Glucocorticoid-induced osteonecrosis in systemic lupus erythematosus patients.

INTRODUCTION

Osteonecrosis (ON) (also known as avascular necrosis (AVN), atraumatic necrosis, aseptic necrosis, or ischemic necrosis) is a pathologic process of bone cell death that typically affects the middle‐aged population. 1 , 2 , 3 ON is a debilitating disease, causing severe pain and compromised quality of life; ON can occur in several circumstances. Trauma is the most common cause. Atraumatic causes of ON are alcohol and glucocorticoid use, hypercholesterolemia, sickle cell anemia, and autoimmune diseases. 4 , 5 , 6 , 7 , 8 , 9 , 10 The use of glucocorticoids is one of the most common causes of nontraumatic ON. 9 , 11 , 12 , 13 , 14

Osteonecrosis is a well‐known complication of adult and juvenile autoimmune diseases 15 , 16 and occurs more frequently in patients with systemic lupus erythematosus (SLE) than in any other rheumatic diseases requiring administration of glucocorticoid. 17 , 18 The prevalence of ON in patients with SLE varies between 1.7% and 52%. However, the etiology of ON in SLE patients is incompletely understood. Among several risk factors, glucocorticoid use is strongly associated with the development of ON in patients with SLE. 19 , 20 , 21 , 22 , 23 At present, strategies for the prevention and treatment of glucocorticoid‐induced ON are limited, with no effective therapy that can reverse the conditions, primarily because the pathogenesis of ON is poorly understood. In this review, we examine recent evidence of the pathogenesis, risk factors, diagnosis, and treatment options of glucocorticoid‐induced ON in SLE patients.

THE ACTION OF GLUCOCORTICOIDS

Corticosteroids, which are endogenous hormones derived from cholesterol in the adrenal glands, have been used exogenously as anti‐inflammatory and immunosuppressive agents for decades. 24 Typically, the human body produces corticosteroids in response to many different stimuli. They are metabolized into glucocorticoids and mineralocorticoids and control many of the body's regulatory processes. Mineralocorticoids such as aldosterone regulate the electrolyte and volume status of the human body. Glucocorticoids, the main actor being cortisol, are endogenously released due to stresses on the body. 25 , 26

HIGHLIGHTS

The use of glucocorticoid treatments is one of the major risk factors for osteonecrosis in SLE patients. The pathogenesis of glucocorticoid‐induced osteonecrosis in SLE patients remains unclear. Glucocorticoid‐mediated changes including changes in angiogenesis, apoptosis of osteocyte, osteoblast, and endothelial cells, as well as adipogenesis and fat hypertrophy, may contribute to the onset of osteonecrosis in SLE patients.

The glucocorticoids from one of the most influential classes of modern medications. Their clinical application began in 1948 when Dr. Philip Showalter Hench used synthetic cortisone for the first time in a patient with rheumatoid arthritis. 14 Due to their immunosuppressive and anti‐inflammatory effects, glucocorticoids have been widely used to manage autoimmune conditions, inflammatory diseases, allergies, and hematological disorders. These disorders include multiple sclerosis, glomerular disease, Sjögren's disease, sarcoidosis, Graves’ disease, SLE, and rheumatoid arthritis. Glucocorticoids are also used for the local symptomatic treatment of osteoarthritis and tenosynovitis.. 27 , 28 However, various side effects of long‐term treatment, such as ON and osteoporosis, have been noted. 29 , 30 , 31

Glucocorticoids robustly impact numerous tissues and cell lineages. They induce apoptosis of immune cells such as T cells, basophils, and eosinophils by modifying cytokine release profiles and dampening the immune response and are used to trigger apoptosis in tumor cells as a treatment for multiple myeloma, Hodgkin's lymphoma, and chronic lymphoblastic leukemia. 32 Glucocorticoids also lead to increased levels of vasoconstriction in peripheral tissues. In addition to the direct impact on immune cells, glucocorticoids lead to changes at the tissue level, leading to side effects such as osteoporosis, euphoria, psychosis, hyperglycemia, and osteonecrosis. 33

GLUCOCORTICOID‐INDUCED OSTEONECROSIS

Methods

A comprehensive and systematic search was performed using the MEDLINE/PubMed (U.S. National Library of Medicine, Bethesda, MD). The database was searched in November 2020 from its inception to 2020 for only articles written in or translated into English. A broad combination of Medical Subject Heading (MeSH) terms were used, including “(systemic lupus erythematosus OR SLE) AND reconstruction AND (osteonecrosis OR avascular osteonecrosis OR aseptic necrosis) AND (glucocorticoids OR corticosteroids).”

Epidemiology

Table 1 summarizes the frequency of ON and the risk factors for the development of ON in SLE patients reported by prospective, retrospective, and cohort studies. The association between SLE and ON was first reported in 1960. 19 Studies have reported incidence rates for ON in SLE patients ranging from 1.7% to 52% (Table 1 ). This wide range reflects the use of different techniques to diagnose ON (from the less sensitive plain film radiograph to the fairly sensitive MRI), variations in glucocorticoid dosing, and different durations of follow‐up. In addition, the wide variation in prevalence may result from a missed diagnosis of asymptomatic ON. 34 Data from prospective studies are similarly variable. 25 , 51 , 91 , 93 , 94 , 103 , 114 , 117 , 118 , 119 , 196 , 199 In one study, the incidence of ON increased constantly during each of the first 5 years after a diagnosis of SLE. Only one (0.27%) of 365 SLE patients developed ON in the first year after diagnosis, compared to 0.88% and 3.3% during the second and fourth years after diagnosis. 35 In another long‐term cohort study, 50% of SLE‐diagnosed patients developed ON within 2 years of diagnosis. 36 In the largest cohort of SLE patients with symptomatic ON, 234 of 1729 (13.5%) patients with SLE had 581 sites of symptomatic ON. The hips and knees were the most common of these sites and 47% of the patients had multiple sites involved. 37

The effect of genetic ancestry and ethnicity on the incidence of ON in SLE patients is poorly characterized. Different cultures have varying genetic risks for developing SLE, 38 and different ethnicities have varying rates of SLE patients developing ON. At present, specific genes or genetic markers specific to certain ethnicities modifying the risk of ON in SLE patients have not been clearly established.

Most of the studies estimating the prevalence of ON development in SLE patients were conducted in Asia (Table 1 ). The prevalence of ON in the general population is low. The average estimated number of annual prevalent cases of ON was 28.91 per 100,000 in Korea, based on the Medical Claims Database of the National Health Insurance Corporation. 38 Although the prevalence of ON in the general population in the United States remains unclear, newly diagnosed patients are estimated to be between 20,000 and 30,000 every year in the United States. Cozen et al reported 7.69% Hispanic, 19.23% Black, and 57.69% white for the incidence of ON in American SLE patients. 39 A prospective study at the University of Toronto Lupus Clinic has followed SLE patients since 1970. Among 235 ON patients, the distribution of ON was in 67.1% in Caucasian patients, 15.4 % in Black patients, 8.1% in Asian patients, and 9.4% in others ethnicities. 40 Arranow et al showed that among eight African‐American SLE patients, 75% of whom developed ON, 41 suggesting that higher disease activity and higher doses of glucocorticoids in African‐American SLE patients may be associated with the higher incidence of ON in patients of African‐American origin. Demographic data of the prevalence of ON in SLE patients needs to be determined to estimate the burden of ON on different ethnicities.

Although ON is a prevalent complication in patients with rheumatic diseases as a whole, the incidence rate of ON is higher in patients with SLE compared to non‐SLE patients (Table 2 ). 17 , 18 , 23 , 42 A retrospective study investigated that the frequency of ON as determined from discharge diagnoses of patients with various rheumatic diseases hospitalized at the Clinical Center of the National Institutes of Health from 1962 to 1977. 43 A prospective MRI study showed that SLE was the most frequent underlying disease for ON patients who received glucocorticoid therapy from 1986 to 2009. 44 In nationwide epidemiologic surveys conducted in Japan and Sweden in the 2000s, 3 , 45 ON occurred more frequently in patients with SLE than in any other rheumatic diseases requiring the administration of glucocorticoids. Therefore, glucocorticoids maybe not the only risk factor for the incidence of ON in SLE patients.

Pathogenesis

Osteonecrosis is a well‐known comorbidity of patients with SLE. 19 , 20 , 21 , 22 , 42 The use of glucocorticoid therapy is a major risk factor for the incidence of ON in SLE patients. 16 , 17 , 34 , 35 , 37 , 40 , 41 , 43 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 Multiple factors have been implicated in the pathogenesis of ON in patients who use glucocorticoids. 9 , 11 , 12 , 13 As glucocorticoids can induce changes in angiogenesis, intravascular coagulation, apoptosis of bone cells, and fat hypertrophy, glucocorticoid‐mediated alterations may contribute to bone ischemia and necrosis by both intra‐ and extraluminal obliteration. Figure 1 summarizes the current understanding of the pathogenesis of ON in SLE patients, which is likely the combined result of multiple factors. However, the pathogenesis of ON in SLE patients remains unclear.

Hypercoagulability and inhibition of angiogenesis

Coagulation and congestion lead to decreased blood flow and oxygen delivery through the microvasculature, leading to an increased risk of developing ON. A genetic association between inherited thrombophilia, hypofibrinolysis, and ON has been established. 61 It has been suggested that hypofibrinolysis results in increased clot formation, decreased blood flow, and a hypoxic environment within the bone structure, which may lead to ON. The dysregulation of coagulation and complement‐related pathways has been found in patients with SLE and contributes to SLE disease activity. 62 Furthermore, the presence of antiphospholipid antibodies in SLE can lead to a hypercoagulable state, which is believed to contribute to ON in SLE by promoting intravascular coagulation and congestion. 63 However, the association between ON and antiphospholipid antibodies in SLE patients remains controversial. The role of antiphospholipid antibodies in the occurrence of ON has been found in only a few studies, 23 , 55 , 64 , 65 , 66 while others have not exhibited any association with ON. 67

Hypercoagulability can be compounded by the glucocorticoid‐mediated inhibition of angiogenesis. 68 Glucocorticoids can directly injure endothelial cells, 69 enhance hypercoagulability, 70 and inhibit angiogenesis by inducing apoptosis of bone marrow endothelial cells (BMECs). 71 Glucocorticoids can inhibit angiogenesis by diminishing proliferating capillary haemangiomas, 72 tube‐like structure formation, 73 new vessel formation, 74 and angiogenic factor generation. 75 This decrease in normal angiogenesis, caused by glucocorticoids, in the femoral head and bone tissue can lead to ON. Atsumi et al found that all patients with unilateral glucocorticoid‐induced ON had abnormal superior retinacular arteries, small arterial penetration, and interruption of revascularization in the contralateral normal hips. 76 Glucocorticoids, in combination with active inflammation or surgery, can also contribute to a hypercoagulable state. 77 ON does not result from a single episode of impaired blood supply, but from a chronic blockade of microcirculation, 78 the alteration of BMECs, 79 and transcriptomic changes in bone microvascular endothelial cells. 80 , 81 Apoptotic endothelial cell death has been hypothesized to function as a mechanism for the capillary rarefaction in glucocorticoid‐mediated hypertension. 82 In turn, glucocorticoid‐induced hypertension in the femoral head disturbs the blood flow in the femoral head vessels and aborts the repair process. 12

Apoptosis of osteoblasts and osteocytes

The apoptosis of osteoblasts or osteocytes plays a crucial role in the pathogenesis of ON. 83 , 84 , 85 Increased apoptotic osteoblasts or osteocytes have been observed in mice and humans under glucocorticoid therapy. 86 It has been reported that apoptosis of osteocytes in the femoral head increases during the development of ON, and the percentage of apoptotic cells is significantly increased in the femoral heads of patients with glucocorticoid‐induced ON. However, apoptotic bone cells are notably rare in bone from patients with alcohol‐induced ON 87 , 88 and absent in those with trauma and sickle cell‐induced ON. Apoptosis of the bone cells can result from increased inducible nitric oxide synthase (iNOS) and cytochrome C expression 89 and aberrant metabolites in the synovial fluids. 90 Although the death of bone cells is observed in the bone of patients with ON, the correlation between the apoptosis of bone cells and SLE‐associated ON has not been clearly established.

