Corticosteroid-associated osteonecrosis in paediatric compared with adult patients: are they the same disease?

Introduction

Osteonecrosis (ON) is the death of bone marrow due to inadequate blood supply, and a debilitating condition with a pathogenesis that remains poorly characterized. 1 Osteonecrosis of the femoral head (ONFH) affects patients’ quality of life (QoL), leading to constant pain, difficulty walking, and limitations in completing activities of daily living as the condition progresses, though some patients may be asymptomatic or minimally symptompatic, especially in the earlier stages.

ONFH accounts for 20,000 new cases per year in the USA, and 8% to 10% of all hip arthroplasties performed in the USA. 2 - 5 ON is associated with corticosteroid use, excessive alcohol intake, radiation, chemotherapy, and trauma. 1 , 6 - 8 Across ages, corticosteroids are often administered as a life-saving treatment for primary autoimmune or oncological conditions. In adults, corticosteroids are also widely used in the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and other diseases such as asthma and kidney transplantation 6 , 9 ( Table I ).

In paediatric populations, primary diseases commonly associated with corticosteroid use include acute lymphoblastic leukaemia (ALL), Hodgkin lymphoma, and SLE. 10 - 13 A recent multicentre review of large health systems database records showed that corticosteroid use is associated with ON development for paediatric patients with acute lymphoblastic leukaemia, systemic lupus erythematous, Crohn’s disease, juvenile idiopathic arthritis, and solid organ transplants, especially renal disease and post renal transplantation. 13 , 14

Due to improvements in the treatment of ALL, the survival rate in paediatric patients is now approximately 90% ten years after diagnosis. 15 However, this improvement in survival rates is closely linked to high-dose corticosteroid treatment, which in turn contributes to increased rates of ON. 16 Corticosteroids are reported to increase the expression of nicotinamide adenine dinucleotide phosphate (NADP)H oxidase (NOX) subunits, suppress the phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signalling pathway, and induce mitochondrial dysfunction, all of which collectively contribute to an increase in reactive oxygen species (ROS) generation ( Figure 1 ).

There are presumed physiological differences between paediatric and adult patients, including the presence of epiphyseal growth plates, 11 blood supply to the femoral head, 17 and metabolic factors, such as bone turnover, lipid metabolism, 18 and glucose metabolism. 12 , 19 However, no previous studies have comprehensively examined corticosteroid-associated ONFH stratified by paediatric and adult populations. This review summarizes and analyzes the latest findings on corticosteroid-associated ONFH with a focus on the differences between paediatric and adult populations. In this review, paediatric ON is defined as patients who developed ON after receiving corticosteroid treatment under the age of 18 years in terms of bone maturity, though several studies include adolescents up to the age of 20 years in combined paediatric and adolescent analyses. By examining age-specific mechanisms and clinical features in the existing literature, this review aims to contribute to a better understanding of the disease’s pathogenesis and to the identification of strategies for early detection and timely intervention.

Corticosteroid-associated ONFH

Pathogenesis

The pathogenesis of corticosteroid-associated ONFH is likely multifactorial with genetic, environmental, and other components contributing to the development and progression of the disease. Corticosteroids have a direct toxic effect that leads to cellular apoptosis, impairment of bone turnover, 20 - 22 and a decrease in arterial blood flow to the femoral head due to thrombus or embolus. 23 - 25 Some studies liken ONFH to an intraosseous compartment syndrome. 26 On the cellular level, corticosteroids have the effect of promoting the differentiation of mesenchymal stem cells (MSCs) into adipocytes, 27 increasing intracellular lipid synthesis, and inducing hypertrophy of adipocytes. This process can lead to intraosseous hypertension, decreased blood flow, and intravascular coagulation that eventually causes ischaemia around the femoral head. 27 - 30 If sufficient fibrinolysis and angiogenesis are not achieved, the persistence of ischaemia can lead to bone marrow necrosis and osteocyte death, resulting in femoral head collapse and subchondral fractures. 26 , 31 Therefore, genetic factors such as vascular thrombosis, decreased fibrinolysis, decreased angiogenesis, and conditions that lead to vascular compromise can impact both the blood flow and recovery in the femoral head. Genetic factors predisposing to ON include Protein C and S deficiencies, mutations in factor V Leiden or the prothrombin 20210 A gene, and polymorphisms of the plasminogen activator inhibitor-1 gene. 26 , 32 In addition, genes related to corticosteroid metabolism, such as CYP3A4, CYP450, and ABCB1, are associated with the onset of ONFH. 33 , 34

Incidence of osteonecrosis ALL and SLE patients

In ALL patients, reported rates of ON are 0.9% to 4% in those under ten years of age, 8.9% to 29% in patients aged ten to 20 years of age, and 8% in those over 20 years, indicating a higher risk in adolescents and young adults. 35 - 38 A recent systematic review of ON in patients between one and 21 years of age, demonstrated rates of ON development in up to 39% of patients on steroids. 13 In patients with SLE, the incidence of ON also increases with age. 39 , 40 Nakamura et al reported that patients over 15 years of age had a tenfold higher incidence of ON than those aged under 15 years. 39 Moreover, corticosteroid-associated ON is also common in SLE patients, with reported rates of 3% to 6% in patients aged under 15 years, 49% to 51% in those aged 15 to 20 years, and 39% to 41% in patients aged over 20 years 40 , 41 ( Table II ). These findings indicate that both age and SLE are important risk factors for the development of ON.

