Is COVID-19 infection an independent etiologic factor in osteonecrosis development beyond corticosteroid exposure?

Edward Y. Cheng; Alireza Mirzaei

doi:10.1016/j.jor.2025.11.003

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72 (); 27-32

doi:

10.1016/j.jor.2025.11.003

Is COVID-19 infection an independent etiologic factor in osteonecrosis development beyond corticosteroid exposure?

Edward Y. Cheng, Alireza Mirzaei

Department of Orthopedic Surgery, University of Minnesota, Minneapolis, MN, USA

⁎Corresponding author: Alireza Mirzaei. mirza093@umn.edu

Received: 2025-10-6, Accepted: 2025-11-2, Published: 2025-11-4

Professor P K Surendran Memorial Education Foundation

Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

An increased incidence of non-traumatic osteonecrosis has been reported during the COVID-19 pandemic. Corticosteroid therapy, particularly dexamethasone, has often been implicated as a major risk factor. However, emerging evidence suggests that the pathogenesis of osteonecrosis in COVID-19 patients may extend beyond corticosteroid exposure.

COVID-19 infection itself may serve as an independent etiologic factor in osteonecrosis, with virus-induced pathogenic mechanisms synergizing with corticosteroid exposure to heighten risk, even at lower doses and shorter treatment durations.

This review synthesizes available literature on COVID-19, corticosteroid therapy, and osteonecrosis pathogenesis. Evidence from clinical observations, mechanistic studies, and prior models of corticosteroid-induced osteonecrosis were examined to identify overlapping and distinct pathways contributing to disease development.

Findings indicate that COVID-19 and corticosteroids converge on common pathogenic pathways—lipid dysregulation, impaired bone homeostasis, endothelial dysfunction, and coagulopathy. COVID-19 additionally promotes osteonecrosis through cytokine storm–driven inflammation. The combined effects of viral infection and corticosteroid therapy amplify disease risk, explaining reported cases of osteonecrosis even under reduced corticosteroid exposure.

COVID-19 may represent an independent etiologic factor for osteonecrosis, with intrinsic viral effects potentiating the impact of corticosteroids. Recognition of this dual risk underscores the need for preventive and therapeutic strategies tailored to COVID-19–associated osteonecrosis.

Keywords

COVID-19

Osteonecrosis

Pathogenesis

Corticosteroid

Cytokine storm

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1 Introduction

Osteonecrosis is a debilitating condition characterized by the death of bone tissue, leading to necrosis and damage to the subchondral bone of affected joints.¹ Based on its underlying cause, osteonecrosis is classified into two types: traumatic and non-traumatic. Non-traumatic osteonecrosis has been associated with a variety of etiological factors, primarily long-term steroid use and chronic alcohol intake.²

Currently, there is no effective pharmacological treatment for non-traumatic osteonecrosis, and most cases eventually progress to severe joint destruction, often necessitating joint replacement surgery.³ Despite the substantial health and economic burden of this condition, its pathogenesis remains poorly understood, highlighting the need for further research to elucidate its mechanisms and develop targeted therapies.²^,³

An increased incidence of non-traumatic osteonecrosis has been observed during the COVID-19 pandemic.⁴ Given that corticosteroids, particularly dexamethasone, have become a cornerstone in the management of moderate-to-severe COVID-19,⁵ this heightened risk of osteonecrosis has often been attributed to corticosteroid therapy.^6–8 However, the duration and cumulative doses of corticosteroids administered in most COVID-19 treatment regimens typically fall below the thresholds traditionally associated with steroid-induced osteonecrosis.⁹ Therefore, the increased osteonecrosis incidence in the COVID-19 era cannot be exclusively attributed to steroids, but additional pathophysiological mechanisms may contribute. Understanding these mechanisms is essential for developing effective prevention strategies, mitigating the long-term musculoskeletal sequelae of COVID-19, and enhancing our overall understanding of osteonecrosis pathogenesis.

In this study, we reviewed the available databases, including PubMed, Scopus, Web of Science, and Cochrane Library, to critically evaluate the potential multifactorial mechanisms contributing to the increased incidence of non-traumatic osteonecrosis in COVID-19 patients. By synthesizing current data, we aim to provide a better understanding of osteonecrosis pathogenesis in COVID-19 patients, identify gaps in knowledge, and propose future directions for research and clinical management.