Fat cell hypertrophy

Fat cell hypertrophy and fat emboli have been detected in rabbits after the exposure to high‐dose cortisone for 5 months. 91 Fat emboli can activate the complement pathway, deposit immune complexes, and increase intravascular coagulation, 92 leading to ON. Glucocorticoids can skew the differentiation of bone marrow stem cells into adipocytes cells by upregulating adipocyte transcription factor gene expression and downregulating the gene expression of osteoblast transcription factors. 91 Glucocorticoids increase lipid deposition leading to larger numbers of fat cells when compared to normal ratios of parenchyma in the mesenchymal stem cells of ON patients. 93

In SLE patients, high‐dose glucocorticoids result in an early and rapid drop in bone mass with a marked increase in body fat. 94 These patients also have elevated levels of serum adiponectin 95 and postmenopausal SLE women were found to have altered body composition and increased visceral adipose tissue. 96 These factors, however, were not correlated with glucocorticoid dose. Intraosseous pressure is increased by the growth of fat cells in the intraosseous compartment and results in sinusoidal compression, leading to decreased perfusion of the bone, which may cause ON. 97

RISK FACTORS FOR THE DEVELOPMENT OF ON IN PATIENTS WITH SLE

Glucocorticoid exposure is a well‐recognized risk factor for ON in SLE patients (Table 1 ). 15 , 16 , 17 , 34 , 35 , 39 , 40 , 41 , 43 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 54 , 55 , 56 , 57 , 58 , 59 , 64 , 65 , 66 , 67 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 In particular, the correlation between ON and the doses of glucocorticoid (GC) therapy has been identified in many studies (Table 1 ) and higher doses of GC therapy have been cited as one of the strongest predictive factors for developing ON. Twenty‐four of 49 studies shown in Table 1 found a significant correlation between the dose of GC therapy and the occurrence of ON in patients with SLE. A meta‐analysis suggests that high‐dose glucocorticoid therapy may increase the risk of ON by as much as 10 times. 22 Daily doses greater than 40 mg are associated with increased risk, with the incidence rate climbing by approximately 3.6% for every 10 mg increase. 21 According to a 12‐year longitudinal study, doses greater than 10 mg in combination with high‐intensity GC use (≧80%) are associated with increased risk of osteonecrosis. 113 A recent large cohort study that has followed SLE patients since 1970 utilized multivariate analysis to identify GC dose as a major predicative factor for the incidence of symptomatic ON. 37 However, the association of the duration or route of GC therapy with the incidence of ON remains contentious. Intravenous pulses of methylprednisolone are often used to treat severe symptoms in SLE patients and have significantly higher immunosuppressive and anti‐inflammatory effects compared to other delivery methods for glucocorticoids. 114 Although high‐dose intravenous pulses of methylprednisolone resulted in higher cumulative doses of GCs, its association with the occurrence of ON has conflicting evidence. An MRI study strongly linked GC pulse therapy with the early development of silent ON in SLE patients, 51 and Massardo et al closely related GC pulse therapy to high‐dose intravenous pulses of methylprednisolone. 109 By contrast, several studies have also shown that GC pulse therapy is uncorrelated with ON. 17 , 23 , 53 , 54 , 56 , 63 A nationwide epidemiologic study in South Korea demonstrated that the route of glucocorticoid therapy does not affect SLE patient outcomes and oral and intravenous high‐dose glucocorticoids carry equal risk. 48 Consistently, in recent investigations, GC‐related damages including ON were associated with high cumulative doses and high intensity of oral GCs and lower doses of GC use significantly diminished GC‐induced damages even in the presence of methylprednisolone use. 60 , 113 , 115 These studies also suggest that pulse methylprednisolone may not be an independent association factor for AVN. 50 , 54 , 115 The duration of GC therapy was significantly longer in the AVN group compared to the control group. 17 , 50 However, Oinuma et al found that all osteonecrotic legions were detected very early, within 5 months after starting high‐dose glucocorticoid therapy in 72 patients with SLE. 52 This study suggests that silent ON can occur early after the onset of glucocorticoid therapy. During long‐term, low‐dose glucocorticoid therapy, there were no new cases of ON 116 and spontaneous repairs were even observed. 117 Although the etiology of ON in SLE patients is multifactorial, high‐dose GC use remains a key risk factor for ON.

Studies show that SLE patients are at increased risk of developing ON as compared with patients who have other autoimmune conditions and receive similar doses of glucocorticoids. The risk factors for ON are not limited to glucocorticoids. 19 Many studies have shown that ON in SLE patients is associated with various clinical factors, such as age, sex, disease duration, symptoms of SLE, laboratory factors, medications, and complications of SLE (Table 1 and Figure 2 ). Although the age at the time of glucocorticoid therapy is considered as a risk factor for ON, 104 most adult studies identified that age is not a key risk factor for ON in SLE patients. The incidence of ON is relatively low in growing individuals but rapidly increases in adolescents and adults. 44 There is a report showing a lower incidence of glucocorticoid‐induced ON in pediatric SLE patients (<15 years old) than in adult SLE patients (>20 years old). 104 Another dynamic MRI study identified higher blood supply in the growth plate of the femoral neck in pediatric SLE patients than adult SLE patients after glucocorticoid therapy. 118

ONOsteonecrosis also has an increased incidence in SLE patients who have not been taking high‐dose glucocorticoids. 15 How SLE is an independent risk factor for ON has not yet been elucidated. Disease‐related factors, including Raynaud's phenomenon and vasculitis, also determine ON risk among patients with SLE. 51 , 65 , 100 , 102 , 106 , 110 A long‐term follow‐up study found that SLE recurrence is a risk factor for ON. Among 106 SLE patients, SLE recurrence occurred in 131 joints. The mean time from SLE recurrence to the appearance of new osteonecrotic lesions was 6.2 months. In one single‐center retrospective study with 88 consecutive SLE patients, a high antiphospholipid score was a risk factor for idiopathic ON in SLE patients. 119 There are conflicting results for the association of antiphospholipid antibodies with ON (Table 1 ). Some studies showed a positive correlation, 20 , 66 , 101 while many other studies showed no significant correlation with the incidence of ON in SLE patients. 39 , 46 , 49 , 55 , 58 , 99 , 100 , 102 , 103 , 106 A higher frequency of Cushingoid body habitus showed an association with the incidence of ON in SLE patients. 40 , 46 , 49 , 55 , 109

It is well known that glucocorticoids induce iatrogenic metabolic syndrome. Due to this, hyperlipidemia is considered to be an important risk factor for glucocorticoid‐induced ON in SLE. Twelve prospective studies of glucocorticoid‐induced ON in SLE patients have been conducted (Table 1 ). In addition to a high dosage of glucocorticoids, hyperlipidemia was commonly seen as a risk factor for ON in prospective studies. One prospective study of 78 SLE patients treated with high‐dose prednisolone, showed a correlation between elevated levels of triglyceride and an increased incidence of ON. 100 In addition, the chronic systemic inflammation or high levels of oxidized LDLs in SLE patients can affect the skeletal phenotype by indirectly influencing bone cells. 120 ON can be caused by the partial or total disruption of blood flow to the femoral head, and SLE patients tend to develop ON through a similar mechanism. SLE patients with ON are more likely to have hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor‐1 gene, methylenetetrahydrofolate reductase gene mutation with a higher concentration of homocysteine, low protein S values, and higher lipoprotein(a) levels than controls. 50 SLE patients are invariably encouraged to avoid sunshine exposure, as this increases the risk of vitamin D deficiency. One juvenile SLE study reported that vitamin D deficiency was significantly associated with subjects who had or developed ON. 23 However, the contribution of the autoimmune pathophysiology in SLE disease to the development of ON has not yet been fully clarified.

Disease‐modifying anti‐rheumatic drugs (DMARDs), such as hydroxychloroquine, azathioprine, and sulfasalazine, are becoming more prevalent in the management of autoimmune conditions. However, there are a few studies investigating the impact of DMARDs on rates of developing ON in SLE patients. Six of the eight studies shown in Table 1 reported an inverse correlation between the use of hydroxycholoroquine and ON development, although this difference was not statistically significant. A recent retrospective study of the Taiwanese population involved 1472 children newly diagnosed with SLE, and 1364 of these patients had DMARDs as a part of their management. 98 Although the patients did not have statistically different usages of DMARD's between the ON and non‐ON groups, the cumulative duration of hydrocychloroquine use was significantly correlated with ON. Association between the use of biologic DMARDs, including Bellimumab 121 and Rituximab, and ON in SLE patients has not been established yet, although Rituximab, an anti‐CD20 antibody, has been suggested as a cause of medication‐related ON of the jaw. 122 The use of DMARDs may result in the use of lower doses of glucocorticoids in SLE patients, which may affect the incidence of ON in SLE patients. Overall, the current research is insufficient to understand the impact of DMARD's on ON in SLE patients and further research needs to be conducted to fully understand the correlation between DMARDs and ON.

Recent studies have also revealed some new genetic risk factors for ON in SLE patients. Several association studies using targeted next‐generation sequencing technologies identified single nucleotide variations (SNVs) for developing ON in SLE patients (Table 3 ). Kim et al. have identified that Asp258Asp (exon 6: rs1549758) and Glu298Asp (exon 7: G895T: rs1799983) polymorphisms in the nitric oxide synthase 3 (NOS3) gene may be related to ON susceptibility in SLE patients under the recessive model. 123 A case‐control study demonstrated that rs3813946 in the 5′‐UTR, rs311306 in intron 1, and the rs17615 in exon 10 of the CR2 (complement receptor type 2, complement C3d Receptor 2) gene. 124 A recent study has also identified that SNPs for ON risk in SLE patients include NOS3 (exon 6: c.814G > A, p.E272K), Collagen Type II Alpha 1 Chain (COL2A1, c.3508G > A, rs41263847: exon 29: c.1913C > T: p.T638I, exon 28: c.1706C > T: p.T569I, and rs371445823: exon 8: c.580G > A: p.A194T, exon 7: c.373G > A: p.A125T), 125 and CR2 (rs45573035: exon 2: c.200C > G: p.T67S). 125 Most of the association studies were conducted in Asia and used a small sample size. Since ethnic difference has been identified across many association studies of genetic polymorphisms in ON, further studies for evaluating these SNPs in other ethnicities are needed. More elaborately designed and larger‐scale studies may clarify more SNPs and their functions in the ON susceptibility of SLE patients. The contribution of genetic predisposition to SLE etiology has been increasingly appreciated, and over 100 susceptibility loci for SLE risk have been identified. 126 , 127 However, the genetic predispositions associated with ON susceptibility in SLE patients, including ancestry effects, have not yet been demonstrated. Polymorphism of T786C NOS3 in the promoter was associated with idiopathic ON 128 but not with ON in SLE patients, 123 suggesting the influence of different ethnic groups on genetic variation. Investigation of the prevalence of genetic risk factors associated with ON susceptibility in both the general population and in patients of varying ancestries, is a consideration for a future study. To summarize, understanding the impact of genetic variation may provide new insight into ON and ultimately lead to new treatment methods.

GLUCOCORTICOID‐INDUCED OSTEONECROSIS ANIMAL MODELS

Animal models of ON of the femoral head (ONFH) are indispensable to the understanding of the mechanism, treatment, and prevention modalities for ON of the femoral head. Different animal models for glucocorticoid‐induced ON have been generated. Of all experimental models, rabbits are most commonly used to establish glucocorticoid‐induced ON. 129 However, these studies were not able to develop joint collapse, which was mainly explained by the lower mechanical loading onto the weight‐bearing joints. Administration of a single glucocorticoid proved to be an efficient way to induce ON in rabbits or mice, 130 , 131 resulting in the incidence of ON with this methodology ranging from 10% to 43%. It is necessary to develop an SLE mouse model with a high incidence of glucocorticoid‐induced ON to elucidate the prevention and treatment efficiency of the pharmacological therapy strategies.

Clinical course and diagnosis

Pain

The earliest clinical symptom of ON is bone pain that limits motion, is persistent, and is aggravated by weight‐bearing and activity. 132 When patients have this persistent bone pain, providers typically order imaging studies to further understand the etiology of this bone pain.

Radiology

Conventional radiography is the first‐line investigation for the diagnosis of ON. 13 ON is usually diagnosed by X‐ray and magnetic resonance imaging (MRI); however, imaging studies at present do not have the sensitivity to screen for ON at earlier and more manageable stages. Scanning with MRI is the most sensitive modality for diagnosing ON, although it is costly. 133 The Canadian and American guidelines for SLE recommend radiography as the initial imaging modality for patients suspected of ON, and magnetic resonance imaging (MRI) or single‐photon emission computed tomography (SPECT) if X‐rays are not informative 134 , . 135 Whole‐body short‐TI inversion recovery MRI (STIR MRI) has shown promising results in early studies, suggesting that it may become one of the most sensitive and rapid tools for detecting ON lesions at early stages. One study used whole‐body STIR MRI to evaluate ON in 40 adolescents with SLE who received glucocorticoid treatment; there they found seven patients (17.5%) with ON in the knee, hip, and ankle and 37 ON lesions overall. 136 In addition, MRI can quantify the area of ON. 137 A 20‐year retrospective study showed that among 30 SLE patients, more than half of those treated with glucocorticoids were already in late‐stage ON when clinical manifestations arose. 138 However, at present, there are no universal screening guidelines for ON to catch disease at an early stage when conservative and minimally invasive treatments are indicated. The routine MRI screening of SLE patients may facilitate the early detection of ON; however, other constraints, such as financial considerations and resource scarcity, need to be evaluated.

