Int. J. Oral Maxillofac. Surg.

2016; 45: 1592–1599

http://dx.doi.org/10.1016/j.ijom.2016.06.016, available online at http://www.sciencedirect.com

Clinical Paper
Clinical Pathology

Osteoradionecrosis and K. Grisar1, M. Schol2,

J. Schoenaers1, T. Dormaar1,
R. Coropciuc1, V. Vander Poorten3,
C. Politis1
medication-related 1
Department of Oral and Maxillofacial
Surgery, University Hospitals Leuven, Leuven,
Belgium; 2Department of Dentistry, University

osteonecrosis of the jaw: Hospitals Leuven, Leuven, Belgium;

3
Department of Otorhinolaryngology,
University Hospitals Leuven, Leuven, Belgium

similarities and differences

K. Grisar, M. Schol, J. Schoenaers, T. Dormaar, R. Coropciuc, V. Vander Poorten,
C. Politis: Osteoradionecrosis and medication-related osteonecrosis of the jaw:
similarities and differences. Int. J. Oral Maxillofac. Surg. 2016; 45: 1592–1599. #
2016 International Association of Oral and Maxillofacial Surgeons. Published by
Elsevier Ltd. All rights reserved.

Abstract. The purpose of this study was to compare medication-related osteonecrosis

of the jaw (MRONJ) with osteoradionecrosis (ORN). Group 1 comprised 74
MRONJ patients (93 lesions) and group 2 comprised 59 ORN patients (69 lesions).
Patient characteristics, clinical presentation of the lesions, the presence of
complications, and the relationship with previous dental extractions were analyzed
for both groups. Significant differences were found between the groups with regard
to the characteristics of the patient populations, extraction as the precipitating event,
the type of initial complaint, the prevalence of pain, and the location of the lesions.
In the ORN group, significantly more patients complained of pain (P = 0.0108)
compared with the MRONJ group. Furthermore, significantly more pathological
fractures (P < 0.0001) and skin fistulae (P < 0.0001) occurred in the ORN group.
The treatment was more often conservative in the MRONJ group than in the ORN
Key words: ORN; MRONJ; osteonecrosis; risk
group (61.3% vs. 36.2%). Despite similarities in terms of imaging, risk factors, factors; treatment.
prevention, and treatment, MRONJ and ORN are two distinct pathological entities,
as highlighted by the differences in patient characteristics, the initial clinical Accepted for publication 21 June 2016
presentation, course of the disease, and outcome. Available online 15 July 2016

In 2003, Marx reported the first cases of
medication-related osteonecrosis of the
jaw.1 Initially, osteonecrosis was reported
only after treatment with bisphosphonates
and was referred to as bisphosphonate-
related osteonecrosis of the jaw (BRONJ).
Since 2014, the American Association of
Oral and Maxillofacial Surgeons
(AAOMS) has recommended the use of
medication-related osteonecrosis of the
jaw (MRONJ) in the nomenclature. The
change is justified to accommodate the
growing number of osteonecrosis cases
associated with other anti-resorptive
(denosumab) and anti-angiogenic thera-
pies in patients without any prior use of
bisphosphonates.2
Radiation therapy is a frequently used
treatment modality for head and neck
cancer. One of the most comprehensively
documented complications of radiation