2 Corticosteroid treatment protocols for COVID-19

COVID-19 can trigger a hyperinflammatory state, often referred to as a “cytokine storm,” in a subset of patients with severe disease.¹⁰ This condition is marked by an excessive and dysregulated release of pro-inflammatory cytokines and chemokines in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.¹⁰ The cytokine storm plays a pivotal role in the progression of acute respiratory distress syndrome (ARDS), multiorgan failure, and increased mortality.¹¹ Prompt recognition and early management are crucial in severe cases to suppress inflammation and mitigate its potentially life-threatening effects.¹²

Corticosteroids, especially dexamethasone, have played a crucial role in managing moderate-to-severe COVID-19 by mitigating the hyperinflammatory response, including the cytokine storm.¹² The RECOVERY trial demonstrated the survival benefits of dexamethasone, leading to the recommendation of a standard dose of 6 mg per day (oral or intravenous) for up to 10 days in hospitalized patients requiring oxygen or mechanical ventilation.¹³ When dexamethasone is not available, alternatives such as prednisolone, hydrocortisone, or methylprednisolone are used with similar dosing strategies.¹⁴ However, corticosteroid protocols have varied worldwide, influenced by local guidelines, resource availability, and individual patient needs, with some cases involving higher doses or longer treatment durations.¹⁵^,¹⁶

3 COVID-19 as an independent osteonecrosis etiologic factor

A comparison of osteonecrosis incidence before and after the COVID-19 pandemic reveals a notable increase of 0.2 % in the post-pandemic era.⁴ Furthermore, osteonecrosis occurred 0.9 % more frequently in total hip arthroplasty (THA) patients with a history of COVID-19 infection compared to those without such a history.⁴ In most studies investigating osteonecrosis in COVID-19 patients, corticosteroid therapy has been highlighted as the primary etiological factor.^6–8 However, evidence indicates that steroid therapy should be considered a contributing factor, rather than the primary or sole cause of osteonecrosis in COVID-19 patients.¹⁷ First, the average cumulative dose of corticosteroid therapy in COVID-19 patients (1156.5 mg)⁹ is lower than the typically reported threshold (2000 mg) required to induce osteonecrosis development.¹⁷ Second, the average time from COVID-19 infection to osteonecrosis development (≈80 days)⁷ appears to be shorter than the typical duration of around 200 days generally required for steroids to induce osteonecrosis.¹⁸^,¹⁹ Third, post-COVID osteonecrosis appears to be more aggressive than pre-COVID osteonecrosis.²⁰ Finally, joint pain following COVID-19 infection is reported in a significant number of patients who have not received corticosteroid therapy,²¹ and osteonecrosis has been documented in COVID-19 patients without a history of corticosteroid therapy.²² Altogether, these observations support the hypothesis that COVID-19 itself contributes to the pathogenesis of osteonecrosis through mechanisms independent of corticosteroid exposure.

4 Osteonecrosis pathogenesis

Osteonecrosis, or the death of bone cells, was traditionally thought to result from oxygen deprivation caused by vascular compromise, which occurs both intrinsically and extrinsically due to increased fat accumulation within the bone. This mechanism led to osteonecrosis being primarily referred to as avascular necrosis (AVN).²³

Today, it is widely recognized that "avascular necrosis" (AVN) is not an accurate term for osteonecrosis, as the condition involves multiple pathogenic mechanisms, with vascular compromise playing only a contributing role.³^,²⁴^,²⁵ The development of osteonecrosis is now understood to result from a complex interplay of factors, including lipid metabolism disorders, chronic inflammation, impaired bone homeostasis, coagulopathy, and endothelial damage, rather than solely from vascular disruption.²^,³^,^25–27

Before the COVID-19 pandemic, long-term steroid use and chronic ethanol exposure were considered the primary etiological factors for non-traumatic osteonecrosis, as they could trigger all the pathogenic mechanisms involved in the condition's development. These factors not only disrupt lipid metabolism but also impair bone homeostasis, induce a chronic inflammatory state, promote endothelial damage, and contribute to coagulopathy.²^,³ However, the post-COVID-19 era suggests a need to revise our understanding of the primary etiological factors for osteonecrosis. The relatively short interval observed between COVID-19 infection and osteonecrosis diagnosis may suggest an etiologic contribution of COVID-19 itself. Nevertheless, this apparent timing must be interpreted cautiously, as it largely reflects the interval between symptom onset and MRI diagnosis, which may not accurately represent the true biological onset of osteonecrosis. Moreover, it is essential to note that this apparent rapid onset may in part reflect heightened clinical vigilance and earlier use of MRI following COVID-19 infection, rather than a fundamentally different biological mechanism.

