Medication-Related Osteonecrosis of the Jaw with Spontaneous Hemimaxilla Exfoliation: Report of a Case in Metastatic Renal Cancer Patient under Multidrug Therapy

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a well-recognized complication of drug therapies for bone metabolic disorders or cancer related to administration of antiresorptive (bisphosphonates and denosumab) and antiangiogenic drugs. This report describes an advanced and unusual case of stage III peri-implantitis-induced MRONJ involving the right upper jaw which was attempting to self-exfoliate. A 61-year-old male patient, rehabilitated with the placement of two implants when he was still healthy, was suffering from metastatic renal cancer previously treated with bevacizumab, interleukin-2, zoledronic acid, denosumab, cabozantinib and nivolumab. He had been under treatment of nonsurgical therapy over a year, based on antibiotic and antiseptic mouth rinse, without improvement of oral conditions. Surgical treatment consisted of massive sequestrectomy and complete surgical debridement of necrotic bone tissues. The specimen was sent for histopathologic analysis, which confirmed bone tissue necrosis with no evidence of metastatic disease. Two-month follow-up revealed a considerable life quality improvement. Although this complication is well known, the uniqueness of this case is given by its severity, related to the administration of multiple antiresorptive and antiangiogenic drugs, by the natural response of the oral cavity with the almost complete self-exfoliation of the massive necrotic zone. This case is emblematic in highlighting the controversies in the management of MRONJ, which certainly require effective collaboration of the multidisciplinary health care team that could improve patient safety and reduce the risk of developing MRONJ.

Full text

Case Report
Medication-Related Osteonecrosis of the Jaw with Spontaneous
Hemimaxilla Exfoliation: Report of a Case in Metastatic Renal
Cancer Patient under Multidrug Therapy
F. Bennardo , C. Buffone, D. Muraca, A. Antonelli, and A. Giudice
School of Dentistry, Department of Health Sciences, Magna Graecia University of Catanzaro, Viale Europa,
Catanzaro 88100, Italy
Correspondence should be addressed to F. Bennardo; fbennardo92@gmail.com
Received 27 February 2020; Revised 9 September 2020; Accepted 12 October 2020; Published 22 October 2020
Academic Editor: Hakan Yaman
Copyright ©2020 F. Bennardo et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Medication-related osteonecrosis of the jaw (MRONJ) is a well-recognized complication of drug therapies for bone metabolic
disorders or cancer related to administration of antiresorptive (bisphosphonates and denosumab) and antiangiogenic drugs. is
report describes an advanced and unusual case of stage III peri-implantitis-induced MRONJ involving the right upper jaw which
was attempting to self-exfoliate. A 61-year-old male patient, rehabilitated with the placement of two implants when he was still
healthy, was suffering from metastatic renal cancer previously treated with bevacizumab, interleukin-2, zoledronic acid,
denosumab, cabozantinib and nivolumab. He had been under treatment of nonsurgical therapy over a year, based on antibiotic
and antiseptic mouth rinse, without improvement of oral conditions. Surgical treatment consisted of massive sequestrectomy and
complete surgical debridement of necrotic bone tissues. e specimen was sent for histopathologic analysis, which confirmed
bone tissue necrosis with no evidence of metastatic disease. Two-month follow-up revealed a considerable life quality im-
provement. Although this complication is well known, the uniqueness of this case is given by its severity, related to the ad-
ministration of multiple antiresorptive and antiangiogenic drugs, by the natural response of the oral cavity with the almost
complete self-exfoliation of the massive necrotic zone. is case is emblematic in highlighting the controversies in the man-
agement of MRONJ, which certainly require effective collaboration of the multidisciplinary health care team that could improve
patient safety and reduce the risk of developing MRONJ.
1. Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is a
well-recognized complication of drug therapies for bone
metabolic disorders or cancer, defined as a persistent bone
exposure within the oral cavity for a minimum period of 8
weeks in patients without a history of radiotherapy in the
head and neck region. Antiresorptive drugs, such as
bisphosphonates (BPs) and denosumab, are successfully
used in low-dose therapy to prevent bone pathological
fractures in patients with osteoporosis and to treat other
bone metabolic diseases such as Paget’s disease and in
high-dose therapy to prevent bone metastasis in patients
with cancer [1].
