Introduction
Osteonecrosis of the femoral head (ONFH), colloquially referred to as a “non-fatal cancer,” is far more than a simple “common orthopedic disease.” It predominantly affects young and middle-aged adults aged 30–50 years, has a high disability rate, and follows an aggressive natural course. The window for hip-preserving treatment is extremely narrow, and late-stage cases often rely solely on joint replacement. At the same time, ONFH is a hot topic in orthopedic regenerative medicine, surgical robotics, and innovative drug development.
For patients, the critical concern with ONFH is not just the pain itself, but the progression to femoral head collapse and significant hip joint dysfunction if the disease is not identified and treated early. Once the stage of obvious collapse is reached, treatment options for preserving the original hip joint diminish significantly. Therefore, early recognition, accurate staging, and timely treatment are crucial. This article provides a systematic overview, from the clinical diagnosis and treatment framework to the latest advances in research and drug clinical development.
I. Epidemiology: An Underestimated Cause of Disability in Young and Middle-Aged Adults
The essence of ONFH is interruption or impairment of the blood supply to the femoral head, leading to necrosis of bone cells and bone marrow components. Subsequent repair responses cause structural changes in the bone, ultimately resulting in femoral head collapse and hip joint dysfunction.
Disease burden: Approximately 2 million new cases of ONFH occur globally each year, with 20,000–30,000 new cases annually in the United States [1]. According to domestic epidemiological surveys in China, the cumulative number of patients with non-traumatic ONFH has reached 8.12 million, with over 70% being young and middle-aged adults (30–50 years old). The incidence rate in males is about twice that in females [2].
Etiological composition: Non-traumatic causes account for about 80% of cases. Among these, corticosteroid-associated ONFH constitutes 30%–40%, alcohol-associated ONFH constitutes 30%–35%, and idiopathic cases account for approximately 15%. Traumatic ONFH is primarily induced by femoral neck fractures and hip dislocations [2, 3].
Clinical features: Bilateral involvement occurs in 60%–80% of non-traumatic ONFH cases, and most patients experience sequential involvement of both hips.
Natural course: Without intervention, approximately 80% of patients progress to femoral head collapse within 2–5 years after diagnosis, ultimately leading to severe osteoarthritis and loss of work capacity.
II. Clinical Manifestations and Diagnosis: Early Missed Diagnosis Remains a Core Clinical Challenge
The clinical manifestations of ONFH are highly dependent on the stage. Early symptoms are insidious and non-specific, which is the main reason for clinical missed diagnosis and misdiagnosis.
Typical clinical manifestations: The most common initial symptom is deep, dull, or aching pain in the groin area, which may radiate to the buttocks, medial thigh, and medial knee (referred pain, easily misdiagnosed as knee osteoarthritis). Pain is initially intermittent, worsens with activity, and alleviates with rest; it later progresses to persistent rest pain with significant night pain. Early signs are atypical. As the disease progresses, limited hip rotation (internal rotation limitation appears earliest), a positive Patrick's test (FABER test), and a positive Thomas test may be observed. Late stages present with limping, leg shortening, and severe limitation of hip movement in all directions [2].
Clinical staging system: The internationally accepted ARCO 2019 staging system is currently the core basis for selecting treatment plans.
Imaging diagnosis: Stratified application from screening to preoperative evaluation
Imaging is the cornerstone for confirming ONFH diagnosis, staging, and efficacy evaluation, with different modalities offering irreplaceable value.
X-ray: Economical and convenient, it is the basic examination for initial diagnosis and follow-up and can demonstrate late-stage femoral head collapse and osteoarthritic changes. Its sensitivity for Stage I lesions is less than 10%; signs such as sclerosis and cystic changes may appear only in Stage II, making X-ray unsuitable for early diagnosis.
CT: Offers higher resolution than X-ray, clearly displaying sclerotic rim boundaries, cystic changes, subchondral microfractures, and assessing the degree and extent of collapse. It is insensitive to bone marrow edema and early ischemia and thus is not suitable for early screening.
