Osteonecrosis of the femoral head: a rare complication of combination therapy with bevacizumab and atezolizumab in a patient with non-small cell lung cancer

Cover Page


Cite item

Full Text

Abstract

BACKGROUND: Anti-angiogenic therapy is used in the treatment of many solid malignant neoplasms, both alone and in combination with immunotherapy, targeted therapy, and chemotherapy. Complications of drug therapy for malignant neoplasms may necessitate the permanent discontinuation of antitumor therapy, resulting in disability. These complications include bone disorders. Osteonecrosis of the jaw is most commonly associated with bone-modifying agents (bisphosphonates); however, it is extremely rare with other drugs. Necrosis of the femur is even less common. CLINICAL CASE DESCRIPTION: This article presents a clinical case of bilateral avascular necrosis of the femoral head in a patient with disseminated non-small cell lung cancer who was receiving long-term combination immunotherapy and targeted therapy. CONCLUSION: Avascular necrosis of the femoral head is a major concern, considering the expanding range of drug therapies for various malignant neoplasms and novel combination therapy options. The lack of a clear algorithm for managing patients with this serious complication of antitumor drug therapy highlights the relevance of this issue.

Full Text

BACKGROUND

Aseptic avascular bone necrosis (osteonecrosis) is a rare condition caused by impaired blood supply. Common causes include local trauma, prolonged corticosteroid use, alcohol abuse, radiotherapy, and systemic diseases. In our clinical practice, we encountered a case of aseptic avascular necrosis of the femoral head in a 51-year-old patient receiving drug therapy for advanced non-small cell lung cancer.

We believe that osteonecrosis in oncology is underrecognized, and there is still no clearly defined algorithm for managing patients with this serious complication of antitumor therapy. The aim of this report is to draw attention to this issue.

CLINICAL CASE DESCRIPTION

Patient Information

A 51-year-old patient with a smoking history of more than 30 years and no remarkable comorbidities.

Anamnesis morbi. In February 2021, adenocarcinoma of the right upper lobe (Fig. 1) with metastases to the right hilar and mediastinal lymph nodes was diagnosed. The patient presented to the N.N. Blokhin National Medical Research Center of Oncology for further treatment. A biopsy was performed: histologically, a wild-type tumor was identified, with no mutations in the ALK, ROS1, or EGFR genes, and no expression of PD-L1 (CD274) (clone 22C3, TPS=0%, CPS=2). The disease extent was staged as T1cN2M1c-IVB, ECOG performance status 1. Based on a multidisciplinary tumor board decision, first-line therapy with paclitaxel/carboplatin/atezolizumab/bevacizumab was initiated.

 

Fig. 1. Computed tomography (axial view) at initial presentation (February 5, 2021). A lesion is identified in segment S2 of the right upper lobe, characterized by an ill-defined, spiculated margin and heterogeneous structure, measuring 3.0×2.0 cm, with a broad base abutting the pleura over a length of up to 3 cm.

 

From March 3, 2021, to May 6, 2021, the patient received four cycles of treatment. On May 21, 2021, a partial response (−36% according to RECIST 1.1; Fig. 2) was demonstrated. Accordingly, on June 1, 2021, the patient was switched to maintenance therapy with atezolizumab and bevacizumab every 21 days, with a reduction in the bevacizumab dose from 7.5 mg/kg to 5 mg/kg due to recurrent episodes of epistaxis. During follow-up, the tumor remained stable.

 

Fig. 2. Computed tomography (axial view), May 21, 2021, after four cycles of first-line systemic therapy. The size of the nodular lesion with an ill-defined, spiculated margin in segment S2 of the right lung decreased to 2.4×1.5 cm. The structure became more heterogeneous due to a reduction in the solid component. Broad-based contact with the pleura persists over a length of up to 2.7 cm.

 

In December 2021, the patient reported migratory pain in the hip, knee, and ankle joints bilaterally, without clear localization or association with physical activity. No joint swelling or hyperemia was observed. A physician and an orthopedic surgeon diagnosed right-sided grade II coxarthrosis. Nonsteroidal anti-inflammatory drugs were prescribed for pain relief, with no effect. Rheumatologic consultation excluded rheumatoid arthritis. The bone pain was interpreted as grade II immune-mediated arthritis associated with immunotherapy. Treatment with oral methylprednisolone at a dose of 0.5 mg/kg was initiated according to established management algorithms for immune-related adverse events associated with immune checkpoint inhibitors.

On January 11, 2022, atezolizumab therapy was suspended. During corticosteroid therapy, clinical improvement was observed: joint pain resolved; mobility improved, and the patient discontinued analgesics.

Corticosteroid therapy was continued for one month with gradual tapering to complete discontinuation. Maintenance therapy with atezolizumab and bevacizumab was subsequently resumed. Follow-up imaging demonstrated persistent partial tumor response, with no evidence of bone metastases.

In March 2022, persistent pain in the hip joint recurred, radiating to the groin and worsening with movement. Nonsteroidal anti-inflammatory drugs and corticosteroid therapy were resumed, but with no effect. On March 22, 2022, weight-bearing on the right leg became nearly impossible, and the patient required crutches for ambulation. Sciatic nerve compression was suspected by a neurologist, and medical therapy was initiated without any clinical benefit. Antitumor therapy was completely discontinued on April 26, 2022.

