi S, Picillo U, Ambrosone L, Di Palma G, Mallozzi M, Tesone ER. Avascular osteonecrosis in patients with SLE: relation to corticosteroid therapy and anticardiolipin antibodies Lupus 1994; 3(1 ): 37-41.], 17 patients received pulse steroid but none of them developed AVN. In addition to the oral and intravenous route of glucocorticoid administration, there were case reports of AVN which developed after intra-articular or intramuscular steroid injection [38 Laroche M, Arlet J, Mazieres B. Osteonecrosis of the femoral and humeral heads after intraarticular corticosteroid injections J Rheumatol 1990; 17(4 ): 549-1., 39 Yamamoto T, Schneider R, Iwamoto Y, Bullough PG. Rapid destruction of the femoral head after a single intraarticular injection of corticosteroid into the hip joint J Rheumatol 2006; 33(8 ): 1701-4.]. The author attributed IMI or intra-articular steroid causing AVN because of the rapid occurrence after the administration.

In a review article summarizing 16 studies of AVN in patients with SLE [13 Drescher W, Schlieper G, Floege J, Eitner F. Steroid-related osteonecrosis-an update Nephrol Dial Transplant 2011; 26(9 ): 2728-31.], recent studies in the 1980s’ or later demonstrated more evidence of an association between the mean daily dose and maximum daily dose with AVN in SLE patients [35 Massardo L, Jacobelli S, Leissner M, González M, Villarroel L, Rivero S. High dose intravenous methylprednisolone therap associated with osteonecrosis in patients with systemic lupus erythematosus Lupus 1992; 1(6 ): 401-5., 40 Ono K, Tohjima T, Komazawa T. Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosus under high-dose corticosteroid therapy Clin Orthop Relat Res 1992; 277: 89-97., 41 Felson DT, Anderson JJ. Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone Lancet 1987; 1(8538 ): 902-6.]. In the retrospective study from Massardo et al. [35 Massardo L, Jacobelli S, Leissner M, González M, Villarroel L, Rivero S. High dose intravenous methylprednisolone therap associated with osteonecrosis in patients with systemic lupus erythematosus Lupus 1992; 1(6 ): 401-5.], it was reported that both daily dose of prednisolone of more than 40mg during the first month of treatment and pulse steroid were risk factors for AVN in 190 SLE patients. Ono et al. [40 Ono K, Tohjima T, Komazawa T. Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosus under high-dose corticosteroid therapy Clin Orthop Relat Res 1992; 277: 89-97.] also showed that use of oral prednisolone 30mg for at least 1 month was an independent factor associated with AVN. Similarly, in post-renal transplant patients, recent studies generally showed positive correlation between mean daily glucocorticoid dose and AVN [42 Tang S, Chan TM, Lui SL, Li FK, Lo WK, Lai KN. Risk factors for avascular bone necrosis after renal transplantation Transplant Proc 2000; 32(7 ): 1873-5.-45 Shibatani M, Fujioka M, Arai Y, et al. Degree of corticosteroid treatment within the first 2 months of renal transplantation has a strong influence on the incidence of osteonecrosis of the femoral head Acta Orthop 2008; 79(5 ): 631-.].