Dosage of corticosteroid as an important risk factor

In adult patients, corticosteroid associated ONFH is defined as a patient who has a history of corticosteroid use of > 2,000 mg of prednisolone or its equivalent within three months according to the Association Research Circulation Osseous (ARCO) classification 26 , 42 ( Table III ). The mean cumulative dose of corticosteroid administered to SLE patients who developed ON was 11,000 mg, and the mean maximum daily dose was 33 mg. 43 A prospective study of SLE patients also reported that corticosteroid administration of 60 mg/day was associated with a ten times higher risk of ONFH compared with patients taking less than 20 mg/day. 44

In children, the dose-dependent relationship between corticosteroids and ONFH has also been characterized. Moriya et al 46 reported that the cumulative dose of dexamethasone is associated with risk of ON. Liu et al 9 investigated the risk factors of ON in children with immune kidney disease, and reported that total cumulative dose of prednisone and methylprednisolone were independent risk factors. In patients with ALL, some articles reported that the cumulative dose of glucocorticoid correlated with the risk of ON. 11 , 47 Girard et al 48 reported the cumulative incidence of ON in childhood with ALL was 23.8% after transplantation for patients with the dose higher than 2,055 mg/m 2 .

The use of alternate week dexamethasone reduces the risk of osteonecrosis in paediatric patients with ALL, compared with continuous use. 37 Dexamethasone has approximately six- to seven-times the potency of prednisolone, a longer half-life, and has less propensity for central nervous system (CNS) recurrence, thereby increasing event-free survival. 49 However, a large multicentre database study demonstrated high rates of ON development in older paediatric patients and those receiving dexamethasone, compared with prednisone or prednisolone. 13

Age-related changes

Skeletal maturity: One of the major differences between younger patients and adults is the degree of skeletal maturity. 11 In addition to differences in height and weight, the epiphyseal growth plate of the femur closes at approximately 14 years of age in females and 16 years in males ( Table IV ). 50 Before physeal closure, the primary blood to the femoral head is provided by the lateral epiphyseal vessels bypassing the physeal barrier; the skeletally immature femoral head is more vulnerable compared with adults. 51 After physeal closure, the blood supply to the femoral head becomes more stable, having a source through the physeal scar region and the lateral epiphyseal vessels. 52 While most clinical and epidemiological studies rely on age-based definitions, future investigation into differences in ON stratified by skeletal maturity are warranted.

Lipid and glucose metabolism over time: Sex hormones decline with age in adults, cholesterol levels rise, and lipid disorders and arteriosclerosis becomes more likely ( Table IV ). 53 Patients with corticosteroid-associated ONFH have significantly higher levels of total cholesterol, triglycerides, compared with control patients, suggesting a relationship with the development of ONFH. 54 Lipid metabolism has been reported to contribute to the development of ONFH; peroxisome proliferator-activated receptor γ(PPARγ) is activated by corticosteroid administration, promoting adipogenesis while inhibiting osteogenesis ( Figure 1 ). 55

In a systematic review, the risk of ON in sites other than the jaw in patients with diabetes was elevated, though not statistically significant. 56 Although the association between diabetes and ON remains inconclusive, increased BMI has been consistently identified as an independent risk factor for ON in paediatric patients with ALL. 57

Oxidative stress: Oxidative stress can induce defects in cellular differentiation and apoptosis, affecting the skeletal system. 55 Peroxidation after corticosteroid administration is considered an important factor in ON. 58 Long-term corticosteroid administration affects physiological balance between oxidative and glycolytic metabolism and leads to oxidative stress. 59 Moreover, antioxidant enzymes (catalase, superoxide dismutase (SOD), γ-glutamylcysteine synthetase (γ-GCSc), and hemeoxygenase-1 (HO-1)) are down-regulated by corticosteroids. 60 , 61 The down-regulation of antioxidant enzymes is related to osteoclast markers (cathepsin K and receptor activator of nuclear factor kappa-Β ligand (RANKL)) and increased osteoclast formation and activity. 59 These reactions cause an increase in ROS levels, osteoclasts, and empty osteocyte lacunae, eventually leading to altered bone structure and ONFH.

ROS are highly reactive oxygen-derived molecules that are generated as by-products of normal cellular metabolism in mitochondria. 55 , 62 ROS increase vascular permeability and cause oxidative damage to DNA, leading to apoptosis and necrosis of cells. 58

Ageing is significantly related to the generation of ROS and the response to oxidative stress. 63 Mitochondrial function declines and oxidative stress increases with age ( Table IV ). 64 Oxidative stress is lower in paediatric patients due to the activation of the antioxidant systems associated with increased growth hormone during adolescence. 65

Diagnosis

MRI is the gold standard to diagnose ONFH in both children and adults. 66 Early detection of ONFH is critical to promote timely intervention to increase the ability to alter the progression of the process. Common imaging features across diagnostic methods in patients with ONFH include:

MRI: Low-intensity band within the femoral head in T1-weighted images, and double-line sign in T2-weighted images.

Radiographs: Femoral head collapse or crescent sign, sclerotic band within the femoral head (without joint space narrowing and acetabular abnormality). Or CT: Osteosclerosis, cystic changes, subchondral bone fracture.

Other described methods that are less common include:

Bone scintigraphy: Cold-in-hot patterns within the femoral head.

