Nontraumatic osteonecrosis continues to be a challenging problem causing debilitating major joint diseases. The etiology is multifactorial, but steroid- and alcohol-induced osteonecrosis contribute to more than two thirds of all cases with genetic risk factors playing an important role in many other cases, especially when they contribute to hypercoagulable states. While the exact mechanisms remain elusive, many new insights have emerged from research in the last decade that have given us a clearer picture of the pathogenesis of nontraumatic osteonecrosis of the femoral head. Progression to end stage osteonecrosis of the femoral head appears to be related to four main factors: interactions involving the differentiation pathway of osteoprogenitor cells that promote adipogenesis, decreased angiogenesis, direct suppression of osteogenic gene expression and proliferation of bone marrow stem cells, and genetic anomalies or other diseases that promote hypercoagulable states.
1. Introduction
Nontraumatic osteonecrosis (ON) of the femoral head continues to represent a significant challenge to orthopaedic surgeons [1–3] and is a devastating disease for affected patients with complete collapse of the femoral head occurring in 80% of untreated patients [4, 5]. Nontraumatic conditions associated with ON are numerous [1, 2, 6, 7]. Some of the well accepted and common associations include corticosteroid use [8, 9], alcohol abuse [10], systemic lupus erythematous [11], hemoglobinopathies including sickle cell anemia [12–14], Legg-Calve Perthes disease [15], and exposure to radiation [16] or cytotoxic agents [17]. Other less common associations include Gaucher’s disease [11, 18, 19], dysbarisms [4], HIV [20], hyperlipidemia [21], pancreatitis, and gout [22]. A substantial number of cases have no identifiable etiologic factors and have been referred as idiopathic [23]. The pathogenic mechanisms leading to impaired circulation in these conditions are most likely multifactorial [3, 21, 24, 25]. Mechanical blood vessel interruption, thrombotic intravascular occlusion, and extravascular compression are the three most commonly accepted general mechanisms leading to ON [1, 3, 24, 26]. Recent attention has been given to the interplay between individual genetic predisposition and environmental factors related to ON [26–50]. Both heritable and acquired risk factors for femoral head ON related to hypercoagulability [28, 32–36, 47, 50–52], hemoglobinopathies [27, 28, 36], steroids [48], angiogenesis [43], and oxidative stress [45] have been identified in many patients. Technological advances in molecular biology have enabled studies on the advanced mechanisms of steroid and alcohol-induced ON [9, 10, 53–73]. Preliminary data with statins and low molecular weight heparin from clinical studies are promising (Table 1) [74, 75]. Still, the exact pathogenesis of ON is controversial and poorly understood. This limited knowledge has impeded the development of any effective prophylaxis or pharmacologic treatment for this debilitating disease [1, 6]. Currently, the primary effective treatments are surgical, consisting of unloading osteotomies, vascularized grafts, and total hip replacements [4, 5, 21, 26]. This report seeks to systematically review the more common causes of pathogenesis of nontraumatic ON of the femoral head, which include steroids, alcohol, genetic factors, and hypercoagulability.
New developments on pathogenesis of nontraumatic osteonecrosis and its clinical significance.
New findings
Clinical significance
Steroids enhance adipogenesis and inhibit osteogenesis and angiogenesis by marrow stem cells [53, 54, 56]
Alcohol stimulate adipogenesis and inhibit osteogenesis by marrow stem cells [40, 65]
Therapeutic modulating marrow stem cell
Heritable hypofibrinolysis and thrombophilia [32, 34, 40, 50, 72]
Anticoagulation therapy is effective [75]
Genetic associations
Mutations in the COL2A1 gene [30]
Familial high risk group
Polymorphisms in alcohol metabolizing enzyme gene [29]
High risk subgroup
Polymorphisms in the multidrug resistance gene 1 [73]
Screening high risk patients [73]
2. Pathophysiology of Osteonecrosis
Ultimately, ON of the femoral head occurs through one final common pathway, which is decreased blood flow to the femoral head that leads to bone ischemia and death [1, 3, 21, 24] (Figure 1). However, the precipitating mechanisms which lead to this final pathway are varied. Vascular occlusion can be caused by local thrombi, fat emboli, nitrogen bubbles, or abnormally shaped red blood cells [52, 76–78]. Extravasated blood along with fat or cellular elements in the marrow cavity can extrinsically compress both arteries and veins [7, 10, 54, 79, 80]. The blood vessels in the femoral head may be directly damaged by vasculitis, irradiation, or chemical toxicity [1, 2, 7]. Bone cells may remain viable if the collateral circulation is sufficient. Although bone has a relatively rich vascular supply, the distribution is inhomogeneous and leaves some areas more vulnerable than others [7, 81]. Once the ischemic threshold is reached, the morphologic changes within the affected bone are similar regardless of the inciting disorder.
Schematic representation of the development of osteonecrosis. (Reprinted, with permission, from [24].)
No histologic evidence of damage is evident until twenty-four to seventy-two hours after vascular compromise [81]. Examination of the bone marrow reveals necrosis of hematopoietic cells, endothelial cells, and lipocytes. Osteocytes atrophy and die, and increasing numbers of empty lacunae become evident with time. The release of lysosomes acidifies the surrounding tissue as dying lypocytes release free fatty acids which saponify with extracellular calcium to form insoluble soaps. A subsequent increase in fatty marrow water content is detectable by magnetic resonance imaging (MRI) and represents the earliest abnormality seen clinically.Saponified fats and other necrotic areas eventually calcify and can be detected by plain radiographs later in the disease process [81–83].
Cell death is followed by initiation of the repair process. An inflammatory cascade is initiated by the adjacent viable tissues, which leads to a fibrous vascular in growth in the regions of cell death. Vascular canals can be seen penetrating the medullary canals of the cancellous bone and the haversian canals in the overlying cortical bone. These vessels are accompanied by primitive mesenchymal cells which differentiate into osteoblasts and osteoclasts [81–84]. Immature woven bone is deposited throughout the network of dead trabecular bone. The nonviable trabecular bone is slowly resorbed by the process of creeping substitution. Unfortunately, the newly deposited bone does not attain the previous structural integrity of that region of the femoral head, leading to subchondral collapse of these regions at appropriate weight bearing loads. Ultimately, this leads to irregularities in the normally smooth cartilaginous surface of the femoral head that progress to end-stage arthritis. Additionally, surrounding viable bone may lose mass and become osteopenic from relative patient inactivity over the course of the disease [1, 25, 81–84].