Studies also showed that cumulative dose of glucocorticoid may be a more important factor for AVN. Mok et al. [8 Mok CC, Lau CS, Wong RW. Risk factors for avascular bone necrosis in systemic lupus erythematosus Br J Rheumatol 1998; 37(8 ): 895-900.] found that the cumulative dose of prednisolone at 1 and 4 months were higher in SLE patients who developed AVN compared to those did not (1.8g vs 1.1g and 4.5g vs 2.8g, respectively; p<0.01 in both). This was supported by Sayarlioglu et al. [46 Sayarlioglu M, Yuzbasioglu N, Inanc M, et al. Risk factors for avascular bone necrosis in patients with systemic lupus erythematosus Rheumatol Int 2012; 32(1 ): 177-82.] and Gladman et al. [47 Gladman DD, Urowitz MB, Chaudhry-Ahluwalia V, Hallet DC, Cook RJ. Predictive factors for symptomatic osteonecrosis in patients with systemic lupus erythematosus J Rheumatol 2001; 28(4 ): 761-5.] who both showed a positive correlation between the cumulative prednisolone dose and AVN risk in SLE patients. In renal transplants patients, the risk of AVN were also related to the cumulative dose of prednisolone received [45 Shibatani M, Fujioka M, Arai Y, et al. Degree of corticosteroid treatment within the first 2 months of renal transplantation has a strong influence on the incidence of osteonecrosis of the femoral head Acta Orthop 2008; 79(5 ): 631-.,48 Saisu T, Sakamoto K, Yamada K, Kashiwabara H, Yokoyama T, Iida S. High incidence of osteonecrosis of femoral head in patients receiving more than 2g of intravenous methylprednisolone after renal transplantation Transplant Proc 1996; 28(3 ): 1559-60.]. Both Shibatani et al. and Saisu et al. demonstrated that there was a statistically significant correlation between the total glucocorticoid dose during first 2 months of renal transplant with femoral head AVN [45 Shibatani M, Fujioka M, Arai Y, et al. Degree of corticosteroid treatment within the first 2 months of renal transplantation has a strong influence on the incidence of osteonecrosis of the femoral head Acta Orthop 2008; 79(5 ): 631-.,48 Saisu T, Sakamoto K, Yamada K, Kashiwabara H, Yokoyama T, Iida S. High incidence of osteonecrosis of femoral head in patients receiving more than 2g of intravenous methylprednisolone after renal transplantation Transplant Proc 1996; 28(3 ): 1559-60.].

With respect to the time of onset of AVN after initiation of glucocorticoid, it can be developed as early as 1 year of glucocorticoid administration [49 Koo KH, Kim R, Ko GH, Song HR, Jeong ST, Cho SH. Preventing collapse in early osteonecrosis of the femoral head. A randomised clinical trial of core decompression J Bone Joint Surg Br 1995; 77(6 ): 870.-52 Sakamoto M, Shimizu K, Iida S, Akita T, Moriya H, Nawata Y. Osteonecrosis of the femoral head: a prospective study with MRI J Bone Joint Surg Br 1997; 79(2 ): 213-9.]. Koo et al. reported that 21 of 22 patients treated with glucocorticoid had MRI evidence of AVN of femoral head within 12 months of initiation of treatment [49 Koo KH, Kim R, Ko GH, Song HR, Jeong ST, Cho SH. Preventing collapse in early osteonecrosis of the femoral head. A randomised clinical trial of core decompression J Bone Joint Surg Br 1995; 77(6 ): 870.]. Similarly, AVN of the hips and knees could be detected in 44% of SLE patients (32/72) by MRI after a mean of 3.1 months of high-dose glucocorticoid treatment [51 Oinuma K, Harada Y, Nawata Y, Takabayashi K, Abe I, Kamikawa K. Ostenecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment Ann Rheum Dis 2001; 60(12 ): 1145-8.]. Another prospective study [52 Sakamoto M, Shimizu K, Iida S, Akita T, Moriya H, Nawata Y. Osteonecrosis of the femoral head: a prospective study with MRI J Bone Joint Surg Br 1997; 79(2 ): 213-9.] described that early MRI change of AVN of femoral head can be observed in mean of 3.6 months after initiation of glucocorticoid among 48 patients receiving high-dose glucocorticoid. It is thus important to remain vigilance for the possibility of development AVN throughout the course of treatment, particularly during the first year of initiation of glucocorticoid therapy.

