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Open Peer Review on Qeios
New-generation anticancer drugs and medication-related
osteonecrosis of the jaw (MRONJ): review of the literature
and single-center experience.
Agostino Guida1, Antonio Grimaldi1, Franco ionna1, Francesco Perri1, PAOLO ANTONIO ASCIERTO
1 Istituto Nazion ale Tumo ri "Fondazi one Pascale"
Funding: The author(s) received no specific funding for this work.
Potential c ompeting interests: The author(s) declared that no potential c ompeting interests exist.
Abstract
Since its first association to Zoledronate in 2004, the number of drugs which may induce medication-related
osteonecrosis of the jaw (MRONJ) increased annually. Nowadays, novel chemotherapy agents, such as
immunotherapy or targeted therapy are increasingly used in the clinical practice. Adopted for Metastatic Melanoma (MM)
therapy, immunotherapy and targeted therapy agents are now used in a wide and increasing variety of cancers, such as
head & neck, urologic, gynecologic and pulmonary neoplasms, especially in regard to bone metastasis control.
We thus investigated literature to understand a possible impact of such novel cancer therapies on MRONJ. A review of
the literature searching PubMed and Scopus was performed. We also report of a case of late MRONJ onset, 3 years
after administration of ipilimumab.
As a result, association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single
therapies, may rarely induce osteonecrosis of the jaw.
Ipilimumab was associated 3 times in literature to MRONJ, both in single therapy and in association with other drugs. In
a paper published by our Institute, Ipilimumab produced late effects, inducing MRONJ 3 years after its administration;
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complete healing was reached with pharmacological therapy. Nivolumab was associated once in literature to MRONJ,
both in patients undergoing multiple therapy both in single therapy. Pembrolizumab was reletad twice to MRONJ in
literature, once when in association with epacadostat and once with Denosumab. Interestingly, 5 out of 7 reported cases
were triggered by periodontal abscess.
New-generation anti-cancer drugs, such as immunotherapy and targeted therapy agents, seems at low risk of
developing MRONJ. Their field of application is widening, and so is the number of patients who are administered with
such drugs.
Yet, mechanisms underlying their action are not fully comprehended and, even if they may be considered safe, literature
suggests that unexpected events in terms of MRONJ break-out may occur.
Multidisciplinary approach, with dental evaluation prior/during/after chemotherapy, is strongly advised.
Background
Events of nonhealing-exposed bone in the maxillofacial region were initially reported in patients treated with intravenous
(IV) bisphosphonates (BP).1 Pamidronate (Aredia) and zoledronic acid (Zometa)—two IV BPs— were thus labeled as at
risk for osteonecrosis of the jaws (ONJ).2 Consequently, in the following years a warning followed for all BPs to be at risk
for ONJ, which was thus renamed as bisphosphonate-related ONJ (BRONJ).3
During subsequent years, other BPs and medications belonging to other classes have been related to the development of
ONJ, including denosumab (humanized monoclonal antibody blocking the acti-vation of receptors for nuclear factor kB-
ligand), bevacizumab (humanized monoclonal antibody), and sunitinib (tyrosine kinase inhibitor).4-10
As sporadic events, case reports have highlighted possible association between ONJ and azacitidine, imatinib,
everolimus, zivaflibercept, ipilimumab, and tocilizumab.11-18 As the number of drug class widened during the years, this
condition was then more widely re-named as medication-related osteonecrosis of the jaw (MRONJ).1
Both pathogenesis and associated risk factors of this disease are not fully comprehended. Nowadays, novel chemotherapy
agents, such as immunotherapy or targeted therapy are increasingly used in the clinical practice. Adopted for Metastatic
Melanoma (MM) therapy, immunotherapy and targeted therapy agents are now used in a wide and increasing variety of
cancers, such as head & neck, urologic, gynecologic and pulmonary neoplasms, also in regard to bone metastasis control.
We thus investigated literature to understand a possible impact of such novel cancer therapies on MRONJ and report our
experience in managing an unusual case of osteonecrosis onset 3 years after the administration of ipilimumab.
Materials & Methods
Literature analysis
Review of the present scientific literature was performed on the research engine SCOPUS and PUBMED. Research query
was: “(Ipilimumab OR Nivolumab OR Pembrolizumab OR anti-PD1 OR Dabrafenib OR Trametinib OR Vemurafenib OR
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Cobimetinib OR Encorafenib OR Binimetinib OR anti-BRAF OR anti-MEK) AND (MRONJ OR BRONJ OR osteonecrosis)”,
deigned to be as wide as possible. The research retrieved 9 results on PUBMED and 49 on Scopus. A first selection was
performed through abstract analysis. Exlcusion criteria were:
articles not in English;
articles off-topic [not reporting case(s) of MRONJ onset as complication of the aforementioned drugs in single/combined
therapy];
reviews of scientific literature;
duplicates results.