Diagnostic assessment

Computed tomography (CT) performed on April 27, 2022, revealed a comminuted fracture of the right femoral head and an impression fracture of the left femoral head without displacement or signs of healing (Fig. 3a). Retrospective review of computed tomography scans dated January 21, 2022 (at the time of symptom onset) demonstrated subchondral changes in the femoral heads, more pronounced on the right, characterized by a geographic pattern and early flattening of the articular surfaces (Fig. 3b). Other potential causes of the identified fractures were excluded, and the complication was attributed to the adverse effects of targeted therapy.

 

Fig. 3. Computed tomography (coronal reconstruction) of the hip joints. April 27, 2022 (a), geographic pattern changes, more extensive on the right, with the appearance of a comminuted fracture without signs of healing; findings on the left remain stable. January 21, 2022 (b), subchondral regions of both femoral heads demonstrate areas with a geographic pattern, characterized by alternating concentric zones of bone rarefaction and sclerosis.

 

Treatment

The patient was prescribed symptomatic therapy, including vitamins, nonsteroidal anti-inflammatory drugs, and bisphosphonates. CT and magnetic resonance imaging (MRI) of the knee joints revealed no similar changes; only early degenerative changes were noted bilaterally. The patient’s ECOG performance status was 2.

The patient declined the proposed surgical treatment of avascular necrosis of the femoral heads, including bilateral hip arthroplasty.

Follow-up and outcomes

During active follow-up, no progression of the tumor process was observed as of November 2022 (Fig. 4, Fig. 5). In the presence of a comminuted fracture, progressive osteolysis was noted at the junction of the femoral head and neck in the right hip joint, with no signs of healing. The fracture fragments demonstrated sclerotic margins, with a tendency toward pseudarthrosis formation. On the left side, partial lysis of the femoral head developed in the setting of avascular necrosis. Bilaterally, synovitis and subluxation of the hip joints progressed, along with worsening of deforming osteoarthritis.

 

Fig. 4. Computed tomography (coronal reconstruction) of the femora (a), and magnetic resonance imaging, T2-TIRM sequence in the coronal plane (b), November 14, 2022. A comminuted fracture of the right femoral head persists without signs of healing, with sclerotic margins of the bone fragments (suggestive of pseudarthrosis formation). On the left, partial lysis of the femoral head is observed. Bilaterally, marked synovitis with para-articular extension is present. The acetabular roofs show erosive changes, while subchondral regions are relatively preserved. Bilateral hip subluxations are noted.

 

Fig. 5. Computed tomography (coronal reconstruction), November 22, 2024. A comminuted fracture of the right femoral head persists without signs of healing. Progressive lysis of the left femoral head is observed. Bilaterally, there is progression of femoral head subluxation and deformity of the acetabular roofs, accompanied by pelvic ring deformity and the development of lower limb length discrepancy.

 

At subsequent follow-up in December 2024, further reduction of mediastinal lymph nodes was observed, whereas the primary tumor in the right lung remained stable. In the femoral bones (see Fig. 5), previously described changes associated with avascular necrosis of the femoral heads showed further negative orthopedic progression. In the area of the comminuted fracture of the right femoral head, no signs of healing were observed, with multiple separated bone fragments persisting, characterized by sclerotic margins. On the left side, femoral head lysis progressed. Bilaterally, the acetabular roofs demonstrated increasing erosive changes. Progressive deformation of the pelvic ring and limb length discrepancy were noted. The patient required a wheelchair for mobility. No progression of degenerative changes in the knee joints was observed.

Prognosis

Combination therapy, integrating chemotherapy with immunotherapy and a targeted agent, followed by maintenance immunotherapy and a targeted agent for one year, achieved a favorable antitumor response and sustained disease stabilization. However, the developed complications led to patient disability and necessitated treatment discontinuation. The patient has been under follow-up for more than 3 years. The prognosis is unfavorable: in the event of disease progression, further antitumor drug therapy will be limited due to the patient’s general condition (ECOG performance status 3) and restricted treatment options.

Timeline

The interval between the onset of initial symptoms and the initiation of antitumor therapy for lung cancer was 4 months. The duration of treatment was 11 months, and the total follow-up period was 4.5 years.

DISCUSSION

The etiology of bone necrosis remains unclear. Interest in this topic is growing due to the expanding array of pharmaceutical agents available for treating malignant neoplasms and developing novel combination regimens.

The issue of avascular necrosis of the femoral head (ANFH) associated with bevacizumab is of increasing relevance because of the widespread use of anti-angiogenic agents and immunotherapies. This is a severe and progressive condition that leads to disability and remarkably impairs patients’ quality of life.

According to the World Health Organization, approximately 100,000–150,000 cases of nontraumatic avascular necrosis of the femoral head are diagnosed annually worldwide. This condition most commonly occurs in young men aged 20–50 years [1, 2]. Bilateral involvement is observed in 70%–80% of cases [3–5]. There are currently no epidemiological data on the incidence of ANFH in the Russian Federation.

It is generally accepted that the most common causes of ANFH are prolonged corticosteroid use (up to 70%) and alcohol consumption (up to 30%), which lead to lipid metabolism disorders, osteoporosis, and arteriopathy [6, 7]. The reported incidence of ANFH associated with bevacizumab is approximately 1%–2% with long-term use [8, 9]. The published data suggests that patients receiving anti-angiogenic agents have an increased risk of osteonecrosis compared with the general population; however, precise data on its prevalence remains limited.

