Open Access
Issue
J Oral Med Oral Surg
Volume 30, Number 3, 2024
Article Number 38
Number of page(s) 5
DOI https://doi.org/10.1051/mbcb/2024041
Published online 31 January 2025

© The authors, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Osteonecrosis of the jaw (ONJ) is a severe bone disorder often linked to the use of medications like bone modifying agents or anti-angiogenics [1]. However, emerging evidence suggests that immune checkpoint inhibitors may also contribute to the development of ONJ. While immunotherapy has revolutionized cancer treatment, it has also been associated with a range of immune-related adverse events, reflecting its mechanism of action [2].

Pembrolizumab is a monoclonal antibody utilized in oncological immunotherapy. It is notably used for the treatment of multiple malignancies including metastatic non-small cell lung cancer (NSCLC), metastatic melanoma, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

This article presents a case of osteonecrosis of the maxilla in a patient treated with pembrolizumab and who was naive to bone-modifying agents (biphosphonates, Denosumab), anti-angiogenics and radiotherapy. This case report aims to explore the potential link between pembrolizumab and ONJ while acknowledging the multifactorial nature of this adverse event. It contributes to the limited but growing body of literature on this association and highlights the need for increased awareness and monitoring of such adverse effects in clinical practices.

Observation

A 83-year-old male was referred to the Oral Medicine department of our hospital in May 2023 with a two-month history of acute pain and dental mobility to the right side of the maxilla. The patient had been under the care of the Respiratory Medicine service since 2018 for a metastatic NSCLC (adenocarcinoma), for which he had refused surgery. He was noted to have diffuse metastases to the sacrum, adrenal gland and liver. Medical history was significant for type 2 diabetes and chronic renal failure. His current medication included pembrolizumab, metformine, tramadol, movicol. The patient also reported having quit smoking years ago. No history of cervicofacial radiotherapy, bone modifying agents (bisphosphonates or denosumab) or anti-angiogenics was retrieved.

Extra oral examination was found to be without particularity. However, intraoral examination revealed an exposed, avascular bone area on the vestibular right side of the maxilla. This yellow grayish area, greater than 5cm in width, extended from tooth number 16 to tooth number 12. The area was surrouned by swollen and inflamed gingiva. Additionally, the maxillary right first molar (tooth number 16) exhibited significant mobility. Palpation produced a purulent discharge, acute pain, and a vestibular bone sequestrum was well delineated and mobile.

CBCT imaging revealed right maxillary osteolysis surrounding teeth number 12 to 16, involving the maxillary sinus, which was consistent with osteonecrosis.

Given the situation, the entire bone sequestrum was removed (Fig. 1), and the sharp bone edges were smoothened. The non-restorable tooth number 16 was extracted and curettage was performed. Platelet-rich-fibrin (PRF) was placed into the alveolar bone following the department's protocol. The patient was started on Amoxicillin 1 g twice a day for 21 days in conjunction with Tramadol. He was also instructed to rinse with 0.12% chlorhexidine twice daily and to maintain proper oral hygiene.

Sequestrum's histopathology was consistent with osteonecrosis. The final diagnosis was stage 3 osteonecrosis (according to AAOMS).

At the three-weeks follow-up there was a significant improvement in symptoms and complete healing of the soft tissues was observed (Fig. 2).

Two months after the sequestrotomy, the patient returned for follow-up (Fig. 3). The right maxillary sinus was spontaneously painful, and upon palpation, a second mobile bone sequestrum, smaller than the first one, was detected and subsequently removed. The patient was prescribed amoxicillin 1g twice a day for 21 days.

Two months later, in September 2023, the patient presented without symptoms. It was noted that the necrotic area had not progressed any further. The preliminary phases of the dental prosthetics were initiated, and the prosthetics were subsequently delivered to the patient. However, the patient unfortunately passed away a few months later.

thumbnail Fig. 1

Photograph of the bone sequestrum after removal.

thumbnail Fig. 2

Intra oral photograph of soft tissue healing at three weeks follow-up.

thumbnail Fig. 3

CT scan at two months follow-up. A : Axial view. B : Coronal view. C : Sagittal view.

Discussion

Pembrolizumab is known for causing immune-related adverse events, including cutaneous, endocrine or gastrointestinal reactions, but there is limited literature on its association with osteonecrosis of the jaw (ONJ).

