Article Type : Research Article
Authors : Silvana Noemi P, Genta R and Eduardo R
Keywords : Bisphosphonates (BPs); Denosumab (DS); Antiangiogenic drugs; Medication Related Osteonecrosis of the Jaw (MRONJ)
Medication-related osteonecrosis of the jaw (MRONJ) can be
difficult to treat and causes significant morbidity but is largely preventable.
Published guidelines strongly recommend dental assessment and necessary
remedial treatment before such drugs are commenced. Specific guidance on who
should provide or arrange this care is lacking, and it may often be delegated
to the patient arranging it with their own dentist. However, numerous factors
can make this difficult [1]. There exists a large and growing group at risk of
MRONJ who have significant amounts of oral disease. However, the risk of the
condition is largely preventable. Promise is shown in several methods to
organize timely dental care before treatment [2].
Antiresorptive drugs: Bisphosphonates (BPs) and
Monoclonal Antibodies: Denosumab (DS) are known to suppress osteoclastic
activity irreversibly in the case of BPs and reversibly in the case of DS [3].
The American Surgery of Bone Mineral Research (ASBMR) in 2007 defined MRONJ as
“necrotic bone area exposed to the oral environment with more than eight weeks
of permanence, in the presence of chronic treatment with BPs, in the absence of
radiation therapy to the head and neck”. In 2014 the American Association of
Oral and Maxillofacial Surgeons (AAOMS) divided the MRONJ into 4 stages from 0
to 3, according to the clinical and radiological aspect of the osteonecrotic
lesion: stage 0: Osteonecrotic lesion without sign-pathognomonic evidence of
osteonecrosis: stage 1: osteonecrotic lesion with clinical signs and absence of
clinical symptoms; Stage 2: Osteonecrotic lesion with sign and evident clinical
symptoms; Stage 3: Osteonecrotic lesion with signs and evident symptoms that
involve noble structures: pathological fractures, anesthesia of the lower
dental nerve, oral-nasal communication, oral-sinus communication, skin fistulas
[4].
Some antiresorptives as BPs, DS or antiangiogenic
drugs may cause MRONJ. BPs, synthesized in the mid-19th century by German
chemists, were initially used in industry due to their capacity to prevent the
deposits of calcium carbonate, which made them especially useful in avoiding
the deposit of calcium salt in pipes. Later it was shown that they had great
affinity with osseous tissue, where they inhibited the conversion of amorphous
calcium phosphate in hydroxyapatite and they reduced the dissolution speed or
the later [5]. BPs are synthetics compounds used in the treatment of various metabolic
and malignant bone diseases: Osteoporosis, Paget Disease, Hypercalcemia,
Multiple Mieloma, Metastatic breast cancer and Metastatic prostate cancer,
Osteogenesis Imperfecta, Fibrous Dysplasia [6,7]. Publications have been
described some cases of MRONJ because of BPs, Ds and antiagiocenic treatment
[8].
According to the 2010 Osteoporosis Canada Clinical
Practice Guidelines, DS is a first-line option for the pharmacological
management of postmenopausal osteoporosis [9]. The discovery of the RANKL–RANK pathway
as the primary mediator of osteoclast differentiation, activation, and survival
facilitated the design of molecules that specifically target this pathway for
the treatment of osteoporosis. By mimicking the effect of endogenous
osteoprotegerin, denosumab, a fully human monoclonal antibody to RANKL,
inhibited bone resorption with a rapid onset of action and a sustained but
reversible effect [10].
Historically, the first drugs associated with the condition were
bisphosphonates, which led to coining of the term MRONJ. However, there was a
need to include other drugs in the etiopathogeny of osteonecrosis, such as
other antiresorptive and antiangiogenic agents. The cases reported of
antiangiogenic agent-related osteonecrosis have been accumulating over the
years and, therefore, the most appropriate term for the condition is MRONJ.
Antiangiogenic drugs are indicated in the treatment of certain tumors, since
they stop the formation of new blood vessels, controlling tumor growth and the
chance of metastasis. The mechanism of action of antiangiogenic agents is, in
simple terms, blocking the direct or indirect action of VEGF [11].
Nowadays, some consensus has been publicated to
established guidelines about MRONJ. Historically some Consensus were studied to
stablish etiology, diagnosis and some resective or atraumatic treatments like
Canada Consensus Marx, et al. 2007 [12]; SECOM Junquera M, et al. 2008 [13];
Task Force Yapanese Yoneda, et al. 2010 [14]; AAOMS Ruggiero SL, et al. 2009
[15], Ruggiero et al: 2014 [16]; Korean Society Consensus Kim KM, et al. 2015
[17], AOCMF ARONJ Fleisher KE, et al. 2016 [18], ASBMR Task Force Burr DB, 2007
[19], Adler RA, et al. 2016 [20], Task Force MRONJ Khan AA, et al. 2017 [21],
Stavropoulos A, et al. 2018 [22], Limones, et al. 2020 [23]. For that reason,
it is so important dentists and physicians ought to attend patients together.
According the publications cited, dental
treatments are incomplete in most studies. Direct comparison is difficult.
However, promising strategies to prevent MRONJ have been demonstrated [1,24].
It is essential that patients with MRONJ be treated in an interdisciplinary
fashion. The patient’s stomatognathic system should be examined preventatively
prior to the initiation of BPs, DS or antiangiogenic treatment in order to
avoid pathological buccal manifestations, following the same healthcare
clinical protocols used for patients receiving head and neck radiotherapy.
Additionally, patients should be informed of the precautions to be taken,
including regular dental appointments for oral health assessment. The risk of
developing MRONJ should be evaluated according to the type of BPs, DS or
antiangiogenic administered and treatment duration [25,26].