Regarding the progression of glucocorticoid-induced AVN, several studies suggested that a proportion of early AVN of hip and knee may undergo spontaneous regression. Spontaneous incomplete regression was seen in 7 out of 17 (41.1%) patients with stage I glucocorticoid-induced AVN of knee without subsequent collapse using serial MRI scan [53 Takao M, Sugano N, Nishii T, Miki H, Yoshikawa H. Spontaneous regression of steroid-related osteonecrosis of the knee Clin Orthop Relat Res 2006; 452: 210-5.]. Similarly, for hip AVN, a few studies have shown spontaneous improvement of necrotic area with follow up MRI [51 Oinuma K, Harada Y, Nawata Y, Takabayashi K, Abe I, Kamikawa K. Ostenecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment Ann Rheum Dis 2001; 60(12 ): 1145-8., 52 Sakamoto M, Shimizu K, Iida S, Akita T, Moriya H, Nawata Y. Osteonecrosis of the femoral head: a prospective study with MRI J Bone Joint Surg Br 1997; 79(2 ): 213-9., 54 Sakai T, Sugano N, Ohzono K, Matsui M, Hiroshima K, Ochi T. MRI evaluation of steroid- or alcohol-related osteonecrosis of the femoral condyle Acta Orthop Scand 1998; 69(6 ): 598-602.]. Sakamoto et al. [52 Sakamoto M, Shimizu K, Iida S, Akita T, Moriya H, Nawata Y. Osteonecrosis of the femoral head: a prospective study with MRI J Bone Joint Surg Br 1997; 79(2 ): 213-9.] showed that 14 of 31 hips (45%) with early MRI evidence of AVN in glucocorticoid users underwent incomplete or complete regression on follow up. The regression was evident around 1 year after initiation of glucocorticoid, after which no addition improvement was noticed. Kopecky et al. [51 Oinuma K, Harada Y, Nawata Y, Takabayashi K, Abe I, Kamikawa K. Ostenecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment Ann Rheum Dis 2001; 60(12 ): 1145-8.] also demonstrated that 7 out of 25 AVN hips (28%) among renal transplant patients regressed in size during follow up. One important factor identified to predict the spontaneous regression is the stage of AVN. Early stage AVN is more likely to regress. Another important predictor factor is the time between diagnosis initiation of glucocorticoid and diagnosis of AVN [53 Takao M, Sugano N, Nishii T, Miki H, Yoshikawa H. Spontaneous regression of steroid-related osteonecrosis of the knee Clin Orthop Relat Res 2006; 452: 210-5.]. Regression is more likely to occur with AVN that were diagnosed early after initiation of glucocorticoid. Some of these patients with AVN regression were still on glucocorticoid, so discontinuation of glucocorticoid did not seem to affect the regression of AVN [53 Takao M, Sugano N, Nishii T, Miki H, Yoshikawa H. Spontaneous regression of steroid-related osteonecrosis of the knee Clin Orthop Relat Res 2006; 452: 210-5.]. Size and location of lesion were not shown to affect the regression of AVN [53 Takao M, Sugano N, Nishii T, Miki H, Yoshikawa H. Spontaneous regression of steroid-related osteonecrosis of the knee Clin Orthop Relat Res 2006; 452: 210-5.].

In summary, current evidence suggests that AVN may develop in patients receiving high dose glucocorticoid within a short period of time, or even after pulse therapy with big doses of glucocorticoids. MRI evidence of AVN may appear within 1 year of initiation of glucocorticoid. Early AVN lesions may undergo spontaneous regression.

TREATMENT OF GLUCOCORTICOID-INDUCED AVN

The management of AVN includes conservative non-surgical and surgical approach. Indication for surgical and non-surgical approach depends on stage of disease, size of lesion, age and co-morbidity of patients. General speaking, the prognosis depends on staging of disease, so it is important to diagnosis AVN early so that prompt treatment can be initiated.

GENERAL APPROACH

In patients with glucocorticoid-induced AVN it is crucial to minimize the dosage and duration of glucocorticoid use. This could be achieved by addition or switching to a steroid sparing agent. In patients with more stable disease the use of oral glucocorticoid might be preferred to pulse high-dose therapy. It is also important to advise patients against other AVN risk factors such as alcohol use.

Conservative management of AVN includes bed rest and reduction of weight bearing with the use of crutches or canes. However it is generally believed that such conservative approach alone will not be sufficient to halt disease progression. In a prospective review of 36 patients with hip AVN [55 Stulberg BN, Davis AW, Bauer TW, Levine M, Easley K. Osteonecrosis of the femoral head. A prospective randomized treatment protocol Clin Orthop Relat Res 1991; 268: 140-51.], the rate of successful treatment outcome (as gauged by Harris Hip Scores) of surgical approach was 70% compared to 20% in conservative approach in Ficat stage I AVN.