0901-5027/01201592 + 08 # 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

therapy in the head and neck region is
osteoradionecrosis (ORN).3,4 The first
descriptions date back to 1922 and
1926.5,6
Both ORN and MRONJ have been de-
scribed extensively in the literature. By
definition, a lesion cannot be named a
MRONJ lesion if it has occurred in a
previously irradiated jaw. In this study,
ORN and MRONJ were compared.
Materials and methods
Subjects
All patients registered with ORN or
MRONJ at university hospitals in Leuven,
Belgium between 2005 and 2014 were
included in the initial study population.
None of the patients in the MRONJ group
were being treated for osteoporosis or
osteopenia. All MRONJ patients had been
treated with intravenous (IV) bisphospho-
nates; none had been treated with oral
bisphosphonates.
Radiographic documentation of the
lesions was available for all patients. Pa-
tient characteristics and treatment and fol-
low-up data were recorded from the
medical files. The first group consisted
of 74 patients (93 lesions) who had devel-
oped MRONJ. The accepted criteria of the
AAOMS were used to establish the diag-
nosis of MRONJ.2 The second group con-
sisted of 59 patients (69 lesions) with
ORN. All patients in both groups were
treated in the department of oral and
maxillofacial surgery of the university
hospitals between 2005 and 2014.
The following data were collected:
identification number, date of birth, sex,
tobacco use as noted in the medical
records, the patient’s first complaint, num-
ber of areas with osteonecrosis and locali-
zation of the lesions, size of the exposed
bony area, relationship with previous den-
tal extractions, oro-antral communica-
tions, intraoral and extraoral fistulae,
and the presence of severe complications.
Table 1. Tumour site and drugs used in the MRONJ group.
Tumour
Breast
Multiple myeloma
Prostate
Lung
Kidney
Other
Medication
Zoledronic acid (Zometa)
Denosumab (Xgeva)
Pamidronate (Aredia)
MRONJ, medication-related osteonecrosis of the jaw.
Similarities and differences of ORN and MRONJ
Statistical analysis
The groups were compared by means of
the t-test for continuous variables and the
x2 test for categorical variables. In the
case of any of the counts for the categori-
cal variables being less than 5, Fisher’s
exact test was applied instead of the x2
test.
Results
Most of the patients in the MRONJ group
had metastatic breast carcinoma or multi-
ple myeloma (Table 1). Fifty-nine patients
(79.7%) had been treated with zoledronic
acid, while 14 patients (18.9%) had been
treated with denosumab and one with
pamidronate.
In the ORN group, the mean  standard
deviation (SD) radiation dose was
63.8  9.5 Gy (range 40–72 Gy). The
mean  SD time between radiation and
the development of ORN was
47.5  62.85 months (range 2 months to
36 years). Sixty-two percent of the lesions
developed within the first 3 years after the
completion of treatment.
The mean age was statistically higher in
the MRONJ group (P < 0.0001). There
was a significantly higher number of
females in the MRONJ group than in
the ORN group (P = 0.0005). Compari-
sons of tobacco habits, the location of
bony exposure, number of exposed bone
areas, largest size of exposed bone areas,
and other clinical characteristics are
shown in Table 2.
A significantly higher number of
patients in the ORN group complained
of pain (P = 0.0108), and significantly
more pathological fractures (P < 0.0001)
and skin fistulae (P < 0.0001) occurred in
the ORN group than in the MRONJ group
(Table 2).
In the MRONJ group, the most frequent
initial complaint was bone exposure
(78.5%), while a large part of the ORN
group initially presented with a patholog-
Number of patients %
28 37.8%
31 41.9%
4 5.4%
3 4.1%
5 6.8%
3 4.1%
59 79.7%
14 18.9%
1 1.4%
1593
ical fracture (23.2%). ORN was signifi-
cantly more frequently associated with
lesions in the mandible (91.3%) when
compared to MRONJ (68.8%)
(P = 0.0012).
While 63.4% of the MRONJ lesions
where precipitated by extractions, this
was the case for only 31.9% of the
ORN lesions (P < 0.001).
The treatment of MRONJ was more
often conservative (57 lesions, 61.3%).
Thirty-six MRONJ lesions (38.7%) re-
quired sequestrectomy, while no MRONJ
lesions were surgically resected and
reconstructed. In contrast to this, only
25 ORN lesions were treated conserva-
tively (36.2%) and 15 ORN lesions
(21.7%) required sequestrectomy, where-
as 26 ORN lesions (37.7%) were treated
with major surgical resection and recon-
struction (22 fibula free flaps, two deep
circumflex iliac artery free flaps, and two
radial forearm free flaps). Three ORN
lesions required other treatment (removal
of dental implants, removal of osteosynth-
esis material, and closure of an oro-antral
fistula with a buccal flap).
Discussion
In 1983, Marx proposed the hypoxic–
hypocellular–hypovascular theory to ex-
plain the pathophysiology of ORN.7 No
other explanations were offered until
Delanian et al. published the fibro-atro-
phic theory in 1993.8 The fibro-atrophic
theory suggests that the activation and
dysregulation of fibroblastic activity leads
to atrophic tissue within a previously ir-
radiated area, resulting in ORN.8,9
The first MRONJ cases were reported in
2003 and 2004 and while there is agree-
ment about the pathophysiology of ORN,
the underlying pathophysiology of
MRONJ has not yet been elucidated fully.
Many hypotheses have been proposed and
it is unlikely that one single hypothesis can
explain the pathophysiology of MRONJ,
as it is a multifactorial disease entity. The
leading proposed hypotheses to explain
the unique localization of MRONJ in
the jaws include remodelling or oversup-
pression of bone resorption, inflammation
and infection, the inhibition of angiogen-
esis, soft tissue toxicity, and immune dys-
function. None of these hypotheses seems
to be able to explain all cases.10
At present, bisphosphonates and anti-
receptor activated nuclear factor kappa B
ligand (anti-RANKL) monoclonal antibo-
dies, such as denosumab, are responsible
for the majority of MRONJ cases. These
drugs have in common that they both
prevent osteoclasts from resorbing bone.
1594 Grisar et al.