In the following sections, we explore the unique characteristics of COVID-19 that make it a potent osteonecrosis-inducing factor beyond corticosteroid therapy.

5 Cytokine storm and systemic inflammation

Recent studies highlight the significant role of an aberrant immune response in the onset and progression of osteonecrosis.²⁸ An improper immune system, whether acute or chronic, contributes to the disease through multiple mechanisms, including vascular disruption,²⁹ oxidative stress,³⁰ impaired bone homeostasis,³¹ hypercoagulability,³² and disturbances in lipid metabolism.³³

COVID-19 triggers an abnormal immune response through multiple mechanisms, primarily by disrupting the body's ability to mount an effective defense against the virus. SARS-CoV-2 inhibits the early production of type I and type III interferons, which are critical for antiviral immunity.³⁴ This delay causes an overproduction of inflammatory cytokines as the immune system overcompensates.³⁴ Additionally, studies have shown that COVID-19 patients often produce autoantibodies targeting immuno-modulatory proteins, including anti-type I interferon antibodies, which are strongly linked to severe disease and higher mortality.³⁵ Furthermore, SARS-CoV-2 enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor, a key regulator of the renin-angiotensin-aldosterone system (RAAS). This process downregulates ACE2, diminishing its anti-inflammatory, antithrombotic, and antifibrotic functions, while activating the angiotensin II-AT1 axis, which exacerbates inflammation and promotes thrombosis.³⁶ These impaired immune responses associated with COVID-19 drive a profound inflammatory state, which is acknowledged as a key contributing factor in the development of osteonecrosis.²⁵

6 Endothelial impairment

Endothelial dysfunction is known as a key factor in the development of osteonecrosis, as it is directly associated with impaired blood flow, which is essential for bone survival.³⁷ The endothelium, which lines blood vessels, regulates vascular tone, facilitates blood circulation, and ensures adequate delivery of oxygen and nutrients to tissues, including bones.³⁸ When endothelial function is disrupted, it triggers a cascade of events that result in reduced blood supply, leading to oxygen deficiency and eventual bone cell death.³⁸

COVID-19 can induce endothelial disruption through several mechanisms. The SARS-CoV-2 virus enters cells via the ACE2 receptors, which are abundantly expressed on endothelial cells. Upon binding to ACE2, the virus can directly infect endothelial cells, causing dysfunction through apoptosis, necrosis, and the release of pro-inflammatory cytokines.³⁹ Infected endothelial cells often lose their structural integrity, resulting in increased vascular permeability and impaired blood flow.³⁹ Moreover, evidence suggests that COVID-19 may induce endothelial-to-mesenchymal transition (EndMT), in which endothelial cells adopt a mesenchymal phenotype. This process can lead to fibrosis and further vascular remodeling, exacerbating endothelial dysfunction and contributing to long-term vascular damage.³⁹^,⁴⁰ COVID-19 infection also indirectly impairs endothelial function by triggering an inflammatory response that damages endothelial cells.⁴¹ Altogether, these direct and indirect mechanisms contribute to a state of widespread endothelial dysfunction, which compromises the delicate blood supply to bone tissue, thereby promoting ischemia and contributing to the development of osteonecrosis.

7 Impaired bone homeostasis

The downstream effect of the well-known pathogenic mechanisms involved in osteonecrosis development is oxygen deprivation, which leads to a dominance of osteoclastogenesis over osteoblastogenesis, termed as impaired bone homeostasis.⁴² Lipid metabolism disorders, inflammation, endothelial damage, and coagulopathy all contribute to impaired blood flow upstream, resulting in oxygen deprivation and disrupted bone homeostasis downstream, ultimately causing bone death and osteonecrosis.⁴³ However, certain pathogenic mechanisms, such as lipid metabolism disorders⁴⁴ and inflammation,⁴⁵ also directly disrupt bone metabolism by promoting the proliferation, differentiation, and activation of osteoclasts while inhibiting osteoblast function and activity.