3. Historical Views on the Pathogenesis of Osteonecrosis
Phemister was the first to propose that the “aseptic necrosis” might result from fractures, bone graft transplantation, radiation and vascular obstruction from thrombosis, or embolization [85]. ON was later regarded as a primitive vascular problem. Some believed that ON of the femoral head resulted from a type of vasculitis [86]. Chandler implicated an extraosseous embolic process and introduced the concept of “coronary disease of the hip” [87]. In a microangiographical study of 31 femoral heads with idiopathic ON, Atsumi found extraossesous interruption of the superior retinacular arteries along with early angiogenesis and compensatory hypertrophy of the unaffected surrounding vasculature. They also found blockage of revascularization occurring along the areas of subchondral collapse in the weight-bearing region [88]. In contrast, Glimcher and Kenzora found no evidence to support blood vessel involvement in 150 adult femoral heads with ON and instead implicated a purely metabolic syndrome leading to cell death [82–84].
Many theories regarding the pathogenesis of nontraumatic ON have been proposed over the past twenty years [1, 6, 21, 24]. Intraosseous hypertension, intravascular fat or gaseous emboli, and extravascular compression by increased marrow fat stores are several accepted theories [7, 52, 54, 78–80, 89–91]. Most support a “multiple hit” theory, with accumulated tissue stress from various insults reaching a critical threshold and initiating the disease process [1, 25]. Many would agree that these theories are not mutually exclusive, but are instead mutually supportive.
4. Association of Osteonecrosis with Hypercoagulopathy and Genetic Alterations
Paul-Jones first suggested that hypercoagulability, and in specific intravascular coagulation could be a cause of ON in 1992 [77]. Thrombotic occlusion of the microcirculation can occur from hereditary thrombophilia, impaired fibrinolysis or antiphospholipid antibodies [16]. Additional causes include environmental or acquired/preexisting conditions, such as hyperlipidemia, hypersensitivity reactions, thromboplastin release during pregnancy, malignant tumors, and inflammatory bowel disease all may contribute additional risk to individuals with an underlying genetic predisposition to form microvascular thrombi [16, 21, 26, 29, 32, 34, 50, 72, 73, 75, 78, 92–94]. The role of sickle cell disease and other hemoglobinopathies in promoting ON of the femoral head has been well documented and also seems to act through the final pathway of intravascular coagulation [12–14, 95–98].
Björkman et al. showed in a retrospective study of 63 adult patients with osteonecrosis of the femoral head, that mutations in the factor V Leiden or the prothrombin 20210A gene were significantly more frequent in patients with idiopathic osteonecrosis than in patients with steroid or alcohol-induced osteonecrosis, as well as in a population of healthy control subjects [99]. This is supported by Zalavras and his colleagues who have demonstrated that the factor V Leiden mutation was presented in 18% of 72 adult Caucasian patients, compared with 4.6% of 300 healthy control subjects [50]. In addition, protein C and protein S deficiencies, which lead to thrombophilia have been associated with ON of the femoral head [32]. Jones et al. have studied the blood samples of 45 patients with osteonecrosis, 5 of which had no known preexisting conditions that could cause ON otherwise. In comparison to 40 age matched healthy controls, patients with ON were 3 times more likely to have a gene abnormality promoting anticoagulation, and further in those with no preexisting condition 100% had a gene abnormality promoting anticoagulation [40]. Glueck et al. have done extensive work in profiling the role of hypercoagulability and ON [30, 33–35, 72, 75, 93]. In a population of 36 patients entering a treatment trial with low-molecular-weight heparin (LMWH) for treatment of femoral head osteonecrosis they found gene polymorphisms that resulted in increased activity of the plasminogen activator inhibitor-1 gene (PAI-1), alterations in the methylenetetrahydrofolate reductase (MTHFR), and resultant hypofibrinolysis concurrent with higher homecysteine and lipoprotein levels than controls [34]. In this same group of patients, they showed that enoxaparin prevented progression of osteonecrosis in patients with early stage disease [75]. Chang et al. found that polymorphism in the MTHFR gene increased the risk for ON in the Korean population [28], while Kim et al. were unable to show a significant association between single nucleotide polymorphisms (SNPs) in the MTHFR gene locus and development of ON in the Korean population [42].
It has become clear that in general, genetic anomalies or heritable diseases that promote intravascular coagulation are associated with the development of osteonecrosis. Future studies will likely focus on ways to screen for and localize polymorphisms associated with hypercoagulability, so that earlier or perhaps even prophylactic treatment can be provided for this patient population.
4.1. Genetic Associations
As previously discussed, thrombophilic disorders caused by both heritable diseases and genetic anomalies such as SNPs play a major role in the etiology and progression of ON due to genetic alterations in key components in the coagulation cascade including Protein C, Protein S, PAI-1, and a number of other factors [12–14, 16, 27, 30, 33–35, 72, 78, 93, 95–98]. Chen et al. evaluated two Taiwanese pedigrees with familial autosomal dominant osteonecrosis of the femoral head. They were able to link the presence of mutations in the Protein C, Protein S, and PAI-1 proteins to the 2q13-q14, 3q11.1-q11.2 and 7q21.3-q22 chromosomal segments respectively [30]. Pierre-Jacques et al. have reported on a familial heterozygous Protein S deficiency in a patient with multifocal osteonecrosis [49].
Numerous other genetic associations have been identified [27, 28, 31, 33, 35–38, 43–48]. Glueck et al. demonstrated that the T-786C Drosophila nitric-oxide synthase (dNOS) SNP results in decreased activity of nitric oxide which is responsible for promoting angiogenesis, bone formation, and inhibiting platelet aggregation. 22% of patients with idiopathic ON in their series had this SNP compared to only 5% of controls [33, 35]. Similarly, Koo et al. have found that polymorphisms in the nitric oxide synthase gene increased the risk of ON in their study population [47]. Hong et al. evaluated SNP in the transferrin (TF), vascular endothelial growth factor C (VEGFC), sterol regulatory element binding transcription protein-3 (IGFBP3), and angiotensin I converting enzyme (ACE) genes in a comparison study between 450 patients with femoral head ON and 300 matched healthy controls. They found that the SNP R2453839S, SNP on the IGFBP3 gene was significantly associated with development of ON and SNPs in the ACE gene were associated with increased chance of progression of steroid induced ON. Surprisingly, they found that SNPs in thekinase insert domain receptor (KDR) and neuropilin 1 (NRP1) gene loci were associated with decreased prevalence of ON [38]. Kim et al. have done extensive work in the Korean population to identify possible genes where SNPs may be related to increased development on ON [38, 41, 43–46]. They have identified SNPs in the SREBP-2 gene [41], interleukin receptor 23 gene [44], annexin gene family [46], catalase gene [45], and promoter polymorphisms in the VEGF gene [43]. Dai et al. have shown that polymorphisms in genes that inhibit the tissue factor pathway may lead to increased risk of osteonecrosis [31]. Beyond the previously discussed genes, polymorphisms invitamin D receptor (VDR) gene, the thymidylate synthase gene (TYMS), and the Type II collagen A1 (COL2A1) gene have all been identified as increasing the risk of ON of the femoral head [36].