A recent literature review identified a wide range of
medications classified as tyrosine kinase inhibitors, mono-
clonal antibodies, mammalian target of rapamycin inhibi-
tors, radiopharmaceuticals, selective estrogen receptor
modulators, and immunosuppressants that have been im-
plicated in MRONJ in addition to the drugs already men-
tioned [2].
MRONJ treatment initially involved nonsurgical therapy
in mild cases and surgical therapy in severe cases, but
currently, the indication for surgical therapy seems to prevail
even in less severe cases [3, 4].
is article presents an unusual and extreme case of
MRONJ triggered by peri-implantitis in a metastatic renal
cancer patient under multidrug therapy.
Hindawi
Case Reports in Medicine
Volume 2020, Article ID 8093293, 5 pages
https://doi.org/10.1155/2020/8093293

2. Presentation of Case
A 61-year-old male was referred in October 2019 to the
Academic Hospital of Magna Graecia University of Cata-
nzaro by his family dentist for the evaluation and treatment
of a probable upper jaw osteonecrosis.
His medical history revealed he was under treatment
since April 2017 for a metastatic renal carcinoma with brain
and vertebral osseous metastasis without jaw involvement.
Additional medical conditions included arterial hyperten-
sion (treated with enalapril 10 mg twice daily), hypothy-
roidism (treated with levothyroxine 60 mg daily), and no
history of smoking.
Starting from May 2017, he received interleukin-2
(500.000 UI) subcutaneously 3 weeks a month, twice a day
for 5 days a week. From June 2017, bevacizumab (25 mg/ml),
every 2 weeks, for 6 months, was administered. He had also
undergone a monthly 4 mg infusion of zoledronic acid
(4 mg) for 5 cycles which was then replaced, in December
2017, by denosumab (120 mg) every 4 weeks, until Sep-
tember 2019. Moreover, from May to September 2019, he
also received nivolumab (10 mg/ml). Now, he is in treatment
only with daily oral doses of cabozantinib (60 mg).
He had been on treatment of nonsurgical therapy over a
year (amoxi/clav 875 mg/125 mg, 2 times a day; metroni-
dazole 500 mg, 3 times a day; and antiseptic mouth rinse
with chlorhexidine 0.12%, 2 times a day) without im-
provement of oral conditions. Periodic follow-up had not
been performed by his family dentist.
At clinical examination, two implants placed by his
general dentist in the upper right jaw were found, only with
the abutments of a cemented prosthesis (this is no longer
present in the oral cavity). e implant rehabilitation, not
combined with normal teeth, had been performed, in June
2015, before developing renal carcinoma and starting
medical therapy, with two-stage surgical approaches. A
partially edentulous maxilla with a totally exposed and
necrotic sequestrum in the right hemimaxilla was observed,
and there were signs of active infection and purulent exudate
with no evidence of fistula formation. Spontaneous avulsion
of a tooth was detected laterally to the right hemimaxilla. No
implants had been lost prior to decementation of the
prosthesis (Figure 1).
Objective exam also revealed a moderate tissue swelling
and an asymmetrical face aspect. e patient reported ap-
parently spontaneous painful symptoms. Exposed necrotic
tissue emanated a persistent fetor.e patient did not re-
member when the osseous tissue exposure had begun be-
cause in the initial phase, the exposed bone did not give any
discomfort. ere were no signs of other pathologies. Signs
of peri-implantitis with clinical inflammation and peri-
implant bone loss were detected.
Various radiological tests have been performed, and an
X-ray of the brain has revealed the presence of various brain
metastatic lesions.
Computerized axial tomography with three-dimensional
reconstruction revealed an extensive structural destruction
of the right maxillary bone (Figure 2) with fractures and
continuous solution of the anterior, inferior, lateral, and
medial walls of the maxillary sinus. e lesion also involved
the hard palate, with bone detachment of the right maxillary
arch. Diagnosis of stage III MRONJ according to American
Association of Oral and Maxillofacial Surgeons (AAOMS)
classification was done.
Considering the severity of the clinical conditions, the
patient received prophylactic antibiotic therapy with amoxi/
clav 875 mg/125 mg. On the same day, the patient underwent
surgery under local anesthesia.
Bone sequestrectomy was performed involving the entire
right hemimaxilla held in place by inflammatory tissues.