Staging

Classically, ON presents in the femoral head, but it can lead to isolated lesions in other locations such as the jaw or knees. It can also be multifocal. Detection and classification, using one of the four classification systems (Ficat, UPenn, ARCO, and Japanese Orthopedic Association), are crucial to choosing the appropriate treatment modality. However, there are still no guidelines on the imaging screening of ON in SLE patients.

Classification

The classification system of ONFH is crucial to deciding the appropriate clinical intervention. Four classification systems are used to classify ONFH, regardless of etiology: the Ficat Classification (used most commonly), the University of Pennsylvania System, the Association Research Circulation Osseous (ARCO) System, and the Japanese Orthopedic Association system (Tables 4 , 5 , 6 , 7 , 8 ). 139 Notably, the Association Research Circulation Osseous (ARCO) classification system has undergone revisions recently to eliminate stage 0 and divide stage III into stages IIIA (femoral head depression less than or equal to 2 mm) and stage IIIB (femoral head depression more than 2 mm; see Table 8 ). 140 Future directions of classification may include combining findings from digital subtraction angiography (DSA) and MRI to establish the staging of intraosseous circulation obstruction based on the blood supply status of the femoral head. 141 This staging is based on changes in blood circulation, which can better provide guidance for the treatment strategy to preserve the femoral head preservation, especially in young patients. 141

Musculoskeletal manifestations of SLE

Glucocorticoid‐induced ON frequently develops at the femoral head in the hip 9 but many other sites, such as the knee, shoulder, ankle, and hand can also be affected simultaneously. 142 , 143 , 144 Multifocal ON, a rare variant appearing in only 3.3% of all patients with ON, is defined as the presence of osteonecrotic lesions in three or more separate anatomical sites. 144 Intriguingly, SLE patients receiving long‐term glucocorticoid treatment have a higher incidence of multifocal ON. 37 , 145 , 146 A multicenter study of patients with multifocal ON reported that 38% (38 of 101) of the multifocal ON patients had a previous SLE diagnosis. 146 Of these patients, chronic exposure to glucocorticoid therapy was the most common risk factor (91%). All 101 patients with multifocal disease had femoral head involvement. The most common additional sites were in the knee (96%), shoulder (80%), and ankle (44%) with seven other joints also being implicated. The clinical manifestations associated with multifocal ON appeared to be similar to those with non‐multifocal involvement. Patients with SLE who develop multifocal ON tend to be younger, have several SLE clinical manifestations and serological abnormalities, and most have been exposed to glucocorticoid and immunosuppressive agents. 147 , 148

Treatment

The treatment of glucocorticoid‐induced ON includes non‐operative management and surgical approaches (Figure 3 ). Treatments range from ON prophylactic medications such as bisphosphonates, statins, and anticoagulants, which show mixed efficacy, to surgical interventions for more advanced diseases such as core decompression with and without bone grafting, rotational osteotomy, and hip replacement. The choice of treatments is dependent on the stage of the ON, the size of the lesion, the age of the patient, and the patient's co‐morbidity.

Non‐operative management

There is no uniformly accepted treatment for ON. 149 Various pharmacological agents, such as bisphosphonates, statins, and anticoagulants, have been used to promote viable bone growth within necrotic lesions and alleviate pain and the progression of ON. The effects of these drugs are limited, and additional research is needed to establish the efficacy of these individual agents before routine use of any of them is recommended. However, reports analyzing the effect of non‐operative management for glucocorticoid‐induced ON in SLE patients are limited. Further studies are needed in order to clarify the effects of these treatments on the incidence of ON in SLE patients,

Bisphosphonates

Open‐label studies show that bisphosphonates have shown efficacy in preventing disease progression in ON and in delaying the progression to surgery, 149 , 150 although the efficacy of alendronate, a bisphosphonate, in ON is still controversial. A study by Agarwala et al of 60 ON patients, 10 of whom had SLE, showed that alendronate reduces pain, improves function, and delays ON progression. 151 One study analyzed the time from a diagnosis of ON to hip replacement as a marker for the ability of alendronate to minimize disease progression. In the placebo control group, seven hips had a total hip arthroplasty (THA) in the first 12 months and 12 hips by 18 months. In the alendronate group, only six patients progressed to THA and the proportion of hips that developed collapse was also significantly smaller. In contrast, another two‐year, multicenter, prospective, randomized, double‐blind, placebo‐controlled trial study stated that there was no statistical difference in progression to THA between placebo (13%) and bisphosphonate (15%) usage. 152 Overall, the evidence of the effects of bisphosphonates on glucocorticoid‐induced ON with SLE is mixed, and further studies are needed to evaluate the effect of various bisphosphonates on glucocorticoid‐induced ON for SLE patients.

Statins

Hyperlipidemia has also been associated with ON. 8 Lipid‐lowering agents such as atorvastatin and Lipitor have been tested as treatments for ON in a randomized controlled clinical trial 153 and in animal models. 154 Lipid‐lowering agents are thought to prevent ON by reducing the differentiation of marrow pluripotent cells into fat cells, which may lead to increased intraosseous pressure. One database review of 284 patients found a reduced incidence of glucocorticoid‐induced ON among individuals who were on a statin before the initiation of glucocorticoid treatment. 155 Only 1% of patients develop ON over the 5‐year period. Prospective clinical studies are needed to clarify the effects of statins on glucocorticoid‐induced ON with SLE.

Anticoagulants

Anticoagulants, such as warfarin or enoxaparin, have not significantly prevented the progression of disease in ON patients with SLE despite a decreasing tendency to progress to THA. 156 One study evaluated 60 patients with SLE receiving high‐dose glucocorticoid treatment, treating about half of the patients for anticoagulation with warfarin. 157 Although the differences were not statistically significant, fewer patients in the warfarin group developed ON compared with the control group (21% versus 33%). Similarly, a prospective study of 35 hips with Ficat stage 1 and two cases of ON with thrombophilia reported that with enoxaparin (60 mg/day for three months) only 20% of patients showed progression of the disease over a 2‐year period. 158 Another prospective study using warfarin in SLE showed no statistically significant effect of anticoagulant therapy on the prevention of glucocorticoid‐induced ON. 159 To summarize, the data suggest that anticoagulants did not significantly alter the progression nor affect the prevention of ON.

Surgical Management

Total hip arthroplasty has become most the effective treatment for ON, while non‐arthroplasty treatment options for the management of ON have produced variable results in SLE‐associated ON. 160 As ON typically affects younger adults, as compared to osteoarthritis, the preservation of the hip joint and the early treatment are equally important for preventing the progression to collapse. Therefore, the interventions including core decompression, stem cell therapy, osteotomies, and non‐vascularized or vascularized bone grafting have been selected in the early stages of ON, with total joint replacement being reserved for end stage disease.

Total joint arthroplasty

Total hip arthroplasty is often seen as the last resort and the most aggressive treatment of ON, typically reserved for late‐stage ON when cortical collapse seems imminent. Despite the advanced stage of the disease, the outcomes of this procedure have been fairly positive. Among SLE patients, the annual numbers of total hip joints arthroplasties, partial hip joints arthroplasties, and total knee arthroplasties have shown a statistically significant increase over time. 161 Figgie et al reviewed the population‐based rate of joint replacement in SLE patients from 1991 to 2005 and demonstrated that the rate of arthroplasty in patients with SLE has been increased from 17% in 1991 to 38% in 2005. 162 However, the rate of THA for ON has been decreased from 53% in 1991 to 24% in 2005. 162 Chen et al used The PearlDiver patient records database and reported a 190% of increase in THA for ON in patients with SLE from 2007 to 2015. 163 THA plays a particularly important role in the treatment of ON in patients with SLE as these patients progress to late stages much more rapidly than other etiologies of ON. Musculoskeletal pain and function are of great concern for these patients.

Core decompression

Core decompression (CD), the most frequently used procedure, preserves the structure of the hip and relieves bone pain. 164 It can reduce intraosseous pressure, penetrate area hardened by fibrotic changes, promote the growth of blood vessels along the tunnel into the femoral head, enhance the formation of new bone, and delay ON. 165 CD is suitable for early‐ stage ON patients. 166 , 167 In addition, CD can provide better clinical or imaging results. 164 However, there is an element of selection bias in these results, given that the majority of patients receive CD at early stages of the disease. 164 An additional long‐term study suggested that CD can be an effective alternative treatment for an early stage of glucocorticoid‐associated ON in SLE patients, especially relieving pain and postponing progression to THA. 168 During the past decade, the efficacy of CD has been improved and techniques such as single large‐diameter drilling and multiple small‐diameter drilling with and without bone grafting have been developed. 169 It has been suggested that CD plus autologous bone therapy or cytotherapy is a better way to reduce the failure rate of conservative treatment in patients with early and mid‐stage ON. 170 , 171

Stem cell treatment

The application of stem cell treatment, which many previously considered experimental, 172 has gained accumulating evidence for clinical improvement. 173 , 174 , 175 A 30‐year follow‐up prospective randomized study based on 125 consecutive patients, bone marrow cell transplantation can be an effective treatment for early‐stage femoral head ON. Bone marrow cell transplantation can delay the progression of the disease, reduce the incidence of collapse, and avoid joint replacement. 176 The study also found that after excluding some factors that may affect clinical and radiological results, CD and bone marrow mesenchymal stem cells (BM‐MSCs) implantation was an effective method to reduce the THA conversion rate of ON patients, especially for the early‐stage patients. However, CD and BM‐MSCs did not prevent the progress of ARCO staging. 176 A recent systematic review and meta‐analysis also found that compared with CD treatment alone, the use of MSCs in early stages of ON patients lowered the rates of disease progression and failure and led to fewer minor complications. 177 , 178 Implantation of ex‐vivo expanded BM‐MSCs, in combination with CD, has shown promise as a treatment for ON. 179 In a study conducted by Mardones et al, five ON patients received ex‐vivo expanded MSCs and the hip function of all patients significantly improved. Concentrated autologous bone marrow aspirate transplantation (CABMAT) slows the progression of ON to THA with only minor side effects. 180

The beneficial effect of stem‐cell therapy has also been shown in the SLE patient population as well. Yoshikoga et al demonstrated that CABMAT significantly improved pain and Harris Hip Scores in eight of nine hips from 18 ON patients with SLE. 181 Mid‐term follow up for CABMAT showed that ON patients with SLE who received CABMAT had lower conversion rates to THA. 182 A recent case report using autologous bone marrow aspirate concentrate (BMAC) injections to treat an 18‐year‐old female SLE patient with glucocorticoid‐related ON in bilateral knees showed that after 24 months follow‐up, the patient had improved in function and had pain relief. 183 Bone marrow aspirate transplantation has the advantages of minimal invasiveness, low cost, simplicity, and the ability to be used in combination to augment other treatment methods as well. 173

Osteotomies

Transtrochanteric rotational osteotomy, an osteotomy procedure predominantly performed in Asia, shifts the weight‐bearing area to a field of healthy bone, relieving the pressure of weight on necrotic bone. 184 Studies show that the 5‐year and 10‐year hip survival rate of ON patients after transtrochanteric rotational osteotomy is satisfactory in both Asian patients and non‐Asian populations. 184 After proper selection of patients, accurate surgical procedures, and appropriate postoperative rehabilitation treatment, transtrochanteric rotational osteotomy can be used as an effective hip protection measure for young patients, people with active symptomatic ON, and ON patients with SLE 185 , . 186

Vascularized and non‐vascularized bone grafting

Bone‐grafting, most commonly as an autogenous vascularized bone or vascularized bone harvested from the fibula or iliac crest, has also been described in the literature as a treatment method for ON. 187 , 188 Both vascularized and non‐vascularized bone grafts have been shown to improve outcomes for ON patients by improving joint function and delaying joint repair surgery. 189 , 190 A recent systematic review of 15 studies demonstrated that compared with core decompression and non‐vascularized fibular bone grafting, free vascularized fibular transplantation is a better treatment option, especially in young patients who have early‐stage ON, before collapse. 189 Eighty hips belonging to 50 SLE patients who underwent free vascularized fibular grafting for ONFH were followed for more than 2 years (average 4.3 years) and the hip score improved in all patients. 190 Numerous studies have shown that a non‐vascularized fibular allograft combined with CD and bone grafting is a cost‐effective way of improving the survival rate for an early stage of ONFH, delaying disease progression, and improving the quality of patients' lives. 191 , 192

Complication of surgical intervention

Although total joint arthroplasty for SLE patients can generally obtain good or excellent clinical results and improve the quality of life, SLE patients receiving total joint arthroplasty have a higher complication rate than non‐SLE counterparts, which requires various measures to prevent. 193 , 194 , 195 Both SLE and long‐term glucocorticoid use increase the risk of perioperative complications such as wound infection. 160 Lin et al showed a dose‐dependent relationship between preoperative GC treatment and postoperative complications and mortality in SLE patients. 196 In patients with SLE, disease activity and infection are the two main causes of death postoperatively. 197 However, the recent studies showed a lower infection rate, which is likely due to careful patient selection and increased provider precautions. 160 , 163 , 193 Although the use of GCs in SLE patients may increase the risk of wound infection, proper care can improve the infection rate. Another consideration is thrombophilia or hypercoagulability, which are often prevalent in SLE patients. In addition, the prevalence of antiphospholipid syndrome is increased from 1% to 5% in healthy individuals to approximately one third of SLE patients. 198 The adequate use of prophylactic anticoagulation following orthopedic surgery may diminish the incidence of thromboembolic complications. 199 It is also crucial to consider that ON patients typically have these components implanted at a younger age, meaning that they must retain these implants for much longer than their non‐autoimmune counterparts. The risks of implant failure and other complications compound as a result. 200 The complication rate reported in the literature varies greatly, making it difficult to ascertain the true risk of post‐THA surgical complications in the SLE population.