Pathology: Empty lacunae in trabecular bones and bone marrow necrosis. In adults, biopsy can be considered when a definitive diagnosis of osteonecrosis cannot be established based on clinical presentation and MRI findings. This methodology is less common given its invasive modality.

Like adults, diagnostic criteria for children with corticosteroid-associated ONFH rely on clinical presentation and imaging with MRI as the gold standard for early detection. 11 Currently, screening MRI has been employed in research settings 67 but is not the standard of care. 68 Corticosteroid-associated ONFH can be detected through careful follow-up including periodic history and physical examination, and selective MRI studies. 9 A high index of suspicion should be maintained in patients treated with corticosteroids.

In adults, the differential diagnoses include osteoarthritis of the hip, transient femoral head necrosis, subchondral fragility fractures of the femoral head, and rapidly destructive arthritis of the hip. 69 In paediatric patients, differential diagnoses include Perthes' disease and slipped capital femoral epiphysis (SCEF). 70 Perthes' disease is an idiopathic condition in which transient interruption of blood flow to the proximal femur leads to ischaemia of the femoral head. 71 Of note, SCFE does not necessarily cause ONFH, but OFNH development is more likely with unstable SCFE, and in some cases, the treatment of this condition may contribute to the development of ONFH secondarily. 72 , 73

Type and staging

ARCO has provided a classification of ONFH based on the stage of subchondral collapse, and type i.e. the size and extent of the lesion ( Table V ). 74 Koo et al 31 reported a classification of the size and extent of the lesion based on coronal plane CT-scan images which is easily applicable to MRI. This system is the second arm of the ARCO classification (Type 1 to 3) ( Figure 2 ). 42

The Steinberg classification was used to classify the extent of necrosis in the femoral head (the ratio of the necrotic area: mild (< 15%); moderate (15% to 30%); and severe (> 30%). In the Modified Kerboul method, the necrotic arc is measured using mid-coronal and mid-sagittal T1-weighted MRI ( Figure 2 ), and the necrotic lesion is classified into four categories (grade I to IV). 75 These classifications are useful for determining surgical indications and potential outcomes.

With regard to classification of ONFH in children, Niinimaki et al 76 suggested the scoring system for young cancer patients should classify osteonecrotic lesions according to whether the lesion involves the weightbearing area and the location of necrosis. Bone Location for Avascular necrosis from STeroids (BLAST) is used to classify children with ON. 10 This classification was developed to systematically evaluate ON in skeletally immature children receiving high-dose corticosteroids. Each long bone is classified into specific anatomical regions. Alayleh et al 10 reported that the most common site was the proximal tibial metaphysis ( Table VI ).

Treatment options

Several treatment options exist for ONFH, including core decompression and cell therapy, femoral osteotomy, total hip arthroplasty (THA), with THA as the definitive treatment. Investigation into strategies to prevent joint collapse and degeneration in patients at risk for ON is an ongoing area of study.

Core decompression and cell therapy: Arlet et al 77 reported core decompression (CD) as a treatment of ONFH in adults that prevents the collapse of the femoral head. 78 CD involves drilling a hole from the lateral side of the femur to the necrotic area of the femoral head to reduce the intraosseous pressure and promote angiogenesis, thereby promoting new bone formation and preventing the progression of the condition. 79 Recently, combination therapy involving the administration of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stromal cells (MSCs) following CD has been reported. 80 In adults, combination therapy with CD and BMAC has been reported to reduce the risk of femoral head collapse and THA compared with CD alone 81 - 83 ( Table VI ).

Zhao et al 84 performed a randomized study in adults with pre-collapse ONFH and demonstrated that CD with MSCs improved Harris Hip Scores and reduced the necrotic volume compared with CD alone. Although, CD with MSC therapy can delay the progression of ONFH in early stage patients, whether regeneration of the necrotic area takes place is still unresolved. 85 Furthermore, ageing is associated with a decrease in the number and proliferative capacity of MSCs in the bone marrow. 86

In paediatric ALL, there are concerns about the risk of seeding leukaemic cells to other sites and about the effects of chemotherapy on the differentiation of MSC. 87 MSCs can differentiate into various types of cells, such as chondrocytes and osteoblasts, and are also involved in macrophage recruitment, making them an essential factor in bone regeneration. 88

Femoral osteotomy: One of the surgeries to address ONFH is transtrochanteric rotational osteotomy. Transtrochanteric rotational osteotomy was first reported by Sugioka. 89 , 90 Kawano et al 91 reported the ten-year survival rate of rotation osteotomy in adult patients with ONFH was 85.4%. Under 20 years of age, the hip joint preservation rate at a mean follow-up period of 14 years was 92%. 92 Another study showed rotational osteotomy had excellent success rates (82% to 100%, three to 15 years) 69 ( Table VI ). This surgery may be indicated for paediatric ONFH.

THA: In paediatric patients, the reported implant survival rate of THA ranges 86% to 95% (five to ten years of follow-up). 93 , 94 However, Swarup et al 95 reported the 20-year implant survival rate was 48% in patients aged under 25 years. In adult patients, the survival rate ranges from 89% to 94% (15 to 16 years) 96 , 97 ( Table VI ). THA is generally considered a last resort option only after other treatment methods have been evaluated and considered non-tenable. Additionally, paediatric patients face a higher risk of implant wear and subsequent revision surgery due to their longer life expectancy.

