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73 (); 55-61
doi:
10.1016/j.jor.2025.12.017

Classical non-traumatic osteonecrosis versus osteonecrosis of the jaw: Distinct manifestations of a shared pathophysiological spectrum

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

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

Received: , Accepted: ,
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

Abstract

Classical non-traumatic osteonecrosis (NTON)—most commonly affecting the femoral head—and osteonecrosis of the jaw (ONJ) represent two major forms of osteonecrosis. Ongoing debate persists regarding whether these conditions reflect manifestations of a shared underlying pathology or represent distinct clinical entities.

We hypothesize that although NTON and ONJ share core mechanisms, their initiating events, osteoclastic responses, and reactions to anti-resorptive therapy differ sufficiently.

A comprehensive literature review was conducted using PubMed, Scopus, Web of Science, and the Cochrane Library. Evidence was synthesized regarding anatomical and mechanical differences, etiologic factors, pathogenic mechanisms, and therapeutic responses in NTON and ONJ.

In NTON, compromised vascular supply is widely recognized as the primary initiating event, leading to hypoxia, increased osteoclastogenesis, and excessive bone resorption. In ONJ, impaired blood flow occurs secondarily, typically following dental trauma, infection, or anti-resorptive therapy. While both conditions involve disturbed bone homeostasis, NTON is characterized by heightened osteoclast activity, whereas ONJ features suppressed osteoclast function. This contrast results in divergent pharmacologic behavior: bisphosphonates and denosumab may be protective during the resorptive stage of NTON but significantly increase the risk of ONJ.

Although NTON and ONJ share fundamental disruptions in bone homeostasis and vascular regulation, their distinct initiating events, osteoclastic dynamics, and responses to anti-resorptive therapy suggest they are best viewed as separate clinical entities rather than variations of a single disease.

Keywords

Non-traumatic osteonecrosis
Osteonecrosis of the femoral head
Osteonecrosis of the jaw
Etiology
Pathogenesis
1

1 Introduction

Osteonecrosis (ON) is a pathological condition characterized by the death of bone tissue in different anatomical locations, leading to the destruction of the affected bone.1 This condition can arise after fractures that might impact the blood supply of a section of bone or from non-traumatic etiologies.1,2 While non-traumatic osteonecrosis (NTON) most commonly occurs in weight-bearing bones, primarily the femoral head,3 a distinct form of the disease also occurs in the jaw.1 NTON is often seen in patients with risk factors such as prolonged corticosteroid use, excessive alcohol consumption, or autoimmune disorders like systemic lupus erythematosus (SLE).4,5 In contrast, osteonecrosis of the jaw (ONJ) primarily affects patients treated with antiresorptive agents such as bisphosphonates and Receptor Activator of Nuclear factor Kappa-Β Ligand (RANK-L) blockade agents such as denosumab.6,7

To date, no pharmacologic therapy is sufficiently effective in the management of NTON and ONJ, primarily due to the limited understanding of their underlying pathogenesis. Although both conditions are associated with a common pathophysiological mechanism of vascular disruption and impaired bone homeostasis,1,8,9 the precise mechanisms driving these diseases remain poorly elucidated. Consequently, there is ongoing debate about whether ONJ and NTON represent manifestations of the same underlying pathology or should be classified as distinct clinical entities.

Understanding the similarities and differences between NTON and ONJ is crucial for advancing clinical knowledge of osteonecrosis pathogenesis and guiding future research into the prevention and treatment of osteonecrosis in both conditions. We reviewed electronic databases, including PubMed, Scopus, Web of Science, and the Cochrane Library, to provide a comparative analysis of NTON and ONJ by examining their similarities and differences and exploring whether these two conditions represent variations of a single disease or distinct pathological entities. In this review, NTON refers to classical non-traumatic osteonecrosis affecting non-jaw bones such as the femoral head, distal femur, proximal tibia, and humeral head. We explicitly exclude osteonecrosis of small bones (e.g., Kienböck's disease) and pediatric forms of osteonecrosis (e.g., Legg-Calvé-Perthes disease).

