Non-traumatic osteonecrosis is a cause of joint pain and deformity, not uncommonly caused by corticosteroid use. Despite this, corticosteroid induced osteonecrosis is poorly represented in the literature. We performed a detailed review of corticosteroid induced osteonecrosis, including aetiology, prevention, screening, clinical presentation, investigations, staging systems and treatment. We present this in the context of a patient at our institution who developed bilateral hip, shoulder and knee osteonecrosis following high dose corticosteroid therapy for dermatomyositis.
Non-traumatic osteonecrosis (NON), or avascular necrosis (AVN), is recognised as a cause of pain, loss of function and bone and joint deformity. The recognition of corticosteroids (CS) as a cause of NON is attributed to Pietrogoni in 1957 [1,2]. With increased steroid use and increasing awareness, it has become the second highest cause of osteonecrosis (ON) [
Interest in CS induced NON at our institution was stimulated by a patient who developed bilateral hip, shoulder and knee NON following high dose CS for dermatomyositis. We present a detailed literature review with this illustrative case.
In 1995 a 43 year old man was diagnosed with dermatomyositis at a tertiary metropolitan hospital and commenced on a treatment protocol of oral steroids (Prednisolone 10 mg bd) and Azathiopine (150 mg daily). Initially poorly responsive to treatment, Azathiopine was ceased, the dose of Prednisolone was altered (maximum 45 mg in a day) and, at various times, Methotrexate (10 mg weekly), Cyclophosphamide (one gram weekly) and Dexamethasone (8 mg IV with Cyclophosphamide) were introduced. After ten months a treatment regime of oral Prednisolone 10 mg bd was adequate for maintenance purposes.
In 2001, now aged 49, he was referred to our institution with debilitating, progressive pain and stiffness in both hips and shoulders. His hip symptoms manifest approximately eight months following the diagnosis of dermatomyositis and commencement of steroids, and progressed to his shoulders and knees. At the time of referral, his hip pain had forced his retirement from his job as a butcher and he required the use of walking aids. Both shoulders were painful and stiff, and his analgesic requirements were substantial. Plain radiology revealed Ficat stage four osteonecrosis of the femoral heads (
Over a two year period he underwent bilateral hip replacement (
Prior to the onset of his symptoms (eight months following commencement of steroid therapy) he had a cumulative Prednisolone dose of 4.2 grams and a
cumulative Dexamethasone dose of 32 mg. This equates to a cumulative Prednisolone equivalent dose of 4.4 grams. His peak Prednisolone dose was 45 mg in one day and his average daily Prednisolone dose over the period was 18mg per day. Six months following commencement of steroid therapy he was diagnosed with difficult to control Hypercholesterolaemia. At that time his cholesterol was approximately 8 mmol/L; it is currently controlled with Atorvastatin therapy.
The pathogenesis of corticosteroid induced NON is still debated, with hypotheses including decreased blood
flow [4,5], bone marrow fat cell hypertrophy [
CS directly cause apoptosis of osteoblasts and osteocytes after prolonged exposure in vitro [8,9], and have been shown to suppress osteoblast and osteoclast precursor production in bone marrow in a mouse model [
Studies have shown CS induce not only increased numbers of bone marrow adipocytes, but also adipocyte hypertrophy [
Bone blood flow in pigs has been shown to be reduced when exposed to CS [
Further, as osteonecrosis is not prevalent in CS excess from endogenous sources [
A dose dependent risk of NON was suspected when the incidence in the renal transplant population decreased dramatically after development of non-steroidal immune modulators (eg. cyclosporine, tacrolimus) and the subsequent reduction in steroid dose, [2,15-17] however a number of studies failed to demonstrate this [14,16-19]. These often included low numbers of patients and dose relationship was not the primary outcome. In some studies different types of CS were compared, further confounding results. More recent studies have suggested an increased risk of steroid induced NON with increased cumulative CS dose [20-29], daily dose [
While it is clear that CS dose influences the development of NON an exact dose dependant relationship or induction threshold has not been shown. Genetic susceptibility, [9,10] the type of CS, [23,31,32] method of delivery [23,27,28] and as yet unknown factors probably combine to alter the patient specific risk. It has been suggested that monitoring other functional effects of CS, such as increase in body mass index (BMI) [17,32] or development of Cushingoid features [
Further confounding research into dose related risk of CS is the finding that different corticosteroids may have different potencies to induce NON. While NON has been described with both Methylprednisolone and Prednisolone, one study using a rabbit model has shown Methylprednisolone to be more likely to induce NON than Prednisolone or Triamcinolone at equivalent doses [
Although the literature, particularly human literature, is limited it appears that a dose dependant relationship of CS induced NON does exist; it is reasonable to suggest that as low a dose of CS as clinically possible, monitoring of steroid related side effects and limited use of Methylprednisolone in favour of other CS may reduce the risk of NON. These are far from proven and require methodologically stringent human trials before they can be recommended with certainty.