PHARMACOLOGICAL INTERVENTION

Several studies have reported the efficacy of the bisphosphonates in the treatment of AVN. However, evidence is controversial. Bisphosphonates increase osteoclasts apoptosis and inhibit the resorptive action of the osteoclasts. On the other hand, they reduce apoptosis of osteoblasts and osteocytes, thus retarding bone turnover. Agarwala et al. [56 Agarwala S, Shah SB. Ten-year follow up of avascular necrosis of femoral head treated with alendronate for 3 years J Arthroplasty 2011; 26(7 ): 1128-34.] showed that alendronate treatment in hip AVN led to a significant improvement in pain and disability score, as well as a significant increase in standing and walking time, with the efficacy lasting up to 10 years. They also reported a decrease in marrow edema in most cases by MRI scan after 1 year’s treatment. In this study, a total of 40 patients were recruited, with 4 patients (10%) being glucocorticoid users. However there was no control group. A randomized controlled study by Lai et al. [57 Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis J Bone Joint Surg Am 2005; 87(10 ): 2155-9.] demonstrated that patients with AVN of the hip treated with 25 weeks of alendronate had a significant lower rate of femoral head collapse (7%) compared to a control group who did not receive alendronate or had received placebo treatment (76%). Thirty-three percent of patients recruited in this study had a history of glucocorticoid use. However, a more recent randomized controlled study demonstrated a different result [58 Chen CH, Chang JK, Lai KA, Hou SM, Chang CH, Wang GJ. Alendronate in the prevention of collapse of the femoral head in nontraumatic osteonecrosis: A two-year multicenter, prospective, randomized, double-blind, placebo-controlled study Arthritis Rheum 2012; 64(5 ): 1572-8.]. Fifty two patients with AVN (in 65 hips) were randomized to alendronate 70mg/week treatment or placebo for 104 weeks. AVN was induced by glucocorticoids in 4 of 26 patients (15%) of the alendronate group and 8 of 26 patients (31%) of the placebo group. No statistical difference in progression of AVN could be demonstrated by plain radiography and MRI between the two groups after 2 years. Four of 32 patients (13%) in alendronate group underwent total hip arthroplasty (THA), whereas 5 of 33 (15 %) patients in placebo group underwent THA. The number of THA in placebo group (5 out of 33 patients) was low compared to previous studies, which might have contributed to the lack of difference between alendronate and placebo groups.

Currently, there is not enough evidence to recommend the routine use of bisphosphonate in patients with AVN. Further studies with a larger number of patients are needed to confirm the therapeutic efficacy of bisphosphonates.

Another non-operative treatment option of AVN is hyperbaric oxygen (HBO) [59 Camporesi EM, Vezzani G, Bosco G, Mangar D, Bernasek TL. Hyperbaric oxygen therapy in femoral head necrosis J Arthroplasty 2010; 25(6 ): 118-23., 60 Reis ND, Schwartz O, Militianu D, et al. Hyperbaric oxygen therapy as a treatment for stage-I avascular necrosis of the femoral head J Bone Joint Surg Br 2003; 85(3 ): 371-5.]. HBO improves the oxygenation of hypoxic tissue and reduces edema by increasing the concentration of dissolved oxygen and inducing vasoconstriction. This accounts for the early pain relief in patients receiving HBO. In a randomized controlled study of 20 patients with Ficat stage II femoral head AVN of all causes, patients who received 30 treatment sessions of HBO in 6 weeks had significant greater improvement in pain and range of movement. Substantial radiographic healing of AVN was observed in 7 of 9 hips with HBO [59 Camporesi EM, Vezzani G, Bosco G, Mangar D, Bernasek TL. Hyperbaric oxygen therapy in femoral head necrosis J Arthroplasty 2010; 25(6 ): 118-23.]. One disadvantage of HBO is its high cost of treatment. More studies are needed to evaluate its use as a primary treatment or adjunctive therapy for AVN.

SURGICAL TREATMENT OF AVN

Core Depression

Core decompression works by reduction of intramedullary pressure inside the femoral head by making a drill hole, thus improving blood flow to bone. This procedure is mainly indicated in early stage AVN. Mont et al. [10 Michael AM, David H. Non-traumatic avascular necrosis of the femoral head J Bone Joint Surg Am 1995; 77(3 ): 459-74.] reviewed 24 reports that included 1206 hips which have undergone core decompression. Seven hundred and eleven out of the 1130 hips (63%) showed no radiographic evidence of progression of disease in follow up X-ray. Mean duration of follow up was 30 months. Patients with earlier stage had better results, in which the average rate of survival was 84% for Ficat stage 1, 65% for stage 2 and 47% for stage 3. The authors concluded that core decompression is effective in delaying the need for total hip arthroplasty. The result was supported by another prospective study [55 Stulberg BN, Davis AW, Bauer TW, Levine M, Easley K. Osteonecrosis of the femoral head. A prospective randomized treatment protocol Clin Orthop Relat Res 1991; 268: 140-51.] which showed that the successful rate (as reflected by the Harris hip score) was higher with core decompression compared to conservative approach in both stage I, II and III hip. However, one smaller prospective study [61 Koo KH, Kim R, Kim YS, et al. Risk period for developing osteonecrosis of the femoral head in patients on steroid treatment Clin Rheumatol 2002; 21(4 ): 299-303.] showed that core decompression could provide pain relief but did not influence the time of collapse in patients with AVN.