1.1

1.1 Anatomical and environmental differences between NTON and ONJ

The anatomical locations affected by classical NTON often bear significant mechanical loads during movement and weight-bearing activities.10 In the femoral head, which is regarded as the most frequent location for classical NTON,11 the primary blood supply is derived from the medial and lateral circumflex femoral arteries, which offer limited collateral circulation.12 As a result, the femoral head is highly vulnerable to ischemia when vascular disruption of these vessels occurs. Composed predominantly of trabecular (spongy) bone,13 it is more susceptible to microdamage and impaired remodeling under stress or hypoxic conditions.14 The high mechanical demands placed on the femoral head, combined with its limited regenerative capacity,15 restrict the potential for recovery from ON.

The jawbone, although involved in mastication and speech, experiences less continuous axial load than the hip.16 It benefits from a more robust blood supply, primarily via branches of the external carotid artery,17 and has superior collateral circulation compared to the femoral head.17 Additionally, the jaw contains a higher proportion of cortical bone, particularly in the mandible, making it less metabolically active but more resistant to osteolysis.18,19 On the other hand, the jaw, especially the mandible, is highly active in bone remodeling due to frequent mechanical forces from chewing.20 This continuous turnover of bone tissue in response to oral activities makes it more prone to the detrimental impact of anti-resorptive agents on the dynamic bone remodeling process.20 Moreover, the jaw is exposed to unique challenges, such as microbial colonization, which can exacerbate necrosis when bone healing is impaired.21

In summary, while both the femoral head and jaw are susceptible to osteonecrosis, their distinct anatomical structures, vascular characteristics, mechanical demands, and bone remodeling dynamics result in different vulnerabilities and pathological responses, contributing to the unique presentation of ON in these different sites.

1.2

1.2 Etiology of NTON vs. ONJ

Classical NTON is recognized as a multifactorial disease, with genetic susceptibility playing a pivotal role in its development when individuals are exposed to specific risk factors.22–25 Among these, long-term or high-dose corticosteroid therapy is one of the most prevalent contributors. Chronic alcohol consumption is the other most common factor associated with NTON onset. Additionally, systemic conditions such as SLE, rheumatoid arthritis, and other autoimmune disorders often contribute to the pathogenesis of NTON.23,26,27

Genetic predisposition also plays a role in the development of ONJ, particularly when associated with medication.28 Bisphosphonates and other anti-resorptive medications used for osteoporosis and cancer metastasis are regarded as the main risk factors for ONJ.29 Radiation treatment that includes the jaw in the treated field, for head and neck cancers, can also result in ONJ.29 Dental infections and periodontal disease can also contribute to the development of ONJ, especially in patients whose bone healing is compromised by bisphosphonates or other drugs.29

Although the primary risk factors for NTON and ONJ differ, there are several shared risk factors. Notably, radiation therapy is a common risk factor for both NTON30,31 and ONJ.7,32 Corticosteroid therapy, a major risk factor for NTON, has also been linked to an increased risk of ONJ, though less frequently.33,34 Additionally, some immunosuppressive medications, such as mTOR inhibitors, have been associated with the risk of both NTON35 and ONJ36,37 (Table 1). Despite these similarities, the use of bisphosphonates and other anti-resorptive agents, such as denosumab, presents a paradoxical scenario when it comes to NTON and ONJ. While these medications are widely recognized as a significant risk factor for the development of ONJ,29 there is some evidence postulating a protective effect against the progression of NTON.38,39 This dual role highlights the complexity of bisphosphonates in bone health, where they can both prevent bone loss in certain anatomic locations and, ironically, contribute to localized necrosis in other anatomic sites.