COVID-19 patients have demonstrated significant bone loss at various skeletal sites post-infection.⁴⁶ While the exact mechanisms behind this bone loss remain unclear, several direct and indirect pathways have been proposed. SARS-CoV-2 infects multiple organs through ACE2 receptors, including bone cells. Infection of osteoblasts may impair their ability to produce the extracellular matrix and promote bone formation, leading to cell death or dysfunction and disrupting bone regeneration and repair.⁴⁷ Preclinical models have demonstrated that SARS-CoV-2 infection also leads to enhanced osteoclastogenesis.⁴⁸ Impaired bone homeostasis in COVID-19 patients may also be induced indirectly, via elevated inflammation, activation of the NOD-, LRR- and pyrin domain-containing protein (NLRP3) inflammasome, recruitment of Th17 cells, the hypoxic environment, and alterations in receptor activator of nuclear factor-κB ligand (RANKL)/Osteoprotegerin (OPG) signaling.⁴⁸ Additionally, COVID-19 infection may have negative impacts on bone metabolism via mechanical unloading (e.g., prolonged bed rest), as well as muscle wasting and BMI loss, both of which are commonly observed in COVID-19 patients.⁴⁸ Furthermore, medications used to manage COVID-19 infection can contribute to the deterioration of bone homeostasis.⁴⁸ Lastly, the infection may exacerbate underlying conditions such as diabetes and impair kidney function, both of which can further contribute to impaired bone metabolism.⁴⁸ This evidence suggests that COVID-19-associated osteonecrosis could also be driven, at least in part, by impaired bone homeostasis, alongside vascular compromise.

8 Coagulopathy

Coagulopathy induces osteonecrosis by impairing blood flow to bone tissue, primarily through microvascular thrombosis. The increased tendency for clot formation obstructs blood vessels, leading to ischemia and depriving bone cells of essential oxygen and nutrients, which causes cell death.⁴⁹

COVID-19 infection induces a hypercoagulable state through multiple mechanisms. The virus infects endothelial cells, causing damage and triggering the release of procoagulant factors like tissue factor, which activates the clotting process.⁵⁰ The systemic inflammatory response, including the cytokine storm, stimulates platelet activation and increases fibrinogen production, further activating the coagulation cascade and leading to thrombin generation and clot formation.⁵⁰ Additionally, immune complexes and autoantibodies, such as antiphospholipid antibodies, heighten the risk of abnormal clotting.⁵⁰ Severe SARS-CoV-2 infection is often associated with elevated levels of von Willebrand factor, ADAMTS13 deficiency, and impaired fibrinolysis.⁵⁰ Laboratory findings in these patients typically include low platelet counts, mildly prolonged prothrombin time, and elevated D-dimer levels, all hallmarks of COVID-19-associated coagulopathy.⁵⁰ Together, these factors significantly increase the risk of thrombotic events, particularly in severe COVID-19 cases.

9 Lipid metabolism disorders

Disorders in lipid metabolism, as previously discussed, can contribute to the development of osteonecrosis by inducing vascular incompetence through fat deposition within blood vessels.¹^,² Additionally, the enlargement of fat cells in the bone marrow exerts extrinsic pressure on the vasculature, further compromising bone blood flow and exacerbating the risk of osteonecrosis.¹^,² Corticosteroids, a leading cause of osteonecrosis and commonly used in COVID-19 management, significantly impair lipid metabolism.⁵¹^,⁵² However, emerging evidence suggests that COVID-19 infection itself is a potent disruptor of lipid metabolism, independent of corticosteroid use.