Other: Bisphosphonates are treatments for osteoporosis to suppress osteoclast activity. Although this drug has been also used wisely for ONFH, evidence of the clinical outcomes is limited. For paediatric patients with ALL, Agarwala et al 98 reported that the combination of intravenous zolendronic acid and oral alendronate provided a satisfactory outcome, 91% had not required any surgical treatment. However, Yuan et al 99 reported that bisphosphonate could not delay the progression of ONFH. As a treatment option, using bisphosphonate for ONFH is still controversial.

Conclusion

The pathogenesis of corticosteroid-associated ONFH is currently considered to be multifactorial and incompletely characterized. Predisposing diseases and risk factors vary with age. Understanding the differences in incidence of ONFH based on primary diseases, as well as the relationship between corticosteroid dosages across different ages, is crucial for estimating the risk of developing ON following corticosteroid administration.

In the existing literature, it is difficult to dissect the individual contribution of underlying diagnosis, corticosteroid exposure, and age in the development of ON. Given that for many of the common autoimmune and oncological conditions in which patients develop ON, few do not receive corticosteroids, there are limited data to allow us to differentiate between the condition compared with corticosteroids; though in vivo studies support that corticosteroid administration alone induces ON, inducing osteonecrosis solely through SLE or renal transplantation remains challenging. Additionally, while some studies compare paediatric with adult ON, 6 others focus on one population limiting our ability to isolate the role of age. We posit that corticosteroids are the primary driver with factors relating to age, skeletal maturity, and cellular differences likely modifying this relationship. The data in paediatric and adults patients remain limited and may be insufficient in many cases. Longitudinal studies investigating ONFH in paediatric patients as well as comparing paediatric and adults patients are warranted.

While there are substantial reports on the combined use of CD and cell therapy in adults, evidence in paediatric patients remains limited. Transtrochanteric rotational osteotomy has been reported to provide favourable prognosis in some patient populations, but THA remains the definitive treatment option for degenerative change associated with ONFH. In summary, this review characterizes the cellular aetiology, epidemiology, risk factors, and treatment options for ONFH in both adults and children. Improved understanding of ONFH, its pathogenesis, and effective interventions may not only allow for improved understanding regarding the similarities and differences between the condition in adults and children but also clinical and research initiatives to promote preservation of the hip joint across all ages.

Take home message

- Corticosteroid-associated osteonecrosis differs between paediatric and adult patients in terms of primary disease, steroid exposure, bone, lipid, and angiogenetic metabolism.

- Recognizing these age-dependent differences may facilitate earlier diagnosis and timely intervention to preserve joint function.

Author contributions

T. Igei: Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing

G. B. Smith: Investigation, Writing – original draft, Writing – review & editing

S. K. Chow: Data curation, Resources, Writing – review & editing

A. Jobanputra: Resources, Writing – review & editing

B. W. Khoo: Resources, Writing – review & editing

K. G. Shea: Conceptualization, Supervision, Writing – review & editing

S. B. Goodman: Conceptualization, Supervision, Writing – review & editing

Funding statement

The author(s) disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: This study was supported, in part, by the Robert L. and Mary Ellenburg Chair in Surgery, Stanford University, USA.

ICMJE COI statement

S. B. Goodman reports grants or contracts from the National Institutes of Health (NIH) for NIAMS and NCATS; royalties or licenses from Hyalex; consulting fees from Wishbone Medical; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck; stock or stock options from Marine Biomedical and Moroxite; and is president of ARCO and on the board for multiple journals. All other authors have no conflicts of interest to disclose.

Data sharing

The data that support the findings for this study are available to other researchers from the corresponding author upon reasonable request.

Open access funding

The open access fee was self-funded.

© 2026 Igei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/

References

1. Assouline-Dayan Y Chang C Greenspan A Shoenfeld Y Gershwin ME Pathogenesis and natural history of osteonecrosis Semin Arthritis Rheum 2002 32 2 94 124 12430099

2. Jones KB Seshadri T Krantz R Keating A Ferguson PC Cell-based therapies for osteonecrosis of the femoral head Biol Blood Marrow Transplant 2008 14 10 1081 1087 10.1016/j.bbmt.2008.06.017 18804037

3. Chen CH Chang JK Lai KA Hou SM Chang CH Wang GJ Alendronate in the prevention of collapse of the femoral head in nontraumatic osteonecrosis: a two-year multicenter, prospective, randomized, double-blind, placebo-controlled study Arthritis Rheum 2012 64 5 1572 1578 10.1002/art.33498 22127729

4. Camporesi EM Vezzani G Bosco G Mangar D Bernasek TL Hyperbaric oxygen therapy in femoral head necrosis J Arthroplasty 2010 25 6 Suppl 118 123 10.1016/j.arth.2010.05.005 20637561

5. Radke S Kirschner S Seipel V Rader C Eulert J Magnetic resonance imaging criteria of successful core decompression in avascular necrosis of the hip Skeletal Radiol 2004 33 9 519 523 10.1007/s00256-004-0811-9 15221216

6. Horton DB Haynes K Denburg MR et al. Oral glucocorticoid use and osteonecrosis in children and adults with chronic inflammatory diseases: a population-based cohort study BMJ Open 2017 7 7 e016788 10.1136/bmjopen-2017-016788 28733303 PMC5642748

7. Harper PG Trask C Souhami RL Avascular necrosis of bone caused by combination chemotherapy without corticosteroids Br Med J (Clin Res Ed) 1984 288 6413 267 268 10.1136/bmj.288.6413.267 6198019 PMC1444026