Not all patients receiving high-dose steroids develop ON. Asano et al. have postulated that differences in drug metabolism related to genetic variation may explain why some develop ON while others do not [73, 92]. They examined 136 patients after a kidney transplant and found a strong association between those expressing a specific nucleotide polymorphism in the gene encoding the transport protein P-glycoprotein (P-gp) and resistance to ON. P-gp plays an important role in the absorption and distribution of drugs. By measuring serum through levels of tacrolimus, an immunosuppressive drug whose bioavailability is known to be influenced by P-gp, they were able to correlate enhanced P-gp activity with resistance to ON. The increased P-gp activity may lead to more rapid steroid clearance and subsequently lower serum steroid concentrations. Furthermore, they found that individuals expressing the C3435TT genotype of the gene encoding P-gp had significantly higher P-gp activity and a significantly lower incidence of ON. Their results demonstrate a genetically linked resistance to steroid-induced ON in patients with the C3435TT genotype of the gene encoding P-gp [73, 92]. He and Li have shown that the P-glycoprotein gene ABCB1 which modulates glucocorticoid uptake may be associated with development of ON [37]. In a comparison of patients on chronic glucocorticoids with and without ON they found that the G2677T/A SNP was associated with development of steroid induced ON [37]. Kim et al. also found SNPs in the ABCB1 (c3435t) gene to be related to increased sensitivity to steroid induced ON and found that concomitant SNPs in the CBP (r3751845s) gene increased the relative sensitivity [45].
Chao et al. proposed that genetic polymorphisms may influence the occurrence of alcohol-induced osteonecrosis [29]. Polymorphisms of several alcohol-metabolizing enzymes were evaluated in alcoholic patients with hip osteonecrosis, pancreatitis, and cirrhosis of the liver. They found that allele frequencies of ADH2*1 (alcohol dehydrogenase) and ALDH2*2(aldehyde dehydrogenase) differed among these disease-defined subpopulations of alcoholics, suggesting that differences in the alcohol metabolizing enzyme genes may be responsible for different organ-specific complications [29].
As our knowledge about to the genetic basis of ON improves, so too will our ability to identify at-risk individuals. Certainly, genetic polymorphisms in the genes that help us to metabolize alcohol and steroids along with alterations in the genetic make-up of genes involved in the coagulation cascade seem to be the main candidates for increasing risk to non-traumatic femoral head osteonecrosis.
5. Steroid and Alcohol-Induced Osteonecrosis
Exogenous corticosteroids and alcohol have all been associated with nontraumatic osteonecrosis. The dose affects of these substances and exact mechanism by which they produce osteonecrosis remains unknown though currently a topic of investigation.
5.1. Steroids
The association between excessive corticosteroid use and the development of ON has been well established since the first case report in a patient with rheumatoid arthritis in 1957 [100]. The incidence of ON has increased in parallel with the rise in glucocorticoid therapy for treatment of systemic conditions as well as organ transplantation. Of the 30 million Americans currently receiving glucocorticoid therapy, as many as 40% will develop some degree of osteonecrosis [70, 101]. Glucocorticoids are the most common cause of nontraumatic osteonecrosis [23]. Patients receiving steroid therapy have an approximately 20-fold increase in their likelihood of developing ON [8]. Though the dose effect of corticosteroid therapy on osteonecrosis remains largely unknown, recent studies suggest that corticosteroid doses above 25–40 mg/day are significant risk factors for nontraumatic ON in renal transplant and SLE patients [94, 102]. Several hypotheses regarding the cause of steroid-induced ON are based around the notions of small vessel occlusion by fatty emboli and the impedance of sinusoidal blood flow secondary to a rise in intraosseous pressure due to fatty infiltration following steroid therapy. While contributing factors from underlying disease processes confound this condition, elucidating the mechanism responsible for ON in patients using corticosteroids has been an area of intense research.
Studies have revealed abnormalities of lipid metabolism in both humans and animals following exposure to corticosteroids [80, 103–106]. In animal studies, induced hypercortisolism resulted in adipocyte hypertrophy, hyperlipidemia, fatty liver, and systemic fat emboli. Although marrow edema and fatty necrosis was frequently observed, in quadrupedal studies, no area of bone necrosis or articular collapse could be identified. On the other hand, chickens treated with steroids did show evidence of ON, suggesting that differences in biomechanics between bipedal and quadrupedal species may be an important contributing factor [54].
Studies in mice and humans have shown that dexamethasone, given in a dose and time-dependent fashion, induces the differentiation of bone marrow derived stem cells into adipocytes, while inhibiting osteogenesis [53, 65, 71, 79]. Fat cell hypertrophy has been observed in histologic specimens of human femoral heads following treatment with dexamethasone for 5 days [62]. Dexamethasone has been shown to inhibit the expression of type-I collagen and osteocalcin, thereby suppressing the differentiation of bone marrow-derived stem cells into osteoblasts [53]. Prednisolone therapy has been found to decrease bone density and cancellous bone area while causing trabecular narrowing [107]. Mesenchymal stem cells derived from patients with corticosteroid-induced osteonecrosis of the femoral head have been shown to have lower proliferative ability, which may explain the low capacity for bone regeneration in these patients [68].
Lovastatin, when added to cell culture medium, had been found to inhibit adipogenesis and fat-specific gene expression caused by dexamethasone supplementation [54]. Additionally, lipid lowering agents counteract the inhibitory effect of steroids on osteoblastic gene expression [54]. These findings have been demonstrated both in vitro and in vivo [54, 74, 79]. In a supporting study, mesenchymal cells transplanted into host mice following transfection with a traceable gene demonstrated increased adipogenesis following systemic steroid treatment [108]. Based on these observations, it has been postulated that steroid-induced ON may be due to intraosseous hypertension from excessive marrow fat accumulation or a shift in the differentiation of marrow stem cells into adipocytes, resulting in a reduction in the pool of stem cells available for osteoblast production, ultimately leading to insufficient repair and remodeling of necrotic bone.