Removal of the sequestrum exposed the ipsilateral nasal
cavity. erefore, careful curettage was performed in order
to remove granulation tissues and fragments of the residual
necrotic bone.
e obtained surgical sample (Figure 3) was sent for
histopathologic analysis, which revealed “compact bone
tissue with morphological aspects coherent with the pro-
posed diagnosis of osteonecrosis.”
Medical therapy with antiseptic mouth rinse (nonalco-
holic chlorhexidine 0.12% at least 2 times a day) and sys-
temic antibiotic administration with amoxi/clav 875 mg/
125 mg (2 times a day) and metronidazole 500mg (3 times a
day) for 2 weeks after surgery was suggested. e patient was
discharged with strict advice to maintain a liquid diet for 2
weeks and an accurate oral hygiene.
After 2 months of follow-up, persistence of oronasal
antral communication and presence of mucus (discharged
from nasal cavity) in the postoperative site were observed
(Figure 4). No further regions of bone necrosis were found,
and the patient was sent to his dentist for rehabilitation with
an obturator prosthesis.
Unfortunately, the prosthetic rehabilitation was never
finalized because the patient’s condition deteriorated, and he
died.
3. Discussion
MRONJ lesions induced by pamidronate and zoledronate
were first reported by Marx in 2003 in oncologic patients [5].
e risk of developing MRONJ and the response to treat-
ment are mainly influenced by the type and dose of drug
therapy, in relation to the patient’s primary disease [1]. With
the recent development of antiresorptive medications and
antiangiogenics used alone or in combination, it seems to be
important to understand the molecular mechanisms that
lead to MRONJ: the evidence-based mechanisms of path-
ogenesis include disturbed bone remodeling, inflammation
or infection, altered immunity, soft tissue toxicity, and
angiogenesis inhibition [6].
e guidelines for MRONJ treatment, assessed by the
AAOMS in 2014, suggested a conservative nonsurgical
treatment for early stages (I and II) of MRONJ and surgery
for advanced stages (III) and mild stages refractory to the
nonsurgical approach [1].
Although nonsurgical conservative therapy could be
successful to control pain and reduce infection, the high
success rate of tissue healing was reported in literature after
surgical necrotic bone resection and also in mild stage,
2Case Reports in Medicine

Figure 4: Patient’s clinical condition at 2-month follow-up visit: persistence of oroantral communication and presence of mucus.
Figure 1: Patient’s preoperative clinical condition: necrotic bone exposure and purulent exudate in quadrant I.
Figure 2: ree-dimensional reconstruction of CT scans that highlighted the detachment of the right hemimaxilla.
Figure 3: e wide bone sequestration of the right hemimaxilla obtained after sequestrectomy.
Case Reports in Medicine 3

improving clinical condition of the patient often expecting
downstaging of the lesions [3, 4, 7–12].
In many cases, surgical treatment of stage III MRONJ
patients leads to oroantral communication in the posterior
maxilla. e closure of these defects represents an additional
challenge to the oral surgeon and is essential to improve the
long-term life quality [13].
In recent years, pedicled buccal fat pad (PBFP), com-
bined with ultrasonic bone surgery and L-PRF, has shown
some effectiveness in exposed bone coverage and soft tissue
healing at the posterior maxillary region. is technique
supplies a rich vascular source of adipose-derived adult stem
cells that could contribute to the esthetic healing of mucosal
defects, prevent further bone weakening, and maximize the
success for prosthetic rehabilitation [14].
e treatment of patients with a medical history of
malignant diseases and a high-dose drug administration is
more complicated with a slower tendency to full healing
[15].
To date, many different surgical approaches have been
proposed in the treatment of MRONJ lesions: laser therapy,
piezoelectric surgery, use of fluorescence for the identifi-
cation of healthy bone margins, and application of platelet
concentrates have become important tools to minimize the
invasiveness of surgical therapy and improve tissue healing
[15–18].
e patient described in this case report had a metastatic
renal cancer treated with multidrug therapy. He was initially
managed with nonsurgical therapy that could have eased the
halitosis and pain, for more than one year, without an
improvement of clinical conditions and with a worsening of
MRONJ stage and quality of life. Association of BPs and
antiangiogenic drugs leads to more severe and frequent cases
of MRONJ than BPs alone [19]. Furthermore, the replace-
ment of a zoledronic acid with denosumab is an additional
risk factor for the development of MRONJ [20].