Potential candidates for the management of ON

Hyperbaric oxygen therapy

Hyperbaric oxygen (HBO) therapy increases the level of tissue oxygenation, 201 which can, in turn, lead to promoting fibroblast proliferation, collagen synthesis, and angiogenesis. 202 Several studies have suggested that HBO therapy improves the symptom of ON by potentially lowering intraosseous pressure within the femoral head and by improving microcirculation. 203 Bosco et al showed that HBO therapy can diminish inflammatory cytokines and ROS in patients with ON. 204 HBO therapy has been suggested to be an effective option for patients with early‐stage ON. 205 A recent meta‐analysis for 10 studies using HBO therapy as the treatment for ON has identified a significant clinical benefit of HBO therapy on ON in Asian populations. 206 It is necessary to clarify the effect of hyperbaric oxygen therapy on glucocorticoid‐induced ON in the future.

Natural compounds

The potential efficacy of several natural compounds on ON has been suggested. These natural compounds have a modulatory effect on bone cells – promoting bone formation and inhibiting bone resorption. Genistein aglycone, an isoflavone widely found in soybeans and seen as a natural alternative to selective estrogen receptor modulators, 207 protected mice from both ovariectomy‐induced bone loss and glucocorticoid‐induced bone loss 208 , 209 , 210 and showed a protective effect on bone loss in postmenopausal women. 211 , 212 Bitto et al also found that, in some cases, genistein aglycone also showed a positive outcome for methylprednisolone‐induced necrotic deterioration of the femoral head. 209 Vinpocetine, a natural compound extracted from the leaves of Phyllostachys pubescens , 213 has also shown a protective role in ON of the femoral head in rat models. 214 However, the protective effect of natural compounds on ON has not been tested in clinical human studies and needs to be further studied in ON patients.

CONCLUSION

Osteonecrosis is a complication that can often cause joint pain and loss of function within the joints leading to physical disability for many SLE patients. SLE patients with ON do not typically respond to conservative treatment and eventually require joint replacement. However, the pathogenesis of ON in SLE patients is still controversial. It is important to note that ON develops only in a subset of SLE patients who received high‐dose glucocorticoids. This discrepancy suggests that there are underlying patient‐specific factors that govern susceptibility to ON in the setting of high‐dose GCs. It remains unclear what patient‐specific factor is associated with the incidence of ON in SLE patients. As the underlying reason for susceptibility of ON in SLE patients remains unclear, it is imperative to identify the risk factors that precipitate ON in SLE patients. As shown in Table 1 , a high glucocorticoid dosage is a strong association factor for the incidence of ON in SLE patients. Thus, many studies suggested that lowering the dose of oral glucocorticoids can minimize the incidence of ON in SLE patients. However, Chen et al demonstrated that SLE patients who received low‐dose glucocorticoid therapy showed a higher risk of GC‐related damages than SLE patients who did not receive GC therapy. 113 Therefore, identifying a safe dose for preventing GC‐related damage would be critical. As there is no cure for SLE patients and glucocorticoid therapy is important for the management of SLE, identifying the lowest effective doses of glucocorticoids in combination with other agents will be required to minimize the incidence of ON.

Multifocal ON is often found in SLE patients with ON and is characterized by the involvement of multiple separate anatomic sites. It has been suggested that there is a strong relationship between multifocal disease and glucocorticoid therapy. However, it is difficult to interpret the potential effect of glucocorticoid use because of the many variables, including dosage, duration of treatment, and route of administration. Between 80% and 90% of patients tested with multifocal ON had hypofibrinolysis or thrombophilia or both. Because of the high incidence of coagulation disorders in patients with ON, it is difficult to evaluate the difference between patients with multifocal ON and those with less musculoskeletal involvement. It is necessary to conduct epidemiological studies to clarify the etiologic factors of multifocal ON.

High‐dose glucocorticoids are a key risk factor for ON in SLE patients. The death of bone cells is evident in ON bone and the biologic responses to glucocorticoids in bone cells have been extensively studied. The dose and duration of glucocorticoids are significantly associated with the likelihood of developing ON. However, the responses to glucocorticoids in ON patients can be altered by the differences between individuals in glucocorticoid sensitivity, which are influenced by multiple factors including genetic predisposition, metabolic factors, and other factors affecting blood supply. 14 Therefore, systematic evaluation of the risk factors in ON patients is warranted for prevention and interventions.

The majority of ON patients are in the middle‐aged population who are physically active. Thus, it is critical to improve pain and the function of affected joints and to delay total joint replacement surgery. Recent advances in stem‐cell therapy allow its usage in many orthopedic procedures. 215 MSC‐based therapy demonstrates promising benefits in animal models, but its therapeutic application is currently limited due to a lack of understanding of the tissue regenerative function of human MSCs in vivo. Autologous MSCs from healthy donors appear to exhibit immunomodulatory and tissue‐protective effects after transplantation. 216 In contrast, autologous MSCs from SLE patients do not carry immunosuppressive properties. 217 , 218 In addition, osteogenesis from the bone marrow aspirate of SLE patients is significantly impaired compared to healthy donors. 219 Thus, it is crucial to develop a systematic approach to determine whether or not the BM‐MSCs of SLE patients with ON still have normal osteogenic potential. 220

While arthroplasty is indicated for advanced‐stage ON, the described non‐surgical and surgical interventions have been shown to be effective in the early stages of ON. It has also been suggested that early detection of ONFH in the pre‐collapse stage is associated with an improved and more favorable clinical outcome. Thus, awareness of the need for prevention of glucocorticoid‐induced ON in the early stage is increasing and advanced techniques and interventions to detect ON early in SLE patients under glucocorticoid therapy are required.

AUTHOR CONTRIBUTIONS

K.K., H.C., and K.‐H.P.‐M. were associated with study conceptualization; K.K., H.C., M.K., and I.S. wrote and prepared the original draft of the manuscript. E.S. and K.‐H.P.‐M. reviewed and edited the final manuscript. K.‐H.P.‐M. acquired funding. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health 5R01 AR069562; 5R01 AR073156 (to P.M.K.H.), Japan Research Foundation for Clinical Pharmacology (K.K), and by Giammaria and Sabrina Gluliani Foundation. Figures were generated using Biorender.

REFERENCES

1 Moya‐Angeler J , Gianakos AL , Villa JC , Ni A , Lane JM . Current concepts on osteonecrosis of the femoral head . World J Orthop . 2015 ; 6 : 590 ‐ 601 . 26396935 10.5312/wjo.v6.i8.590 PMC4573503

2 Zalavras CG , Lieberman JR . Osteonecrosis of the femoral head: evaluation and treatment . J Am Acad Orthop Surg . 2014 ; 22 : 455 ‐ 464 . 24966252 10.5435/JAAOS-22-07-455

3 Fukushima W , et al. Nationwide epidemiologic survey of idiopathic osteonecrosis of the femoral head . Clin Orthop Relat Res . 2010 ; 468 : 2715 ‐ 2724 . 20224959 10.1007/s11999-010-1292-x PMC2939331

4 Wang Y , et al. Alcohol‐induced adipogenesis in bone and marrow: a possible mechanism for osteonecrosis . Clin Orthop Relat Res . 2003 : 213 ‐ 224 . 10.1097/01.blo.0000063602.67412.83 12771833

5 Shigemura T , 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 : 701 ‐ 706 . 22179736 10.1093/rheumatology/ker426

6 MacNicol MF , Ludlam CA . Does avascular necrosis cause collapse of the dome of the talus in severe haemophilia? . Haemophilia . 1999 ; 5 : 139 ‐ 142 . 10215965

7 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 : 156 ‐ 162 . 22258003 10.2106/JBJS.J.00919

8 Moskal JT , Topping RE , Franklin LL . Hypercholesterolemia: an association with osteonecrosis of the femoral head . Am J Orthop (Belle Mead NJ) . 1997 ; 26 : 609 ‐ 612 . 9316722

9 Assouline‐Dayan Y , Chang C , Greenspan A , Shoenfeld Y , Gershwin ME . Pathogenesis and natural history of osteonecrosis . Semin Arthritis Rheum . 2002 ; 32 : 94 ‐ 124 . 12430099

10 Adesina OO , Neumayr LD . Osteonecrosis in sickle cell disease: an update on risk factors, diagnosis, and management . Hematology Am Soc Hematol Educ Program . 2019 ; 2019 : 351 ‐ 358 . 31808856 10.1182/hematology.2019000038 PMC6913430

11 Weinstein RS , Glucocorticoid‐induced osteonecrosis . Endocrine . 41 , 183 ‐ 190 ( 2012 ). 22169965 10.1007/s12020-011-9580-0 PMC3712793

12 Wang A , Ren M , Wang J . The pathogenesis of steroid‐induced osteonecrosis of the femoral head: a systematic review of the literature . Gene . 2018 ; 671 : 103 ‐ 109 . 29859289 10.1016/j.gene.2018.05.091

13 Chan KL , Mok CC . Glucocorticoid‐induced avascular bone necrosis: diagnosis and management . Open Orthop J . 2012 ; 6 : 449 ‐ 457 . 23115605 10.2174/1874325001206010449 PMC3480825

14 Mont MA , Hungerford DS . Non‐traumatic avascular necrosis of the femoral head . J Bone Joint Surg Am . 1995 ; 77 : 459 ‐ 474 . 7890797 10.2106/00004623-199503000-00018

15 Gurion R , et al. Avascular necrosis in pediatric systemic lupus erythematosus: a brief report and review of the literature . Pediatr Rheumatol Online J . 2015 ; 13 : 13 . 25902709 10.1186/s12969-015-0008-x PMC4415214

16 Yang Y , Kumar S , Lim LS , Silverman ED , Levy DM . Risk Factors for Symptomatic Avascular Necrosis in Childhood‐onset Systemic Lupus Erythematosus . J Rheumatol . 2015 ; 42 : 2304 ‐ 2309 . 26568601 10.3899/jrheum.150464

17 Zizic TM , Marcoux C , Hungerford DS , Dansereau JV , Stevens MB . Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythematosus . Am J Med . 1985 ; 79 : 596 ‐ 604 . 4061472 10.1016/0002-9343(85)90057-9

18 Dubois EL , Cozen L . Avascular (aseptic) bone necrosis associated with systemic lupus erythematosus . JAMA . 1960 ; 174 : 966 ‐ 971 . 13724595 10.1001/jama.1960.03030080028005

19 Hussein S , et al. Monitoring of Osteonecrosis in Systemic Lupus Erythematosus: a Systematic Review and Metaanalysis . J Rheumatol . 2018 ; 45 : 1462 ‐ 1476 . 29961688 10.3899/jrheum.170837

20 Nevskaya T , Gamble MP , Pope JE . A meta‐analysis of avascular necrosis in systemic lupus erythematosus: prevalence and risk factors . Clin Exp Rheumatol . 2017 ; 35 : 700 ‐ 710 . 28240590

21 Mont MA , et al. High‐Dose Corticosteroid Use and Risk of Hip Osteonecrosis: meta‐Analysis and Systematic Literature Review . J Arthroplasty . 2015 ; 30 : 1506‐1512 e1505 . 25900167 10.1016/j.arth.2015.03.036 PMC7127809