8. Lafforgue P Pathophysiology and natural history of avascular necrosis of bone Joint Bone Spine 2006 73 5 500 507 10.1016/j.jbspin.2006.01.025 16931094

9. Liu J Liu S Su Y Risk factors for steroid-induced osteonecrosis of the femoral head in children with immune kidney disease Clin Kidney J 2025 18 3 sfaf011 10.1093/ckj/sfaf011 40078520 PMC11897701

10. Alayleh A Naz H Taylor V et al. Retrospective analysis and characterization of avascular necrosis by bone location in pediatric leukemia/lymphoma patients J Pediatr Orthop 2025 45 7 e641 e647 10.1097/BPO.0000000000002963 40214168

11. Kunstreich M Kummer S Laws HJ Borkhardt A Kuhlen M Osteonecrosis in children with acute lymphoblastic leukemia Haematologica 2016 101 11 1295 1305 10.3324/haematol.2016.147595 27742768 PMC5394877

12. Basu R Breda E Oberg AL et al. Mechanisms of the age-associated deterioration in glucose tolerance: contribution of alterations in insulin secretion, action, and clearance Diabetes 2003 52 7 1738 1748 10.2337/diabetes.52.7.1738 12829641

13. Smith GB Pham NS Alayleh A et al. Risk factors for corticosteroid-associated osteonecrosis in children: a national database study J Pediatr Soc North Am 2025 12 100199 10.1016/j.jposna.2025.100199 40756153 PMC12317409

14. Balani SS Jensen CJ Kouri AM Kizilbash SJ Induction and maintenance immunosuppression in pediatric kidney transplantation-advances and controversies Pediatr Transplant 2021 25 7 e14077 10.1111/petr.14077 34216190

15. Hunger SP Mullighan CG Acute lymphoblastic leukemia in children N Engl J Med 2015 373 16 1541 1552 10.1056/NEJMra1400972 26465987

16. Aricò M Boccalatte MFP Silvestri D et al. Osteonecrosis: an emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia Haematologica 2003 88 7 747 753 12857552

17. Cazzulino A Wu W Allahabadi S Swarup I Diagnosis and management of unstable slipped capital femoral epiphysis: a critical analysis review JBJS Rev 2021 9 7 10.2106/JBJS.RVW.20.00268 34270502

18. Robinson GA Peng J Peckham H et al. Sex hormones drive changes in lipoprotein metabolism iScience 2021 24 11 103257 10.1016/j.isci.2021.103257 34761181 PMC8567005

19. Goran MI Gower BA Longitudinal study on pubertal insulin resistance Diabetes 2001 50 11 2444 2450 10.2337/diabetes.50.11.2444 11679420

20. Te Winkel ML Pieters R Wind E-JD Bessems JHJMG van den Heuvel-Eibrink MM Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia Haematologica 2014 99 3 430 436 10.3324/haematol.2013.095562 24598854 PMC3943305

21. Shim SS Hawk HE Yu WY The relationship between blood flow and marrow cavity pressure of bone Surg Gynecol Obstet 1972 135 3 353 360 5054155

22. Rao SS El Abiad JM Puvanesarajah V Levin AS Jones LC Morris CD Osteonecrosis in pediatric cancer survivors: epidemiology, risk factors, and treatment Surg Oncol 2019 28 214 221 10.1016/j.suronc.2019.02.001 30851903

23. Fisher DE Bickel WH Holley KE Histologic demonstration of fat emboli in aseptic necrosis associated with hypercortisonism Mayo Clin Proc 1969 44 4 252 259 4888919

24. 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 1995 316 235 243 7634712

25. Ramsey LB Pounds S Cheng C et al. Genetics of pleiotropic effects of dexamethasone Pharmacogenet Genomics 2017 27 8 294 302 10.1097/FPC.0000000000000293 28628558 PMC5523978

26. Hines JT Jo WL Cui Q et al. Osteonecrosis of the femoral head: an updated review of ARCO on pathogenesis, staging and treatment J Korean Med Sci 2021 36 24 e177 10.3346/jkms.2021.36.e177 34155839 PMC8216992

27. Cui Q Wang GJ Balian G Steroid-induced adipogenesis in a pluripotential cell line from bone marrow J Bone Joint Surg Am 1997 79 7 1054 1063 10.2106/00004623-199707000-00012 9234882

28. Cui Q Wang Y Saleh KJ Wang GJ Balian G Alcohol-induced adipogenesis in a cloned bone-marrow stem cell J Bone Joint Surg Am 2006 88 Suppl 3 148 154 10.2106/JBJS.F.00534 17079381

29. Miyanishi K Yamamoto T Irisa T et al. Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis Bone 2002 30 1 185 190 10.1016/s8756-3282(01)00663-9 11792583

30. Motomura G Yamamoto T Miyanishi K Yamashita A Sueishi K Iwamoto Y Bone marrow fat-cell enlargement in early steroid-induced osteonecrosis--a histomorphometric study of autopsy cases Pathol Res Pract 2005 200 11–12 807 811 10.1016/j.prp.2004.10.003 15792124

31. Koo KH Jeong ST Jones JP Borderline necrosis of the femoral head Clin Orthop Relat Res 1999 358 358 158 165 10.1097/00003086-199901000-00019 9973987

32. Björkman A Svensson PJ Hillarp A Burtscher IM Rünow A Benoni G Factor V leiden and prothrombin gene mutation: risk factors for osteonecrosis of the femoral head in adults Clin Orthop Relat Res 2004 2004 425 168 172 15292803