Personal experience: case report19
During November 2018, a 58 year-old-woman affected by BRAF-mutated metastatic melanoma, under treatment at the
Immunotherapy Unit of Naples Cancer Institute “G. Pascale”, was referred to the Oral Pathology outpatient clinic. While in
follow-up, the patient reported severe pain in the oral cavity, which was ongoing for 4 months, due to a nonhealing
alveolus after the avulsion of the lower right third molar. Patient referred that she had been treated by her dentist for an
alveolar osteitis (AO, dry sockets) with 1-week cycle of amoxicillin + clavulanic acid (2.25 + 0.75 g/d per os) and
chlorhexidine 0.2% mouthwash daily/weekly socket irrigation. Such therapies had been repeated three times during those
months, continuing chlorhexidine 0.2% home mouthwash daily socket irrigation among the antibiotic cycles. Application of
zinc oxide eugenol in the alveolus had also been performed. Every treatment she had undergone had been unsuccessful.
She showed no extra-oral sign of swelling nor abscess. Clinically, intraoral inspection showed presence of a nonhealed
alveolar socket; the bottom and the walls of the alveolus were clearly visible, made of nonvascularized nonsuppurated
bone, surrounded by swollen mucosa (Figure 1).
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Figure 1: Intraoral inspection revealed the nonhealing alveolus.
A 3-day-old orthopantomography (OPT) was exhibited, with radiographic sign of non-healed alveolus (Figure 2).
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Figure 2: Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 months after tooth
extraction.
Anamnesis was carefully harvested. The patient had been diagnosed with cutaneous melanoma in 2009. She thus
underwent surgical resection of primary tumour. Lung progression of disease was found in 2015, which lead to treatment
with ipilimumab (3 mg/kg mg iv, every 3 weeks for 4 cycles). Complete remission of the disease was reached. In 2017, the
patient suffered from hepatic progression; as Melanoma was BRAF-mutated, she underwent dabrafenib + trametinib (300 +
2 mg per os/die). The patient thus suffered from G. 3 toxicity (fever),which lead to treatment stopping and replacement with
vemurafenib + cobimetinib (vemurafenib: 1920 per os/die for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg per
os/die for 3 weeks then 1-week pause). Such treatment was still ongoing at the time her dental problem. She reffered no
history of smoking nor head and neck radiation therapy. Ipilimumab was the only medication administered to her that has
been related to MRONJ12,17. Her MRONJ was thus evaluated as a “stage 2” according to the AAOMS classification,
showing “Exposed and necrotic bone(…) with evidence of infection, (…) symptomatic”1. She was thus administered with
amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per
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os) was prescribed for pain control.
Results
Literature analysis
Seven papers (6 case reports and 1 case series) did not match the exclusion criteria and could be included in our
study12,17,19-23 (full-texts are added as supplementary data of the present article). Form the case series17, 2 cases were
treaceable to Ipilimumab (one in single and one in multiple therapy), but one was already reported in another study12, so
we considered only one additional case. Drugs reported to have caused MRONJ, oncological anamnesis and reported
trigger factors are summarised in Table 1.
Drug(s) Oncological anames is Trigger factor
E+P20 Metastatic Melanoma Period ontal abscess
D+P21 Lung Ca ncer Peri-implant abscess
I12 Metastatic Melanoma Pe riodontal abscess
I+D17 Not specified Not specified
I19 (late) Metastatic Mela noma Too th extraction
B+IL2+Z+D+C+N22 Re nal Ca ncer Peri-implant abscess
N23 Metastatic Melanoma Period ontal abscess
Table 1: Drug(s), oncological anamnesis and trigger factor of MRONJ cases (B: Bevacizumab; C: Cabozantinib; D:
Denosumab; E: Epacadostat; I: Ipilimumab; IL-2: Interleukin-2; N: Nivolumab; P: Pembrolizumab; Z: Zolendronate)
Different class groups for drugs identified in our literature research are reported in Table 2.
