| Factor type | Factor | Quantitative details | Evidence type (consensus/review/cohort/MR) | Notes (mechanism) | Source (author year) | URL |
|---|---|---|---|---|---|---|
| Etiology/risk | Glucocorticoid exposure | ARCO etiologic classification: cumulative **>2 g prednisolone-equivalent within 3 months**; ONFH diagnosed **within 2 years** of exposure; no other major risk factor (pqac-00000019, pqac-00000020, pqac-00000021) | Consensus | Standardized research definition for glucocorticoid-associated ONFH | Yoon 2019 | https://doi.org/10.1016/j.arth.2018.09.005 |
| Risk | Higher daily glucocorticoid dose | **+4.6% ONFH rate per additional 10 mg/day**; **daily dose >40 mg** associated with **OR 4.2** for ONFH (pqac-00000019) | Consensus summarizing prior cohort evidence | Dose-response effect supports steroid toxicity as major risk driver | Yoon 2019 | https://doi.org/10.1016/j.arth.2018.09.005 |
| Risk | Early high cumulative steroid dose after transplant | ONFH incidence by first-2-week dose: **6% (≤520 mg)**, **17% (520–600 mg)**, **28% (>600 mg)** (pqac-00000019) | Consensus summarizing prior cohort evidence | Illustrates strong early cumulative-dose effect | Yoon 2019 | https://doi.org/10.1016/j.arth.2018.09.005 |
| Etiology/risk | Alcohol-associated ONFH | ARCO etiologic classification: alcohol consumption **>320 g/week** (summarized as **>400 mL/week**) with diagnosis **within 1 year** and no other major risk factor (pqac-00000016) | Review summarizing consensus | Standardized research definition for alcohol-associated ONFH | Ko 2023 | https://doi.org/10.5371/hp.2023.35.3.147 |
| Risk | Heavy alcohol use | Alcohol accounts for **32.4–45.3% of non-traumatic ONFH cases in Asia** (pqac-00000013) | Literature synthesis/review | Alcohol metabolites, oxidative stress, lipid dysregulation implicated | Pang 2025 | https://doi.org/10.1186/s13018-025-06138-8 |
| Etiology/risk | Trauma/femoral neck fracture | Postoperative adolescent ONFH incidence after femoral neck fracture surgery **24.02%** (95% CI **21.18%–27.12%**) (pqac-00000005) | Meta-analysis | Traumatic vascular disruption around femoral head | Gu 2024 | https://doi.org/10.1186/s13018-024-05275-w |
| Risk | Continued corticosteroid use after decompression | Continued steroid use at time of decompression associated with THA conversion **HR 4.15** (p=0.039) (pqac-00000032) | Cohort | Ongoing exposure worsens progression despite hip-preserving procedure | Houdek 2021 | https://doi.org/10.1302/2633-1462.211.bjo-2021-0132.r1 |
| Risk | Large necrotic lesion / high modified Kerboul angle | Modified Kerboul angle grade 3–4 associated with THA conversion **HR 3.96** (p=0.047); 7-year survivorship much worse than grades 1–2 (pqac-00000032) | Cohort | Larger lesion size predicts collapse and failure of joint preservation | Houdek 2021 | https://doi.org/10.1302/2633-1462.211.bjo-2021-0132.r1 |
| Risk | Steroid use, alcohol use, hypercholesterolemia, smoking | No pooled threshold given; repeatedly cited as major ONFH risks (pqac-00000009) | Review | Chronic inflammation and endothelial dysfunction promote thrombosis, poor angiogenesis, ischemia | Shao 2024 | https://doi.org/10.3390/biomedicines12030664 |
| Risk | Long-term glucocorticoid therapy | **5–40%** may develop osteonecrosis; **30–50%** may sustain fractures (pqac-00000012) | Systematic review | Glucocorticoids impair microcirculation, angiogenesis, and bone remodeling | Ma 2024 | https://doi.org/10.1186/s13018-024-04748-2 |