Patients receiving CS often have conditions that have themselves been implicated in causing NON including vasculitis or collagen synthesis disorders, such as systemic lupus erythematosus (SLE) [1,9,14,30,36,37]. Studies investigating the contribution of these disorders to NON are difficult as the treatment, high dose or long term CS, confound the conclusions. Patients with SLE and Raynaud’s phenomenon (a disorder of peripheral vasoconstriction) have been shown to be at higher risk of CS induced NON [
Recent interest in a possible vascular, coagulopathy [
Some authors claim that statin therapy (lipid lowering agents), which is known to reduce the adverse effects of steroids on lipid metabolism [
It is clear that, at least in vitro, both lipid lowering agents and anticoagulants have some protective effect on the development of CS induced NON. Just as the pathophysiology of CS induced NON appears multifactorial, any effective prophylactic regime may require modification of multiple physiologic factors. The development of such a regime would represent a significant advance in the management of this patient population and therefore needs to be the focus of further well designed prospective human trials.
The radiologic screening of patients for NON is debated. Given the benefits of early diagnosis and treatment, some authors recommend MRI screening for young patients receiving high dose CS [28,38,39], particularly if there is NON of another joint. This may be local [2,49] or whole body [
Most of the literature describing the clinical presentation of NON refers to the femoral head and is related to all causes of NON. A careful medical and social history must be elicited, including a thorough investigation of risk factors including previous corticosteroid use [2,49, 51]. A high index of suspicion for NON must accompany a patient with a painful hip, normal x-rays and risk factors for NON, particularly AVN of the contralateral joint [
On examination, there is usually a painful range of motion, [52,55] especially on forced internal rotation, [51,53,55] and range may be decreased [53,57-59]. A limp or decreased function may be present in later stages. Examination of the contralateral hip, regardless of symptoms, is recommended due to the high incidence of bilateral disease [
There have been recent reports of NON of the shoulder, describing poorly localised shoulder pain [2,49,60] which is exacerbated by use [
Investigations include radiology and histology. The majority of literature regarding investigations into NON is decades old with the exception of articles regarding MRI, which has markedly altered early diagnosis. Historically Ficat described “every case of AVN goes through a pre (plain) radiologic stage” [
The mainstay of investigation remains the plain radiograph. AP and frogleg lateral radiographs should be obtained of the hip [51,55], and AP, axillary lateral, internal rotation and external rotation images of the shoulder [2,49,60]. A cross table lateral hip x-ray will not show subtle bony architecture of the femoral head well [
Bone scintography, typically with technetium 99 methylene-diphsophonate, may show AVN with areas of increased uptake (reactive bone) [49,51,53,55] possibly surrounding an area of decreased uptake (necrotic zone) [1,49,53,55]. It is not specific for AVN [1,51,53] and is less sensitive than MRI [1,60]. There may be no changes in the first two weeks [
Computed tomography (CT) scanning is not widely used [
Early and accurate diagnosis of NON is imperative. A high index of suspicion should accompany a previous history of high dose or prolonged steroid use, NON of other joints and a young patient presenting with a painful joint and unremarkable plain radiographs. Examination may reveal pain on range of motion only, particularly forced IR of the hip. A full series of plain radiographs are likely to provide the diagnosis; if they are unremarkable an MRI scan should be obtained as symptoms predate plain radiology by several months [36,53] and early diagnosis and treatment affords the best outcomes [51,55].