Osteotomy

Osteotomy aims to relocate the necrotic area of bone from the weight loading area of acetabulum, so as to redistribute the weight loading to articular cartilage, which is supported by healthy bone. Results of studies of osteotomy vary according to different types of osteotomy. Transtrochanteric anterior rotational osteotomy has showed good results but was technically demanding [62 Atsumi T, Kajiwara T, Hiranuma Y, Tamaoki S, Asakura Y. Posterior rotational osteotomy for nontraumatic osteonecrosis with extensive collapsed lesions in young patients J Bone Joint Surg 2006; 88(A(Suppl) ): 42-7.]. Varus osteotomy aims to relocate the necrotic bone medially and shift the intact lateral articular surface into the weight bearing position. One study [63 Mont MA, Fairbank AC, Krackow KA, Hungerford DS. Corrective osteotomy for osteonecrosis of the femoral head J Bone Joint Surg Am 1996; 78(7 ): 1032-8.] showed that 28 of 32 hips (76%) with Ficat stage II or III AVN had good and durable surgical results according to Harris hips-scoring system after corrective osteotomy for 11.5 years. The results were even better in those who had not received glucocorticoids (85% achieved good excellent results). This operation, however, has several disadvantages that include elevation or lateral displacement of the greater trochanter.

Bone Graft

Bone graft aims to provide mechanical support to subchondral bone or cartilage. There are various types of bone grafting, some combined with osteotomy, osteochondral grafts, muscle pedicle bone grafts, and some are vascularized grafts to improve blood flow of the bone by achieving revascularization. Vascularized bone grafting is reported to have a higher successful rate than cortical graft, only 11% with stage II hips with free vascularized fibular grafting need to undergo total hip replacement in a 5 year follow up period [64 Urbaniak JR, Coogan PG, Gunneson EB, Nunley JA. Treatment of osteonecrosis of the femoral head with free vascularized fibular grafting. A long-term follow-up study of one hundred and three hips J Bone Joint Surg Am 1995; 77(5 ): 681-94.]. In another study with longer follow up period of 10 years time, only 10.5% patients with vascularized graft had failed and required total hip replacement [65 Yoo MC, Kim KI, Hahn CS, Parvizi J. Long-term followup of vascularized fibular grafting for femoral head necrosis Clin Orthop Relat Res 2008; 466(5 ): 1133-40.]. Possible morbidities after operation include weakness, sensory deficit and pain [66 Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002; 32(2 ): 94-124.]. A study done in 1996 which looked into patients who underwent vascularized fibular grafts showed that at five years, 2.7% patients have lower limb motor weakness, 11% has sensory deficit and 8% has pain at sites other than ankle [67 Vail TP, Urbaniak JR. Donor-site morbidity with use of vascularised autogenous fibular grafts J Bone Surg Am 1996; 78(2 ): 204-11.].

Tantalum Rod

The new tantalum rod is made up of a biocompatible material with a porosity of 75%. It has been used to replace the necrotic bone segment to prevent collapse in Steinberg stage I-III femoral AVN. The presence of pores allows rapid bony ingrowth [68 Varitimidis SE, Dimitroulias AP, Karachalios TS, Dailiana ZH, Malizos KN. Outcome after tantalum rod implantation for treatment of femoral head osteonecrosis: 26 hips followed for an average of 3 years Acta Orthop 2009; 80(1 ): 20-5.]. Recent studies showed encouraging results of this treatment modality [68 Varitimidis SE, Dimitroulias AP, Karachalios TS, Dailiana ZH, Malizos KN. Outcome after tantalum rod implantation for treatment of femoral head osteonecrosis: 26 hips followed for an average of 3 years Acta Orthop 2009; 80(1 ): 20-5.-70 Saito S, Saito M, Nishina T, Ohzono K, Ono K. Long term results of total hip arthroplasty for osteonecrosis of the femoral head. A comparison with osteoarthritis Clin Orthop 1989; 244: 198-207.]. Survivorship of the hip without the need to conversion to total hip arthroplasty was up to 70% at 6 years [68 Varitimidis SE, Dimitroulias AP, Karachalios TS, Dailiana ZH, Malizos KN. Outcome after tantalum rod implantation for treatment of femoral head osteonecrosis: 26 hips followed for an average of 3 years Acta Orthop 2009; 80(1 ): 20-5.]. The disadvantage of the tantalum rod is that if the disease progresses, the tip of tantalum rod in the collapsed femoral head may protrude into the acetabulum. Moreover, there will be technical difficulty in removal of the tantalum rod in case of complications because of its strong bio-integration to the surrounding bone.