| Risk | Endothelial dysfunction / coagulopathy / hypofibrinolysis | Quantitative threshold not specified (pqac-00000009, pqac-00000011) | Review/systematic review | Impaired vasodilation, thrombosis, hypoxia, reduced revascularization | Shao 2024; Ma 2024 | https://doi.org/10.3390/biomedicines12030664 |
| Risk | Lipid metabolism disorder | Quantitative threshold not standardized; TG and HDL independently associated with steroid-induced ONFH in predictive model (pqac-00000007) | Cohort/multi-omics | Adipogenesis, lipid accumulation, intraosseous pressure, atherosclerosis-like injury | Jia 2024 | https://doi.org/10.1186/s13018-024-05245-2 |
| Risk | Wnt/β-catenin pathway variants | GSK3β rs334558, SFRP4 rs1052981, LRP5 rs312778 associated with ONFH risk; paired interactions linked with bilateral lesions and stage IV disease (**P <0.044–0.004**) (pqac-00000041, pqac-00000039) | Genetic case-control | Variant interactions linked to osteogenesis/adipogenesis imbalance plus lipid/coagulation abnormalities | Shi 2024 | https://doi.org/10.1038/s41598-024-57929-8 |
| Risk | Inflammatory cytokine genetics | bFGF **OR 1.942** (95% CI **1.13–3.35**), IL-2 **OR 0.688** (95% CI **0.50–0.94**), IL2-RA **OR 1.386** (95% CI **1.04–1.85**) for osteonecrosis; SCF **OR 3.356** (95% CI **1.09–10.30**) for drug-related osteonecrosis (from abstract) (pqac-00000004) | MR | Supports causal contribution of immune-inflammatory pathways | Lu 2024 | https://doi.org/10.3389/fendo.2024.1344917 |
| Protective | Higher lumbar spine bone mineral density | **OR 0.662** (95% CI **0.48–0.91**, P=0.010) for ONFH (pqac-00000043) | MR | Suggests systemic skeletal robustness may reduce susceptibility | Jia 2024 | https://doi.org/10.1186/s12891-024-08130-5 |
| Protective | Higher heel bone mineral density | **OR 0.726** (95% CI **0.62–0.85**, P<0.001) for ONFH (pqac-00000043) | MR | Protective association observed in genetic causal analysis | Jia 2024 | https://doi.org/10.1186/s12891-024-08130-5 |
| Protective | Higher total body bone mineral density | **OR 0.726** (95% CI **0.62–0.85**, P<0.001) for ONFH (pqac-00000043) | MR | Protective association observed in genetic causal analysis | Jia 2024 | https://doi.org/10.1186/s12891-024-08130-5 |
| Not supported as protective/risk | 25-hydroxyvitamin D, serum calcium, alkaline phosphatase | No significant genetic causal association: 25OHD **OR 1.006**; Ca **OR 0.856**; ALP **OR 1.022** (pqac-00000043) | MR | Current MR evidence does not support these serum markers as causal determinants | Jia 2024 | https://doi.org/10.1186/s12891-024-08130-5 |
| Risk | Deep-sea diving / dysbaric exposure | Quantitative threshold not provided (pqac-00000008, pqac-00000016) | Review | Dysbaric ONFH/Caisson disease recognized occupational etiology | Yang 2024; Ko 2023 | https://doi.org/10.1186/s13018-024-05247-0 |
| Risk | Occupational/behavioral factors and male sex in CD failure model | In ARCO I–II patients after core decompression, male sex **HR 75.449**; seated occupation **HR 3.937**; age **HR 1.045/year**; longer disease duration **HR 1.217**; combined necrosis angle **HR 1.025** (pqac-00000027) | Cohort | Prognostic factors for failure after core decompression rather than primary causation | Wei 2023 | https://doi.org/10.1186/s12891-023-06321-0 |


*Table: This table summarizes major etiologies, risk factors, and protective factors for osteonecrosis of the femoral head, emphasizing quantitative thresholds and effect sizes where available. It is useful for comparing consensus definitions, epidemiologic risks, and recent genetic/MR findings in one place.*