Drug (Si,Mu) Drug class
D (Mu*), I (Si, Mu), N (Si, Mu), P (Mu) Monoclonal an tibodi es
B (Mu) Antiang ioge nics
C(Mu) Cance r growth ih ibitor (CGI)
E(Mu) Inhi bitors of indoleamine di oxygenase-1 (IDO-1)
IL-2 (Mu) Synthetic cytokine
Z (Mu*) Bipho sphon ate
Table 2: Drugs and their class of belonging, specifying if they were identified during single (Si) or multiple (Mu) therapy. (B:
Bevacizumab; C: Cabozantinib; D: Denosumab; E: Epacadostat; I: Ipilimumab; IL-2: Interleukin-2; N: Nivolumab; P:
Pembrolizumab; Z: Zolendronate).*This drugs were identified during multiple therapy in our reasearch, but are a well-
known cause of MRONJ1.
If case reports in which patients were admistered also drugs which are well-known cause of MRONJ1 (denosumab,
zolendronate, bevacizumab) are excluded, only nivolumab, epacadostat, pembrolizumab and ipilimumab are reported to
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have caused MRONJ in single (nivolumab, ipilimumab12) or multiple (epacadostat+pembrolizumab) therapy.
Only one MRONJ case (ipilimumab, single therapy three years before) onset after tooth extraction; the other cases arose
were reported to be in relation to periodontal/peri-implant conditions.
Personal experience: case report
At the 2-week follow-up visit, clinical improvement was clearly visible. She referred that a 10 × 5 mm bone sequestrum had
been spountaneously ejected after 6 days of therapy and that her symptoms had therefore disappeared; clinically, she still
showed incomplete wound healing. Two additional weeks of therapy were thus administered and so the patient reached
complete alveolar healing (Figure 3).
Figure 3: Complete clinical resolution after 4 wks of antibiotic/ disinfectant therapy
(amoxicillin + metronidazole −3 + 1.5 g per os/ die- and chlorhexidine 0.2% mouth rinse).
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No further treatment for MRONJ was prescribed. Patient underwent monthly follow-up. During the 6th month, a new OPT
confirmed alveolar healing. (Figure 4).
Figure 4: Radiographic appearance at OP T after 6 months of follow-up, showing complete bone healing.
Discussions
Several new medications have been added to the potential cause of MRONJ drug list during the past years. In addition to
well-known medication, as highlighted by our review, MRONJ may be a major adverse reaction to several new-generation
anticancer drugs. These drugs may have unexpected mechanisms, being their pharmacodynamic not fully comprehended
yet.
Pembrolizumab, a humanized monoclonal antibody targeting the programmed cell death protein 1 (PD-1), has become the
standard treatment for metastatic non-small-cell lung cancer (NSCLC) patients since it has been shown to prolong
progression-free survival and overall survival of these patients21. In one report21, authors speculate that it may have
boosted Denosumab (a humanized monoclonal antibody against receptor activator of NF-kB ligand-RANKL) effect in
triggering MRONJ, as both of their molecular pathways results in an anti-osteoclastogenic effects. Similarly, in another
case report20 , Pembrolizumab effect on bone metabolism through T-Cells modulation may have been reinforced by
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Epacadostat, which inhibits IDO1 increasing the efficacy and growth of T-Cells and NK cell growth with increased
production of IFNg, which inhibits osteoclastogenesis. Therefore, up until now, there is no evidence that Pembrolizumab or
Epacadostat may cause MRONJ in single therapy.
Alongside with Pembrolizumab, Nivolumab is an anti-PD-1 checkpoint inhibitor. Our literature research showed two cases
of MRONJ possible realted to this drug, one in single therapy23 and on in multiple therapy22 . In the single therapy case,
authors remarked the link between inflammation -deeply influenced by Nivolumab administration- and bone metabolism.
Similarly, in the multiple therapy case, authors remark how the administration of various monoclonal antibody may have
boosted Zolendronate and Bevacizumab effect.
Ipilimumab is a humanized monoclonal antibody against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). CTLA-4
is expressed both in activated T cells and in suppressor T-regulatory cells, binding to antigen-presenting cells and
therefore diminishing T-cell responses. The block of the CTLA-4 is able to improve the antitumor responses of activated T
cells. In a case report12 it is indicated as cause of MRONJ through by empowering the number of systemic activated T-cell
presence. CTLA4-deficient activated T cells have been shown to be associated with osteonecrosis, as activated T cells
may ignite osteoclastogenesis via osteoprotegerin ligand, resulting in bone loss. Such effects is also reported to empower
denosumab effect in another case report17 .
