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RANK-Ligand inhibitor associated osteonecrosis of the jaw

Authors:
Ashkan Rashad at RWTH Aachen University
Ashkan Rashad
Ralf Smeets at University Medical Center Hamburg - Eppendorf
Ralf Smeets
Max Heiland at Charité Universitätsmedizin Berlin
Max Heiland
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Osteonecrosis of the jaw may be caused by many different triggers. One of them is described to be the drug or medication related osteonecrosis Ashkan Rashad 1 Ralf Smeets 1 of the jaw. Since many years bisphosphonates induced the dreaded Max Heiland 1 diagnosis. Recently a drug named denosumab is reported to show similar effects on the jaw. In this case report we present a RANK-Ligand inhibitor associated osteonecrosis of the lower jaw and discuss the lights and shadows of this newly introduced drug. Zusammenfassung Die Osteonekrose des Kiefers kann durch verschiedene Auslöser verur-sacht sein. Einer dieser Auslöser wird als die Medikamenten-assoziierte Osteonekrose des Kiefers beschrieben. Seit mehreren Jahren induzieren Bisphosphonate die gefürchtete Diagnose. Kürzlich wurden ähnliche Auswirkungen durch Gabe des Arzneimittels Denosumab beobachtet. Anhand des Fallberichtes präsentieren wir eine RANK-Ligand Inhibitor assoziierte Osteonekrose des Unterkiefers und erörtern die Licht-und Schattenseiten des neuartigen Medikaments.
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RANK-Ligand inhibitor associated osteonecrosis of the
jaw
RANK-Ligand Inhibitor-assoziierte Osteonekrose des Kiefers
Abstract
Osteonecrosis of the jaw may be caused by many different triggers. One
of them is described to be the drug or medication related osteonecrosis
Ashkan Rashad1
Ralf Smeets1
of the jaw. Since many years bisphosphonates induced the dreaded Max Heiland1
diagnosis. Recently a drug named denosumab is reported to show
similar effects on the jaw. In this case report we present a RANK-Ligand
inhibitor associated osteonecrosis of the lower jaw and discuss the
lights and shadows of this newly introduced drug. 1 Department of Oral and
Maxillofacial Surgery,
Keywords: RANK-Ligand inhibitor, denosumab, osteonecrosis, jaw,
bisphosphonates
University Medical Center
Hamburg-Eppendorf,
Hamburg, Germany
Zusammenfassung
Die Osteonekrose des Kiefers kann durch verschiedene Auslöser verur-
sacht sein. Einer dieser Auslöser wird als die Medikamenten-assoziierte
Osteonekrose des Kiefers beschrieben. Seit mehreren Jahren induzieren
Bisphosphonate die gefürchtete Diagnose. Kürzlich wurden ähnliche
Auswirkungen durch Gabe des Arzneimittels Denosumab beobachtet.
Anhand des Fallberichtes präsentieren wir eine RANK-Ligand Inhibitor
assoziierte Osteonekrose des Unterkiefers und erörtern die Licht- und
Schattenseiten des neuartigen Medikaments.
Schlüsselwörter: RANK-Ligand Inhibitor, Denosumab, Osteonekrose,
Kiefer, Bisphosphonate
Introduction
Many patients suffer from bisphosphonate related os-
teonecrosis of the jaw (BRONJ). Bearing in mind increas-
ing administration of bisphosphonates (BPs) worldwide,
the peak is not yet reached [1]. BPs are drugs widely used
in the treatment of various bone related disorders such
as osteoporosis, multiple myeloma and bone metastases
[2].
Chemically, BPs are small molecular size stable analogues
of natural inorganic pyrophosphates, with a carbon atom
replacing the oxygen atom that connects the two phos-
phates [3]. They are classified as aminobisphosphonates
or non-aminobisphosphonates and administered orally
or intravenously. The mechanism of action concerns ap-
optosis of osteoclasts, decreased resorption activity and
hence limited bone remodeling [4].
RANK-Ligands (Receptor Activator of Nuclear Factor
Kappa-B Ligand) are produced by osteoblasts and pro-
mote differentiation of osteoclasts by binding to RANK-
receptors located on these. A new drug group, namely
denosumab (Prolia®), acts by attaching to RANK-Ligands
in order to prevent binding ofthe complex to RANK-recept-
ors resulting in an impaired function of osteoclasts. While
the pharmaceutical aim is the same as for BPs, the way
of action differs [5]. In general, the area of indication is
similar to widely distributed BPs [6], [7].
