Denosumab a case report

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CASE REPORT
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sected in 2005. In 2007, the patient fell and sustained an L2–L5
fracture. At that time she was placed on 120-mg Denosumab
subcutaneous injections weekly for 3 weeks, followed by a
Rec
Angeles, Los Angeles, CA.
*Associate Professor, Section of Oral and Maxillofacial Surgery.
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2-week hiatus, and continued with a single Denosumab
120-mg injection every 4 weeks as long as she continued to
improve. Approximately 2 to 3 years before her visit to our
clinic, the patient reported a 4-month course of alendronate,
70 mg per week, “for [her] bones.”
Her dental history was significant for pain in the posterior
right mandible with an onset in late 2008. This resulted in
endodontic treatment of the second premolar and first and
second molars in the right mandible. In April 2009 at her
oncology follow-up, a suspected area of exposed bone in
the posterior right mandible was noted. At that time, the
Professor of Clinical Dentistry, Section of Oral and Maxillofacial
gery.
Professor, Section of Oral and Maxillofacial Radiology.
This work was supported by NIH/NIDCR DE019465 grant.
Address correspondence and reprint requests to Dr Aghaloo:
iversity of California, Los Angeles, 10833 Le Conte Avenue, CHS
076, Los Angeles, CA 90095; e-mail: taghaloo@dentistry.ucla.edu
010 American Association of Oral and Maxillofacial Surgeons
8-2391/10/6805-0002$36.00/0
:10.1016/j.joms.2009.10.010
959
Osteonecrosis of th
on Den
Tara L. Aghaloo, DDS, MD, PhD
and Sotirios Tetr
teonecrosis of the jaw (ONJ) presents clinically as
posed, necrotic bone in the maxilla or mandible of
least 8 weeks’ duration, with or without the pres-
ce of pain, infection, or previous trauma in a pa-
nt who has not received radiation to the jaws.1-3
hough necrotic bone exposure has been reported
the jaws of a variety of patients not receiving
phosphonates (BPs),4-9 the number of BP-related
J cases has continued to increase steadily since the
t report in 2003.10 To date, a direct causal relation-
ip between BP use and ONJ has not been estab-
ed.11,12 However, many retrospective and pro-
ective analyses have identified cases of ONJ in
ich BP therapy, especially the more potent intra-
nous preparations, was the only consistent variable,
ongly suggesting that BPs play a significant role in
J pathophysiology.13-24
Potential mechanisms underlying the pathophysiol-
y of bisphosphonate-related osteonecrosis of the
(BRONJ) have generated great debate in the liter-
re.25,26 It is not surprising that many hypotheses
empt to explain the unique localization of BRONJ
clusively to the jaws, including altered bone remod-
ng, angiogenesis inhibition, constant microtrauma,
ft tissue BP toxicity, and bacterial infec-
n.15,18,25,27-29 Importantly, ONJ incidence correla-
n with BP potency suggests that inhibition of oste-
last function and differentiation might be a key
tor in the pathophysiology of the disease.