Specific features of ANFH development may be related to the mechanism of action of bevacizumab. This recombinant humanized monoclonal antibody inhibits vascular endothelial growth factor (VEGF) by binding with high-affinity to two receptors VEGFR-1 and VEGFR-2 on the surface of endothelial cells. Angiogenesis is regulated by a balance between proteins with opposing functions, including proangiogenic factors such as VEGF and antiangiogenic factors such as thrombospondin-1. This balance is maintained under normal homeostatic conditions; however, in malignancy, it shifts toward proangiogenesis due to tumor hypoxia associated with rapid cell proliferation, as well as activation of plasminogen and collagenase by macrophages and tumor-associated fibroblasts [10–12]. VEGF is considered a key mediator of tumor angiogenesis and is highly expressed in many solid tumors; therefore, inhibition of VEGF signaling has antitumor activity. Bevacizumab blocks VEGF, leading to reduced vascular permeability and the development of ischemic changes, particularly in bone structures with pre-existing impairment of blood supply. The predilection of these adverse effects for specific skeletal sites remains unclear.

According to the publications, the most common serious complications associated with bevacizumab include thromboembolic events, bleeding, hypertension, gastrointestinal perforation, and impaired wound healing [13]. Cases of laryngeal necrosis [14], nasal septum perforation [15], and osteonecrosis of the jaw [16, 17] have also been reported. In the pathogenesis of osteonecrosis, functional activity of T and B lymphocytes may play its role, as they influence osteoclast regulation. The total count of lymphocytes, T-suppressor cells (CD3+, CD8+), CD3+ T cells, and B1 lymphocytes (CD5+, CD19+) is remarkably higher in patients with ANFH compared with healthy individuals [18, 19], which may contribute to the development of ANFH during antitumor immunotherapy. Genetic predisposition cannot be excluded, including the C677T mutation of the MTHFR gene [20] and polymorphisms of platelet integrins (ITGA2, ITGB3) [21]. Anatomical and structural features of the femoral head may also play an important role.

The diagnosis of osteonecrosis of the ANFH is challenging, particularly in the early stages, as its clinical presentation is often subtle and variable. Patients typically report pain in the groin, buttock, lower back, or knee region. The pain may be associated with movement or, conversely, may worsen at night and at rest [6, 22]. Physical examination usually reveals no swelling, hyperemia, joint deformity, or sensory disturbances; however, limitation of hip mobility and muscle atrophy may develop in cases of prolonged pain (more than 6 weeks).

Accurate determination of disease stage, as well as the extent and location of necrosis, is essential for selecting a treatment strategy and predicting prognosis. Several staging systems for ANFH have been proposed [23–29]:

  • Ficat and Arlet classification;
  • Steinberg classification;
  • Association Research Circulation Osseous (ARCO) classification;
  • Japanese Orthopedic Association (JOA) classification;
  • modified Kerboul classification.

Each of these systems has its advantages and limitations, and none has been universally accepted. The ARCO classification is the most commonly used; it was first proposed in 1994 and has undergone periodic revisions. The most recent update (2019) incorporates radiographic findings in combination with MRI data and clinical presentation. A variety of imaging modalities are used in the diagnosis of ANFH, including plain radiography, bone scintigraphy, MRI, and CT. Radiography of the hip joint has low sensitivity, particularly in the early stages of necrosis; therefore, MRI is the modality of choice in this setting [30–32].

In 2017, ARCO proposed a classification scheme for ANFH associated with corticosteroid use and alcohol consumption to standardize clinical research, developed using Delphi consensus methods. The diagnostic criteria for corticosteroid-associated ANFH include the following:

  1. a history of corticosteroid use (prednisolone) for more than 2 years or high-dose exposure for at least 3 months;
  2. diagnosis of osteonecrosis within 2 years after corticosteroid use;
  3. absence of other risk factors aside from corticosteroid exposure [33].

In our case, the dose of methylprednisolone was remarkably below the threshold, which precludes classification of this case as glucocorticoid-associated ANFH.

If the development of ANFH is related to alcohol consumption, the patient should meet the following criteria:

  1. a history of alcohol intake exceeding 400 mL per week (approximately 320 g/week of ethanol, regardless of beverage type) for more than 6 months;
  2. diagnosis of osteonecrosis of the femoral head within 1 year after such alcohol exposure;
  3. absence of other risk factors apart from alcohol abuse [32, 34].

In our case, the patient did not abuse alcohol.

ARCO staging system:

  • Stage 0: No clinical signs or abnormalities on X-ray or MRI scans. The diagnosis is established by biopsy findings only. However, because patients are asymptomatic and do not seek medical attention, diagnosis at this stage is virtually impossible; therefore, it was removed in the 2019 revision of the classification.
  • Stage I: Minimal clinical manifestations with no abnormalities on plain radiographs. Lesions are detectable by radionuclide imaging and/or MRI.
  • Stage II: Persistent clinical signs are present. Plain X-ray, MRI, and radionuclide studies demonstrate early signs of osteonecrosis in the femoral head, characterized by trabecular bone changes without alteration of the articular surface or joint space, and without subchondral fracture.
  • Stage III: Persistent clinical signs are present. Imaging studies confirm trabecular bone changes and the presence of a subchondral fracture (crescent sign or subchondral collapse), whereas the joint space is preserved. This stage is subdivided into IIIA (depression ≤2 mm) and IIIB (depression >2 mm), depending on the depth of femoral head collapse.
  • Stage IV: Clinical signs are present. Imaging studies demonstrate signs of osteoarthritis, including deformity of the femoral head, acetabular changes, and joint space narrowing. Flattening (impression) of the femoral head is observed.

It should be acknowledged that in patients with active malignancy, particularly those with bone metastases, the diagnosis of ANFH may be challenging.

