The present case report describes the occurrence of
ONJ in an elderly woman with AS who received longterm
oral alendronate for osteoporosis treatment. This
patient had had a history of concomitant etanercept
treatment for more than three years. Unlike high doses
of bisphosphonates given by the intravenous route, as in
the case of cancer patients, the prevalence of ONJ due to
oral bisphosphonates for osteoporosis treatment is very
low and reported to be 0.00038%.
5 To our knowledge,
the occurrence of this very rare complication in a
patient with AS receiving concomitant etanercept
treatment has not been previously reported in the
literature.
In the present case, the diagnosis of ONJ was
made based on the presence of relevant clinical and
radiological findings as well as the past history of oral
alendronate treatment for 10 years and occurrence after
tooth extraction. These features are consistent with the
data in the literature documenting that being an older
female and having long term bisphosphonate treatment
(generally longer than 3 years) along with previous
invasive dental treatment were the most common
characteristics of the previously reported cases who
developed ONJ during osteoporosis treatment.6,7 By
collaborating with dental surgeons, we made a detailed
differential diagnosis in this patient and excluded
other possibilities, such as periodontitis, osteomyelitis,
periapical disease, gingivitis, tumors or metastasis, and
temporomandibular joint disease.
Although the exact mechanism of ONJ remains
unknown, suppression of bone remodeling and
angiogenesis as well as toxic effects due to oral
epithelium seem to be responsible.8,9 Bisphosphonates
substantially reduce bone turnover, impairing the
repair of microdamage. They also cause increased
bone mineralization which increases the bone
brittleness. The microdamage and microfractures
that occur either physiologically as the result of the
constant stress of masticatory forces or pathologically
as the result of local infections and dental extractions
cannot be repaired. The impaired bone architecture
and quality increases bone fragility, finally leading
to the development of ONJ.8,9 Infections generally
accompany ONJ, which not only increases the tendency
for ONJ development, but also exacerbates the clinical
symptoms. Likewise, it is well known that ONJ may
be asymptomatic in early stages. These symptoms
mostly occur due to secondary infections,9,10 as was
observed in the present case. Osteonecrosis of the
jaw preferentially involves the bones that have a
high intracortical remodeling rate, which explains
why it occurs mostly in the mandible (70%) and less
frequently in the maxilla (30%).9,10
The development of ONJ has not been known to be
directly caused by the presence of AS nor by treatment
with etanercept. Dental tooth extraction seemed to
be the main triggering factor for ONJ in our patient.
Comorbid diseases or other concomitant medications
should also be considered as potential precipitating
factors; however, our case did not have any comorbid
diseases. With respect to concomitant medications,
corticosteroids and immunosupressive agents are
reported to contribute to osteonecrosis development.11
Therefore, the past history of intermittent corticosteroid use in our patient should also be kept in mind. Besides,
thrombogenic aPL antibodies may also precipitate
osteonecrosis;12 however, our patient was negative for
these antibodies.
To our knowledge, ONJ should not be included as
one of the complications of anti-TNF agents. In our
case, etanercept treatment cannot be hold responsible
from the occurrence of the ONJ complication. If
anti-TNF agents really facilitated ONJ development,
this effect could not be explained solely by causing
a tendency toward infection. Anti-TNF agents are
well known to cause a modest increase in bone
formation and suppression in bone resorption.13
Consequently, this resorption may contribute to ONJ
development. Evidence supporting this assumption
comes from the fact that anti-RANKL (receptor
activator of nuclear factor-κB ligand) antibody
(denosumab) treatment for osteoporosis may also
induce osteonecrosis development, which is similar
to that of bisphosphonates.14 This may imply that any
therapeutic agent which suppresses bone resorption,
including etanercept and denosumab, may facilitate
osteonecrosis development.
The management of ONJ is initially conservative,
including ending the bisphosphonate treatment,
eliminating pain, controlling the infection, and
preventing the progression of osteonecrosis.9-10 A good
oral hygiene regimen with oral antimicrobial rinses is
necessary. Identifying the stage of ONJ is also important
for determining proper management. Osteonecrosis
of the jaw is classified as having stages from 0 to 3
according to clinical signs and symptoms.10 No imaging
criteria are used for this classification. Delaying surgical
interventions until stage 3 is recommended. If surgery
becomes necessary, the necrotic area should be extracted
with minimal trauma to surrounding healthy tissues.10
Our patient was accepted as stage 2 and a conservative
approach proved to be sufficient with no surgical
treatment needed.
Although the risk of ONJ development is low
during osteoporosis treatment, preventive measures
should always be considered. Before starting the
treatment, a dentist should be consulted and, if needed,
should initiate it. It is also recommended that the
bisphosphonate treatment be stopped temporarily
before a dental surgery. It should only be restarted
after complete healing of the bone, especially for
patients who received bisphosphonate for more than
three years.8
In conclusion, ONJ development during oral
bisphosphonate treatment in osteoporosis patients is a very rare, but well-recognized complication. To our
knowledge, occurrence of this very rare complication in
an osteoporotic patient with AS has not been reported
in literature. Although, dental tooth extraction along
with long term alendronate treatment seem to be the
main causative factors for this patient, the possibility
of even a minor contribution of etanercept by means
of facilitating oral infection and suppressing bone
resorption is speculative. Osteoporosis may commonly
accompany AS, and bisphosphonate treatment has a
potential to be used in AS, both for disease control and
OP treatment.15 As the use of bisphosphonates in AS
patients increases, the incidence of ONJ may also be
expected to rise in the future.
Declaration of conflicting interests
The authors declared no conflicts of interest with respect
to the authorship and/or publication of this article.
Funding
The authors received no financial support for the
research and/or authorship of this article.
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