eived from the School of Dentistry, University of California, Los
J Oral Maxillofac Surg
68:959-963, 2010
Jaw in a Patient
mab
an L. Felsenfeld, DDS, MA,†
, DDS, PhD‡
Currently, other inhibitors of osteoclast differentia-
n and function are entering the pharmacologic
amentarium for the treatment of diseases with
reased bone turnover. The association of these
w therapies with ONJ is uncertain. We report a
se of ONJ in a patient receiving Denosumab (Am-
n, Thousand Oaks, CA), a human receptor activator
nuclear factor � B ligand (RANKL) monoclonal
tibody currently in clinical trials for the treatment
osteoporosis, primary and metastatic bone cancer,
nt cell tumor, and rheumatoid arthritis.30-33
port of a Case
65-year-old woman presented to the oral and maxillo-
ial surgery clinic at the University of California, Los An-
es (UCLA) School of Dentistry with pain and exposed
ne in the posterior mandible of unknown duration. Her
dical history was significant for non–insulin-dependent
betes mellitus, morbid obesity, a below-the-knee ampu-
ion for congenitally missing right fibula, hypertension,
ngestive heart failure, hyperlipidemia hypothyroidism,
a sacral giant cell tumor (GCT). Her medications at the
e of presentation included Lipitor (Pfizer, New York,
), Omeprazole (Procter & Gamble, Cincinnati, OH), Lis-
pril (Merck & Co, Whitehouse Station, NJ), Premarin
zer), Lasix (Sanofi-Aventis, Paris, France), Lyrica (Pfizer),
throid (Abbott Pharmaceuticals, Pasadena, CA), Actos
keda Pharmaceuticals, Deerfield, IL), Glyburide (Bristol
ers Squibb, New York, NY), potassium chloride (Abbott
armaceuticals), GlycoLax (Schwarz Pharmaceuticals, Me-
on, WI), Lorazepam (Bioval Technologies, Lugano, Swit-
land), Dilaudid (Purdue Pharmaceuticals, Stamford, CT),
rofurantoin (Procter & Gamble), and a fentanyl patch (My-
Technologies, St Albans, VT). The GCT was partially re-
pat
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960 OSTEONECROSIS IN A PATIENT ON DENOSUMAB
ient was referred to UCLA for an oral and maxillofacial
gery consultation.
pon oral examination, a 4 � 6 mm rectangular area of
posed bone was noted on the lingual surface of the right
sterior mandible, 1 to 2 mm inferior to the gingival
rgin of the right mandibular second molar (Fig 1). There
re no signs of infection other than mild erythema sur-
nding the exposed bone. The area was extremely tender
palpation. The bone surface felt smooth, without sharp
ges, and was firmly attached, with no clinical evidence of
uestration.
panoramic radiograph (Fig 2) revealed irregular trabe-
lation with increased density at the right retromolar area,
tending to the roof of the inferior alveolar canal (IAC).
e external oblique ridge and IAC cortication appeared
htly ill defined. For more detailed evaluation, a limited
ld of view cone beam computed tomography (CBCT) was
rformed (Fig 3). The CBCT image confirmed the pan-
mic findings and furthermore demonstrated slight peri-
eal new bone formation, irregular cortication of the lin-
al mandibular plate at the area of the right mandibular
t molar to third molar region that corresponded to the
a of clinically exposed bone, and irregular trabeculation
th increased density throughout the whole buccal-lingual
ckness of the mandible from the retromolar area to the
a of the right mandibular first molar.
he patient history, coupled with the clinical and radio-
phic findings, was consistent with a working diagnosis of
J. The disease was classified as stage 2, characterized by
posed and necrotic bone with pain and erythema, with-
t purulent drainage.34 To prevent infection, clindamycin
0 mg orally 4 times per day and chlorhexidine 0.12%
uth rinse twice per day were prescribed. For pain con-
l, Darvon-N-100 (Xanodyne Pharmaceuticals, Newport,
) every 4 to 6 hours was given. The patient was seen 2
4 weeks after the initial visit, with no change in the
ical severity of exposed bone or erythematous soft tis-
s.
fter 8 weeks, the patient presented for follow-up with
nimal change in the area of exposed bone but with
htly more erythematous gingival tissue surrounding the
ny exposure. Because the patient now had had clinically
posed bone in the mandible for more than 8 weeks
URE 1. Clinicalpresentation of the case patient. Exposed bone
een lingual to the right mandibular second molar, with minimal
rginal gingival erythema.
aloo, Felsenfeld, and Tetradis. Osteonecrosis in a Patient on
nosumab. J Oral Maxillofac Surg 2010.
thout a history of radiation therapy, she was diagnosed
th ONJ. In this case it was not associated with BP therapy.