A number of different staging systems have been described for the femoral head, and one for the humeral head [2,49,51,60]. They are based on a combination of plain radiographs, MRI and clinical data. Ficat and Arlet described the first staging system based on plain radiographs [
Steinberg [
The Association Research Circulation Osseous (Toulouse, France) [
The natural history of CS induced NON and NON from all causes remains largely undefined. There is no specific information regarding CS induced NON in the English literature. The literature in general is inconclusive, with confounding factors including the method and stage of diagnosis and length of follow up.
Historically, symptomatic ON of the femoral head from all causes has been investigated with non operative management; in 1995 Mont and Hungerford [
The use of MRI to detect asymptomatic hips remains a point of contention as to their clinical relevance [38,70]. It remains contentious whether NON lesions can repair and revascularise to normal bone. Early revascularisation has been shown experimentally in animal models [31, 71,72] and MRI studies in humans suggests early spontaneous incomplete [70,73] and even complete [
The true natural history of NON remains unknown. Progression from necrosis through sclerosis to collapse is likely although revascularisation and repair appear possible in some cases. Further research into the progression of MRI detected asymptomatic lesions is necessary to determine their significance and the true natural history of NON.
The literature focusing on treatment of NON does not investigate CS induced NON specifically. The few authors who attempt to stratify treatment outcomes according to causes of NON suffer from small numbers and multiple confounding factors and have contradictory results [1,49,51]. A vast number of treatments have been described and are broadly categorised into joint preserveing or joint replacing (arthroplasty) treatments. Treatment options are according to stage of disease [2,51,56], particularly pre collapse or post collapse. Pre collapse treatment is the most debated. The literature is almost exclusively focused on the treatment of femoral head NON, although limited literature on humeral head NON suggests that it may have a better prognosis [49,56,60], perhaps as it is a non weight-bearing joint. We will discuss the treatment of femoral head NON initially.
Non-operative management, including bed rest, nonweight bearing, partial weight bearing and traction appears to have the same progression as the natural history of NON [1,51,65] in the hip, the specifics of which are unknown but 85% of symptomatic pre-collapse hips progress to collapse within 2 years [51,69]. Historically, only 22% of hips treated non-operatively have a satisfactory clinical outcome, with radiologic progression in 74% of patients and 76% of patients going on to arthroplasty [
Core decompression for ON of the femoral head is controversial [
Core decompression associated with autologous bone marrow aspirate transplantation has been described [
Multiple proximal femoral osteotomies have been described including varus, valgus, rotational and combinations of the above. The aim is to move the necrotic segment away from the major load transmitting area [51,65]. Again, success rates in the literature are variable, with reports from 55% to 89% for stage 2 and 3 disease [51, 65,81,82]. Better results were found with a combined necrotic angle of less than 200 degrees [51,65,81] and if the intact area of the head is >30% [1,82]. Worse results have been described with CS induced NON compared with other causes [51,81]. Critics of osteotomy to treat NON describe the technical difficulty [
THJR (total hip arthroplasty) is reserved for severe stage three and stage four disease. Hemiarthroplasty and femoral head resurfacing have been advocated in the past but have inferior results due to rapid accetabular degeneration [
The literature regarding treatment of femoral head CS induced NON in general is plagued with low numbers of patients, poor methodology and short follow up. Variable techniques, inclusion criteria and diagnostic methods make comparisons difficult and conclusions unsure. Non operative management is unlikely to prevent progression, the exception to this may be pharmaceutical agents which are promising although grossly under investigated to allow any conclusions. Core decompression may be effective in delaying the need for total hip joint replacement in stage 1 and 2 disease; it should not be considered for post collapse lesions [
Trends would suggest that early, pre collapse treatment is likely to achieve better results, as are smaller, medial lesions, regardless of treatment modality. Patients with CS induced NON may do worse than other causes of NON, as may SLE patients, however these relationships are far from certain.