The mechanisms by which steroid-treated mesenchymal stem cells demonstrate increased adipogenesis and decreased osteogenesis have been studied at the molecular level [53, 55, 56]. Peroxisome proliferator activated receptor-γ (PPAR-γ) and core-binding factor a1 (Cbfa1) are transcription factors found to be important in the differentiation of pluripotent cells into adipogenic and osteogenic cell lines, respectively. Dexamethasone has been shown to increase mRNA expression of PPAR-γ (Figure 2) and decrease mRNA expression of Cbfa1 (Figure 3). These findings support the idea that dexamethasone promotes adipogenesis while inhibiting osteogenesis. Additionally, these studies also suggest that dexamethasone impairs angiogenesis by suppressing the production of VEGF (Figure 4). Osteoblasts derived from femoral heads have been found to exhibit downregulation of VEGF within 24 hours of incubation with glucocorticoids [67]. In a rabbit steroid-induced osteonecrosis model, however, VEGF levels increased to peak levels 3 days after methylprednisolone treatment [59]. These studies suggest that while steroids inhibit VEGF expression in isolated osteoblast cultures, steroid associated ischemic events occurring in vivo likely contribute to an upregulated VEGF response. The shunting of osteoprogenitor cells into the adipocytic pathway in conjunction with the suppression of angiogenic growth factor production may at least partially explain the basis of steroid-induced ON.
PPARγ2 upregulation by dexamethasone is concentration and time dependent. Quantitation of the relative PPARγ2 gene expression of the D1 cells treated with (a) different concentrations of dexamethasone for 48h and (b) 10−7 mol/L dexamethasone for different time points. Error bars represent the standard deviation of triplicate experiments (P*<0.05). (Reprinted, with permission, from: [56].)
Concentration and time response of Cbfa1/Runx2 mRNA downregulation by dexamethasone. Quantitation of the relative Cbfa1/Runx2 gene expression of the D1 cells treated with (a) different concentrations of dexamethasone for 48 h and (b) 10−7 mol/L dexamethasone for different time points. Error bars represent the standard deviation of triplicate experiments (P*<0.05). (Reprinted, with permission, from: [56].)
Inhibition of VEGF production of D1 cells by dexamethasone is dose and time dependent. VEGF expression in supernatant medium of the D1 cells treated with (a) different concentrations of dexamethasone for 24 h and (b) 10−7 mol/L dexamethasone for different time points was assessed by ELISA. Each column shows mean ± SD of data from three experiments (P*<0.05). (Reprinted, with permission, from: [56].)
Using a porcine model, Drescher et al. investigated the effects of methylprednisolone on the response of femoral head epiphyseal arteries to vasoactive substances [57]. Steroid-treated vessels demonstrated an increased response to endothelin-1 and a decreased response to bradykinin in comparison to untreated controls. Because endothelin-1 effectively vasoconstricts while bradykinin vasodilates, the overall conclusion of this work is that methylprednisolone, when coupled with vasoactive substances, modulates femoral head epiphyseal artery contraction. These findings support the hypothesis that the pathomechanism of steroid-induced femoral head ON is related to disturbed femoral head blood flow.
Ischemia and subsequent reperfusion of the femoral head is also thought to contribute to ON. Drescher et al. studied the influence of short-term high-dose steroid treatment on femoral head reperfusion following ischemic insult in a porcine model [109]. Femoral head ischemia was achieved by pressurizing the hip to 250 mm Hg for 6 hours. Radiolabeled microspheres released into the bloodstream were used to estimate blood flow to the femoral head. In comparison to untreated controls, methylprednisolone treatment was not shown to have an effect on reperfusion of the femoral head following an ischemic insult. Despite these findings, baseline blood flow was profoundly reduced in groups treated with methylprednisolone.
Zaidi et al. have suggested that adrenocorticotropic hormone (ACTH) may protect against methylprednisolone-induced osteonecrosis of the femoral head [9]. In preliminary studies, this group documented functional ACTH receptors on osteoblasts which, when activated, enhanced osteoblastic proliferation [110]. In an in vivo osteonecrosis model, rabbits treated with depomedrol plus ACTH for 1 month demonstrated fewer signs of trabecular necrosis and increased expression of VEGF in comparison to groups treated with the steroid depomedrol alone [9]. Though statistical significance was not reached, quantitative DXA and tetracycline labeling showed a trend towards greater femoral head density and subarticular bone integrity in groups treated with ACTH. These findings support further examination into the efficacy of ACTH in preventing steroid-induced osteonecrosis.
5.2. Alcohol
One study showed a clear increase in the risk of femoral head ON in individuals consuming greater than 400 mL of alcohol per week [111]. Mouse and rabbit in vitro studies investigating the effect of alcohol on bone marrow stromal cells demonstrate that alcohol induces the differentiation of marrow stromal cells into adipocytes in a dose dependent manner [10]. Alcohol-induced a significant increase in serum triglyceride and cholesterol levels, in addition to liver and bone marrow fatty infiltration. In the subchondral areas of the femoral head, fat cell hypertrophy and proliferation were observed. Triglyceride deposition in osteocytes lead to pyknosis and an increased percentage of empty osteocyte lacunae. None of these findings were apparent in untreated control groups. Alcohol treated groups demonstrated intracellular lipid deposition which ultimately lead to death of osteocytes. Cells treated with ethanol showed diminished alkaline phosphatase activity and expression of osteocalcin. Similar to the effects of corticosteroids, alcohol increases adipogenesis and decreases osteogenesis. Unlike the effect of steroids on stromal cells, alcohol-treated cells did not show increases in PPAR-γ expression, supporting the idea that alcohol influences fatty acid metabolism through a differing mechanism.
Wang et al. have suggested, from in vitro and in vivo studies, that the Chinese herbal puerarin, with its antioxidative and antithrombotic effects, can prevent alcohol-induced osteonecrosis [69]. Cells treated with ethanol for 21 days, and mice treated with ethanol for up to 10 months demonstrated a decrease in alcohol-induced adipogenic gene expression when treated simultaneously with puerarin. It is postulated that the inhibitive effects of puerarin on bone-marrow adipogenesis leads to diminished fat marrow changes and subsequent maintenance of osteogenic differentiation of marrow stem cells.