When the patient came to our attention, the surgical
therapy choice was mandatory with the removal of the wide
sequestrum.
is case is emblematic in pointing out controversies in
MRONJ management according to Schiodt et al [4]:
(i) Early surgical intervention on localized disease may
prevent progression and the need for subsequent
extensive surgery
(ii) Accurate risk assessment with evaluation of anti-
resorptive and antiangiogenetic therapies is man-
datory before starting MRONJ lesion treatment
In our opinion, the lack of interdisciplinary collabora-
tion and accurate follow-up played a key role in the de-
velopment of this advanced stage of MRONJ case. e role of
general dental practitioners, maxillofacial and oral surgeons,
and oncologists in this area must be regularly checked for
oral and dental health and must be motivated before starting
antiresorptive and antiangiogenic drugs.
Patients continue to be at risk of developing MRONJ
with a significant detrimental impact on quality of life due to
limited preventive multidisciplinary interventions. MRONJ-
education programs and an effective collaboration with the
other professional groups could potentially reduce the risk of
MRONJ and improve patient safety [21].
4. Conclusion
In conclusion, though surgical therapy already in the early
stages of MRONJ might prevent the progression of the
disease, a multidisciplinary approach to the prevention of
MRONJ is essential to optimize high-risk cancer patient
management and to improve quality of life.
is outcome, in addition to a better communication
among dentists and other health care personnel experienced
is the best choice both for primary prevention (improvement
of periodontal and peri-implant status and restoration of
compromised teeth) and for secondary prevention with
follow-up in order to identify MRONJ lesions in the early
stage.
Consent
According to the Declaration of Helsinki on medical protocol
and ethics, informed consent was obtained from the patient.
Conflicts of Interest
e authors declare no conflicts of interest.
References
[1] S. L. Ruggiero, T. B. Dodson, J. Fantasia et al., “American as-
sociation of oral and maxillofacial surgeons position paper on
medication-related osteonecrosis of the jaw—2014 update,”
Journal of Oral and Maxillofacial Surgery, vol. 72, no. 10,
pp. 1938–1956, 2014.
[2] R. King, N. Tanna, and V. Patel, “Medication-related osteo-
necrosis of the jaw unrelated to bisphosphonates and
denosumab–a review,” Oral Surgery, Oral Medicine, Oral
Pathology and Oral Radiology, vol. 127, no. 4, pp. 289–299,
2019.
[3] O. Ristow, T. R ¨uckschloß, M. M¨uller et al., “Is the conservative
non-surgical management of medication-related osteonec-
rosis of the jaw an appropriate treatment option for early
stages? a long-term single-center cohort study,” Journal of
Cranio-Maxillofacial Surgery, vol. 47, no. 3, pp. 491–499, 2019.
[4] M. Schiodt, S. Otto, S. Fedele et al., “Workshop of European
task force on medication-related osteonecrosis of the
jaw–current challenges,” Oral Diseases, vol. 25, no. 7,
pp. 1815–1821, 2019.
[5] R. E. Marx, “Pamidronate (Aredia) and zoledronate (Zometa)
induced avascular necrosis of the jaws: a growing epidemic,”
Journal of Oral and Maxillofacial Surgery, vol. 61, no. 9,
pp. 1115–1117, 2003.
[6] J. Chang, A. E. Hakam, and L. K. McCauley, “Current un-
derstanding of the pathophysiology of osteonecrosis of the
jaw,” Current Osteoporosis Reports, vol. 16, no. 5, pp. 584–595,
2018.
[7] E. R. Carlson and J. D. Basile, “e role of surgical resection in
the management of bisphosphonate-related osteonecrosis of
the jaws,” Journal of Oral and Maxillofacial Surgery, vol. 67,
no. 5, pp. 85–95, 2009.
4Case Reports in Medicine

[8] R. G. Coropciuc, K. Grisar, T. Aerden, M. Schol, J. Schoenaers,
and C. Politis, “Medication-related osteonecrosis of the jaw in
oncological patients with skeletal metastases: conservative
treatment is effective up to stage 2,” British Journal of Oral and
Maxillofacial Surgery, vol. 55, no. 8, pp. 787–792, 2017.