wo weeks later, the patient presented to our clinic with
-day history of moderate, erythematous, tender submen-
swelling causing her difficulty swallowing. No dental or
er source of infection was noted. She was admitted to
hospital for intravenous antibiotics and incision and
inage. A CT scan demonstrated localized fluid collection
the submental region. Purulent fluid (20 to 25 cc) was
ined from the abscess. While the patient was in surgery,
horough oral examination revealed no direct etiology for
submental infection and no connection to the ONJ area.
er the surgery, the infection subsided and the patient
s discharged.
everal days later, the patient was admitted to a commu-
y hospital with symptoms of shortness of breath. A diag-
sis of pulmonary edema and congestive heart failure was
de. The patient’s condition deteriorated, and she devel-
ed adult respiratory distress syndrome and multisystem
an failure. She died during this hospitalization.
scussion
ONJ is a complicated disease most commonly asso-
ted with BP treatment. Here we report develop-
nt of ONJ in a patient on Denosumab therapy for
management of a GCT. Although this patient was
URE 2. Panoramic radiograph of the patient at the time of
sentation. A, Panoramic radiograph demonstrates increased
ecular density of posterior right mandible compared with the
ffected left side. B, Magnified view of the right posterior man-
le demonstrates irregular trabeculation with increased density
loss of cortical definition of the external oblique ridge and roof
the IAC.
aloo, Felsenfeld, and Tetradis. Osteonecrosis in a Patient on
nosumab. J Oral Maxillofac Surg 2010.
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AGHALOO, FELSENFELD, AND TETRADIS 961
dically compromised and on multiple medications,
ommon thread in ONJ development may be inhi-
ion of osteoclastic activity, mediated in this case by
nosumab.
Osteoclasts are derived from the hematopoietic
m cell lineage and depend on other cells, such as
rrow stromal cells and osteoblasts, to secrete mac-
hage colony stimulating factor (M-CSF) and
NKL for their differentiation and function.35 In
dition to promoting the fusion of preosteoclasts
o osteoclasts, RANKL is required for activation and
ction of mature osteoclasts.35-37 Vital to the regu-
ion and balance of osteoclastogenesis is osteopro-
erin (OPG), an osteoclast decoy receptor that com-
tes with RANK for RANKL binding.38 Together,
NKL and OPG maintain a balance of bone resorp-
n in a healthy state. However, an increase in the
NKL/OPG ratio may shift the balance in favor of
ne resorption in skeletal disease.36,39 Because oste-
last-mediated bone resorption is pathologic in dis-
ses such as multiple myeloma, metastatic breast and
ostate cancer, osteoporosis, rheumatoid arthritis,
d giant-cell tumor of bone, inhibition of osteoclast
ferentiation and function is a primary therapeutic
get.
In this case report, Denosumab was used to combat
teoclast-mediated bone resorption in a patient with
unresectable sacral GCT. Although GCT is a benign
or, it may metastasize, undergo malignant transfor-
tion, or cause significant skeletal-related events.32
e efficacy of Denosumab in GCT is not surprising,
the tumor contains tartrate-resistant acid phospha-
e–positive, multinucleated giant cells that express
URE 3. CBCT image of the
ient. Sagittal (A, D), coronal
E), and axial (C, F) slices of
affected (upper panel) and
ffected sides (lower panel)
onstrate periosteal bone re-
ion (arrows), irregular cortica-
of the lingual mandibular
te (long arrowhead), and in-
ased trabecular density (short
owheads).
aloo, Felsenfeld, and Tetra-
. Osteonecrosis in a Patient on
osumab. J Oral Maxillofac
g 2010.