Management of patients with ANFH is typically undertaken by rheumatologists and orthopedic surgeons. Treatment approaches can be broadly divided into two groups: conservative (pain control, joint unloading through activity restriction, osteotropic therapy, antiresorptive therapy, vascular pharmacotherapy, vitamin supplementation, physiotherapy, and therapeutic exercise) and surgical (core decompression of the necrotic lesion, osteotomy, arthroplasty, vascularized bone grafting, and joint-preserving reconstructive procedures).

At early stages (ARCO I–II), conservative treatment may be considered, aiming to improve microcirculation and bone nutrition with preserving joint function and reducing load on the affected limb. A multimodal therapeutic approach may include nonsteroidal anti-inflammatory drugs, calcium supplements, bisphosphonates, anticoagulants and antiplatelet agents, statins, as well as vitamins B and D [32, 35–42]. However, the efficacy of these pharmacological interventions has not been conclusively established yet.

Additionally, intra-articular injections of hyaluronic acid may be used at all stages to improve joint function, along with modern physiotherapeutic modalities (shockwave therapy, phonophoresis/electrophonophoresis, high-intensity laser therapy [HILT], electromagnetic field therapy, and massage) [43–50].

There is no ideal surgical treatment for ANFH. Core decompression of the necrotic lesion remains the standard approach at early stages of ANFH [50–54]. However, over time, the effectiveness of decompression techniques has been questioned [55], leading to the development of combined approaches, including decompression with intra-articular administration of bone marrow aspirate or stem cells, which require further investigation [56–61].

For ARCO stage IIIA, treatment options include osteotomy with the use of a vascularized bone autograft [50, 62, 63], whereas total hip arthroplasty is considered for advanced stages IIIB and IV [50, 64–67]. The use of vascularized fibular autografts has been associated with remission in 64.5% of cases, with preservation of the anatomical shape of the femoral head during follow-up of ≥5 years [68–71].

Diagnostic and therapeutic algorithms for the management of patients with ANFH are outlined in the clinical guidelines of the Russian Association of Traumatologists and Orthopedists (2020) [50]. In all cases, the treatment strategy should be individualized, taking into account patient age, extent of bone involvement, severity of symptoms, comorbidities, and patient preferences.

CONCLUSION

In oncology practice, ANFH is a relatively rare condition. Affected patients typically have multiple risk factors, including corticosteroid use, chemotherapy, hormone-deprivation therapy, malnutrition, and physical inactivity. Additionally, anti-angiogenic agents and mixed-origin coagulopathy may contribute to angiopathy, leading to degenerative changes in bone and cartilage tissue.

Evaluation of the hip joint is not part of routine assessment in patients with solid tumors, which creates additional challenges in diagnosing this serious complication. Delayed diagnosis may adversely affect prognosis; therefore, clinicians should remain aware of the potential development of ANFH and promote interdisciplinary collaboration with related specialties.

ADDITIONAL INFORMATION

Author contributions: T.D. Barbolina, S.G. Bagrova, concept and design of the article, literary search; T.D. Barbolina, collection, processing of the material and writing of the text; S.G. Bagrova, A.V. Fedorova, final edits and editing; A.V. Fedorova, selection of illustrations. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication: Informed oral consent has been received from the patient. The patient received a copy of the article. The patient is not a participant in a clinical (registration) study. Medications (or medical devices) were not used for indications other than those specified in the instructions. No confidential information about the individual (personal data, medical records, or any other information about the patient’s life, including photographs) was provided.

Funding sources: The study had no sponsorship.

Disclosure of interests: The authors declare that they have no competing interests.

Statement of originality: The authors did not use previously published information (text, illustrations, data) while conducting this work.

Data availability statement: All data obtained in this study are available in this article.

Generative AI: Generative AI technologies were not used for this article creation.

×

About the authors

Tatyana D. Barbolina

National Medical Research Center of Oncology named after N.N. Blokhin; Russian University of Medicine

Author for correspondence.
Email: katan4ik@list.ru
ORCID iD: 0000-0002-4548-1026
SPIN-code: 3940-0321

MD, PhD

Russian Federation, Moscow; Moscow

Svetlana G. Bagrova

National Medical Research Center of Oncology named after N.N. Blokhin

Email: s.bagrova@mail.ru
ORCID iD: 0000-0003-2981-7666
SPIN-code: 3642-5948

MD, PhD

Russian Federation, Moscow

Aleksandra V. Fedorova

National Medical Research Center of Oncology named after N.N. Blokhin; Yaroslavl State Medical University

Email: fedorova.ronc@gmail.com
ORCID iD: 0000-0002-4516-3255
SPIN-code: 1198-9039