33. Huang R Zhan Q Hu W et al. Association of ABCB1 and CYP450 gene polymorphisms and their DNA methylation status with steroid-induced osteonecrosis of the femoral head in the Chinese population Genet Test Mol Biomarkers 2020 24 12 789 797 10.1089/gtmb.2020.0201 33252269 PMC7755856

34. Wang Y Li X Gao Y et al. Genetic polymorphisms of CYP3A4 among Chinese patients with steroid-induced osteonecrosis of the femoral head Medicine (Baltimore) 2016 95 44 e5332 10.1097/MD.0000000000005332 27858915 PMC5591163

35. Bürger B Beier R Zimmermann M Beck JD Reiter A Schrappe M Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95 Pediatr Blood Cancer 2005 44 3 220 225 10.1002/pbc.20244 15514916

36. Patel B Richards SM Rowe JM Goldstone AH Fielding AK High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis Leukemia 2008 22 2 308 312 10.1038/sj.leu.2405032 17989709

37. Mattano LA Devidas M Nachman JB et al. Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial Lancet Oncol 2012 13 9 906 915 10.1016/S1470-2045(12)70274-7 22901620 PMC3448283

38. Arakawa Y Masutani S Oshima K et al. Asian population may have a lower incidence of hip osteonecrosis in childhood acute lymphoblastic leukemia Int J Hematol 2021 114 2 271 279 10.1007/s12185-021-03163-1 34008044

39. Nakamura J Saisu T Yamashita K Suzuki C Kamegaya M Takahashi K 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 2 609 615 10.1002/art.27236 20112393

40. Shigemura T Nakamura J Kishida S et al. Incidence of osteonecrosis associated with corticosteroid therapy among different underlying diseases: prospective MRI study Rheumatology (Oxford) 2011 50 11 2023 2028 10.1093/rheumatology/ker277 21865285

41. Sugano N Tsuda K Miki H Takao M Suzuki N Nakamura N Dynamic measurements of hip movement in deep bending activities after total hip arthroplasty using a 4-dimensional motion analysis system J Arthroplasty 2012 27 8 1562 1568 10.1016/j.arth.2012.01.029 22459125

42. Yoon B-H Jones LC Chen C-H et al. Etiologic classification criteria of ARCO on femoral head osteonecrosis part 1: glucocorticoid-associated osteonecrosis J Arthroplasty 2019 34 1 163 168 10.1016/j.arth.2018.09.005 30348552

43. Davidson JE Fu Q Rao S Magder LS Petri M Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort Lupus Sci Med 2018 5 1 e000237 10.1136/lupus-2017-000237 29765616 PMC5950698

44. Kallas R Li J Petri M Predictors of osteonecrosis in systemic lupus erythematosus: a prospective cohort study Arthritis Care Res (Hoboken) 2022 74 7 1122 1132 10.1002/acr.24541 33342072 PMC10725725

45. Mont MA Pivec R Banerjee S Issa K Elmallah RK Jones LC High-dose corticosteroid use and risk of hip osteonecrosis: meta-analysis and systematic literature review J Arthroplasty 2015 30 9 1506 1512 10.1016/j.arth.2015.03.036 25900167 PMC7127809

46. Moriya K Imamura T Katayama S et al. The incidence of symptomatic osteonecrosis is similar between Japanese children and children in Western countries with acute lymphoblastic leukaemia treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol Br J Haematol 2022 196 5 1257 1261 10.1111/bjh.17988 34879431

47. McAvoy S Baker KS Mulrooney D Blaes A Arora M Burns LJ et al. Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation Biol Blood Marrow Transplant 2010 16 9 1231 1236 10.1016/j.bbmt.2010.03.008 20302963

48. Girard P Auquier P Barlogis V et al. Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood Haematologica 2013 98 7 1089 1097 10.3324/haematol.2012.081265 23645686 PMC3696613

49. Inaba H Pui CH Glucocorticoid use in acute lymphoblastic leukaemia Lancet Oncol 2010 11 11 1096 1106 10.1016/S1470-2045(10)70114-5 20947430 PMC3309707

50. Migliorini F Maffulli N Baroncini A Eschweiler J Tingart M Betsch M Failure and progression to total hip arthroplasty among the treatments for femoral head osteonecrosis: a Bayesian network meta-analysis Br Med Bull 2021 138 1 112 125 10.1093/bmb/ldab006 34009284

51. Yadav S Agrawal A Kar B Sakale H Sahoo B Chandan R Pediatric fracture neck of femur J Orthop Dis Traumatol 2018 1 1 11 10.4103/jodp.JODP_7_18

52. Pinto DA Aroojis A Fractures of the proximal femur in childhood: a review Indian J Orthop 2021 55 1 23 34 10.1007/s43465-020-00259-4 33569096 PMC7851244

53. Arnold AP Cassis LA Eghbali M Reue K Sandberg K Sex hormones and sex chromosomes cause sex differences in the development of cardiovascular diseases Arterioscler Thromb Vasc Biol 2017 37 5 746 756 10.1161/ATVBAHA.116.307301 28279969 PMC5437981

54. Yu X Zhang S Zhang B Dai M Relationship of idiopathic femoral head necrosis with blood lipid metabolism and coagulation function: a propensity score-based analysis Front Surg 2022 9 938565 10.3389/fsurg.2022.938565 36684312 PMC9852306