teoclastogenic markers, mononuclear monocytes,
d stromal cells.32,40,41 RANKL expression is signifi-
ntly increased in the stromal cells of GCTs, with a
cial role in its pathogenesis.32,41 BPs such as
ledronic acid have been used as adjuvant treatment
GCT, with improved symptoms and lower recur-
ce,42,43 but the specific involvement of RANKL in
T pathophysiology has contributed to the interest
Denosumab for these patients.32 A current proof-
principle study demonstrates decreased bone turn-
er markers, near elimination of giant cells, reduced
in, and stability of disease in GCT patients without
y serious adverse effects.32,44
BPs, especially the nitrogen-containing subset such
zoledronic acid and pamidronate, similarly de-
ase bone resorption, but through inhibition of far-
syl diphosphate synthetase in the cholesterol bio-
thesis mevalonate pathway.45 This leads to osteoclast
toskeleton disruption, intracellular vesicular traffick-
impairment, increased osteoclast apoptosis, and
creased osteoclast function.46-53 BPs bind physio-
emically to exposed hydroxyapatite54,55 and incor-
rate into the bone matrix with a half-life of many
ars. However, unlike BPs, the incorporation and
g-term effect of Denosumab on bone remodeling
d half-life in the bone matrix are not well defined.31
Denosumab is a high-affinity, highly specific human
2 monoclonal antibody that specifically binds hu-
n RANK and not other members of the TNF ligand
erfamily.30,56,57 In clinical trials, Denosumab causes
id, profound, and prolonged decreases in bone turn-
er markers without a change in bone formation,
ggesting its mostly antiresorptive properties.58-60
an
as
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ne
syn
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ing
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lon
an
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De
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the
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all
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ab
ple
ou
ho
tic
de
pa
tre
he
ale
the
Ho
syn
teo
co
tak
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tho
fac
co
eq
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bo
oc
po
rol
oc
ma
po
be
de
su
Re
1.
2.
3.
4. Woodmansey KF, White RK, He J: Osteonecrosis related to
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
962 OSTEONECROSIS IN A PATIENT ON DENOSUMAB
nosumab has also shown excellent clinical results
comparison with BPs in cancer and osteoporosis
rapy, with greater increase in bone mineral density
d suppression of bone turnover markers,61-63 with
cacy even in patients previously resistant to BPs.33
Importantly, ONJ has been reported in patients not
eiving osteoclast inhibitors. These ONJ cases usu-
y appear in the presence of glucocorticoids, infec-
n, heat-induced bone necrosis, trauma, and coagu-
ion disorders.4-9 The patient in this case had a
ltitude of medical problems including obesity, di-
etes, and a short course of alendronate. This com-
x medical history could have contributed to the
tcome of this case and might have impaired bone
meostasis.
We believe that the potent inhibition of osteoclas-
activity by Denosumab played a central role in the
velopment of ONJ in this patient. Although the
tient reported a history of oral BP use, the short
atment duration is unlikely to have contributed to
r ONJ. In a large series of ONJ patients taking
ndronate, no cases of BRONJ were reported when
medication was taken for fewer than 3 years.64
wever, the possibility of alendronate treatment
ergistically enhancing Denosumab inhibition of os-
clastic activity and ONJ development should be
nsidered.
We report the development of ONJ in apatient
ing Denosumab, a human monoclonal antibody
t blocks the binding of RANKL to RANK, therefore
ibiting osteoclast differentiation and function. Al-
ugh we recognize the many complicated medical
tors in this patient, we believe that Denosumab
ntributed to the ONJ. A recent press release reports
ual ONJ incidence for patients treated with Deno-
mab versus zoledronic acid for the management of
ne metastases or multiple myeloma.65 As oste-
lasts are the common target of BPs and Denosumab,
tent osteoclast inhibition appears to play a central
e in the pathophysiology of ONJ. As more oste-
lastic inhibitors enter clinical practice to be used in
naging diseases with increased bone turnover, the
ssibility that these agents might cause ONJ should
investigated. Ongoing clinical trials will ultimately
monstrate whether an association between Deno-
mab or other osteoclast inhibitors and ONJ exists.
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	Osteonecrosis of the Jaw in a Patient on Denosumab
	Report of a Case
	Discussion
	References