Denosumab was approved by European Medicines Agency
in May 2010 for the treatment of osteoporosis of women
in postmenopause and osteoporosis in men caused by
hormone therapy due to prostate cancer [8]. The US Food
and Drug Administration followed that approval in June
2010 [9] and extended the therapeutic field for osteo-
porosis in men independent of hormone therapy in
September 2012, which is still outstanding in European
Union [10].
Case description
A 74-year-old edentulous woman with osteoporosis and
fibromyalgia complained about growing pressure pain of
the mandible following extraction of the lower anterior
teeth and insertion of mucosa supported complete den-
ture 6 months ago. Her medical history revealed 6 time
administration of denosumab (Prolia®60 mg) subcu-
taneously over the past 2.5 years. Fibromyalgia was
1/3GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW 2013, Vol. 2, ISSN 2193-8091
Case Report
OPEN ACCESS
treated with decortin. While intraorally no dehiscence was
detected (Figure 1), a panoramic view indicated irregular
bone morphology especially in anterior mandible
(Figure 2) compared to preoperative imaging 10 months
ago (Figure 3). A CT scan illustrated the whole extent
(Figure 4). A RANK-Ligand inhibitor (denosumab) associ-
ated osteonecrosis of the mandible was diagnosed and
reminded us of known BP effects on the jaw. Due to
missing dehiscence she was treated conservatively with
sultamicillin and prosthesis leave for 2 months with slight
improvement of complaints. On the other hand with re-
spect to the great extent of the osteonecrosis, we clarified
the potential need of microvascular free flap for recon-
struction.
Figure 1: Intraoral illustration of lower jaw with absence of any
dehiscence
Figure 2: Panoramic view reveals edentulous site after
extraction and disturbed presentation of mainly anterior part
of the mandible
Figure 3: Panoramic pre-extraction view with remaining anterior
teeth 10 months ago
Figure 4: Finally CT scan showed up whole extent of
osteonecrosis
Discussion and conclusion
About 10 years after the first reported and published
cases of BRONJ [11], [12], a new drug group seems to
be associated with similar or even more serious impact.
Denosumab is a human monoclonal antibody and inhibits
osteoclast differentiation and proliferation. It has shown
great clinical results with even better bone density values
compared to BPs [13], [14]. However, the costs are many
times higher than for BPs. But due to higher and improved
bioavailability, administration of denosumab would be
sufficient subcutaneously every 6 months.
In contrast to BPs, half-life is not supposed to be several
years. Denosumab’s median half-life period amounts 26
days and could not be detected in more than half of
probands after 6 months. This fact could be beneficial
with respect to necessary dentoalveolar surgery. While
that kind of treatment should be performed necessarily
before BP uptake, denosumab could theoretically allow
operation even after administration requiring absence of
the drug for several months.
Nevertheless, above presented case suggests that the
RANK-Ligand inhibitor is able to harm the jaw seriously
in short period of time. Further studies have to investigate
possible angiogenesis inhibition and soft tissue toxicity
as reported for BPs [15], [16]. That is why we favor to
treat conservatively if possible at the moment. Surgical
procedures should be held limited and gentle to the
periosteum as for BRONJ.
2/3GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW 2013, Vol. 2, ISSN 2193-8091
Rashad et al.: RANK-Ligand inhibitor associated osteonecrosis of ...
Notes
Competing interests
The authors declare that they have no competing in-
terests.
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Corresponding author:
Dr. Ashkan Rashad, MD, DMD
Department of Oral and Maxillofacial Surgery, University
Medical Center Hamburg-Eppendorf, Martinistraße 52,
D-20246 Hamburg, Germany, Tel.: +49-177/856-2393,
Fax: +49-40/7410-55467
a.rashad@uke.de
Please cite as
Rashad A, Smeets R, Heiland M. RANK-Ligand inhibitor associated
osteonecrosis of the jaw. GMS Interdiscip Plast Reconstr Surg DGPW.
2013;2:Doc17.
DOI: 10.3205/iprs000037, URN: urn:nbn:de:0183-iprs0000374
This article is freely available from
http://www.egms.de/en/journals/iprs/2013-2/iprs000037.shtml
Published:
2013-11-19
Copyright
©2013 Rashad et al. This is an Open Access article distributed under
the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You
are free: to Share — to copy, distribute and transmit the work, provided
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3/3GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW 2013, Vol. 2, ISSN 2193-8091
Rashad et al.: RANK-Ligand inhibitor associated osteonecrosis of ...
... Adverse effects to denosumab are reported in dentistry. A 74-year-old woman treated with denosumab developed osteonecrosis of the mandible [23]. In a recent review article [24], the authors studied bone biopsies collected from patients exposed to denosumab that presented infectious, inflammatory and necrotic jaw diseases. ...
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