MD, PhD

Russian Federation, Moscow; Yaroslavl

References

  1. Shannon BD, Trousdale RT. Femoral osteotomies for avascular necrosis of the femoral head. Clin Orthop Relat Res. 2004;(418):34–40. doi: 10.1097/00003086-200401000-00007
  2. DeSmet AA, Dalinka MK, Alazraki NP, et al. Expert Panel on Musculoskeletal Imaging. Diagnostic imaging of avascular necrosis of the hip. Reston, VA: American College of Radiology (ACR); 2005.
  3. Murphey MD, Roberts CC, Bencardino JT, et al. ACR appropriateness criteria osteonecrosis of the hip. J Am Coll Radiol. 2016;13(2):147–155. doi: 10.1016/j.jacr.2015.10.033
  4. Arbab D, Konig DP. Atraumatic femoral head necrosis in adults. Dtsch Arztebl Int. 2016;113(3):31–38. doi: 10.3238/arztebl.2016.0031
  5. Fukushima W, Fujioka M, Kubo T, et al. Nationwide epidemiologic survey of idiopathic osteonecrosis of the femoral head. Clin Orthop Relat Res. 2010;468(10):2715–2724. doi: 10.1007/s11999-010-1292-x
  6. Шостак Н.А., Демидова Н.А., Кондрашов А.А., и др. Остеонекроз головки бедренной кости, не связанный с травмой: патогенетические аспекты, клиническая и инструментальная картина (часть 1) // Лечебное дело. 2021. № 2. С. 4–16. [Shostak NA, Demidova NA, Kondrashov AA, et al. Osteonecrosis of femoral head not associated with trauma: pathogenetic aspects, clinical and instrumental picture (part 1). Lechebnoe delo. 2021;(2):4–16]. doi: 10.24412/2071-5315-2021-12326 EDN: XQPEIW
  7. Панин М.А., Загородний Н.В., Карчебный Н.Н., и др. Современный взгляд на патогенез нетравматического остеонекроза // Вестник травматологии и ортопедии имени Н.Н. Приорова. 2017. № 2. С. 69–75. [Panin MA, Zagorodny NV, Karchebny NN, et al. Modern view to the pathogenesis of non-traumatic osteonecrosis. N.N. Priorov journal of traumatology and orthopedics. 2017;(2):69–75]. EDN: ZATDZH
  8. Rizzo S, Ricci F, Berti P. Osteonecrosis of the femoral head in patients treated with anti-VEGF agents: a systematic review. Bone. 2020;137:115448. doi: 10.1016/j.bone.2020.115448
  9. Wang P, Shao W, Wang Y, et al. Angiogenesis of avascular necrosis of the femoral head: a classic treatment strategy. Biomedicines. 2024;12(11):2577. doi: 10.3390/biomedicines12112577 EDN: DQNGCY
  10. Lafforgue P. Pathophysiology and natural history of avascular necrosis of bone. Joint Bone Spine. 2006;73(5):500–507. doi: 10.1016/j.jbspin.2006.01.025
  11. Nifosi AF, Zuccarello M, Nifosi L, et al. Osteonecrosis of the jaw in the era of targeted therapy and immunotherapy in oncology. J Korean Assoc Oral Maxillofac Surg. 2019;45(1):3–8. doi: 10.5125/jkaoms.2019.45.1.3
  12. Rajabi M, Mousa SA. The role of angiogenesis in cancer treatment. Biomedicines. 2017;5(2):34. doi: 10.3390/biomedicines5020034
  13. Touyz RM, Herrmann SM, Herrmann J. Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. J Am Soc Hypertens. 2018;12(6):409–425. doi: 10.1016/j.jash.2018.03.008
  14. Hartl DM, Bahleda R, Hollebecque A, et al. Bevacizumab-induced laryngeal necrosis. Ann Oncol. 2012;23(1):276–278. doi: 10.1093/annonc/mdr515
  15. Mailliez A, Baldini C, Van JT, et al. Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients. Br J Cancer. 2010;103(6):772–775. doi: 10.1038/sj.bjc.6605828 EDN: GJDCWF
  16. Wynn RL. Bevacizumab (Avastin): an anti-angiogenic drug associated with osteonecrosis of the jaw. Gen Dent. 2011;59(6):410–413.
  17. Dişel U, Beşen AA, Özyılkan Ö, et al. A case report of bevacizumab-related osteonecrosis of the jaw: old problem, new culprit. Oral Oncol. 2012;48(2):e2–3. doi: 10.1016/j.oraloncology.2011.07.030
  18. Ma J, Ge J, Gao F, et al. The role of immune regulatory cells in nontraumatic osteonecrosis of the femoral head: a retrospective clinical study. BioMed Res Int. 2019;2019:1302015. doi: 10.1155/2019/1302015
  19. Zhang H, Xiao F, Liu Y, et al. A higher frequency of peripheral blood activated B cells in patients with non-traumatic osteonecrosis of the femoral head. Int Immunopharmacol. 2014;20(1):95–100. doi: 10.1016/j.intimp.2014.02.016
  20. Панин М.А., Загородний Н.В., Самоходская Л.М., Бойко А.В. Значение полиморфизмов гена метилентетрагидрофолатредуктазы (MTHFR) в патогенезе нетравматического асептического некроза головки бедренной кости // Вестник травматологии и ортопедии имени Н.Н. Приорова. 2020. Т. 27, № 2. С. 19–23. [Panin MA, Zagorodny NV, Karchebny NN, Samokhodskaya LM, Boyko AV. The value of the mthfr polymorphisms in pathogenesis of nontraumatic necrosis of femoral head. N.N. Priorov journal of traumatology and orthopedics. 2020;27(2):19–23]. doi: 10.17816/vto202027219-23 EDN: ETWCJP
  21. Панин М.А., Загородний Н.В., Самоходская Л.М., Бойко А.В. Значение полиморфизмов генов тромбоцитарных интегринов (ITGα2, ITGβ3) впатогенеза нетравматического асептического некроза головки бедренной кости // Медицинский вестник Северного Кавказа. 2020. Т. 15, № 1. С. 84–86. [Panin MA, Zagorodny NV, Karchebny NN, Samokhodskaya LM, Boyko AV. He role of the genetic polymorphism of thrombocyte integrins (ITGα2, ITGβ3) in the pathogenesis of non-traumatic aseptic necrosis of the femoral head. Medical news of North Caucasus. 2020;15(1):84–86]. doi: 10.14300/mnnc.2020.15019 EDN: XSLWGU
  22. Hauzeur JP, Malaise M, de Maertelaer V. A prospective cohort study of the clinical presentation of non-traumatic osteonecrosis of the femoral head: spine and knee symptoms as clinical presentation of hip osteonecrosis. Int Orthop. 2016;40(7):1347–1351. doi: 10.1007/s00264-015-3079-x EDN: YLXNEZ
  23. El-Feky M, Gaillard F, Kearns C, et al. Ficat and Arlet classification of osteonecrosis of the femoral head. In book: Radiopaedia.org. 2008. doi: 10.53347/rID-951