22 Zhu KK , et al. The risk factors of avascular necrosis in patients with systemic lupus erythematosus: a meta‐analysis . Inflammation . 2014 ; 37 : 1852 ‐ 1864 . 24862229 10.1007/s10753-014-9917-y

23 Mok CC , LC WongRW . Risk factors for avascular bone necrosis in systemic lupus erythematosus . Br J Rheumatol . 1998 ; 37 : 895 ‐ 900 . 9734682 10.1093/rheumatology/37.8.895

24 Hardy RS , Raza K , Cooper MS . Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases . Nat Rev Rheumatol . 2020 ; 16 : 133 ‐ 144 . 32034322 10.1038/s41584-020-0371-y

25 Cain DW , Cidlowski JA . Immune regulation by glucocorticoids . Nat Rev Immunol . 2017 ; 17 : 233 ‐ 247 . 28192415 10.1038/nri.2017.1 PMC9761406

26 Barnes PJ . Corticosteroids: the drugs to beat . Eur J Pharmacol . 2006 ; 533 : 2 ‐ 14 . 16436275 10.1016/j.ejphar.2005.12.052

27 Rhen T , Cidlowski JA . Antiinflammatory action of glucocorticoids–new mechanisms for old drugs . N Engl J Med . 2005 ; 353 : 1711 ‐ 1723 . 16236742 10.1056/NEJMra050541

28 Cruz‐Topete D , Cidlowski JA . One hormone, two actions: anti‐ and pro‐inflammatory effects of glucocorticoids . Neuroimmunomodulation . 2015 ; 22 : 20 ‐ 32 . 25227506 10.1159/000362724 PMC4243162

29 Buckley L , Humphrey MB . Glucocorticoid‐Induced Osteoporosis . N Engl J Med . 2018 ; 379 : 2547 ‐ 2556 . 30586507 10.1056/NEJMcp1800214

30 Henneicke H , Gasparini SJ , Brennan‐Speranza TC , Zhou H , Seibel MJ . Glucocorticoids and bone: local effects and systemic implications . Trends Endocrinol Metab . 2014 ; 25 : 197 ‐ 211 . 24418120 10.1016/j.tem.2013.12.006

31 Cohen‐Rosenblum A , Cui Q . Osteonecrosis of the Femoral Head . Orthop Clin North Am . 2019 ; 50 : 139 ‐ 149 . 30850073 10.1016/j.ocl.2018.10.001

32 Greenstein S , Ghias K , Krett NL , Rosen ST . Mechanisms of glucocorticoid‐mediated apoptosis in hematological malignancies . Clin Cancer Res . 2002 ; 8 : 1681 ‐ 1694 . 12060604

33 Becker M , Raasch U . Sustainable stormwater concepts as an essential instrument for river basin management . Water Sci Technol . 2003 ; 48 : 25 ‐ 32 . 15137149

34 Nagasawa K , et al. Imaging study on the mode of development and changes in avascular necrosis of the femoral head in systemic lupus erythematosus: long‐term observations . Br J Rheumatol . 1994 ; 33 : 343 ‐ 347 . 8156306 10.1093/rheumatology/33.4.343

35 Albeles M , U J , Rothfield NF . Aseptic necrosis of bone in systemic lupus erythematosus. Relationship to corticosteroid therapy . Arch Intern Med . 1978 ; 138 : 750 ‐ 754 . 646538

36 Gladman DD , C‐AV IbañezD , Bogoch E , Urowitz MB . Outcomes of symptomatic osteonecrosis in 95 patients with systemic lupus erythematosus . J Rheumatol . 2001 ; 28 : 2226 ‐ 2229 . 11669161

37 Gladman DD , DN SuJ , Urowitz MB . Osteonecrosis in SLE: prevalence, patterns, outcomes and predictors . Lupus . 2018 ; 27 : 76 ‐ 81 . 28530464 10.1177/0961203317711012

38 Kang JS , et al. Prevalence of osteonecrosis of the femoral head: a nationwide epidemiologic analysis in Korea . J Arthroplasty . 2009 ; 24 : 1178 ‐ 1183 . 19640674 10.1016/j.arth.2009.05.022

39 Cozen L , Wallace DJ . Risk factors for avascular necrosis in systemic lupus erythematosus . J Rheumatol . 1998 ; 25 : 188 . 9458231

40 Dogan I , et al. Avascular necrosis less frequently found in systemic lupus erythematosus patients with the use of alternate day corticosteroid . Turk J Med Sci . 2020 ; 50 : 219 ‐ 224 . 31905492 10.3906/sag-1908-182 PMC7080371

41 Arranow C , et al. Clinically occult avascular necrosis of the hip in systemic lupus erythematosus . J Rheumatol . 1997 ; 24 : 2318 ‐ 2322 . 9415635

42 Mok CC , Lau CS , Wong RW . Risk factors for avascular bone necrosis in systemic lupus erythematosus . Br J Rheumatol . 1998 ; 37 : 895 ‐ 900 . 9734682 10.1093/rheumatology/37.8.895

43 Klippel JH , Gerber LH , Pollak L , Decker JL . Avascular necrosis in systemic lupus erythematosus. Silent symmetric osteonecroses . Am J Med . 1979 ; 67 : 83 ‐ 87 . 313707 10.1016/0002-9343(79)90077-9

44 Shigemura T , et al. Incidence of osteonecrosis associated with corticosteroid therapy among different underlying diseases: prospective MRI study . Rheumatology (Oxford) . 2011 ; 50 : 2023 ‐ 2028 . 21865285 10.1093/rheumatology/ker277

45 Bergman J , Nordstrom A , Nordstrom P . Epidemiology of osteonecrosis among older adults in Sweden . Osteoporos Int . 2019 ; 30 : 965 ‐ 973 . 30627759 10.1007/s00198-018-04826-2 PMC6502772

46 Tse SM , Mok CC . Time trend and risk factors of avascular bone necrosis in patients with systemic lupus erythematosus . Lupus . 2017 ; 26 : 715 ‐ 722 . 27831540 10.1177/0961203316676384

47 Sheane BJ , Gladman DD , Su J , Urowitz MB . Disease Outcomes in Glucocorticosteroid‐Naive Patients With Systemic Lupus Erythematosus . Arthritis Care Res (Hoboken) . 2017 ; 69 : 252 ‐ 256 . 27214378 10.1002/acr.22938

48 Joo YB , et al. Prevalence, incidence, and associated factors of avascular necrosis in Korean patients with systemic lupus erythematosus: a nationwide epidemiologic study . Rheumatol Int . 2015 ; 35 : 879 ‐ 886 . 25300729 10.1007/s00296-014-3147-3

49 Lee J , et al. Osteonecrosis of the hip in Korean patients with systemic lupus erythematosus: risk factors and clinical outcome . Lupus . 2014 ; 23 : 39 ‐ 45 . 24335586 10.1177/0961203313512880

50 Sayarlioglu M , et al. Risk factors for avascular bone necrosis in patients with systemic lupus erythematosus . Rheumatol Int . 2012 ; 32 : 177 ‐ 182 . 20711782 10.1007/s00296-010-1597-9

51 Nagasawa K , et al. Very early development of steroid‐associated osteonecrosis of femoral head in systemic lupus erythematosus: prospective study by MRI . Lupus . 2005 ; 14 : 385 ‐ 390 . 15934439 10.1191/0961203305lu2103oa

52 Oinuma K , et al. Osteonecrosis in patients with systemic lupus erythematosus develops very early after starting high dose corticosteroid treatment . Ann Rheum Dis . 2001 ; 60 : 1145 ‐ 1148 . 11709458 10.1136/ard.60.12.1145 PMC1753447

53 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 : 761 ‐ 765 . 11327247

54 Zonana‐Nacach A , Barr SG , Magder LS , Petri M . Damage in systemic lupus erythematosus and its association with corticosteroids . Arthritis Rheum . 2000 ; 43 : 1801 ‐ 1808 . 10943870 10.1002/1529-0131(200008)43:8<1801::AID-ANR16>3.0.CO;2-O

55 Mont MA , et al. Risk factors for osteonecrosis in systemic lupus erythematosus . J Rheumatol . 1997 ; 24 : 654 ‐ 662 . 9101497

56 Migliaresi S , et al. Avascular osteonecrosis in patients with SLE: relation to corticosteroid therapy and anticardiolipin antibodies . Lupus . 1994 ; 3 : 37 ‐ 41 . 8025584 10.1177/096120339400300108

57 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 : 89 ‐ 97 . 1555361

58 Weiner ES , Albeles M . Aseptic necrosis and glucocorticosteroids in systemic lupus erythematosus: a reevaluation . J Rheumatol . 1989 ; 16 : 604 ‐ 608 . 2666654

59 Bergstein JM , Wiens C , Fish AJ , Vernier RL , Michael A . Avascular necrosis of bone in systemic lupus erythematosus . J Pediatr . 1974 ; 85 : 31 ‐ 35 . 4850716 10.1016/s0022-3476(74)80281-7

60 Ruiz‐Arruza I , et al. Restrictive Use of Oral Glucocorticoids in Systemic Lupus Erythematosus and Prevention of Damage Without Worsening Long‐Term Disease Control: an Observational Study . Arthritis Care Res (Hoboken) . 2018 ; 70 : 582 ‐ 591 . 28704598 10.1002/acr.23322

61 Glueck CJ , Freiberg RA , Wang P . Heritable thrombophilia‐hypofibrinolysis and osteonecrosis of the femoral head . Clin Orthop Relat Res . 2008 ; 466 : 1034 ‐ 1040 . 18350351 10.1007/s11999-008-0148-0 PMC2311469

62 Liang Y , et al. Coagulation cascade and complement system in systemic lupus erythematosus . Oncotarget . 2018 ; 9 : 14862 ‐ 14881 . 29599912 10.18632/oncotarget.23206 PMC5871083

63 Nagasawa K , IY MayumiT , Tada Y , et al. Avascular necrosis of bone in systemic lupus erythematosus: possible role of haemostatic abnormalities . Ann Rheum Dis . 1989 ; 48 : 672 ‐ 676 . 2506841 10.1136/ard.48.8.672 PMC1003845

64 Asherson RA , et al. Avascular necrosis of bone and antiphospholipid antibodies in systemic lupus erythematosus . J Rheumatol . 1993 ; 20 : 284 ‐ 288 . 8474066

65 Sekiya F , Yamaji K , Yang K , Tsuda H , Takasaki Y . Investigation of occurrence of osteonecrosis of the femoral head after increasing corticosteroids in patients with recurring systemic lupus erythematosus . Rheumatol Int . 2010 ; 30 : 1587 ‐ 1593 . 19809818 10.1007/s00296-009-1194-y

66 Saleh Al , et al. Predictors of avascular necrosis of the hip in Emiratis patients with systemic lupus erythematosus . Egypt J Immunol . 2010 ; 17 : 29 ‐ 40 . 22053607

67 Mok MY , Farewell VT , Isenberg DA . Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? . Ann Rheum Dis . 2000 ; 59 : 462 ‐ 467 . 10834864 10.1136/ard.59.6.462 PMC1753161

68 Folkman J , Langer R , Linhardt RJ , Haudenschild C , Taylor S . Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone . Science . 1983 ; 221 : 719 ‐ 725 . 6192498 10.1126/science.6192498

69 Kerachian MA , Harvey EJ , Cournoyer D , Chow TY , Seguin C . Avascular necrosis of the femoral head: vascular hypotheses . Endothelium . 2006 ; 13 : 237 ‐ 244 . 16990180 10.1080/10623320600904211

70 Boss JH , Misselevich I . Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals . Vet Pathol . 2003 ; 40 : 345 ‐ 354 . 12824505 10.1354/vp.40-4-345

71 Vogt CJ , Schmid‐Schonbein GW . Microvascular endothelial cell death and rarefaction in the glucocorticoid‐induced hypertensive rat . Microcirculation . 2001 ; 8 : 129 ‐ 139 . 11379792

72 Hasan Q , Tan ST , Gush J , Peters SG , Davis PF . Steroid therapy of a proliferating hemangioma: histochemical and molecular changes . Pediatrics . 2000 ; 105 : 117 ‐ 120 . 10617714 10.1542/peds.105.1.117

73 Logie JJ , et al. Glucocorticoid‐mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration . PLoS One . 2010 ; 5 : e14476 . 21217824 10.1371/journal.pone.0014476 PMC3013101

74 Hadoke PW , Iqbal J , Walker BR . Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease . Br J Pharmacol . 2009 ; 156 : 689 ‐ 712 . 19239478 10.1111/j.1476-5381.2008.00047.x PMC2697748