There is very limited literature focusing on the treatment of humeral head NON, primarily small case series and review articles, again not specific to CS induced NON. In contrast to femoral head NON, non operative treatment may be used in early (stage one and two) disease of the shoulder, including maintenance of range of movement and limiting over head activities [2,49]. Nonoperative management of stage 3 disease has poor results [
Humeral head hemiarthroplasty has good to excellent results in low numbers of reports for stage four disease [
Literature on the treatment of NON affecting other areas is limited to case series and case reports. Osteochondral autograft transplantation for CS induced NON of the elbow [
We present a thorough review of the English literature and an illustrative case report of corticosteroid induced osteonecrosis. Whilst it is difficult to make firm recommendations due to the heterogeneity of the literature a number of trends are apparent.
It appears that there is, albeit undefined, a dose dependant relationship and probably a preparation dependant relationship to corticosteroid induced osteonecrosis. This may be markedly different between patients and may have a genetic component. If steroid therapy is to be commenced, we recommend that the lowest possible dose be used for the shortest possible duration and that oral preparations, such as prednisolone, are used in place of parenteral preparations where possible.
It seems appropriate to assess the functional effect of steroid treatment such as change in body mass or serum triglyceride levels to assess a patient’s risk of developing osteonecrosis. We are unable to recommend a preventative regimen. All patients being commenced on a corticosteroid should be educated regarding the risk of nontraumatic osteonecrosis, the early clinical symptoms and the benefits of early diagnosis. We recommend regular follow up with clinical examination and aggressive investigation to achieve early diagnosis. Investigations should include plain radiographs and, if required for diagnosis, MRI. If nontraumatic osteonecrosis is diagnosed imaging of other at risk joints (such as the contralateral hip) should be performed. The routine radiographic screening of high risk patients remains controversial due to the uncertain significance of early MRI findings of and the unproven treatment benefits of asymptomatic lesions and therefore cannot be recommended.
We recommend core decompression for Ficat stage one or two osteonecrosis of the femoral head; the addition of bone graft is of unproven benefit. For late stage disease we recommend total hip arthroplasty in appropriate patients. Osteotomy may be appropriate for certain lesions or patients although the technical difficulties and improvements in total hip arthroplasty make this less appealing. Arthrodesis remains relatively contraindicated in NON. Due to the low representation in the literature it is not possible to make any evidence based conclusions regarding the treatment of corticosteroid induced osteonecrosis of other areas, however the basic principles of management still apply. It seems reasonable to perform joint preserving operations for pre collapse lesions and joint replacement or arthrodesis procedures for post collapse lesions as appropriate to the involved area.
The clinical investigation of osteonecrosis, particularly non-traumatic osteonecrosis, is made difficult by the low incidence in the general population, late onset of clinical symptoms, concurrent medical comorbidities and the uncertain significance of early radiologic findings. Despite this, good quality future investigations need to focus on the early treatment of corticosteroid induced osteonecrosis, particularly the pharmacologic treatment and core decompression. The recent investigation of corticosteroid induced osteonecrosis is largely in vitro experiments focusing on pathophysiology with interesting yet inconclusive results. More effort needs to be focused in this area and that of pharmacologic prevention. The intriguing possibility of spontaneous healing of osteonecrotic lesions also warrants further exploration.
The authors would like to acknowledge Mr. Craig Donohue for his contribution to the case report.