In a study by Suh et al., marrow was collected from the proximal femurs of 33 patients following hip replacement for either alcohol-induced osteonecrosis of the femoral head or femoral neck fractures [65]. After isolating the mesenchymal stem cells and expanding them in culture, cells obtained from the osteonecrotic hips showed diminished osteogenic differentiation as compared to cells taken from fractured hips.
The critical dose of corticosteroids and alcohol necessary to induce ON is largely unknown. It appears that serum corticosteroid concentration is a more important risk factor than cumulative dose or duration of therapy. There exists a strong association between daily total dose and oral dosing (as opposed to parenteral dosing) of corticosteroids in patients with femoral head ON [112]. Most cases of femoral head ON occur after high-dose oral corticosteroid treatment for longer than 1 month, though rare cases have occurred after shorter treatment intervals [113]. Changes indicative of evolving femoral head ON have been appreciated on MRI within three months in patients treated with high-dose prednisolone for 4–8 weeks [114]. These changes occurred prior to symptomatic onset.
From these studies it seems clear that both steroids and alcohol promote adipogenesis at the expense of osteoblastic proliferation or function. Although the exact molecular mechanisms may differ between these two implicating substances, the consequences of increased marrow fat, impaired vascularity, and diminished reparative capability all contribute to the final pathway of cell death. The role of an underlying genetic predisposition in the development of ON in these patients has not been fully elucidated but could explain why some chronic users of steroids or alcohol fail to acquire the disease [29, 73, 92].
In summary, the exact pathogenesis of ON is still unknown. However, many new insights have emerged from research in the last decade (Table 1). Recent studies have demonstrated that both steroids and alcohol promote adipogenesis while inhibiting osteogenesis and angiogenesis, leading to osteonecrosis and osteoporosis. Genetic factors and heritable coagulopathy including hypofibrinolysis and thrombophilia may also play an important role in the development of ON. Statins and anticoagulation therapy have shown promise in amelioration of ON. Further investigation in this area is needed.
Acknowledgments
The study is supported by Orthopaedic Research and Education Foundation/Zachary B. Friedenberg, MD, Clinician Scientist Award and a Grant from Arthritis National Research Foundation.
ArletJ.Nontraumatic avascular necrosis of the femoral head: past, present, and future199227712212-s2.0-0026582311JacobsB.Epidemiology of traumatic and nontraumatic osteonecrosis197813051672-s2.0-0017862195MontM. A.HungerfordD. S.Non-traumatic avascular necrosis of the femoral head19957734594742-s2.0-0028969471MontM. A.JonesL. C.HungerfordD. S.Current concepts review—nontraumatic osteonecrosis of the femoral head: ten years later2006885111711322-s2.0-3364644876510.2106/JBJS.E.01041MontM. A.MarulandaG. A.JonesL. C.SalehK. J.GordonN.HungerfordD. S.SteinbergM. E.Systematic analysis of classification systems for osteonecrosis of the femoral head200688316262-s2.0-3375071854410.2106/JBJS.F.00457EtienneG.MontM. A.RaglandP. S.The diagnosis and treatment of nontraumatic osteonecrosis of the femoral head20045367852-s2.0-2342612195HungerfordD. S.LennoxD. W.The importance of increased intraosseous pressure in the development of osteonecrosis of the femoral head: implications for treatment19851646356542-s2.0-0022350721SakaguchiM.TanakaT.FukushimaW.KuboT.HirotaY.Impact of oral corticosteroid use for idiopathic osteonecrosis of the femoral head: a nationwide multicenter case-control study in Japan20101521851912-s2.0-7795331010710.1007/s00776-009-1439-3ZaidiM.SunL.RobinsonL. J.TourkovaI. L.LiuL.WangY.ZhuL. L.LiuX.LiJ.PengY.YangG.ShiX.LevineA.IqbalJ.YaroslavskiyB. B.IsalesC.BlairH. C.ACTH protects against glucocorticoid-induced osteonecrosis of bone201010719878287872-s2.0-7795274015510.1073/pnas.0912176107WangY.LiY.MaoK.LiJ.CuiQ.WangG. J.Alcohol-induced adipogenesis in bone and marrow: a possible mechanism for osteonecrosis20034102132242-s2.0-0038066762Abu-ShakraM.BuskilaD.ShoenfeldY.Osteonecrosis in patients with SLE200325113232-s2.0-003766842310.1385/CRIAI:25:1:13AkinyoolaA. L.AdediranI. A.AsaleyeC. M.BolarinwaA. R.Risk factors for osteonecrosis of the femoral head in patients with sickle cell disease20093349239262-s2.0-6834910429210.1007/s00264-008-0584-1BuckJ.DaviesS. C.Surgery in sickle cell disease20051958979022-s2.0-2644460685710.1016/j.hoc.2005.07.004MukisiM. M.BashounK.BurnyF.Sickle-cell hip necrosis and intraosseous pressure20099521341382-s2.0-6524917846510.1016/j.otsr.2009.01.001WallE. J.Legg-Calve-Perthes' disease199911176792-s2.0-003258823510.1097/00008480-199902000-00015RuedaJ. C.DuqueM. A. Q.MantillaR. D.Iglesias-GamarraA.Osteonecrosis and antiphospholipid syndrome20091531301322-s2.0-6764968431310.1097/RHU.0b013e31819dbd20ShimK.MacKenzieM. J.WinquistE.Chemotherapy-associated osteonecrosis in cancer patients with solid tumours: a systematic review20083153593712-s2.0-4244914261410.2165/00002018-200831050-00001BubbarV.Las HerasF.AmatoD.PritzkerK. P. H.GrossA. E.Total hip replacement in Gaucher's disease: effects of enzyme replacement therapy20099112162316272-s2.0-7224911159910.1302/0301-620X.91B12.22515LebelE.PhillipsM.ElsteinD.ZimranA.ItzchakiM.Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease20098022012042-s2.0-6544917009510.3109/17453670902930032MatosM. A.de AlencarR. W.da Rocha MatosS. S.Avascular necrosis of the femoral head in HIV infected patients200711131342-s2.0-34347408080LiebermanJ. R.BerryD. J.MontM. A.AaronR. K.CallaghanJ. J.RajadhyakshaA. D.UrbaniakJ. R.Osteonecrosis of the hip: management in the 21st century2003523373552-s2.0-0037852061BaksiD. P.PalA. K.BaksiD. D.Long-term results of decompression and muscle-pedicle bone grafting for osteonecrosis of the femoral head200933141472-s2.0-5944910399010.1007/s00264-007-0455-1Assouline-DayanY.ChangC.GreenspanA.ShoenfeldY.GershwinM. E.Pathogenesis and natural history of osteonecrosis2002322941242-s2.0-003681033710.1053/sarh.2002.33724bAaronR. K.CallaghanJ. J.RosenbergA. G.RubashH.Osteonecrosis: etiology, pathophysiology and diagnosis1998Philadelphia, Pa, USALippencott-RavenKenzoraJ. E.GlimcherM. J.Accumulative cell stress: the multifactorial etiology of idiopathic osteonecrosis19851646696792-s2.0-0022383143JonesL. C.HungerfordD. S.Osteonecrosis: etiology, diagnosis, and treatment20041644434492-s2.0-304258070210.1097/01.moo.0000127829.34643.fdAdekileA.HaiderM. Z.MaroufR.AdekileA. D.HLA-DRB1 alleles in Hb SS patients with avascular necrosis of the femoral head20057918102-s2.0-1804438442410.1002/ajh.20311ChangJ. D.HurM.LeeS. S.YooJ. H.LeeK. M.Genetic background of nontraumatic osteonecrosis of the femoral head in the Korean population20084665104110462-s2.0-4464912145710.1007/s11999-008-0147-1ChaoY. C.WangS. J.ChuH. C.ChangW. K.HsiehT. Y.Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver20033854314362-s2.0-004132774510.1093/alcalc/agg106ChenW. M.LiuY. F.LinM. W.ChenI. C.LinP. Y.LinG. L.JouY. S.LinY. T.FannC. S. J.WuJ. Y.HsiaoK. J.TsaiS. F.Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12q1320047523103172-s2.0-324271327810.1086/422702DaiX. L.HongJ. M.OhB.ChoY. S.LeeJ. Y.ParkE. K.KimC. Y.KimS. Y.KimT. H.Association analysis of Tissue factor pathway inhibitor polymorphisms and haplotypes with Osteonecrosis of the femoral head in the Korean population20082654904952-s2.0-58049100393GlueckC. J.FreibergR.TracyT.StroopD.WangP.Thrombophilia and hypofibrinolysis: pathophysiologies of osteonecrosis199733443562-s2.0-0031033325GlueckC. J.FreibergR. A.BoppanaS.WangP.Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis20089010222022292-s2.0-5354911081010.2106/JBJS.G.00616GlueckC. J.FreibergR. A.FontaineR. N.TracyT.WangP.Hypofibrinolysis, thrombophilia, osteonecrosis200138619332-s2.0-0035029684GlueckC. J.FreibergR. A.OgheneJ.FontaineR. N.WangP.Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur20078911246024682-s2.0-3604897813910.2106/JBJS.F.01421HadjigeorgiouG.DardiotisE.DardiotiM.KarantanasA.DimitrouliasA.MalizosK.Genetic association studies in osteonecrosis of the femoral head: mini review of the literature2008371172-s2.0-3634895452210.1007/s00256-007-0395-2HeW.LiK.Incidence of genetic polymorphisms involved in lipid metabolism among Chinese patients with osteonecrosis of the femoral head20098033253292-s2.0-7424908353510.3109/17453670903025378HongJ. M.KimT. H.KimH. J.ParkE. K.YangE. K.KimS. Y.Genetic association of angiogenesis- and hypoxia-related gene polymorphisms with osteonecrosis of the femoral head20104253763852-s2.0-7795349481710.3858/emm.2010.42.5.039HungerfordD. S.JonesL. C.Asymptomatic osteonecrosis: should it be treated?20044291241302-s2.0-964426807110.1097/01.blo.0000150275.98701.4eJonesL. C.MontM. A.LeT. B.PetriM.HungerfordD. S.WangP.GlueckC. J.Procoagulants and osteonecrosis20033047837912-s2.0-0037384606KimT. H.BaekJ. I.HongJ. M.ChoiS. J.LeeH. J.ChoH. J.ParkE. K.KimU. K.KimS. Y.Significant association of SREBP-2 genetic polymorphisms with avascular necrosis in the Korean population20089, article 942-s2.0-5784913499810.1186/1471-2350-9-94KimT. H.HongJ. M.KimH. J.ParkE. K.KimS. Y.Lack of association of MTHFR gene polymorphisms with the risk of osteonecrosis of the femoral head in a Korean population20102943433482-s2.0-7795602485910.1007/s10059-010-0054-7KimT. H.HongJ. M.LeeJ. Y.OhB.ParkE. K.LeeC. K.BaeS. C.KimS. Y.Promoter polymorphisms of the vascular endothelial growth factor gene is associated with an osteonecrosis of the femoral head in the Korean population20081632872912-s2.0-3974917049310.1016/j.joca.2007.06.017KimT. H.HongJ. M.OhB.ChoY. S.LeeJ. Y.KimH. L.LeeJ. E.HaM. H.ParkE. K.KimS. Y.Association of polymorphisms in the Interleukin 23 receptor gene with osteonecrosis of femoral head in Korean population20084044184262-s2.0-5194911007510.3858/emm.2008.40.4.418KimT. H.HongJ. M.OhB.ChoY. S.LeeJ. Y.KimH. L.ShinE. S.LeeJ. E.ParkE. K.KimS. Y.Genetic association study of polymorphisms in the catalase gene with the risk of osteonecrosis of the femoral head in the Korean population2008169106010662-s2.0-4914911101210.1016/j.joca.2008.02.004KimT. H.HongJ. M.ShinE. S.KimH. J.ChoY. S.LeeJ. Y.LeeS. H.ParkE. K.KimS. Y.Polymorphisms in the Annexin gene family and the risk of osteonecrosis of the femoral head in the Korean population20094511251312-s2.0-6734914958710.1016/j.bone.2009.03.670KooK. H.LeeJ. S.LeeY. J.KimK. J.YooJ. J.KimH. J.Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis2006248172217282-s2.0-3374698967510.1002/jor.20164KuribayashiM.FujiokaM.TakahashiK. A.AraiY.HirataT.NakajimaS.YoshimuraN.SatomiY.NishinoH.KondoK.FukushimaW.HirotaY.KuboT.Combination analysis of three polymorphisms for predicting the risk for steroid-induced osteonecrosis of the femoral head20081342973032-s2.0-4964908641110.1007/s00776-008-1244-4Pierre-JacquesH.GlueckC. J.MontM. A.HungerfordD. S.Familial heterozygous protein-s deficiency in a patient who had multifocal osteonecrosis: a case report1997797107910842-s2.0-0030805655ZalavrasC. G.VartholomatosG.DokouE.MalizosK. N.Genetic background of osteonecrosis: associated with thrombophilic mutations?20044222512552-s2.0-2542494950GlueckC. J.FreibergR. A.WangP.Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head20084665103410402-s2.0-4464908639910.1007/s11999-008-0148-0JonesJ. P.Jr.Fat embolism, intravascular coagulation, and osteonecrosis19932922943082-s2.0-0027321087CuiQ.WangG. J.BalianG.Steroid-induced adipogenesis in a pluripotential cell line from bone marrow1997797105410632-s2.0-0030858452CuiQ.WangG. J.SuC. C.BalianG.Lovastatin prevents steroid induced adipogenesis and osteonecrosis19973448192-s2.0-0031278834LiX.CuiQ.KaoC.WangG. J.BalianG.Lovastatin inhibits adipogenic and stimulates osteogenic differentiation by suppressing PPARγ2 and increasing Cbfa1/Runx2 expression in bone marrow mesenchymal cell cultures20033346526592-s2.0-014175065110.1016/S8756-3282(03)00239-4LiX.JinL.CuiQ.WangG. J.BalianG.Steroid effects on osteogenesis through mesenchymal cell gene expression20051611011082-s2.0-1324425537910.1007/s00198-004-1649-7DrescherW.BüngerM. H.WeigertK.BüngerC.HansenE. S.Methylprednisolone enhances contraction of porcine femoral head epiphyseal arteries20044231121172-s2.0-2942729753FengY.YangS. H.XiaoB. J.XuW. H.YeS. N.XiaT.ZhengD.LiuX. Z.liaoY. F.Decreased in the number and function of circulation endothelial progenitor cells in patients with avascular necrosis of the femoral head201046132402-s2.0-7204911078710.1016/j.bone.2009.09.001KabataT.MatsumotoT.YagishitaS.WakayamaT.IsekiS.TomitaK.Vascular endothelial growth factor in rabbits during development of corticosteroid-induced osteonecrosis: a controlled experiment20083512238323902-s2.0-5734912624510.3899/jrheum.070838KaneshiroY.OdaY.IwakiriK.MasadaT.IwakiH.HirotaY.KondoK.TakaokaK.Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis20068043964022-s2.0-3374924851410.1016/j.clpt.2006.07.004KerachianM. A.SéguinC.HarveyE. J.Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action20091143-51211282-s2.0-6324910227510.1016/j.jsbmb.2009.02.007KitajimaM.ShigematsuM.OgawaK.SugiharaH.HotokebuchiT.Effects of glucocorticoid on adipocyte size in human bone marrow20074031501562-s2.0-3454868234010.1007/s00795-007-0367-6MasadaT.IwakiriK.OdaY.KaneshiroY.IwakiH.OhashiH.TakaokaK.Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid-induced osteonecrosis in a rabbit model200826191952-s2.0-3804908565910.1002/jor.20484OkazakiS.NishitaniY.NagoyaS.KayaM.YamashitaT.MatsumotoH.Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway20094832272322-s2.0-6134915437910.1093/rheumatology/ken462SuhK. T.KimS. W.RohH. L.YounM. S.JungJ. S.Decreased osteogenic differentiation of mesenchymal stem cells in alcohol-induced osteonecrosis20054312202252-s2.0-1324427950910.1097/01.blo.0000150568.16133.3cTakano-MurakamiR.TokunagaK.KondoN.ItoT.KitaharaH.ItoM.EndoN.Glucocorticoid inhibits bone regeneration after osteonecrosis of the femoral head in aged female rats2009217151582-s2.0-6304914004410.1620/tjem.217.51VarogaD.DrescherW.PufeM.GrothG.PufeT.Differential expression of vascular endothelial growth factor in glucocorticoid-related osteonecrosis of the femoral head200946712327332822-s2.0-7044953460910.1007/s11999-009-1076-3WangB. L.SunW.ShiZ. C.LouJ. N.ZhangN. F.ShiS. H.GuoW. S.ChengL. M.YeL. Y.ZhangW. J.LiZ. R.Decreased proliferation of mesenchymal stem cells in corticosteroid-induced osteonecrosis of femoral head20083154442-s2.0-64949160868WangY.YinL.LiY.LiuP.CuiQ.Preventive effects of puerarin on alcohol-induced osteonecrosis20084665105910672-s2.0-4464915504510.1007/s11999-008-0178-7WeinsteinR. S.NicholasR. W.ManolagasS. C.Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip2000858290729122-s2.0-003445653910.1210/jc.85.8.2907YinL.LiY. B.WangY. S.Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures: mechanism of steroid-induced osteonecrosis200611975815882-s2.0-33646826837GlueckC. J.FreibergR. A.CrawfordA.GruppoR.RoyD.TracyT.Sieve-SmithL.WangP.Secondhand smoke, hypofibrinolysis, and Legg-Perthes disease19983521591672-s2.0-0031841753AsanoT.TakahashiK. A.FujiokaM.InoueS.OkamotoM.SugiokaN.NishinoH.TanakaT.HirotaY.KuboT.ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation200313116756822-s2.0-1214429084510.1097/00008571-200311000-00003PritchettJ. W.Statin therapy decreases the risk of osteonecrosis in patients receiving steroids20013861731782-s2.0-0035035839GlueckC. J.FreibergR. A.SieveL.WangP.Enoxaparin prevents progression of Stages I and II osteonecrosis of the hip20054351641702-s2.0-2044436544910.1097/01.blo.0000157539.67567.03JonesJ. P.Jr.Fat embolism and osteonecrosis19851645956332-s2.0-0022350720Paul-JonesJ.Jr.Intravascular coagulation and osteonecrosis199227741532-s2.0-0026518233JonesJ. P.Jr.Alcoholism, hypercortisonism, fat embolism and osseous avascular necrosis. 