Table 1 Comparison of risk factors for classical nontraumatic osteonecrosis (NTON) and osteonecrosis of the jaw (ONJ).
Risk factor NTON ONJ
Steroid Major risk factor Risk factor, but not primary
Alcohol Major risk factor No association reported
Bisphosphonate Preventive effects Major risk factor
Denosumab Preventive effects Major risk factor
Autoimmune Diseases Major risk factor No association reported
Metabolic disorder Gusher disease is a major risk factor Diabetes is a major risk factor
Radiation Therapy Major risk factor Major risk factor
Bacterial infection No association reported Major risk factor
mTOR inhibitors Some associations are reported as risk factors Some associations are reported as risk factors
1.3

1.3 Pathogenesis of NTON vs. ONJ

The pathogenic mechanisms underlying the development of NTON can be broadly divided into two main categories: compromised blood flow and disrupted bone homeostasis.40 Various impairments contribute to compromised blood flow to the femoral head, including lipid metabolism disorders, chronic inflammation, endothelial damage, and coagulopathy.23,26 Lipid metabolism disorders primarily reduce blood flow by accumulation of lipids in blood vessels and hypertrophic bone marrow fat cells in the bone.23,26 Chronic inflammation promotes the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, which damage blood vessels.23,26 Endothelial damage directly impairs blood flow, while a hypercoagulable state heightens the risk of thrombotic events, thereby obstructing blood flow.23,26

Compromised blood flow results in oxygen deprivation in the bone microenvironment, leading to impaired bone homeostasis, characterized by the predominance of bone resorption (osteoclastogenesis) over bone formation (osteoblastogenesis), ultimately causing bone cell death.23,26 All osteonecrosis risk factors can also directly induce impaired bone homeostasis through circulation-independent pathways,23,26 potentially leading to NTON even in the absence of compromised blood flow.40

Similar to NTON, disrupted bone homeostasis and compromised blood flow are considered the main pathogenic mechanisms underlying ONJ, although their manifestations vary between the two conditions. The primary difference between the pathogenesis of NTON and ONJ lies in the pattern of impaired bone homeostasis.41 In NTONs, increased bone resorption enhances osteoclast activity and leads to bone degradation42 (Fig. 1). In contrast, ONJ is characterized by decreased bone resorption, disrupting normal bone remodeling and impairing the healing process.43 Thus, osteoclastogenesis impacts these two anatomical sites differently.44 Uncoordinated osteoclastic activity is coupled with impaired osteoblast function in both conditions.45,46

Balanced vs. Imbalanced Bone Homeostasis in the Femoral Head: Under normal conditions, bone homeostasis is maintained by a balance between bone resorption by osteoclasts (red cells) and bone formation by osteoblasts (blue cells). In osteonecrosis, this balance is disrupted as increased osteoclast number and activity outweigh osteoblast function, shifting bone homeostasis toward excessive resorption and bone death.
Fig. 1 Balanced vs. Imbalanced Bone Homeostasis in the Femoral Head: Under normal conditions, bone homeostasis is maintained by a balance between bone resorption by osteoclasts (red cells) and bone formation by osteoblasts (blue cells). In osteonecrosis, this balance is disrupted as increased osteoclast number and activity outweigh osteoblast function, shifting bone homeostasis toward excessive resorption and bone death.

Although impaired blood flow contributes to both NTON and ONJ, its role in disease initiation differs markedly between the two. In NTONs, such as the osteonecrosis of the femoral head (ONFH), compromised vascular supply is widely recognized as the primary initiating event, leading to ischemia, impaired bone homeostasis, bone cell death, and subsequent structural collapse.5 In contrast, ONJ typically arises from a multifactorial process in which anti-resorptive therapy impairs bone remodeling and local immune response. When combined with dental trauma or infection, these factors trigger necrosis, with impaired blood flow developing secondarily as a consequence of inflammation, infection, local vascular damage, and anti-angiogenic effects of anti-resorptive agents.47 Thus, while ischemia is the central driver of NTON pathogenesis, it is a downstream contributor in ONJ.