Interestingly, in the case report we have described in this paper too19, Ipilimumb may have caused MRONJ 3 years after its
administration. Ipilimumab is known to have a 14.7-day blood halflife19 but the real advantage of the drug is in the long-
term efficacy, due to the immune responses induced by checkpoint inhibitors. Similiarly like the anticancer effects, side
effects such as pruritus, diarrhea, vitiligo, hepatitis, and endocrinopathies may occur many years after administration12. It is
conceivable that MRONJ may be also a late side effect under certain circumstances, which may have been co-caused by
the ongoing target therapy (vemurafenib + cobimetinib) of the patient. The effect of BRAF and MEK inhibitors in BRAF-
mutant melanoma can lead to an immune-stimulating microenvironment by enhancing expression of immune-stimulating
molecules and cytokines, reducing immunosuppressive cell populations, and decreasing immunosuppressive cytokines.
The cell damage to the tumor by the target therapy may have induced a tumor-antigen spreading, restimulating T-cell
activity whose response had been increased and modulated by the effect of ipilimumab. Moreover, it has been
demonstrated that anti-BRAF therapy enhances the reactivity and cytotoxicity of T cells19 .The re-activation of such
empowered T-cell clones may have lead the patient into a window of time in which she was at risk for MRONJ, similarly to
when the patient was on treatment with ipilimumab.
Conclusions
MRONJ pathologic pathways are not fully comprehended. Yet, decreased bone turnover by modulation of osteoclast
function, inhibition of angiogenesis, infection, inflammation and soft tissue toxicity have been identified as playing an
important role24. It is well acquired in scientific literature that T-Cells may interfere with osteoclasts both with cell-to-cell
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contact and the production of different cytokines (CKs). Proinflammatory CKs are pro-osteoclastogenic, while anti-
inflammatory CKs inhibit osteoclastogenesis by direct or indirect RANKL inhibition. The immune system is thus
involved in bone loss and bone regeneration21. Trauma from regular oral activity, oral surgery (eg, tooth extraction) or
teeth/periodontal diseases, increasing the demand for bone to mend itself12 , may result in localized bone necrosis in
patients with altered immunologic state due to ongoing/past immunotherapy.
In our literature review, 5 out of 7 MRONJ cases were triggered by periodontal/periimplant abscess/acute inflammatory
phase. Periodontal patients are well-known for having altered cytokines productions/immunologic cell function when not
treated, as they stay in a local chronic inflammation state, which may also reflect on systemic inflammation state. This
may both lead to novel prespective in investigating MRONJ pathologic mechanism, confirmig inflammation as a key
moment in its comprehension, both underline the necessity of periodontal surveillance for patients undergoing
immunotherapy.
New-generation anti-cancer drugs seem at low risk of developing MRONJ, with isolated cases reported in literature.
Yet, literature suggests that unexpected events in terms of MRONJ break-out may occur. The authors thus recommend
caution and strict vigilance in the dental management of patients treated with chemotherapy interfering with
immunological function of the patients. Multidisciplinary evaluation is thus strongly advised prior/during/after
chemotherapy. The administration of the prophylactic antibiotic protocol (amoxicillin + metronidazole; 3 + 1.5 g per
os/die) in case of oral surgery and/or continous dental surveillance may be arranged in accordance between the dental
surgeon and the oncologist, with the best possible evaluation of both oral and systemic conditions. Such cooperation
may reduce the occurrence of adverse events which, as we have shown in our review, may result in patient's discomfort,
pain and, as reported in one paper, major complications such as mandible fracture.
Further studies are needed on a large number of cases, in order to fully comprehend the relation between new-
generation anti-cancer drugs and MRONJ.
References
1. Ruggiero SL, Dodson TB, Fantasia J, et al. American association of oral and maxillofacial surgeons position paper on
medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg. 2014;72:1938-1956.
2. Hohnecker JA. DearDoctor. Precautions Added to the Label of Aredia and Zometa. East Hanover, NJ: Novartis
Oncology; 2004:2.
3. United States Food and Drug Administration, Office of Drug Safety: Postmarketing safety review. Bisphosphonates.
http://www.fda.gov/ohrms/ docke ts/ac/05/brief ing/20054 095B2_03_04-FDATab3. pdf. Accessed October 09, 2019.
4. Lipton A, Steger GG, Figueroa J, et al. Randomized active controlled phase II study of denosumab efficacy and safety
in patientswith breast cancer-related bone metastases. J Clin Oncol. 2007;25:4431-4437.
5. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases
Qeios, CC-BY 4.0 · Article, April 9, 2021
Qeios ID: 48DL31 · https://doi.org/10.32388/48DL31 10/12
in patients with advanced breast cancer: a randomized, double-blind study.J Clin Oncol. 2010;28:5132-5139.
6. Malan J, Ettinger K, Naumann E, Beirne OR. The relationship of denosumab pharmacology and osteonecrosis of the
jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:671-676.
7. Owosho AA, Blanchard A, Levi L, et al. Osteonecrosis of the jaw in patients treated with denosumab for metastatic
tumors to the bone: a series of thirteen patients. J Craniomaxillofac Surg. 2016;44(3):265-270.
8. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol
Oral Radiol. 2012;113:e1-e3.
9. Estilo CL, Fornier M, Farooki A, et al. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol. 2008;26:4037-
4038.
10. Nicolatou-Galitis O, Migkou M, Psyrri A, et al. Gingival bleeding and jaw bone necrosis in patients with metastatic renal
cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral
Radiol. 2012;113:234-238.
11. Kim DW, Jung YS, Park HS, Jung HD. Osteonecrosis of the jaw related to everolimus: a case report. Br J Oral
Maxillofac Surg. 2013;51:e302-e304.
12. Owosho AA, Scordo M, Yom SK, et al. Osteonecrosis of the jaw a new complication related to Ipilimumab. Oral Oncol.
2015;51:e100-e101.
13. Ponzetti A, Pinta F, Spadi R, et al. Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention
to oral district. Tumori. 2016;102(suppl.2).
14. Mawardi H, Enzinger P, McCleary N, et al. Osteonecrosis of the jaw associated with zivaflibercept. J Gastrointest
Oncol. 2016;7:E81-E87.
15. Nicolatou-Galitis O, Galiti D, Moschogianni M, et al. Osteonecrosis of the jaw in a patient with acute myeloid leukemia,
who received azacitidine. J Cancer Metasta Treat. 2016;2:220-223.
16. Nicolatou-Galitis O, Razis E, Galiti D, Vardas E, Tzerbos F, Labropoulos S. Osteonecrosis of the jaw in a patient with
chronic myelogenous leukemia receiving imatinib: a case report with clinical implications. Forum Clin Oncol.
2013;4:29-33.
17. Owosho AA, Liang STY, Sax AZ, et al. Medication-related osteonecrosis of the jaw: An update on the memorial sloan
kettering cancer center experience and the role of premedication dental evaluation in prevention. Oral Surg Oral Med
Oral Pathol Oral Radiol. 2018;125:440-445.
18. Bennardo F, Buffone C, Giudice A. New therapeutic opportunities for COVID-19 patients with Tocilizumab: possible
correlation of interleukin-6 receptor inhibitors with osteonecrosis of the jaws. Oral Oncol. 2020;106:104659.
19. Guida A, Perri F, Ionna F, Ascierto PA, Grimaldi AM. New-generation anticancer drugs and medication-related
osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role
of target therapy. Clin Case Rep. 2020 Dec 2;9(1):61-66.
20. Decaux J, Magremanne M. Medication-related osteonecrosis of the jaw related to epacadostat and pembrolizumab. J
Stomatol Oral Maxillofac Surg. 2020 Dec;121(6):740-742.
21. Myoken Y, Fujita Y, Kawamoto K, Toratani S. Osteonecrosis of the jaw in a metastatic lung cancer patient with bone
metastases undergoing pembrolizumab + denosumab combination therapy: Case report and literature review. Oral
Qeios, CC-BY 4.0 · Article, April 9, 2021
Qeios ID: 48DL31 · https://doi.org/10.32388/48DL31 11/12
Oncol. 2020 Dec;111:104874.
22. Bennardo F, Buffone C, Muraca D, Antonelli A, Giudice A. Medication-Related Osteonecrosis of the Jaw with
Spontaneous Hemimaxilla Exfoliation: Report of a Case in Metastatic Renal Cancer Patient under Multidrug Therapy.
Case Rep Med. 2020 Oct 22;2020:8093293.
23. Pundole X, Jones AL, Tetzlaff MT, Williams MD, Murphy WA Jr, Otun A, Goepfert RP, Davies MA. Osteonecrosis of the
jaw induced by treatment with anti-PD-1 immunotherapy: a case report. Immunotherapy. 2020 Dec;12(17):1213-1219.
24. Chang J, Hakam AE, McCauley LK. Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw. Curr
Osteoporos Rep 2018;16:584–95.
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