Only few case reports have documented ONJ in patients treated with Pembrolizumab, often in combination with additional cancer therapies including chemotherapy (Tab. I). However, the current case is unique in its presentation, as the patient was naive to other commonly implicated therapies or anatomical risk factors. This suggests that Pembrolizumab alone, without adjunctive agents, could potentially lead to the development of ONJ, though the precise mechanisms remain unclear.

Pembrolizumab's mechanism of action, which involves the inhibition of the PD-1 pathway and subsequent activation of T-cell-mediated tumor responses, is thought to contribute to a spectrum of immune related adverse events. The adverse effects arise from the enhanced immune activity, which may inadvertently target normal tissues, including bone [7]. The pathophysiological link between immune checkpoint inhibition and ONJ is not entirely clear but may involve an imbalance in bone remodeling processes, where excessive immune activation leads to impaired healing and increased susceptibility to necrosis.

In the studies by Decaux et al. (2020) [4] and Myoken et al. (2020) [6], Pembrolizumab was administered in combination with other agents: Epacadostat and Denosumab. Importantly, neither Epacadostat nor Pembrolizumab alone is typically associated with ONJ. The combination of these agents, as described by Decaux et al. (2020), suggests a potential for enhanced risk when these drugs are used together, possibly due to their combined effects on the immune system and bone health [4]. Similarly, Myoken et al. (2020), reported ONJ in a patient treated with Pembrolizumab and Denosumab. While Denosumab is known to be associated with osteonecrosis of the jaw, the addition of Pembrolizumab may have heightened the risk by further disrupting bone remodeling and immune regulation [6].

Penings et al. (2023) described a case of ONJ in a patient treated with a combination of Pembrolizumab and a chemotherapy regimen known as GVD (gemcitabine, vinorelbine and doxorubicin). While GVD is not typically associated with ONJ, the occurrence of osteonecrosis in this context suggests that Pembrolizumab may play a significant role in increasing susceptibility to osteonecrosis, possibly by intensifying the effects of chemotherapy on bone health [3].

Patel et al. (2023) and Penings et al. (2023) both reported ONJ cases, in patients treated with Pembrolizumab, located on mandibular torus. The mandibular torus is an area of the jaw with thin mucosal coverage and increased vulnerability to trauma making it particularly susceptible to osteonecrosis [8].

It is important to note that in the case reported by Patel et al. (2023), the patient, as in the current case, was also naive to other agents typically associated with ONJ [5]. However, the osteonecrosis in Patel's case was located on a mandibular torus, an anatomical site known to be a risk factor for ONJ [8].

Additionally, the patient's history of diabetes, a condition known to impair wound healing, likely contributed to the development and progression of osteonecrosis [1]. Diabetes can lead to micro vascular complications and reduced immune response, which negatively affects bone healing and increases susceptibility to necrosis. This comorbidity highlights the multi factorial nature of ONJ.

The patient's passing shortly after the follow-up illustrates the difficulty in gathering long-term data and feedback on treatment outcomes. This underscores the importance of early detection and intervention in managing complications like ONJ, particularly in patients with advanced cancer, where the prognosis may restrict the ability for extended follow-up. Regular dental assessments and timely management of oral symptoms are crucial to mitigate the risk of severe complications.

Table I

Studies included in the literature review.

Conclusion

In conclusion, while the exact causality between Pembrolizumab and ONJ cannot be definitively established based on current data, this case contributes to the emerging narrative that immune checkpoint inhibitors may play a role in the pathogenesis of ONJ. As the use of immune checkpoint inhibitors continues to expand in oncology, further research, including larger cohort studies and mechanistic investigations, is warranted to clarify this association and to develop guidelines for prevention and management in affected patients.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

The authors declare that they have no conflicts of interest in relation to this article.

Data availability statement

This article has no associated data generated and/or analyzed.

Informed consent

Informed consent was obtained from the patient.

References

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Cite this article as: Gosselin-Rousselle L, Gaudimier Z, Pamelard P-O, Sader P, Moizan H. 2024. Maxillary osteonecrosis linked to Pembrolizumab therapy: a case report. J Oral Med Oral Surg. 30, 38: https://doi.org/10.1051/mbcb/2024041.

All Tables

Table I

Studies included in the literature review.

All Figures

thumbnail Fig. 1

Photograph of the bone sequestrum after removal.

In the text
thumbnail Fig. 2

Intra oral photograph of soft tissue healing at three weeks follow-up.

In the text
thumbnail Fig. 3

CT scan at two months follow-up. A : Axial view. B : Coronal view. C : Sagittal view.

In the text

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