SARS-CoV-2 infects host cells and alters lipid metabolism to facilitate viral replication. The virus hijacks host cell membranes to form replication organelles and disrupts lipid synthesis pathways by activating the unfolded protein response (UPR), which downregulates enzymes involved in lipid production. As a result, cholesterol levels, particularly HDL-C and LDL-C, decrease, while triglyceride levels rise. Additionally, the virus targets cellular organelles that store lipids, further depleting lipid reserves to support replication.⁵³^,⁵⁴ Notably, statin therapy, which has been reported as a valuable tool in improving COVID-19 outcomes,⁵⁵^,⁵⁶ has also shown beneficial effects on osteonecrosis management.²⁶^,²⁷^,⁵⁶^,⁵⁷

The available evidence suggests that the infection of bone cells by SARS-CoV-2 may lead to an increase in lipid content within these cells, potentially disrupting blood flow and bone homeostasis. However, further research is needed to fully elucidate the effects of COVID-19-induced alterations in lipid metabolism on the development of osteonecrosis.

10 Interconnected aggravating pathways driving osteonecrosis

Osteonecrosis arises from a complex interplay of inflammation, lipid metabolism disorders, endothelial dysfunction, impaired bone homeostasis, and coagulopathy, with each factor amplifying the others in a self-perpetuating cycle.^58–64 Chronic inflammation triggers oxidative stress and the release of pro-inflammatory cytokines, impairing bone remodeling, inducing endothelial dysfunction, disrupting lipid metabolism, and promoting coagulopathy.⁶⁵ Lipid metabolism disorders, in turn, lead to fat embolism and marrow fat accumulation, which exacerbate vascular stress and incompetency, oxygen deprivation, oxidative stress, amplify inflammation, and aggravate endothelial damage and coagulopathy.⁶³ Endothelial dysfunction compromises blood flow and oxygen delivery to the bone, resulting in ischemia, cell death, and impaired bone homeostasis. Furthermore, endothelial damage perpetuates all other pathological mechanisms driving osteonecrosis.⁶⁶^,⁶⁷ Coagulopathy, through microvascular thrombosis, restricts blood supply to the bone, intensifying ischemia and disrupting bone remodeling.⁶⁸ Additionally, coagulopathy induces inflammation via feedback loops between the coagulation cascade and the immune system, further contributing to endothelial dysfunction.⁶⁹ It also disrupts lipid metabolism by impairing vascular and systemic processes that regulate lipid transport, storage, and metabolism.⁷⁰ Impaired bone homeostasis diminishes the bone's regenerative capacity by shifting toward osteoclastogenesis, further exacerbating lipid metabolism disorders, inflammation, endothelial dysfunction, and coagulopathy.⁶⁴^,⁷¹^,⁷² Together, these interconnected mechanisms create a synergistic cascade that culminates in localized ischemia, necrosis of bone tissue, and the hallmark pathology of osteonecrosis, particularly in the context of COVID-19 infection (Fig. 1).

Complex interplay between lipid metabolism disorder, inflammation, endothelial disruption, impaired bone homeostasis, and coagulopathy in the induction of nontraumatic osteonecrosis in COVID-19 patients.

11 Conclusion

Available evidence suggests corticosteroids as a contributing factor in the development of non-traumatic osteonecrosis in COVID-19 patients. However, COVID-19 itself activates several pathogenic processes that are already established as key drivers of osteonecrosis, including inflammation, endothelial disruption, lipid metabolism dysregulation, coagulopathy, and impaired bone homeostasis. These mechanisms interact in complex ways, amplifying the risk of osteonecrosis in COVID-19 patients. Current evidence, along with a better understanding of osteonecrosis pathophysiology, suggests that COVID may be an independent risk factor and therefore should be tracked in future studies to determine if it is statistically independent from other known risk factors.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

Edward Y Cheng: Conceptualization and critical review of the manuscript.

Alireza Mirzaei: Conceptualization and drafting the manuscript.

Authors' contributions

Edward Y Cheng: Conceptualization and critical review of the manuscript.

Alireza Mirzaei: Conceptualization and drafting the manuscript.

Ethics approval

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

No AI technology was used in the creation of the content of this article. However, after the draft manuscript was written, the authors used ChatGPT for grammatical editing only, in order to improve the readability, syntax, and general style. After using this tool/service, the author(s) reviewed and edited the content as needed and take (s) full responsibility for the content of the publication.

Funding

“This research was supported in part by the Mairs Family Endowed Chair Fund. No industry funding supported this research.”

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Is COVID-19 infection an independent etiologic factor in osteonecrosis development beyond corticosteroid exposure?

Abstract