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].