MRI: Sensitivity for Stage I ONFH is 99%, and specificity is 98%, making it the preferred method for early diagnosis. Typical signs include a low-signal band surrounding a fatty signal area on T1WI, and the characteristic double-line sign (high-signal granulation tissue band + low-signal sclerotic band) on T2WI; bone marrow edema is a marker of disease activity and pain.
Radionuclide bone scan: Primarily used for screening multifocal osteonecrosis, providing supplementary value for patients suspected of having widespread necrosis.
Approximately 30% of patients with early ONFH are initially misdiagnosed as having lumbar disc herniation or knee osteoarthritis, leading to examinations focused on the lumbar spine or knee while the hip is overlooked. For high-risk individuals (e.g., a history of steroid use, alcohol abuse, or hip trauma), hip pain should prompt direct referral for hip MRI as the first-choice imaging modality.
III. Current Standard Treatment Paradigm: Stratified Treatment with Defined Boundaries Between Hip Preservation and Replacement
The core principle of ONFH treatment is staged, individualized approach: hip preservation in early stages, replacement in late stages; prioritizing hip preservation for younger patients and replacement for older patients [2, 4-6].
1. Non-Surgical Treatment: Basic Intervention for Early-Stage Lesions
Indications: ARCO Stage I–II, small necrotic area located in non-weight-bearing regions; or as adjuvant therapy before or after surgery.
Etiological control: Abstinence from alcohol, gradual discontinuation or reduction of corticosteroids, and treatment of underlying diseases; strict weight-bearing restriction, with crutches or wheelchair use recommended to reduce load.
Pharmacological Therapy:
Bisphosphonates: Inhibit osteoclast activity, delaying bone resorption and collapse, e.g., zoledronic acid, alendronate sodium. Some clinicians use them empirically to attempt slowing ONFH progression, but their role in ONFH treatment is highly controversial, with unconfirmed efficacy.
Microcirculation-Improving Drugs: Alprostadil, beraprost sodium, which vasodilate and improve femoral head perfusion.
Statins: Lower lipids while improving bone metabolism, reducing the risk of steroid-induced ONFH.
Anticoagulants: Low molecular weight heparin, for patients with a prothrombotic state.
Traditional Chinese Medicine: Represented by Tongluo Shenggu Capsules and Xianling Gubao, among others. There is some clinical evidence for symptom improvement and progression delay, constituting a characteristic domestic treatment approach.
Physical Therapy: Extracorporeal Shock Wave Therapy (ESWT), hyperbaric oxygen therapy, pulsed electromagnetic fields can serve as adjuvant treatments.
According to the "International Evidence-Based Clinical Practice Guidelines for Non-Traumatic Osteonecrosis of the Femoral Head" [6], evidence supporting the efficacy of the aforementioned treatments for improving ONFH outcomes is insufficient, indicating a current lack of effective hip-preserving drugs.
2. Hip-Preserving Surgical Treatment: Core Strategy for Young and Middle-Aged Patients
Indications: Patients with ARCO Stage II or IIIa (collapse < 2 mm), aged < 50 years, who are willing to undergo hip-preserving treatment.
Core decompression (CD): The most classic hip-preserving procedure, which reduces intraosseous pressure and re-establishes blood supply channels by drilling. Simple core decompression is suitable for early-stage, small-area necrosis; combining it with bone grafting or cell therapy can enhance efficacy.
Vascularized bone grafting: Represented by free vascularized fibular grafting (FVFG) and deep circumflex iliac artery (DCIA) vascularized bone grafting, it provides both mechanical support and revascularization. It is an effective hip-preserving procedure for intermediate to advanced pre-collapse stages, with a 5-year hip preservation success rate of approximately 70%–85%.