  24. Zalavras CG, Lieberman JR. Osteonecrosis of the femoral head: evaluation and treatment. J Am Acad Orthop Surg. 2014;22(7):455–464. doi: 10.5435/JAAOS-22-07-455
  25. Lee GC, Steinberg ME. Are we evaluating osteonecrosis adequately? Int Orthop. 2012;36(12):2433–2439. doi: 10.1007/s00264-012-1658-7 EDN: RJECYA
  26. Meier R, Kraus TM, Schaeffeler C, et al. Bone marrow oedema on MR imaging indicates ARCO stage 3 disease in patients with AVN of the femoral head. Eur Radiol. 2014;24(9):2271–2278. doi: 10.1007/s00330-014-3216-8 EDN: SAKRUH
  27. Lee GC, Khoury V, Steinberg D, et al. How do radiologists evaluate osteonecrosis? Skeletal Radiol. 2014;43(5):607–614. doi: 10.1007/s00256-013-1803-4 EDN: YUAOQV
  28. Stoica Z, Dumitrescu D, Popescu M, et al. Imaging of avascular necrosis of femoral head: familiar methods and newer trends. Curr Health Sci J. 2009;35(1):23–28.
  29. Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis. J Bone Joint Surg Br. 1995;77(1):34–41.
  30. Yoon B, Mont M, Koo K, et al. The 2019 revised version of association research circulation osseous staging system of osteonecrosis of the femoral head. J Arthroplasty. 2020;35(4):933–940. doi: 10.1016/j.arth.2019.11.029 EDN: KUYCOR
  31. Murphey M, Foreman K, Klassen-Fischer M, et al. From the radiologic pathology archives imaging of osteonecrosis: radiologic-pathologic correlation. Radiographics. 2014;34(4):1003–1028. doi: 10.1148/rg.344140019
  32. 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. doi: 10.3346/jkms.2021.36.e177 EDN: MDILPA
  33. Yoon BH, Jones LC, Chen CH, et al. Etiologic classification criteria of ARCO on femoral head osteonecrosis: part 1: glucocorticoid-associated osteonecrosis. J Arthroplasty. 2019;34(1):163–168.e1. doi: 10.1016/j.arth.2018.09.005
  34. Yoon BH, Jones LC, Chen CH, et al. Etiologic classification criteria of ARCO on femoral head osteonecrosis: part 2: alcohol-associated osteonecrosis. J Arthroplasty. 2019;34(1):169–174.e1. doi: 10.1016/j.arth.2018.09.006
  35. Ajmal M, Matas AJ, Kuskowski M, Cheng EY. Does statin usage reduce the risk of corticosteroid-related osteonecrosis in renal transplant population? Orthop Clin North Am. 2009;40(2):235–239. doi: 10.1016/j.ocl.2009.01.004
  36. 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;(435):164–170. doi: 10.1097/01.blo.0000157539.67567.03
  37. Glueck CJ, Freiberg RA, Wissman R, Wang P. Long term anticoagulation (4–16 years) stops progression of idiopathic hip osteonecrosis associated with familial thrombophilia. Adv Orthop. 2015;2015:138382. doi: 10.1155/2015/138382
  38. Pritchett JW. Statin therapy decreases the risk of osteonecrosis in patients receiving steroids. Clin Orthop Relat Res. 2001;(386):173–178. doi: 10.1097/00003086-200105000-00022
  39. Chen CH, Chang JK, Lai KA, 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(5):1572–1578. doi: 10.1002/art.33498
  40. Lee YK, Ha YC, Cho YJ, et al. Does zoledronate prevent femoral head collapse from osteonecrosis? A prospective, randomized, open-label, multicenter study. J Bone Joint Surg Am. 2015;97(14):1142–1148. doi: 10.2106/JBJS.N.01157
  41. Albers A, Carli A, Routy B, et al. Treatment with acetylsalicylic acid prevents short to mid-term radiographic progression of nontraumatic osteonecrosis of the femoral head: a pilot study. Can J Surg. 2015;58(3):198–205. doi: 10.1503/cjs.016814
  42. Tammas AJ, Albehlal LB, Alabbas F. Vitamin D deficiency and avascular necrosis in patients with sickle cell disease: a retrospective cohort study. Cureus. 2024;16(10):e72269. doi: 10.7759/cureus.72269 EDN: PLLDAO
  43. Гайдукова И.З., Трофимов Е.А., Насруллаева А.А., Морозова К.П. Выбор методов лечения мужчины с множественными асептическими некрозами головок трубчатых костей // Терапия. 2023. Т. 9, № 5. C. 104–112. [Gaidukova IZ, Trofimov EA, Nasrullayeva AA, Morozova KP. Choice of treatment methods for a male patient with multiple aseptic necrosis of the heads of tubular bones. Therapy. 2023;9(5):104–112]. doi: 10.18565/therapy.2023.5.104-112 EDN: CZCTAU
  44. Bal Z, Takakura N. Hydrogel use in osteonecrosis of the femoral head. Gels. 2024;10(8):544. doi: 10.3390/gels10080544 EDN: SCYUZA
  45. Mei J, Pang L, Jiang Z. The effect of extracorporeal shock wave on osteonecrosis of femoral head: a systematic review and meta-analysis. Phys Sportsmed. 2022;50(4):280–288. doi: 10.1080/00913847.2021.1936685 EDN: AVNXUJ
  46. Qi T, Yan Y, Qi W, et al. Hip joint-preserving strategies for treating osteonecrosis of the femoral head: From nonoperative to operative procedures. J Orthop Translat. 2025;51:256–277. doi: 10.1016/j.jot.2025.02.001 EDN: HSRFHV
  47. Шушарин А.Г., Половинка М.П., Прохоренко В.М., и др. Комплексный подход к лечению асептического некроза головки бедренной кости // Фундаментальные исследования. 2012. № 8-1. С. 93–196. [Shusharin AG, Polovinka MP, Prokhorenko VM, et al. Comprehensive approach to the treatment of aseptic necrosis of femoral head. Fundamental researches. 2012;(8-1):93–196]. EDN: PBHMPT
  48. Zhai L, Sun N, Zhang B, et al. Effects of focused extracorporeal shock waves on bone marrow mesenchymal stem cells in patients with avascular necrosis of the femoral head. Ultrasound Med Biol. 2016;42(3):753–762. doi: 10.1016/j.ultrasmedbio.2015.10.021
  49. Russo S, Sadile F, Esposito R, et al. Italian experience on use of E.S.W. therapy for avascular necrosis of femoral head. Int J Surg. 2015;24(Pt B):188–190. doi: 10.1016/j.ijsu.2015.11.038