55. Shinohara I Morita M Chow SK-H et al. Pathophysiology of the effects of oxidative stress on the skeletal system J Orthop Res 2025 43 6 1059 1072 10.1002/jor.26075 40143581

56. Konarski W Poboży T Kotela A et al. Does diabetes mellitus increase the risk of avascular osteonecrosis? A systematic review and meta-analysis Int J Environ Res Public Health 2022 19 22 15219 10.3390/ijerph192215219 36429946 PMC9690760

57. Niinimäki RA Harila-Saari AH Jartti AE et al. High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia J Clin Oncol 2007 25 12 1498 1504 10.1200/JCO.2006.06.2539 17442991

58. Ichiseki T Kaneuji A Katsuda S Ueda Y Sugimori T Matsumoto T DNA oxidation injury in bone early after steroid administration is involved in the pathogenesis of steroid-induced osteonecrosis Rheumatology (Oxford) 2005 44 4 456 460 10.1093/rheumatology/keh518 15598705

59. Chen K Liu Y He J et al. Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts Int J Biol Sci 2020 16 11 1888 1900 10.7150/ijbs.40917 32398957 PMC7211180

60. Tsuchiya M Ichiseki T Ueda S et al. Mitochondrial stress and redox failure in steroid-associated osteonecrosis Int J Med Sci 2018 15 3 205 209 10.7150/ijms.22525 29483810 PMC5820848

61. Kanzaki H Shinohara F Kanako I et al. Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes Redox Biol 2016 8 186 191 10.1016/j.redox.2016.01.006 26795736 PMC4732015

62. Tarafdar A Pula G The role of NADPH oxidases and oxidative stress in neurodegenerative disorders Int J Mol Sci 2018 19 12 3824 10.3390/ijms19123824 30513656 PMC6321244

63. Finkel T Holbrook NJ Oxidants, oxidative stress and the biology of ageing Nature New Biol 2000 408 6809 239 247 10.1038/35041687 11089981

64. Tan BL Norhaizan ME Liew W-P-P Sulaiman Rahman H Antioxidant and oxidative stress: a mutual interplay in age-related diseases Front Pharmacol 2018 9 1162 10.3389/fphar.2018.01162 30405405 PMC6204759

65. Samsonov A Urlacher SS Oxidative stress in children and adolescents: insights into human biology Am J Hum Biol 2025 37 1 e24200 10.1002/ajhb.24200 39815753 PMC11736247

66. Manenti G Altobelli S Pugliese L Tarantino U The role of imaging in diagnosis and management of femoral head avascular necrosis Clin Cases Miner Bone Metab 2015 12 Suppl 1 31 38 10.11138/ccmbm/2015.12.3s.031 27134630 PMC4832402

67. Kaste SC Pei D Cheng C et al. Utility of early screening magnetic resonance imaging for extensive hip osteonecrosis in pediatric patients treated with glucocorticoids J Clin Oncol 2015 33 6 610 615 10.1200/JCO.2014.57.5480 25605853 PMC4322260

68. Kuhlen M Kunstreich M Gökbuget N Osteonecrosis in adults with acute lymphoblastic leukemia: an unmet clinical need Hemasphere 2021 5 4 e544 10.1097/HS9.0000000000000544 33718802 PMC7951118

69. George G Lane JM Osteonecrosis of the femoral head JAAOS Glob Res Rev 2022 6 5 10.5435/JAAOSGlobal-D-21-00176 35511598 PMC9076447

70. Chang C Greenspan A Gershwin ME The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis J Autoimmun 2020 110 102460 10.1016/j.jaut.2020.102460 32307211

71. Beckish L Ging M Mosman M et al. Diagnosis and management of Legg-Calvé-Perthes disease in the obese pediatric population J Orthop Physician Assist 2024 12 3 e24.00013 10.2106/jbjs.jopa.24.00013 39759267 PMC11698501

72. Tokmakova KP Stanton RP Mason DE Factors influencing the development of osteonecrosis in patients treated for slipped capital femoral epiphysis J Bone Joint Surg Am 2003 85-A 5 798 801 10.2106/00004623-200305000-00004 12728027

73. Mathew SE Larson AN Natural history of slipped capital femoral epiphysis J Pediatr Orthop 2019 39 Issue 6, Suppl 1 S23 S27 10.1097/BPO.0000000000001369 31169643

74. Koo K-H Mont MA Cui Q et al. The 2021 association research circulation osseous classification for early-stage osteonecrosis of the femoral head to computed tomography-based study J Arthroplasty 2022 37 6 1074 1082 10.1016/j.arth.2022.02.009 35151809

75. Ha Y-C Jung WH Kim J-R Seong NH Kim S-Y Koo K-H Prediction of collapse in femoral head osteonecrosis: a modified Kerboul method with use of magnetic resonance images J Bone Joint Surg Am 2006 88 suppl_3 35 40 10.2106/JBJS.F.00535 17079365

76. Niinimäki T Niinimäki J Halonen J Hänninen P Harila-Saari A Niinimäki R The classification of osteonecrosis in patients with cancer: validation of a new radiological classification system Clin Radiol 2015 70 12 1439 1444 10.1016/j.crad.2015.08.011 26453406

77. Arlet J Ficat P Lartigue G Tran MA Clinical research on intraosseous pressure in the upper femoral metaphysis and epiphysis in humans. Application to the diagnosis of ischemia and necrosis Rev Rhum Mal Osteoartic 1972 39 11 717 723 4654969