197120013934122-s2.0-0035653441WangG. J.CuiQ.BalianG.The pathogenesis and prevention of steroid induced osteonecrosis20003702953102-s2.0-0033969351WangG. J.SweetD. E.RegerS. I.Fat-cell changes as a mechanism of avascular necrosis of the femoral head in cortisone-treated rabbits19775967297352-s2.0-0017717144DayS.OstrumR. F.ChaoE. Y. S.RubinC. T.AroH. T.EinhornT. A.BuckwalterJ.EinhornT. A.SimonS. R.Bone injury, regeneration and repairRosemont, Ill, USAAmerican Academy of Orthopaedic Surgeons372375GlimcherM. J.KenzoraJ. E.The biology of osteonecrosis of the human femoral head and its clinical implications: II. The pathological changes in the femoral head as an organ and in the hip joint19791392833122-s2.0-0018422401GlimcherM. J.KenzoraJ. E.The biology of osteonecrosis of the human femoral head and its clinical implication: I. Tissue biology19791382843092-s2.0-0018747525GlimcherM. J.KenzoraJ. E.The biology of osteonecrosis of the human femoral head and its clinical implications. III. Discussion of the etiology and genesis of the pathological sequelae; comments on treatment19791402733122-s2.0-0018324958PhemisterD. B.Repair of bone in the presence of aseptic necrosis resulting from fractures, transplantations, and vascular obstruction20058736722-s2.0-14644436416PhemisterD. B.Treatment of the necrotic head of the femur in adults194915566ChandlerF. A.Coronary disease of the hip. 194920013867102-s2.0-0035344280AtsumiT.KurokiY.YamanoK.A microangiographic study of idiopathic osteonecrosis of the femoral head19892461861942-s2.0-0024469160CruessR. L.Osteonecrosis of bone: current concepts as to etiology and pathogenesis198620830392-s2.0-0022513615HungerfordD. S.ZizicT. M.Pathogenesis of ischemic necrosis of the femoral head19832492622-s2.0-0020988429JonesJ. P.Jr.BehnkeA. R.Jr.Prevention of dysbaric osteonecrosis in compressed air workers19781301181282-s2.0-0018187545AsanoT.TakahashiK. A.FujiokaM.InoueS.SatomiY.NishinoH.TanakaT.HirotaY.TakaokaK.NakajimaS.KuboT.Genetic analysis of steroid-induced osteonecrosis of the femoral head2003833293332-s2.0-003879780210.1007/s10776-003-0646-7GlueckC. J.FontaineR. N.GruppoR.StroopD.Sieve-SmithL.TracyT.WangP.The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis19993661331462-s2.0-0032820732InoueS.HoriiM.AsanoT.FujiokaM.OguraT.ShibataniM.KimW. C.NakagawaM.TanakaT.HirotaY.KuboT.Risk factors for nontraumatic osteonecrosis of the femoral head after renal transplantation2003867517562-s2.0-914422635210.1007/s00776-003-0716-9Al-MousawiF. R.MalkiA. A.Managing femoral head osteonecrosis in patients with sickle cell disease2007552822892-s2.0-34848878423De GheldereA.NdjokoR.DocquierP. L.MousnyM.RomboutsJ. J.Orthopaedic complications associated with sickle-cell disease20067267417472-s2.0-33846004776EholiéS. P.OuimingaM.EhuiE.NzunetuG.OuattaraS. I.KonanA. V.AnglaretX.BissagnénéE.Avascular osteonecrosis of the femoral head in three West African HIV-infected adults with heterozygous sickle cell disease2009147101110142-s2.0-7224910670510.3851/IMP1398Mukisi-MukazaM.ManicomO.AlexisC.BashounK.DonkerwolckeM.BurnyF.Treatment of Sickle cell disease's hip necrosis by core decompression: a prospective case-control study20099574985042-s2.0-7214909626110.1016/j.otsr.2009.07.009BjörkmanA.SvenssonP. J.HillarpA.BurtscherI. M.RünowA.BenoniG.Factor V Leiden and prothrombin gene mutation: risk factors for osteonecrosis of the femoral head in adults20044251681722-s2.0-4043052344KemperJ. W.BaggenstossA. H.SlocumbC. H.The relationship of therapy with cortisone to the incidence of vascular lesions in rheumatoid arthritis19575831851KooK. H.KimR.KimY. S.AhnI. O.ChoS. H.SongH. R.ParkY. S.KimH.WangG. J.Risk period for developing osteonecrosis of the femoral head in patients on steroid treatment20022142993032-s2.0-003669297010.1007/s100670200078NagasawaK.TadaY.KoaradaS.HoriuchiT.TsukamotoH.MuraiK.UedaA.YoshizawaS.OhtaA.Very early development of steroid-associated osteonecrosis of femoral head in systemic lupus erythematosus: prospective study by MRI20051453853902-s2.0-1994440183810.1191/0961203305lu2103oaFisherD. E.The role of fat embolism in the etiology of corticosteroid induced avascular necrosis: clinical and experimental results197813068802-s2.0-0017817135GoldE. W.FoxO. D.WeissfeldS.CurtissP. H.Corticosteroid-induced avascular necrosis: an experimental study in rabbits19781352722802-s2.0-0018128392MiyanishiK.YamamotoT.IrisaT.YamashitaA.JingushiS.NoguchiY.IwamotoY.Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis20023011851902-s2.0-003613792610.1016/S8756-3282(01)00663-9WarnerJ. J. P.PhilipsJ. H.BrodskyG. L.ThornhillT. S.Studies of nontraumatic osteonecrosis. Manometric and histologic studies of the femoral head after chronic steroid treatment: an experimental study in rabbits19872251281402-s2.0-0023507295WeinsteinR. S.JilkaR. L.Michael ParfittA.ManolagasS. C.Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts end osteocytes by glucocorticoids potential mechanisms of their deleterious effects on bone199810222742822-s2.0-0032528180CuiQ.WangG. J.BalianG.Pluripotential marrow cells produce adipocytes when transplanted into steroid-treated mice200041145562-s2.0-0034057844DrescherW.SchneiderT.BeckerC.HobolthL.RütherW.BüngerC.HansenE. S.Effect of methylprednisolone on reperfusion after femoral head ischemia20024022702772-s2.0-0036711760ZhongQ.SridharS.RuanL.DingK. H.XieD.InsognaK.KangB.XuJ.BollagR. J.IsalesC. M.Multiple melanocortin receptors are expressed in bone cells20053658208312-s2.0-2094443490610.1016/j.bone.2005.01.020MatsuoK.HirohataT.SugiokaY.IkedaM.FukudaA.Influence of alcohol intake, cigarette smoking, and occupational status on idiopathic osteonecrosis of the femoral head19882341151232-s2.0-0023680679FelsonD. T.AndersonJ. J.Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone1987185389029052-s2.0-0023136208WeldonD.The effects of corticosteroids on bone: osteonecrosis (avascular necrosis of the bone)2009103291982-s2.0-6824909433210.1016/S1081-1206(10)60159-7IidaS.HaradaY.ShimizuK.SakamotoM.IkenoueS.AkitaT.KitaharaH.MoriyaH.Correlation between bone marrow edema and collapse of the femoral head in steroid-induced osteonecrosis200017437357432-s2.0-0033994744