75 Yano A , Fujii Y , Iwai A , Kageyama Y , Kihara K . Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells . Clin Cancer Res . 2006 ; 12 : 3003 ‐ 3009 . 16707595 10.1158/1078-0432.CCR-05-2085

76 Atsumi T , Kuroki Y . Role of impairment of blood supply of the femoral head in the pathogenesis of idiopathic osteonecrosis . Clin Orthop Relat Res . 1992 : 22 ‐ 30 . 1372850

77 van Zaane B , et al. Systematic review on the effect of glucocorticoid use on procoagulant, anti‐coagulant and fibrinolytic factors . J Thromb Haemost . 2010 ; 8 : 2483 ‐ 2493 . 20735729 10.1111/j.1538-7836.2010.04034.x

78 Tomita M , et al. Serial histopathologic myocardial findings in a patient with ectopic atrial tachycardia‐induced cardiomyopathy . J Cardiol . 1997 ; 29 : 37 ‐ 42 . 9023678

79 Kerachian MA , Seguin C , Harvey EJ . Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action . J Steroid Biochem Mol Biol . 2009 ; 114 : 121 ‐ 128 . 19429441 10.1016/j.jsbmb.2009.02.007 PMC7126235

80 Yu QS , et al. Glucocorticoids Significantly Influence the Transcriptome of Bone Microvascular Endothelial Cells of Human Femoral Head . Chin Med J (Engl) . 2015 ; 128 : 1956 ‐ 1963 . 26168838 10.4103/0366-6999.160564 PMC4717923

81 Yue J , et al. Effect of glucocorticoids on miRNA expression spectrum of rat femoral head microcirculation endothelial cells . Gene . 2018 ; 651 : 126 ‐ 133 . 29408208 10.1016/j.gene.2018.01.057

82 Vogt CJ , Schmid‐Schönbein GW . Microvascular endothelial cell death and rarefaction in the glucocorticoid‐induced hypertensive rat . Microcirculation . 2001 ; 8 : 129 ‐ 139 . 11379792

83 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 : 1209 ‐ 1213 . 15568539 10.1302/0301-620x.86b8.14834

84 Mutijima E , De Maertelaer V , Deprez M , Malaise M , Hauzeur JP . The apoptosis of osteoblasts and osteocytes in femoral head osteonecrosis: its specificity and its distribution . Clin Rheumatol . 2014 ; 33 : 1791 ‐ 1795 . 24733252 10.1007/s10067-014-2607-1

85 Kabata T , et al. Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits . J Rheumatol . 2000 ; 27 : 2166 ‐ 2171 . 10990229

86 Weinstein RS , Jilka RL , Parfitt AM , Manolagas SC . Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone . J Clin Invest . 1998 ; 102 : 274 ‐ 282 . 9664068 10.1172/JCI2799 PMC508885

87 Youm YS , Lee SY , Lee SH . Apoptosis in the osteonecrosis of the femoral head . Clin Orthop Surg . 2010 ; 2 : 250 ‐ 255 . 21119943 10.4055/cios.2010.2.4.250 PMC2981783

88 Weinstein RS , Nicholas RW , Manolagas SC . Apoptosis of osteocytes in glucocorticoid‐induced osteonecrosis of the hip . J Clin Endocrinol Metab . 2000 ; 85 : 2907 ‐ 2912 . 10946902 10.1210/jcem.85.8.6714

89 Wang J , et al. iNOS expression and osteocyte apoptosis in idiopathic, non‐traumatic osteonecrosis . Acta Orthop . 2015 ; 86 : 134 ‐ 141 . 25191931 10.3109/17453674.2014.960997 PMC4366673

90 Huffman KM , et al. Synovial fluid metabolites in osteonecrosis . Rheumatology (Oxford) . 2007 ; 46 : 523 ‐ 528 . 17003168 10.1093/rheumatology/kel302

91 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 ‐ 735 . 908695

92 Jones JP Jr . Fat embolism and osteonecrosis . Orthop Clin North Am . 1985 ; 16 : 595 ‐ 633 . 3903602

93 Hernigou P , BF LambotteJC . Decrease in the mesenchymal stem‐cell pool in the proximal femur in corticosteroid‐induced osteonecrosis . J Bone Joint Surg Br . 1999 ; 81 : 349 ‐ 355 . 10204950 10.1302/0301-620x.81b2.8818

94 Mok CC , To CH , Ma KM . Changes in body composition after glucocorticoid therapy in patients with systemic lupus erythematosus . Lupus . 2008 ; 17 : 1018 ‐ 1022 . 18852226 10.1177/0961203308093552

95 Toussirot E , et al. Elevated adiponectin serum levels in women with systemic autoimmune diseases . Mediators Inflamm . 2010 ; 2010 : 938408 . 21234350 10.1155/2010/938408 PMC3017955

96 Li Z , et al. Altered body composition and increased visceral adipose tissue in premenopausal and late postmenopausal patients with SLE . Clin Rheumatol . 2019 ; 38 : 3117 ‐ 3127 . 31363873 10.1007/s10067-019-04701-3

97 Drescher W , LH JensenSD , Ingerslev J , Hansen ES , Hauge EM , Bünger C . The effect of long‐term methylprednisolone treatment on the femoral head in growing pigs . J Orthop Res . 2002 ; 20 : 662 ‐ 668 . 12168652 10.1016/S0736-0266(01)00183-8

98 Tsai HL , Chang JW , Lu JH , Liu CS . Epidemiology and risk factors for avascular necrosis in childhood systemic lupus erythematosus in a Taiwanese population . Sci Rep . 2020 ; 10 : 15563 . 32968109 10.1038/s41598-020-71923-w PMC7512010

99 Kwon HH , et al. Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus . Lupus . 2018 ; 27 : 1644 ‐ 1651 . 29950160 10.1177/0961203318784648

100 Kuroda T , et al. High triglyceride is a risk factor for silent osteonecrosis of the femoral head in systemic lupus erythematosus . Clin Rheumatol . 2015 ; 34 : 2071 ‐ 2077 . 26384821 10.1007/s10067-015-3075-y

101 Faezi ST , et al. Non‐corticosteroid risk factors of symptomatic avascular necrosis of bone in systemic lupus erythematosus: a retrospective case‐control study . Mod Rheumatol . 2015 ; 25 : 590 ‐ 594 . 25528860 10.3109/14397595.2014.987366

102 Gontero RP , Bedoya ME , Benavente E , Roverano SG , Paira SO . Osteonecrosis in systemic lupus erythematosus . Reumatol Clin . 2015 ; 11 : 151 ‐ 155 . 25441491 10.1016/j.reuma.2014.05.005

103 Kunyakham W , Foocharoen C , Mahakkanukrauh A , Suwannaroj S , Nanagara R . Prevalence and risk factor for symptomatic avascular necrosis development in Thai systemic lupus erythematosus patients . Asian Pac J Allergy Immunol . 2012 ; 30 : 152 ‐ 157 . 22830295

104 Nakamura J , et al. Age at time of corticosteroid administration is a risk factor for osteonecrosis in pediatric patients with systemic lupus erythematosus: a prospective magnetic resonance imaging study . Arthritis Rheum . 2010 ; 62 : 609 ‐ 615 . 20112393 10.1002/art.27236

105 Uea‐areewongsa P , Chaiamnuay S , Narongroeknawin P , Asavatanabodee P . Factors associated with osteonecrosis in Thai lupus patients: a case control study . J Clin Rheumatol . 2009 ; 15 : 345 ‐ 349 . 20009970 10.1097/RHU.0b013e3181ba3423

106 Fialho SC , et al. Disease activity as a major risk factor for osteonecrosis in early systemic lupus erythematosus . Lupus . 2007 ; 16 : 239 ‐ 244 . 17439929 10.1177/0961203307076771

107 Prasad R , Ibanez D , Gladman D , Urowitz M . The role of non‐corticosteroid related factors in osteonecrosis (ON) in systemic lupus erythematosus: a nested case‐control study of inception patients . Lupus . 2007 ; 16 : 157 ‐ 162 . 17432099 10.1177/0961203306075771

108 Rascu A , Manger K , Kraetsch HG , Kalden JR , Manger B . Osteonecrosis in systemic lupus erythematosus, steroid‐induced or a lupus‐dependent manifestation? . Lupus . 1996 ; 5 : 323 ‐ 327 . 8869906 10.1177/096120339600500414

109 Massardo L , et al. High‐dose intravenous methylprednisolone therapy associated with osteonecrosis in patients with systemic lupus erythematosus . Lupus . 1992 ; 1 : 401 ‐ 405 . 1304409 10.1177/096120339200100610

110 Kalla AA , Learmonth ID , Klemp P . Early treatment of avascular necrosis in systemic lupus erythematosus . Ann Rheum Dis . 1986 ; 45 : 649 ‐ 652 . 3740994 10.1136/ard.45.8.649 PMC1001961

111 Dimant J , et al. Computer analysis of factors influencing the appearance of aseptic necrosis in patients with SLE . J Rheumatol . 1978 ; 5 : 136 ‐ 141 . 671430

112 Smith FE , Sweet DE , Brunner CM , Davis JS . Avascular necrosis in SLE. An apparent predilection for young patients . Ann Rheum Dis . 1976 ; 35 : 227 ‐ 232 . 984903 10.1136/ard.35.3.227 PMC1006545

113 Chen HL , et al. Cumulative Burden of Glucocorticoid‐related Adverse Events in Patients with Systemic Lupus Erythematosus: findings from a 12‐year Longitudinal Study . J Rheumatol . 2018 ; 45 : 83 ‐ 89 . 29142034 10.3899/jrheum.160214

114 Badsha H , Edwards CJ . Intravenous pulses of methylprednisolone for systemic lupus erythematosus . Semin Arthritis Rheum . 2003 ; 32 : 370 ‐ 377 . 12833245 10.1053/sarh.2002.50003

115 Ruiz‐Arruza I , et al. Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus . Rheumatology (Oxford) . 2014 ; 53 : 1470 ‐ 1476 . 24681836 10.1093/rheumatology/keu148

116 Nakamura J , et al. Development of new osteonecrosis in systemic lupus erythematosus patients in association with long‐term corticosteroid therapy after disease recurrence . Clin Exp Rheumatol . 2010 ; 28 : 13 ‐ 18 . 20346232

117 Nakamura J , et al. Spontaneous repair of asymptomatic osteonecrosis associated with corticosteroid therapy in systemic lupus erythematosus: 10‐year minimum follow‐up with MRI . Lupus . 2010 ; 19 : 1307 ‐ 1314 . 20605878 10.1177/0961203310372951

118 Nakamura J , et al. Recovery of the blood flow around the femoral head during early corticosteroid therapy: dynamic magnetic resonance imaging in systemic lupus erythematosus patients . Lupus . 2012 ; 21 : 264 ‐ 270 . 22020268 10.1177/0961203311425521

119 Hisada R , et al. Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus . Rheumatology (Oxford) . 2019 ; 58 : 645 ‐ 649 . 30521019 10.1093/rheumatology/key365

120 Furnrohr BG , et al. Osteoclast Differentiation Is Impaired in a Subgroup of SLE Patients and Correlates Inversely with Mycophenolate Mofetil Treatment . Int J Mol Sci . 2015 ; 16 : 18825 ‐ 18835 . 26274951 10.3390/ijms160818825 PMC4581274

121 Navarra SV , et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo‐controlled, phase 3 trial . Lancet . 2011 ; 377 : 721 ‐ 731 . 21296403 10.1016/S0140-6736(10)61354-2

122 Javelot MJ , et al. Rituximab as a trigger factor of medication‐related osteonecrosis of the jaw. A case report . J Stomatol Oral Maxillofac Surg . 2020 ; 121 : 300 ‐ 304 . 31301390 10.1016/j.jormas.2019.06.009

123 Kim TH , Bae SC , Lee SH , Kim SY , Baek SH . Association of Complement Receptor 2 Gene Polymorphisms with Susceptibility to Osteonecrosis of the Femoral Head in Systemic Lupus Erythematosus . Biomed Res Int . 2016 ; 2016 : 9208035 . 27446959 10.1155/2016/9208035 PMC4944048

124 Kim HS , Bae SC , Kim TH , Kim SY . Endothelial nitric oxide synthase gene polymorphisms and the risk of osteonecrosis of the femoral head in systemic lupus erythematosus . Int Orthop . 2013 ; 37 : 2289 ‐ 2296 . 23775455 10.1007/s00264-013-1966-6 PMC3824903

125 Sun HS , et al. Gene testing for osteonecrosis of the femoral head in systemic lupus erythematosus using targeted next‐generation sequencing: a pilot study . World J Clin Cases . 2020 ; 8 : 2530 ‐ 2541 . 32607330 10.12998/wjcc.v8.i12.2530 PMC7322418