Joint Replacement

In the advanced stage of AVN, once the femoral head has collapsed or the destruction process has involved the acetabulum, joint replacement is indicated. These include femoral resurfacing arthroplasty, hemiarthroplasty, and total hip arthroplasty. Compared with total hip replacement due to other causes like osteoarthritis, patients with AVN in general have a less favorable long term durability or high failure rate [71 Lee JH, Lee BW, Lee BJ, Kim SY. Midterm results of primary total hip arthroplasty using high cross-linked polyethylene: minimum 7 year follow-up study J Arthroplasty 2011; 26(7 ): 1014-9.], likely because the patients are of younger age and are functionally more active. There is a concern for the need of repeated revision of hip replacement in younger patients due to the wear and osteolysis of joint surface, thus the use of joint preserving procedures should be explored in younger patients whenever possible especially in early stage of AVN. Recent advances include the use of more wear resistant bearing surfaces. Highly cross-linked polyethylene was shown to have excellent results with decreased wear rate and lower incidence of osteolysis. One recent study showed that the annual penetration was below 0.01mm/ year during 7 year follow up in patients with primary total hip arthroplasties using highly cross-linked polyethylene (81 out of 113 hips with AVN) [71 Lee JH, Lee BW, Lee BJ, Kim SY. Midterm results of primary total hip arthroplasty using high cross-linked polyethylene: minimum 7 year follow-up study J Arthroplasty 2011; 26(7 ): 1014-9.]. Another more wear resistant bearing surface is ceramic- on- ceramic which also showed satisfactory clinical and radiological results especially in active and young patients [72 Byun JW, Yoon TR, Park KS, Seon JK. Third generation ceramicon- ceramic total hip arthroplasty in patients younger than 30 years with osteonecrosis of femora head J Arthroplasty 2012; 27(7 ): 1337-43.]. However, squeaking, which is a high pitch noise related to the movement of prosthetic joint, is a concern [73 Baek Sh, Kim SY. Cementless total hip arthroplasty with alumina bearings in patients younger than fifty with femoral head osteonecrosis J Bone Joint Surg Am 2008; 90(6 ): 1314-20.].

CONCLUSION

In conclusion, glucocorticoid use is one of the commonest and most important causes of non-traumatic AVN. Postulated pathogenetic mechanisms of glucocorticoid-induced AVN include fat hypertrophy, fat emboli and intravascular coagulation. MRI is the most sensitive modality in picking up early stage of AVN. In patients receiving glucocorticoids, AVN can develop as early as in the first 12 months. At present there is no consensus to recommend universal screening for asymptomatic AVN in long-term users of glucocorticoids. Physicians should have a high index of suspicion for persistent pain at typical sites after commencement of glucocorticoids. Judicious use of glucocorticoids, such as the use of lowest effective doses, avoiding prolonged courses, minimizing the use of intravenous pulse methylprednisolone and early institution of glucocorticoid sparing agents may help to decrease the risk of AVN. Conservative management includes bed rest, reduction of weight bearing with use of crutches or canes and pharmacological therapy. At present there is not enough evidence to support the routine use of bisphosphonates or hyperbaric oxygen in glucocorticoid-induced AVN. Surgical treatment of AVN includes core decompression, osteotomy, bone graft and tantalum rod that may help to delay the progression of AVN. Arthroplasty are indicated for advanced AVN and articular collapse. Durability is a concern as patients suffered from glucocorticoid- induced AVN are mostly young. More wear resistant hip prostheses are being developed.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

Declared none.

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