New Mexico Dental Journal Fall 2016

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12 New Mexico Dental Journal, Fall 2016
AReview of Medication Related Osteonecrosis of the Jaw
In 2014, a special committee of the American Association
of Oral and Maxillofacial Surgeons adopted this new
nomenclature to describe what was previously known as
bisphosphonate related osteonecrosis of the jaw to include a
number of new drugs demonstrating similar effects on the
musculoskeletal structures. The original position papers were
limited to those drugs known as bisphosphonates. The 2014
update provided insight to the newest antiresorptive drugs and
antiangiogenic therapy.
Antiresorptive drugs include intravenous and oral
bisphosphonates and subcutaneous denosumab. The newest
of these drugs known as RANKL inhibitors or anti-RANKL
agents are marketed as Prolia and Xgeva. Both are a form of
denosumab. RANKL is an acronym for Receptor Activator
of Nuclear factor Kappa-light-chain Ligand or receptor acti-
vator of nuclear factor kappa-light-chain enhancer of activated
B cells. These drugs act by blocking the RANKL receptor on
the osteoclast cell and their precursors creating inhibition of
osteoclastic formation, function and survival. The RANKL
inhibitors in the form of Prolia are administered every six
months if employed for the use of osteoporotic patients and
every month, in the form of Xgeva, if used to combat skeletal
related events from metastatic bone disease from solid tumors.
A similar affect is reported with the bisphosphonate drugs in
inhibiting osteoclastic function, however, the RANKL drug
effect is diminished within six months of drug termination,
whereas, the drug effect of the bisphosphonates may last up
to 10 years depending on duration and modality of drug use
due to the bisphosphonate binding to osseous components.
Interestingly, the RANKL inhibitors are not indicated for the
treatment of multiple myeloma.
Antiangiogenic therapy includes drugs that inhibit the
vascular endothelial growth factors (VEGF) in the form of
tyrosine kinase inhibitors (TKI) and monoclonal antibody-
targeting. This process plays a critical role in the growth and
spread of cancer cells as cancer cells stimulate angiogenesis
to enable their growth. By inhibiting the endothelial growth
factors, it is postulated that the cancer cells will be inhibited
in their ability to spread or increase in number essentially
limiting invasion into tissue or bone. The monoclonal anti-
body targeting drug approved by the FDA is bevacizumab
(Avastin) and the other antiangiogenic FDA approved
drugs are sorafenib (Nexavar), sunitinib (Sutent), pazopanib
(Votrient), and everolimus (Afinitor). The use of these medica-
tions are predominantly for battling gastrointestinal tumors,
renal tumors, and neuroendocrine malignancies.
The newest update from the 2014 position paper
regarding the diagnosis of medication related
osteonecrosis of the jaw (MRONJ) must include
all of the following:
• Current or previous treatment with antiresorptive or anti-
angiogenic agents
• Exposed bone or bone that can be probed through an
intraoral or extraoral fistula/parulis in the maxillofacial
region that has persisted for longer than eight weeks
• No history of radiation therapy to the jaws or obvious
metastatic disease to the jaws
The risk factors associated with MRONJ are divided
into two parameters defined as diagnosis and medications. The
diagnosis categories are osteopenia/osteoporosis and cancer.
The medication categories are defined as bisphosphonate
drugs, other antiresorptive drugs, and antiangiogenic drugs.
The AAOMS position paper determined the risk for patients
with cancer treated with zoledronate (Zometa) or aredia (pami-
dronate) to be in the low single digits. However, this is a 50
to 100 times higher rate than those patients with cancer not
exposed to the same regimen of drugs. The risk for MRONJ
for cancer patients treated with RANKL inhibitors is similar
to the bisphosphonate group. At this time, the rate for patients
treated with antiangiogenic therapy is lower than the other two
groups, but it is postulated that this is only true due to the
limited data available for this regiment of therapy.
The risk for patients being treated for osteoporosis/osteo-
penia with bisphosphonates is controversial, and oddly, has the
poorest level of evidence based studies. Astonishingly, in 2008
over 5.1 million patients over the age of 55 received prescrip-
tion bisphosphonate therapy. The most quoted studies demon-
strate an incidence risk from 0.004 (less than 1 in 10,000) to
0.21% (21 in 10,000). This ranges for patients being treated
for less than 4 years (0.4 cases per 10,000) and those treated
longer than 4 years (0.21% incidence). The risk for patients
treated with intravenous bisphosphonates or subcutaneous
RANKL inhibitors for osteoporosis ranges from a yearly dose
of intravenous bisphosphonate of over a three year period of
1.7 cases per 10,000 to those treated with Prolia with a risk of
4 cases per 10,000 patients (an incidence of 0.04%). It is widely
held that duration of therapy is an additional risk factor in the
use of bisphosphonates and other antiresorptive drugs. The
incidence of MRONJ in cancer patients receiving bisphospho-
nate therapy ranged from 0.6% at one year of therapy to 1.3%
at 3 years of therapy, while those receiving bisphosphonates
By Christopher Buttner, DDS