126 Guerra SG , Vyse TJ , Graham Cunninghame . The genetics of lupus: a functional perspective . Arthritis Res Ther . 2012 ; 14 : 211 . 22640752 10.1186/ar3844 PMC3446495

127 Yin X , et al. Meta‐analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus . Ann Rheum Dis . 2020 . 10.1136/annrheumdis-2020-219209 PMC8053352 33272962

128 Glueck CJ , Freiberg RA , Oghene J , Fontaine RN , Wang P . Association between the T‐786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur . J Bone Joint Surg Am . 2007 ; 89 : 2460 ‐ 2468 . 17974890 10.2106/JBJS.F.01421

129 Xu J , Gong H , Lu S , Deasey MJ , Cui Q . Animal models of steroid‐induced osteonecrosis of the femoral head‐a comprehensive research review up to 2018 . Int Orthop . 2018 ; 42 : 1729 ‐ 1737 . 29705870 10.1007/s00264-018-3956-1

130 Yamamoto T , Hirano K , Tsutsui H , Sugioka Y , Sueishi K . Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Shwartzman reaction . Clin Orthop Relat Res . 1995 : 235 ‐ 243 . 7634712

131 Liu C , et al. Asparaginase Potentiates Glucocorticoid‐Induced Osteonecrosis in a Mouse Model . PLoS One . 2016 ; 11 : e0151433 . 26967741 10.1371/journal.pone.0151433 PMC4788417

132 Mont MA , Jones LC , Hungerford DS . Nontraumatic osteonecrosis of the femoral head: ten years later . J Bone Joint Surg Am . 2006 ; 88 : 1117 ‐ 1132 . 16651589 10.2106/JBJS.E.01041

133 Chan KL , Mok CC . Glucocorticoid‐induced avascular bone necrosis: diagnosis and management . Open Orthop J . 2012 ; 6 : 449 ‐ 457 . 23115605 10.2174/1874325001206010449 PMC3480825

134 Keeling SO , et al. Canadian Rheumatology Association Recommendations for the Assessment and Monitoring of Systemic Lupus Erythematosus . J Rheumatol . 2018 ; 45 : 1426 ‐ 1439 . 30173152 10.3899/jrheum.171459

135 GUIDELINES, A.C.O.R.A.H.C.O.S.L.E . Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines . Arthritis Rheum . 42 , 1785 ‐ 1796 ( 1999 ). 10513791 10.1002/1529-0131(199909)42:9<1785::AID-ANR1>3.0.CO;2-#

136 Castro TC , et al. The use of joint‐specific and whole‐body MRI in osteonecrosis: a study in patients with juvenile systemic lupus erythematosus . Br J Radiol . 2011 ; 84 : 621 ‐ 628 . 21081568 10.1259/bjr/34972239 PMC3473496

137 Karantanas AH , Drakonaki EE . The role of MR imaging in avascular necrosis of the femoral head . Semin Musculoskelet Radiol . 2011 ; 15 : 281 ‐ 300 . 21644201 10.1055/s-0031-1278427

138 Boontanapibul K , et al. Diagnosis of Osteonecrosis of the Femoral Head: too Little, Too Late, and Independent of Etiology . J Arthroplasty . 2020 ; 35 : 2342 ‐ 2349 . 32456965 10.1016/j.arth.2020.04.092

139 BY Mont MA , Marulanda GA , Jones LC , et al. Systematic Analysis of Classification Systems for Osteonecrosis of the Femoral Head . J Bone Joint Surg Am . 2006 ; 88 : 16 ‐ 26 . BY. 17079363 10.2106/JBJS.F.00457

140 Yoon BH , et al. The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head . J Arthroplasty . 2020 ; 35 : 933 ‐ 940 . 31866252 10.1016/j.arth.2019.11.029

141 Wang B , et al. Digital Subtraction Angiography and Magnetic Resonance Imaging‐Based Staging of Circulatory Obstruction in the Femoral Head During Osteonecrosis of the Femoral Head Development . Ann Plast Surg . 2020 . 10.1097/SAP.0000000000002424 32501844

142 Kelman GJ , Williams GW , Colwell CW Jr , Walker RH . Steroid‐related osteonecrosis of the knee. Two case reports and a literature review . Clin Orthop Relat Res . 1990 : 171 ‐ 176 . 2199116

143 An YS , Park S , Jung JY , Suh CH , Kim HA . Clinical characteristics and role of whole‐body bone scan in multifocal osteonecrosis . BMC Musculoskelet Disord . 2019 ; 20 : 23 . 30646869 10.1186/s12891-019-2401-y PMC6334418

144 LaPorte DM , Mont MA , Mohan V , Jones LC , Hungerford DS . Multifocal osteonecrosis . J Rheumatol . 1998 ; 25 : 1968 ‐ 1974 . 9779852

145 Oh SN , et al. Osteonecrosis in patients with systemic lupus erythematosus: mR imaging and scintigraphic evaluation . Clin Imaging . 2004 ; 28 : 305 ‐ 309 . 15246483 10.1016/S0899-7071(03)00192-X

146 Symptomatic multifocal osteonecrosis. A multicenter study. Collaborative Osteonecrosis Group . Clin Orthop Relat Res . 312 ‐ 326 ( 1999 ). 10611887

147 Fajardo‐Hermosillo LD , Lopez‐Lopez L , Nadal A , Vila LM . Multifocal osteonecrosis in systemic lupus erythematosus: case report and review of the literature . BMJ Case Rep . 2013 ; 2013 . 10.1136/bcr-2013-008980 PMC3645777 23595183

148 Caramaschi P , Biasi D , Forno Dal , Adami S . Osteonecrosis in systemic lupus erythematosus: an early, frequent, and not always symptomatic complication . Autoimmune Dis . 2012 ; 2012 : 725249 . 22919470 10.1155/2012/725249 PMC3419396

149 Cardozo JB , Andrade DM , Santiago MB . The use of bisphosphonate in the treatment of avascular necrosis: a systematic review . Clin Rheumatol . 2008 ; 27 : 685 ‐ 688 . 18270760 10.1007/s10067-008-0861-9

150 Lai KA , SW YangCY , Shao CJ , Hsu JT , Lin RM . The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study . J Bone Joint Surg Am . 2005 ; 87 : 2155 ‐ 2159 . 16203877 10.2106/JBJS.D.02959

151 Agarwala S , Jain D , Joshi VR , Sule A . Efficacy of alendronate, a bisphosphonate, in the treatment of AVN of the hip. A prospective open‐label study . Rheumatology (Oxford) . 2005 ; 44 : 352 ‐ 359 . 15572396 10.1093/rheumatology/keh481

152 Chen CH , et al. 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 : 1572 ‐ 1578 . 22127729 10.1002/art.33498

153 Belmont HM , Lydon E . Avascular necrosis prevention with lipitor in lupus erythematosus . Lupus . 2005 ; 14 : 869 ‐ 870 . 16302686 10.1191/0961203305lu2189xx

154 Yang Z , et al. The efficacy of statins in preventing glucocorticoid‐related osteonecrosis in animal models: a meta‐analysis . Bone Joint Res . 2016 ; 5 : 393 ‐ 402 . 27660333 10.1302/2046-3758.59.2000500 PMC5032300

155 JW P . Statin therapy decreases the risk of osteonecrosis in patients receiving steroids . Clin Orthop Relat Res . 2001 : 173 ‐ 178 . 10.1097/00003086-200105000-00022 11347831

156 Guo P , et al. The use of anticoagulants for prevention and treatment of osteonecrosis of the femoral head: a systematic review . Medicine (Baltimore) . 2017 ; 96 : e6646 . 28422866 10.1097/MD.0000000000006646 PMC5406082

157 Nagasawa K , TY KoaradaS , Tsukamoto H , et al. revention of steroid‐induced osteonecrosis of femoral head in systemic lupus erythematosus by anti‐coagulant . Lupus . 2006 ; 15 : 354 ‐ 357 . 16830881 10.1191/0961203306lu2311oa

158 Glueck CJ , Freiberg RA , Sieve L , Wang P . Enoxaparin prevents progression of stages I and II osteonecrosis of the hip . Clin Orthop Relat Res . 2005 : 164 ‐ 170 . 10.1097/01.blo.0000157539.67567.03 15930934

159 Nagasawa K , et al. Prevention of steroid‐induced osteonecrosis of femoral head in systemic lupus erythematosus by anti‐coagulant . Lupus . 2006 ; 15 : 354 ‐ 357 . 16830881 10.1191/0961203306lu2311oa

160 Kennedy JW , Khan W . Total Hip Arthroplasty in Systemic Lupus Erythematosus: a Systematic Review . Int J Rheumatol . 2015 : 475489 . 26236340 10.1155/2015/475489 PMC4510251

161 Mertelsmann‐Voss Christina , S.L., Pan TingJung , Goodman Susan , Figgie MarkP , Mandl LisaA . Arthroplasty Rates Are Increased Among US Patients with Systemic Lupus Erythematosus: 1991–2005 . J Rheumatol . 2014 ; 41 : 867 ‐ 874 . 24692528 10.3899/jrheum.130617

162 Mertelsmann‐Voss C , et al. Arthroplasty rates are increased among US patients with systemic lupus erythematosus: 1991–2005 . J Rheumatol . 2014 ; 41 : 867 ‐ 874 . 24692528 10.3899/jrheum.130617

163 Chen DQ , Cancienne JM , Werner BC , Cui Q . Is osteonecrosis due to systemic lupus erythematosus associated with increased risk of complications following total hip arthroplasty? . Int Orthop . 2018 ; 42 : 1485 ‐ 1490 . 29550912 10.1007/s00264-018-3871-5

164 Marker DR , Seyler TM , Ulrich SD , Srivastava S , Mont MA . Do modern techniques improve core decompression outcomes for hip osteonecrosis? . Clin Orthop Relat Res . 2008 ; 466 : 1093 ‐ 1103 . 18392909 10.1007/s11999-008-0184-9 PMC2311489

165 Pierce TP , et al. A current review of core decompression in the treatment of osteonecrosis of the femoral head . Curr Rev Musculoskelet Med . 2015 ; 8 : 228 ‐ 232 . 26045085 10.1007/s12178-015-9280-0 PMC4596206

166 Iorio R , Healy WL , Abramowitz AJ , Pfeifer BA . Clinical outcome and survivorship analysis of core decompression for early osteonecrosis of the femoral head . J Arthroplasty . 1998 ; 13 : 34 ‐ 41 . 9493536 10.1016/s0883-5403(98)90073-0

167 Ficat RP . Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment . J Bone Joint Surg Br . 1985 ; 67 : 3 ‐ 9 . 3155745 10.1302/0301-620X.67B1.3155745

168 Maniwa S , TN SFurukawa , Kajitani K , Iwata A , Nishikawa U , Ochi M . Evaluation of core decompression for early osteonecrosis of the femoral head . Arch Orthop Trauma Surg . 2000 ; 120 : 241 ‐ 244 . 10853887 10.1007/s004020050456

169 Song WS , Yoo JJ , Kim YM , Kim HJ . Results of multiple drilling compared with those of conventional methods of core decompression . Clin Orthop Relat Res . 2007 ; 454 : 139 ‐ 146 . 16906081 10.1097/01.blo.0000229342.96103.73

170 Hua KC , et al. The efficacy and safety of core decompression for the treatment of femoral head necrosis: a systematic review and meta‐analysis . J Orthop Surg Res . 2019 ; 14 : 306 . 31511030 10.1186/s13018-019-1359-7 PMC6737645

171 Yu X , et al. Effectiveness of various hip preservation treatments for non‐traumatic osteonecrosis of the femoral head: a network meta‐analysis of randomized controlled trials . J Orthop Sci . 2018 ; 23 : 356 ‐ 364 . 29291916 10.1016/j.jos.2017.12.004

172 Hernigou P , Beaujean F . Treatment of osteonecrosis with autologous bone marrow grafting . Clin Orthop Relat Res . 2002 : 14 ‐ 23 . 10.1097/00003086-200212000-00003 12461352

173 Perez JR , et al. Tissue Engineering and Cell‐Based Therapies for Fractures and Bone Defects . Front Bioeng Biotechnol . 2018 ; 6 : 105 . 30109228 10.3389/fbioe.2018.00105 PMC6079270

174 Hernigou P , et al. Osteonecrosis repair with bone marrow cell therapies: state of the clinical art . Bone . 2015 ; 70 : 102 ‐ 109 . 25016964 10.1016/j.bone.2014.04.034

175 Hernigou P , et al. Stem Cell Therapy for the Treatment of Hip Osteonecrosis: a 30‐Year Review of Progress . Clin Orthop Surg . 2016 ; 8 : 1 ‐ 8 . 26929793 10.4055/cios.2016.8.1.1 PMC4761591