1.4

1.4 Differential effect of bisphosphonates in NTON and ONJ

Anti-resorptive agents have shown potential therapeutic benefits in the management of NTON by modulating bone remodeling and reducing structural deterioration.48 Bisphosphonates, such as alendronate and zoledronic acid, inhibit osteoclast-mediated resorption of the bone, thereby preserving the structural integrity of the subchondral bone and delaying collapse.49 Several clinical studies have reported that bisphosphonate therapy can slow NTON progression, reduce pain, and lower the rate of bony collapse, potentially delaying or avoiding the need for surgical intervention.48,50

In contrast, bisphosphonates have been associated with an enhanced risk of ONJ.51 The exact pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not understood. However, some hypotheses have been proposed, with the leading one suggesting that the jawbone exhibits higher bone turnover compared to other skeletal sites, making it particularly susceptible to the suppressive effects of bisphosphonates. Impaired osteoclastogenesis in the jaw results in the accumulation of old bone that cannot be replaced or repaired, weakening the bone and making it more prone to necrosis, especially under conditions of reduced blood supply or trauma.20 However, this hypothesis was rejected by later investigations.52,53 The most updated mechanism for BRONJ emphasizes the contributory role of dental disorders.44 In the absence of anti-resorptive agents, dental disease triggers mucosal and submucosal inflammation, which damages the underlying alveolar bone. This inflammation activates osteoclasts to resorb the damaged bone and facilitate repair. However, when both anti-resorptive agents and dental disease are present, the ongoing inflammation continuously activates osteoclasts, but bisphosphonates suppress their function. This inhibition prevents normal bone remodeling, leaving the alveolar bone exposed to persistent inflammation, which leads to necrosis (Fig. 2). The necrotic bone further intensifies the inflammatory response through oxidative stress, pro-inflammatory cytokines (e.g., IL-17, IL-1, IL-6), and immune dysregulation, creating a vicious cycle of tissue damage. This cycle is exacerbated by bacterial colonization and impaired healing following tooth extraction.44

Impact of Anti-Resorptive Exposure on Dental Disorder Microenvironment: In the absence of anti-resorptive agents (left picture), activated osteoclasts resorb damaged bone, facilitating natural repair and regeneration. Conversely, in the presence of anti-resorptive agents (right picture), osteoclast activity is suppressed, inhibiting normal bone repair and regeneration. This suppression leaves the alveolar bone exposed to persistent inflammation, ultimately progressing to necrosis.
Fig. 2 Impact of Anti-Resorptive Exposure on Dental Disorder Microenvironment: In the absence of anti-resorptive agents (left picture), activated osteoclasts resorb damaged bone, facilitating natural repair and regeneration. Conversely, in the presence of anti-resorptive agents (right picture), osteoclast activity is suppressed, inhibiting normal bone repair and regeneration. This suppression leaves the alveolar bone exposed to persistent inflammation, ultimately progressing to necrosis.
1.5

1.5 Management of NTON vs. ONJ

A variety of pharmacologic agents have been explored for the treatment of NTON, with anti-resorptive agents showing the most promising results. A 20-year study demonstrated that oral alendronate therapy, either alone or in combination with other bisphosphonates, significantly slowed disease progression, reduced the rate of femoral head collapse, and decreased the need for joint replacement surgery.39,54,55 These findings positioned bisphosphonates as a paradigm shift in the management of NTON, offering a viable strategy to delay or prevent the debilitating consequences of the condition. Additionally, denosumab, another antiresorptive agent, has shown potential in reducing necrotic volume and preventing femoral head collapse, further expanding the pharmacologic options for managing NTON.38,56