[9] G. Favia, A. Tempesta, L. Limongelli, V. Crincoli, and
E. Maiorano, “Medication-related osteonecrosis of the jaw:
surgical or non-surgical treatment?” Oral Disease, vol. 24,
no. 1-2, pp. 238–242, 2018.
[10] W. Reich, U. Bilkenroth, J. Schubert, C. Wickenhauser, and
A. W. Eckert, “Surgical treatment of bisphosphonate-asso-
ciated osteonecrosis: prognostic score and long-term results,”
Journal of Cranio-Maxillofacial Surgery, vol. 43, no. 9,
pp. 1809–1822, 2015.
[11] S. H. Kang, Y. J. Won, and M. K. Kim, “Surgical treatment of
stage 2 medication-related osteonecrosis of the jaw compared
to osteomyelitis,” Cranio, vol. 36, no. 6, pp. 373–380, 2018.
[12] M. El-Rabbany, A. Sgro, D. K. Lam, P. S. Shah, and
A. Azarpazhooh, “Effectiveness of treatments for medication-
related osteonecrosis of the jaw: a systematic review and meta-
analysis,” e Journal of the American Dental Association,
vol. 148, no. 8, pp. 584–594, 2017.
[13] S. Aljohani, M. Troeltzsch, S. Hafner, G. Kaeppler, G. Mast,
and S. Otto, “Surgical treatment of medication-related
osteonecrosis of the upper jaw: case series,” Oral Diseases,
vol. 25, no. 2, pp. 497–507, 2019.
[14] O. S
¸ahin, O. Odabas¸i, and C. Ekmekcio˘glu, “Ultrasonic pi-
ezoelectric bone surgery combined with leukocyte and
platelet-rich fibrin and pedicled buccal fat pad flap in
denosumab-related osteonecrosis of the jaw,” Journal of
Craniofacial Surgery, vol. 30, no. 5, pp. e434–e436, 2019.
[15] A. Giudice, S. Barone, C. Giudice, F. Bennardo, and
L. Fortunato, “Can platelet-rich fibrin improve healing after
surgical treatment of medication-related osteonecrosis of the
jaw? A pilot study,” Oral Surgery, Oral Medicine, Oral Pa-
thology and Oral Radiology, vol. 126, no. 5, pp. 390–403, 2018.
[16] A. Giudice, F. Bennardo, S. Barone, A. Antonelli, M. M. Figliuzzi,
and L. Fortunato, “Can autofluorescence guide surgeons in the
treatment of medication-related osteonecrosis of the jaw? A
prospective feasibility study,” Journal of Oral and Maxillofacial
Surgery, vol. 76, no. 5, pp. 982–995, 2018.
[17] P. J. Voss, P. Poxleitner, R. Schmelzeisen, A. Stricker, and
W. Semper-Hogg, “Update MRONJ and perspectives of its
treatment,” Journal of Stomatology, Oral and Maxillofacial
Surgery, vol. 118, no. 4, pp. 232–235, 2017.
[18] L. Fortunato, F. Bennardo, C. Buffone, and A. Giudice, “Is the
application of platelet concentrates effective in the prevention
and treatment of medication-related osteonecrosis of the jaw?
A systematic review,” Journal of Cranio-Maxillofacial Surgery,
vol. 48, no. 3, pp. 268–285, 2020.
[19] C. Christodoulou, A. Pervena, G. Klouvas et al., “Combina-
tion of bisphosphonates and antiangiogenic factors induces
osteonecrosis of the jaw more frequently than bisphospho-
nates alone,” Oncology, vol. 76, no. 3, pp. 209–211, 2009.
[20] T. Higuchi, Y. Soga, M. Muro et al., “Replacing zoledronic
acid with denosumab is a risk factor for developing osteo-
necrosis of the jaw,” Oral Surgery, Oral Medicine, Oral Pa-
thology and Oral Radiology, vol. 125, no. 6, pp. 547–551, 2018.
[21] A. Sturrock, P. M. Preshaw, C. Hayes, and S. Wilkes, “General
dental practitioners’ perceptions of, and attitudes towards,
improving patient safety through a multidisciplinary ap-
proach to the prevention of medication-related osteonecrosis
of the jaw (MRONJ): a qualitative study in the North East of
England,” BMJ Open, vol. 9, no. 6, Article ID e029951, 2019.
Case Reports in Medicine 5