78. Martinot P Dartus J Justo A et al. Does augmented core decompression decrease the rate of collapse and improve survival of femoral head avascular necrosis? Case-control study comparing 184 augmented core decompressions to 79 standard core decompressions with a minimum 2 years’ follow-up Orthop Traumatol Surg Res 2020 106 8 1561 1568 10.1016/j.otsr.2020.03.040 33121926

79. Hua K-C Yang X-G Feng J-T 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 1 306 10.1186/s13018-019-1359-7 31511030 PMC6737645

80. Pawar N Vaish A Vaishya R Core decompression and bone marrow aspirate concentrate injection for avascular necrosis (AVN) of the femoral head: a scoping review J Clin Orthop Trauma 2022 24 101691 10.1016/j.jcot.2021.101691 34820262 PMC8591486

81. Yu X Zhang D Chen X Yang J Shi L Pang Q 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 2 356 364 10.1016/j.jos.2017.12.004 29291916

82. Hernigou P Dubory A Homma Y 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 7 1639 1649 10.1007/s00264-018-3941-8 29744647

83. Baghdadi S Chern I Hanstein R Mehraban Alvandi L Fornari E Femoral head core decompression and bone marrow concentrate injection in pediatric sickle-cell related avascular necrosis J Pediatr Orthop 2023 43 6 e433 e439 10.1097/BPO.0000000000002415 37043417

84. Zhao D Cui D Wang B et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells Bone 2012 50 1 325 330 10.1016/j.bone.2011.11.002 22094904

85. Kuhlen M Kunstreich M Krull K Meisel R Borkhardt A Osteonecrosis in children and adolescents with acute lymphoblastic leukemia: a therapeutic challenge Blood Adv 2017 1 14 981 994 10.1182/bloodadvances.2017007286 29296741 PMC5737600

86. Kushioka J Chow SK-H Toya M et al. Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy Inflamm Regen 2023 43 1 29 10.1186/s41232-023-00279-1 37231450 PMC10210469

87. Jones LC Kaste SC Karol SE et al. Team approach: management of osteonecrosis in children with acute lymphoblastic leukemia Pediatr Blood Cancer 2020 67 11 e28509 10.1002/pbc.28509 32860663

88. Ito H Chemokines in mesenchymal stem cell therapy for bone repair: a novel concept of recruiting mesenchymal stem cells and the possible cell sources Mod Rheumatol 2011 21 2 113 121 10.1007/s10165-010-0357-8 20830500

89. Sugioka Y 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 1978 130 191 201 639389

90. Sugioka Y Katsuki I Hotokebuchi T Transtrochanteric rotational osteotomy of the femoral head for the treatment of osteonecrosis. Follow-up statistics Clin Orthop Relat Res 1982 1982 169 115 126 7105566

91. Kawano K Motomura G Ikemura S et al. Long-term hip survival and factors influencing patient-reported outcomes after transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head: a minimum 10-year follow-up case series Mod Rheumatol 2020 30 1 184 190 10.1080/14397595.2018.1558917 30556788

92. Ikemura S Yamamoto T Nakashima Y Mawatari T Motomura G Iwamoto Y Transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head in patients 20 years or younger J Pediatr Orthop 2009 29 3 219 223 10.1097/BPO.0b013e31819bc746 19305269

93. Sedrakyan A Romero L Graves S et al. Survivorship of hip and knee implants in pediatric and young adult populations: analysis of registry and published data J Bone Joint Surg Am 2014 96-A Suppl 1 Suppl 1 73 78 10.2106/JBJS.N.00541 25520422 PMC4271428

94. Halvorsen V Fenstad AM Engesæter LB et al. Outcome of 881 total hip arthroplasties in 747 patients 21 years or younger: data from the Nordic Arthroplasty Register Association (NARA) 1995-2016 Acta Orthop 2019 90 4 331 337 10.1080/17453674.2019.1615263 31088343 PMC6718182

95. Swarup I Lee YY Chiu YF Sutherland R Shields M Figgie MP Implant survival and patient-reported outcomes after total hip arthroplasty in young patients J Arthroplasty 2018 33 9 2893 2898 10.1016/j.arth.2018.04.016 29754980

96. Hart A Janz V Trousdale RT Sierra RJ Berry DJ Abdel MP Long-term survivorship of total hip arthroplasty with highly cross-linked polyethylene for osteonecrosis J Bone Joint Surg Am 2019 101-A 17 1563 1568 10.2106/JBJS.18.01218 31483399

97. Chughtai M Piuzzi NS Khlopas A Jones LC Goodman SB Mont MA An evidence-based guide to the treatment of osteonecrosis of the femoral head Bone Joint J 2017 99-B 10 1267 1279 10.1302/0301-620X.99B10.BJJ-2017-0233.R2 28963146

98. Agarwala S Banavali SD Vijayvargiya M Bisphosphonate combination therapy in the management of postchemotherapy avascular necrosis of the femoral head in adolescents and young adults: a retrospective study from India J Glob Oncol 2018 4 1 11 10.1200/JGO.17.00083 30241233 PMC6223416

99. Yuan HF Guo CA Yan ZQ The use of bisphosphonate in the treatment of osteonecrosis of the femoral head: a meta-analysis of randomized control trials Osteoporos Int 2016 27 1 295 299 10.1007/s00198-015-3317-5 26370828

Data Availability

The data that support the findings for this study are available to other researchers from the corresponding author upon reasonable request.