The first-line pharmacologic treatment for ONJ focuses on antibiotic therapy to control infection, as infection plays a significant role in the development and progression of this condition. Exposed necrotic bone in the jaw increases the risk of bacterial colonization, which can exacerbate bone destruction and delay healing, particularly in patients treated with antiresorptive agents like bisphosphonates or denosumab. Antibiotics help prevent secondary infections, reduce bacterial load, and minimize tissue damage, thus preventing the infection from spreading and worsening the condition. Effective infection control also creates a more favorable environment for bone and tissue healing, ultimately improving outcomes in ONJ management.57,58

Statins, primarily known as lipid-lowering agents, have demonstrated promising therapeutic effects in the treatment of NTON.24,25 Beyond their lipid-lowering properties, the pleiotropic effects of statins include enhancing bone metabolism, reducing inflammation, and improving vascular endothelial function59—critical factors in preventing the progression of NTON. These findings suggest that statins could serve as a valuable adjunctive therapy in the management of NTON.60–63 In contrast, the data on the effects of statins on ONJ have been contradictory. While some studies have suggested an increased risk of ONJ with long-term use of statins,64,65 others have reported therapeutic benefits, indicating potential protective effects.66,67

While anti-resorptive agents affect NTON and ONJ in the opposite direction, there are some medications that have shown protective effects against both ONFH and ONJ. Teriparatide (recombinant human parathyroid hormone, PTH 1–34), an anabolic agent primarily used to stimulate bone formation, is one of these agents.68–71 Teriparatide increases osteoblast activity and enhances the deposition of new bone,72 which can be crucial in repairing necrotic bone in both ONJ and ONFH. It also promotes the remodeling process by increasing the turnover of bone tissue, potentially improving the balance between bone resorption and formation, which is impaired in osteonecrosis.73

Positive effects of other, less-widely used medications, including various types of antioxidants,74,75 anti-inflammatory agents,76 anti-coagulants,77 vasodilators,78,79 and angiogenic factors80–82 have also been reported in the treatment of ONFH and/or ONJ. These medications, while not part of the standard treatment regimens, have shown potential in addressing specific aspects of these conditions, such as improving bone health, reducing inflammation, enhancing circulation, or mitigating oxidative stress. Although the clinical evidence supporting their widespread use is limited, these drugs may offer adjunctive benefits when used alongside more established treatments. The key findings and therapeutic effects of these medications are summarized in Table 2, highlighting their potential contributions to the management of ONFH and ONJ.

Table 2 Comparison of available pharmacologic interventions for nontraumatic osteonecrosis (NTON) and osteonecrosis of the jaw (ONJ).
Pharmacologic agents ONFH ONJ
Antiresorptive Agents Protective effect Risk factor
Statins Protective effect Contradictory effects
Antibiotics No effect Protective effect
Teriparatide Protective effect Protective effect
Anti-inflammatory medications Protective effect No report
Anticoagulants Protective effect No report
Antioxidants Protective effect Protective effect
Angiogenic factors Protective effect Protective effect
2

2 Conclusion

ONJ and NTON share disrupted bone homeostasis and compromised blood flow as the leading causes of bone death. However, the underlying mechanisms may differ between ONJ and NTON. In NTON, compromised vascular supply is widely recognized as the primary event, while in ONJ, it is regarded as a secondary consequence of other pathological processes. In NTON, the imbalanced bone homeostasis favors bone resorption over bone formation, driven by excessive osteoclast activity. In contrast, ONJ is marked by decreased osteoclast activity, which disrupts normal bone remodeling and impairs the healing process. This distinction could be attributed to the unique anatomical and environmental characteristics of the jaw and non-jaw bones, such as differences in blood supply, bone structure, and mechanical loading. Moreover, these differences contribute to the divergent effects of bisphosphonates in NTON and ONJ; while bisphosphonates are protective against NTON, they are strongly associated with an increased risk of ONJ. These variations highlight the importance of recognizing NTON and ONJ as distinct clinical conditions, despite representing manifestations of a shared pathophysiological spectrum of osteonecrosis.

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.

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 by the Mairs Family Endowed Chair Fund. No industry funding supported this research.”

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