  50. Торгашин А.Н., Родионова С.С., Шумский А.А., и др. Лечение асептического некроза головки бедренной кости. Клинические рекомендации // Научно-практическая ревматология. 2020;58(6):637–645. [Torgashin AN, Rodionova SS, Shumsky AA, et al. Treatment of aseptic necrosis of the femoral head. Clinical guidelines. Rheumatology Science & Practice. 2020;58(6):637–645]. doi: 10.47360/1995-4484-2020-637-645 EDN: EWKHOY
  51. Антонов А.В., Воловик В.Е., Рыков А.Г., Березуцкий С.Н. Обоснование малоинвазивной хирургии и ее клиническое применение на ранних стадиях АНГБК // Тихоокеанский медицинский журнал. 2022;(3):70–74. [Antonov AV, Volovik VE, Rykov AG, Berezutsky SN. Rationale for minimally invasive surgery and its clinical use in early ANFH. Pacific medical journal. 2022;(3):70–74]. doi: 10.34215/1609-1175-2022-3-70-74 EDN: TFDOYH
  52. Zhu HY, Zhu B. Treatment of early-stage avascular necrosis of the femoral head. (In Chinese). Zhongguo Gu Shang. 2012;25(7):616–620.
  53. Тихилов Р.М., Шубняков И.И., Мясоедов А.А., Иржанский А.А. Сравнительная характеристика результатов лечения ранних стадий остеонекроза головки бедренной кости различными методами декомпрессии // Травматология и ортопедия России. 2016. Т. 22, № 3. С. 7–21. [Tikhilov RM, Shubnyakov II, Myasoedov AA, Irzhansky AA. Comparison of different core decompression techniques for treatment of early stages of osteonecrosis of the femoral head. Traumatology and orthopedics of Russia. 2016;22(3):7–21]. doi: 10.21823/2311-2905-2016-22-3-7-21 EDN: WYPMTH
  54. Liu D, Chen Q, Chen Y, Liu Y. Long-term follow-up of early-middle stage avascular necrosis of femoral head with core decompression and bone grafting. (In Chinese). Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012;26(10):1165–1168.
  55. Yoon BH, Lee YK, Kim KC, et al. No differences in the efficacy among various core decompression modalities and non-operative treatment: a network meta-analysis. Int Orthop. 2018;42(12):2737–2743. doi: 10.1007/s00264-018-3977-9 EDN: BPJKLY
  56. 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. doi: 10.1007/s00264-018-3941-8 EDN: KZIVFS
  57. 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(8):5024–5030.
  58. Sen RK, Tripathy SK, Aggarwal S, et al. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplasty. 2012;27(5):679–686. doi: 10.1016/j.arth.2011.08.008
  59. Nally FJ, Zanotti G, Buttaro MA, et al. THA conversion rate comparing decompression alone, with autologous bone graft or stem cells in osteonecrosis. Hip Int. 2018;28(2):189–193. doi: 10.5301/hipint.5000552
  60. Pepke W, Kasten P, Beckmann NA, et al. Core decompression and autologous bone marrow concentrate for treatment of femoral head osteonecrosis: a randomized prospective study. Orthop Rev (Pavia). 2016;8(1):6162. doi: 10.4081/or.2016.6162
  61. Peng W, Wang L, Zhang J, et al. A novel tissue-engineered bone in repairing femoral head defect and necrosis. J Clin Experimental Med. 2015;8(1):1087–1093.
  62. Ali SA, Christy JM, Griesser MJ, et al. Treatment of avascular necrosis of the femoral head utilising free vascularised fibular graft: a systematic review. Hip Int. 2014;24(1):5–13. doi: 10.5301/hipint.5000076
  63. Ha YC, Kim HJ, Kim SY, et al. Effects of age and body mass index on the results of transtrochanteric rotational osteotomy for femoral head osteonecrosis. J Bone Joint Surg Am. 2010;92(2):314–321. doi: 10.2106/JBJS.H.01020
  64. Кирпичев И.В. Структура коксартроза в различных возрастных группах у больных, нуждающихся в первичном эндопротезировании тазобедренного сустава // Современные проблемы науки и образования. 2015. № 3. С. 10. [Kirpichev IV. Structure coxarthrosis in different age groups in patients requiring primary hip arthroplasty. Sovremennye problemy nauki i obrazovaniya. 2015;(3):10]. EDN: TYSGOX
  65. Лоскутов А.Е., Олейник А.Е., Алтанец А.В., Ковбаса Е.А. Алгоритм выбора вертлужного компонента эндопротеза тазобедренного сустава у больных с асептическим некрозом головки бедренной кости // Медицинские перспективы. 2015. Т. 20, № 1. С. 27–34. [Loskutov AE, Oleinik AE, Altanets AV, Kovbasa EA. Algorithm of selection of acetabular component of hip joint endoprothesis in patients with femoral head aseptic necrosis. Medical perspectives. 2015;20(1):27–34]. EDN: TLJKWX
  66. Якупов Р.Р., Гафаров И.Р., Филимонов Г.Н., и др. Хирургическое лечение асептического некроза головки бедренной кости по технологии артропластики тазобедренного сустава // Уральский медицинский журнал. 2015. № 2. С. 148–152. [Yakupov RR, Gafarov IR, Filimonov GN, et al. Surgical treatment of aseptic necrosis of the femoral head technology hip arthroplasty. Ural medical journal. 2015;(2):148–152]. EDN: TQTZZZ
  67. Bilge O, Doral MN, Yel M, et al. Treatment of osteonecrosis of the femoral head with focal anatomic-resurfacing implantation (HemiCAP): preliminary results of an alternative option. J Orthop Surg Res. 2015;10:56. doi: 10.1186/s13018-015-0199-3 EDN: UMBNNL
  68. Wang B, Li K, Liao Q, et al. Treatment of ischemic necrosis of the femoral head by transplantation of pedicled bone flap with deep iliac circumflex vessel. (In Chinese). Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2005;19(6):443–445.
  69. Zhou GQ, Pang ZH, Chen QQ, et al. Reconstruction of the biomechanical transfer path of femoral head necrosis: a subject-specific finite element investigation. Comput Biol Med. 2014;52:96–101. doi: 10.1016/j.compbiomed.2014.04.002
  70. Park YS, Park SJ, Lim SJ. Ten-year results after cementless THA with a sandwich-type alumina ceramic bearing. Orthopedics. 2010;33(11):796. doi: 10.3928/01477447-20100924-11
  71. Konan S, Alazzawi S, Yoon BH, et al. A focused update on preventing ceramic fractures in hip arthroplasty: is the ‘cup’ half full? Bone Joint J. 2019;101-B(8):897–901. doi: 10.1302/0301-620X.101B8.BJJ-2019-0309.R1