176 Hernigou P , et al. Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow‐up prospective randomized study of one hundred and twenty five adult patients . Int Orthop . 2018 ; 42 : 1639 ‐ 1649 . 29744647 10.1007/s00264-018-3941-8

177 Li X , Xu X , Wu W . Comparison of bone marrow mesenchymal stem cells and core decompression in treatment of osteonecrosis of the femoral head: a meta‐analysis . Int J Clin Exp Pathol . 2014 ; 7 : 5024 ‐ 5030 . 25197374 PMC4152064

178 Piuzzi NS , et al. Evidence for the Use of Cell‐Based Therapy for the Treatment of Osteonecrosis of the Femoral Head: a Systematic Review of the Literature . J Arthroplasty . 2017 ; 32 : 1698 ‐ 1708 . 28162838 10.1016/j.arth.2016.12.049

179 Mardones R , et al. Treatment of osteonecrosis of the femoral head by core decompression and implantation of fully functional ex vivo‐expanded bone marrow‐derived mesenchymal stem cells: a proof‐of‐concept study . Stem Cells Cloning . 2019 ; 12 : 11 ‐ 16 . 30881048 10.2147/SCCAA.S181883 PMC6402444

180 Gangji V , Hauzeur JP . Treatment of osteonecrosis of the femoral head with implantation of autologous bone‐marrow cells. Surgical technique . J Bone Joint Surg Am . 2005 ; 87 ( 1 ): 106 ‐ 112 . Suppl . 15743852 10.2106/JBJS.D.02662

181 Yoshioka T , et al. Concentrated autologous bone marrow aspirate transplantation treatment for corticosteroid‐induced osteonecrosis of the femoral head in systemic lupus erythematosus . Int Orthop . 2011 ; 35 : 823 ‐ 829 . 20512330 10.1007/s00264-010-1048-y PMC3103953

182 Tomaru Y , et al. Mid‐term results of concentrated autologous bone marrow aspirate transplantation for corticosteroid‐associated osteonecrosis of the femoral head in systemic lupus erythematosus . Int Orthop . 2018 ; 42 : 1623 ‐ 1630 . 29705871 10.1007/s00264-018-3959-y

183 Kouroupis D , Ahari AF , Correa D , Shammaa R . Intralesional Injection of Bone Marrow Aspirate Concentrate for the Treatment of Osteonecrosis of the Knee Secondary to Systemic Lupus Erythematosus: a Case Report . Front Bioeng Biotechnol . 2020 ; 8 : 202 . 32266233 10.3389/fbioe.2020.00202 PMC7100546

184 Y S . Transtrochanteric Anterior Rotational Osteotomy of the Femoral Head in the Treatment of Osteonecrosis Affecting the Hip: a New Osteotomy Operation . Clin Orthop Relat Res . 1978 : 191 ‐ 201 . 639389

185 Xu YX , et al. Hip survival rate in the patients with avascular necrosis of femoral head after transtrochanteric rotational osteotomy: a systematic review and meta‐analysis . Chin Med J (Engl) . 2019 ; 132 : 2960 ‐ 2971 . 31855958 10.1097/CM9.0000000000000562 PMC6964954

186 Motomura G , YT SuenagaK , Nakashima Y , Mawatari T , Ikemura S , Iwamoto Y . Long‐term outcome of transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head in patients with systemic lupus erythematosus . Lupus . 2010 ; 19 : 860 ‐ 865 . 20305049 10.1177/0961203310361896

187 Pierce TP , et al. A current review of non‐vascularized bone grafting in osteonecrosis of the femoral head . Curr Rev Musculoskelet Med . 2015 ; 8 : 240 ‐ 245 . 26009009 10.1007/s12178-015-9282-y PMC4596204

188 Millikan PD , Karas V , Wellman SS . Treatment of osteonecrosis of the femoral head with vascularized bone grafting . Curr Rev Musculoskelet Med . 2015 ; 8 : 252 ‐ 259 . 26068178 10.1007/s12178-015-9285-8 PMC4596199

189 Ali SA , et al. Treatment of avascular necrosis of the femoral head utilising free vascularised fibular graft: a systematic review . Hip Int . 2014 ; 24 : 5 ‐ 13 . 24062224 10.5301/hipint.5000076

190 Sun Y , CZ SBChen , Sheng JG , Jin DX , Zeng BF . Treatment of femoral head osteonecrosis in patients with systemic lupus erythematosus by free vascularised fibular grafting . Lupus . 2009 ; 18 : 1061 ‐ 1065 . 19762379 10.1177/0961203309106490

191 Changjun C , et al. Mid‐ to long‐term results of modified non‐vascularized allogeneic fibula grafting combined with core decompression and bone grafting for early femoral head necrosis . J Orthop Surg Res . 2020 ; 15 : 116 . 32209127 10.1186/s13018-020-1565-3 PMC7092607

192 Vahid Farahmandi M , Abbasian M , Safdari F , Emami Moghaddam Tehrani M . Midterm results of treating femoral head osteonecrosis with autogenous corticocancellous bone grafting . Trauma Mon . 2014 ; 19 : e17092 . 25717446 10.5812/traumamon.17092 PMC4310157

193 Kang Y , et al. Total hip arthroplasty for vascular necrosis of the femoral head in patients with systemic lupus erythematosus: a midterm follow‐up study of 28 hips in 24 patients . Eur J Orthop Surg Traumatol . 2013 ; 23 : 73 ‐ 79 . 23412411 10.1007/s00590-012-0939-6

194 Mak A . Orthopedic surgery and its complication in systemic lupus erythematosus . World J Orthop . 2014 ; 5 : 38 ‐ 44 . 24653977 10.5312/wjo.v5.i1.38 PMC3955778

195 Goodman SM , Bass AR . Perioperative medical management for patients with RA, SPA, and SLE undergoing total hip and total knee replacement: a narrative review . BMC Rheumatol . 2018 ; 2 : 2 . 30886953 10.1186/s41927-018-0008-9 PMC6390575

196 Lin JA , et al. Adverse outcomes after major surgery in patients with systemic lupus erythematosus: a nationwide population‐based study . Ann Rheum Dis . 2014 ; 73 : 1646 ‐ 1651 . 23740232 10.1136/annrheumdis-2012-202758

197 Jung JY , Yoon D , Choi Y , Kim HA , Suh CH . Associated clinical factors for serious infections in patients with systemic lupus erythematosus . Sci Rep . 2019 ; 9 : 9704 . 31273256 10.1038/s41598-019-46039-5 PMC6609713

198 Love PE , Santoro SA . Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non‐SLE disorders. Prevalence and clinical significance . Ann Intern Med . 1990 ; 112 : 682 ‐ 698 . 2110431 10.7326/0003-4819-112-9-682

199 Bergqvist D , et al. Low‐molecular‐weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement . N Engl J Med . 1996 ; 335 : 696 ‐ 700 . 8703168 10.1056/NEJM199609053351002

200 Mourão AF , MA JCaetano‐Lopes , Isenberg D . An analysis of joint replacement in patients with systemic lupus erythematosus . Lupus . 2009 ; 18 : 1298 ‐ 1302 . 19850657 10.1177/0961203309345795

201 Thom SR . Hyperbaric oxygen: its mechanisms and efficacy . Plast Reconstr Surg . 2011 ; 127 ( 1 ): 131S ‐ 141S . Suppl . 21200283 10.1097/PRS.0b013e3181fbe2bf PMC3058327

202 Reis ND , et al. Hyperbaric oxygen therapy as a treatment for stage‐I avascular necrosis of the femoral head . J Bone Joint Surg Br . 2003 ; 85 : 371 ‐ 375 . 12729112 10.1302/0301-620x.85b3.13237

203 Bosco G , et al. Femoral condylar necrosis: treatment with hyperbaric oxygen therapy . Arthroplast Today . 2018 ; 4 : 510 ‐ 515 . 30560184 10.1016/j.artd.2018.02.010 PMC6287235

204 Bosco G , et al. Hyperbaric oxygen therapy ameliorates osteonecrosis in patients by modulating inflammation and oxidative stress . J Enzyme Inhib Med Chem . 2018 ; 33 : 1501 ‐ 1505 . 30274530 10.1080/14756366.2018.1485149 PMC6171420

205 Camporesi EM , Vezzani G , Bosco G , Mangar D , Bernasek TL . Hyperbaric oxygen therapy in femoral head necrosis . J Arthroplasty . 2010 ; 25 : 118 ‐ 123 . 10.1016/j.arth.2010.05.005 20637561

206 Paderno E , et al. Evidence‐Supported HBO Therapy in Femoral Head Necrosis: a Systematic Review and Meta‐Analysis . Int J Environ Res Public Health . 2021 ; 18 . 10.3390/ijerph18062888 PMC7999152 33808951

207 Messina M , Ho S , Alekel DL . Skeletal benefits of soy isoflavones: a review of the clinical trial and epidemiologic data . Curr Opin Clin Nutr Metab Care . 2004 ; 7 : 649 ‐ 658 . 15534433 10.1097/00075197-200411000-00010

208 Bitto A , et al. Genistein aglycone reverses glucocorticoid‐induced osteoporosis and increases bone breaking strength in rats: a comparative study with alendronate . Br J Pharmacol . 2009 ; 156 : 1287 ‐ 1295 . 19302595 10.1111/j.1476-5381.2008.00100.x PMC2697728

209 Bitto A , et al. Protective effect of genistein aglycone on the development of osteonecrosis of the femoral head and secondary osteoporosis induced by methylprednisolone in rats . J Endocrinol . 2009 ; 201 : 321 ‐ 328 . 19332450 10.1677/JOE-08-0552

210 Bitto A , et al. Effects of genistein aglycone in osteoporotic, ovariectomized rats: a comparison with alendronate, raloxifene and oestradiol . Br J Pharmacol . 2008 ; 155 : 896 ‐ 905 . 18695641 10.1038/bjp.2008.305 PMC2515927

211 Arcoraci V , et al. Antiosteoporotic Activity of Genistein Aglycone in Postmenopausal Women: evidence from a Post‐Hoc Analysis of a Multicenter Randomized Controlled Trial . Nutrients . 2017 ; 9 . 10.3390/nu9020179 PMC5331610 28241420

212 Atteritano M , et al. Genistein effects on quantitative ultrasound parameters and bone mineral density in osteopenic postmenopausal women . Osteoporos Int . 2009 ; 20 : 1947 ‐ 1954 . 19238303 10.1007/s00198-009-0883-4

213 Hao TB , et al. Light‐harvesting protein Lhcx3 is essential for high light acclimation of Phaeodactylum tricornutum . AMB Express . 2018 ; 8 : 174 . 30353255 10.1186/s13568-018-0703-3 PMC6199207

214 Shen ZH , et al. Activation of AKT signaling via small molecule natural compound prevents against osteoblast apoptosis and osteonecrosis of the femoral head . Am J Transl Res . 2020 ; 12 : 7211 ‐ 7222 . 33312361 PMC7724333

215 Akpancar S , Tatar O , Turgut H , Akyildiz F , Ekinci S . The Current Perspectives of Stem Cell Therapy in Orthopedic Surgery . Arch Trauma Res . 2016 ; 5 : e37976 . 28144608 10.5812/atr.37976 PMC5253188

216 Fan XL , Zhang Y , Li X , Fu QL . Mechanisms underlying the protective effects of mesenchymal stem cell‐based therapy . Cell Mol Life Sci . 2020 ; 77 : 2771 ‐ 2794 . 31965214 10.1007/s00018-020-03454-6 PMC7223321

217 Cheng RJ , et al. Mesenchymal Stem Cells: allogeneic MSC May Be Immunosuppressive but Autologous MSC Are Dysfunctional in Lupus Patients . Front Cell Dev Biol . 2019 ; 7 : 285 . 31799252 10.3389/fcell.2019.00285 PMC6874144

218 Barbado J , Tabera S , Sanchez A , Garcia‐Sancho J . Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis . Lupus . 2018 ; 27 : 2161 ‐ 2165 . 30290717 10.1177/0961203318804922

219 Gao L , Liesveld J , Anolik J , McDavid A , Looney RJ . IFNbeta signaling inhibits osteogenesis in human SLE bone marrow . Lupus . 2020 ; 29 : 1040 ‐ 1049 . 32515653 10.1177/0961203320930088

220 Mont MA , Cherian JJ , Sierra RJ , Jones LC , Lieberman JR . Nontraumatic Osteonecrosis of the Femoral Head: where Do We Stand Today? A Ten‐Year Update . J Bone Joint Surg Am . 2015 ; 97 : 1604 ‐ 1627 . 26446969 10.2106/JBJS.O.00071