Porous tantalum rod implantation: This technique uses the biocompatibility and supportive properties of porous tantalum as an alternative to fibular grafting and involves less surgical trauma. However, its efficacy is limited in patients with extensive necrosis or significant collapse, and its indications are relatively narrow.
Osteotomy: This includes transtrochanteric rotational osteotomy and varus/valgus osteotomy, which shift the necrotic area away from the weight-bearing zone. It requires high technical skill and has strict indications; it is more commonly used in Japan and Korea, with relatively limited application in China.
3. Total Hip Arthroplasty (THA): Standard Treatment for Advanced-Stage Disease
Indications: ARCO Stage IIIb–IV, significant collapse of the femoral head; failure of hip-preserving treatment; severe pain and significant functional impairment affecting quality of life.
Total hip arthroplasty (THA): Currently the gold standard treatment for advanced ONFH, providing reliable pain relief and functional recovery. Because the patient population is generally younger, the long-term revision rate is higher than that in elderly patients with osteoarthritis, making long-term clinical management a key focus.
IV. Research Frontiers: From Pharmaceuticals to Cell Therapy, Hip Preservation is the Core Direction
In the fields of pharmaceuticals and clinical trials, the research focus for ONFH centers on early intervention, delaying collapse, and avoiding or postponing arthroplasty [1,7].
1. Innovative Drug Development
Dual-target formulations: These simultaneously target angiogenesis and osteogenic repair, such as locally sustained-release formulations loaded with VEGF/BMP.
Novel bone resorption inhibitors: The application of denosumab in ONFH is being explored; compared with bisphosphonates, it offers stronger effects and more convenient administration.
Stem cell-mobilizing agents: CXCR4 antagonists (e.g., plerixafor) mobilize autologous bone marrow mesenchymal stem cells to home to the necrotic area and promote endogenous repair, showing potential in early clinical studies.
Anti-inflammatory and anti-fibrotic inhibitors: Small-molecule drugs targeting the local inflammatory microenvironment and fibrotic process in necrotic tissue; these are currently in basic and preclinical research stages.
2. Cell and Biological Therapy: The Most Active Area in Clinical Trials
Cell therapy is currently the most prominent direction in the field of ONFH hip preservation, with multiple registered clinical trials already conducted in China.
Bone marrow mesenchymal stem cells: Core decompression combined with autologous BMSC infusion/transplantation. Multiple phase II/III clinical trials have shown that this approach can significantly improve hip-preservation success rates and delay collapse.
Stem cells from other sources: Umbilical cord mesenchymal stem cells and adipose-derived stem cells are also under clinical investigation because of their convenient sourcing and strong expansion capacity.
Platelet-rich plasma: When used in combination with core decompression, it promotes bone repair by releasing growth factors.
Stem cell exosomes: A cell-free therapeutic strategy that avoids the safety and ethical issues associated with cell therapy; it is a hot topic in basic research.
Conclusion
Behind the nickname “a cancer that does not kill” lies the long-term toll of osteonecrosis of the femoral head on the working-age population: it may not take lives, but it progressively robs patients of their ability to walk. Due to its insidious onset and atypical early imaging findings, a significant proportion of patients are diagnosed after missing the window for hip preservation, ultimately leading to total joint replacement.
For professionals in pharmaceutical R&D and clinical trials, this unmet clinical need is precisely the challenge we are committed to addressing. In this process, novel drugs and cell therapies carry the hope of altering the natural course of the disease. As diagnostic and treatment thresholds continue to shift earlier, our ultimate goal is to identify and intervene in more patients before collapse occurs, truly “preserving” their native joints.
References
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6.Cheng EY, Mirzaei A, Goodman SB, Cui Q, Mont MA, Jones LC; the ARCO Clinical Practice Guideline workgroup. Nontraumatic Osteonecrosis of the Femoral Head: An International Evidence-Based Clinical Practice Guideline. J Bone Joint Surg Am. 2026 Jun 17;108(12):903-906.
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