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Computed tomography (axial view) at initial presentation (February 5, 2021). A lesion is identified in segment S2 of the right upper lobe, characterized by an ill-defined, spiculated margin and heterogeneous structure, measuring 3.0×2.0 cm, with a broad base abutting the pleura over a length of up to 3 cm.

Download (1MB)
Indexing metadata
3. Fig. 2. Computed tomography (axial view), May 21, 2021, after four cycles of first-line systemic therapy. The size of the nodular lesion with an ill-defined, spiculated margin in segment S2 of the right lung decreased to 2.4×1.5 cm. The structure became more heterogeneous due to a reduction in the solid component. Broad-based contact with the pleura persists over a length of up to 2.7 cm.

Download (1MB)
Indexing metadata
4. Fig. 3. Computed tomography (coronal reconstruction) of the hip joints. April 27, 2022 (a), geographic pattern changes, more extensive on the right, with the appearance of a comminuted fracture without signs of healing; findings on the left remain stable. January 21, 2022 (b), subchondral regions of both femoral heads demonstrate areas with a geographic pattern, characterized by alternating concentric zones of bone rarefaction and sclerosis.

Download (1MB)
Indexing metadata
5. Fig. 4. Computed tomography (coronal reconstruction) of the femora (a), and magnetic resonance imaging, T2-TIRM sequence in the coronal plane (b), November 14, 2022. A comminuted fracture of the right femoral head persists without signs of healing, with sclerotic margins of the bone fragments (suggestive of pseudarthrosis formation). On the left, partial lysis of the femoral head is observed. Bilaterally, marked synovitis with para-articular extension is present. The acetabular roofs show erosive changes, while subchondral regions are relatively preserved. Bilateral hip subluxations are noted.

Download (1MB)
Indexing metadata
6. Fig. 5. Computed tomography (coronal reconstruction), November 22, 2024. A comminuted fracture of the right femoral head persists without signs of healing. Progressive lysis of the left femoral head is observed. Bilaterally, there is progression of femoral head subluxation and deformity of the acetabular roofs, accompanied by pelvic ring deformity and the development of lower limb length discrepancy.

Download (1MB)
Indexing metadata

Copyright (c) 2026 Eco-Vector

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 38032 от 11 ноября 2009 года.