Table 2. Comparisons of the clinical characteristics and treatment of MRONJ and ORN.
Group 1: MRONJ Group 2: ORN
(74 patients, 93 lesions) (59 patients, 69 lesions) P-value
Age, years, mean  SD 68.59  11.98 59.54  8.77 <0.0001a
Sex 0.0005b
Male 36 (48.6%) 47 (79.7%)
Female 38 (51.4%) 12 (20.3%)
Tobacco use 18 (24.3%) 39 (66.1%) <0.0001b
First sign <0.0001c
Pain 16 (17.2%) 15 (20.3%)
Bone exposure 73 (78.5%) 31 (43.5%)
Pain and EO fistula 0 (0%) 3 (4.3%)
Pathological fracture 0 (0%) 16 (23.2%)
Otherd 4 (4.3%) 4 (8.7%)
Location 0.0012b
Mandible 64 (68.8%) 63 (91.3%)
Maxilla 29 (31.2%) 6 (8.7%)
Number of exposed bone areas 0.2111b
1 55 (74.3%) 50 (84.7%)
2 19 (25.7%) 9 (15.3%)
Largest size of the exposed bone areas, mean  SD 1.48  1.46 1.83  1.18 0.1707a
Pain 57 (61.3%) 56 (81.2%) 0.0108b
Infection 53 (57.0%) 50 (72.5%) 0.0631b
Jaw fracture 1 (1.1%) 20 (29.0%) <0.0001c
Intraoral fistulae 10 (10.8%) 10 (14.5%) 0.6355b
Skin fistulae 0 (0%) 12 (17.4%) <0.0001c
Nerve hypoesthesia 4 (4.3%) 10 (14.5%) 0.0443c
Aetiology <0.0001c
Extraction 59 (63.4%) 22 (31.9%)
Implant 0 (0%) 2 (2.9%)
Prosthesis 5 (5.4%) 0 (0%)
Unknown 29 (31.2%) 45 (65.2%)
Treatment <0.0001c
Conservative 57 (61.3%) 25 (36.2%)
Sequestrectomy 36 (38.7%) 15 (21.7%)
Surgical resection and reconstruction 0 (0%) 26 (37.7%)
Other 0 (0%) 3 (4.3%)
MRONJ, medication-related osteonecrosis of the jaw; ORN, osteoradionecrosis; SD, standard deviation; EO, extraoral.
a
Student t-test.
b 2
x test.
c
Fisher’s exact test.

Although this occurs through a different
mechanism, it makes the inhibition of
bone remodelling a critical factor in the
pathogenesis of MRONJ.11 It has been
reported that the pharmacokinetics of
bisphosphonates, and in particular the
half-life, are less favourable than those
of denosumab in the management of
MRONJ.11–13 While the half-life of the
absorbed bisphosphonates may be in the
region of approximately 10 years, deno-
sumab has a more reversible interaction
with bone.13
While the incidence of MRONJ con-
tinues to increase due to the implementa-
tion of new drugs, the opposite is true for
ORN, thanks to improved dental preven-
tive care and new developments in radia-
tion therapy. Conventional radiotherapy
was associated with an ORN prevalence
of 7.4%. Intensity-modulated radiation
therapy (IMRT) has proven to be success-
ful in reducing the incidence of ORN to
5.1%.14
ORN affects the mandible more often
than the maxilla or any other bone in the
head and neck region, and is rare after a
radiation dose of less than 60 Gy.14 ORN
usually develops during the first 4 to 24
months after radiation therapy, although
the risk remains present lifelong.9 Ithe
ORN group in the present study, 62% of
the lesions developed within the first 3
years after the completion of irradiation
treatment and three lesions (4.3%)
developed more than 9 years after receiv-
ing radiation therapy.
Oral bisphosphonates are prescribed
worldwide in huge numbers, therefore
the absolute number of patients suffering
from this complication is not negligible.15
A recent review concluded that the risk of
MRONJ developing after exposure to oral
bisphosphonates is approximately 0.1%
(range 0.004–0.2%). In the population
treated with IV bisphosphonates, this risk
is increased by a factor of 10 (range 0.2–
6.7%).16
The risk of developing MRONJ after the
administration of IV bisphosphonates does
not differ significantly from that following
the administration of denosumab (1.9%).17
The risk of developing MRONJ in patients
with cancer exposed to bevacizumab, an
anti-angiogenic agent, has been reported to
be 0.2%. The risk may be higher in patients
exposed to both bevacizumab and zoledro-
nate (0.9%).18–20 There are several case
reports describing jaw necrosis in patients
with cancer receiving targeted therapies,
specifically tyrosine kinase inhibitors and
monoclonal antibody targeting vascular
endothelial growth factor.21–23
The reported incidences of ORN and
MRONJ vary. This may be explained by
differences in diagnostic criteria, as well
as genetic factors. However, differences in
dental hygiene, patient compliance, mode
of radiation, frequency of dental examina-
tions, and the quality of dental and surgical
care may also be explanatory factors for
this variation in incidence.24

Table 3. Risk factors for developing ORN
and MRONJ.
 Age over 60 years
 Diabetes mellitus
 Pre-existing oral infection
 Previous dental treatment
 Dental hygiene
 Chemotherapy
 Regular steroid use
 Smoking
 Local risk factors including dental
extractions; denture use; oral, periodontal, and
peri-apical surgery; local anatomical
considerations; dental implant placement
 Systemic factors including infection;
immune deficient states; systemic co-
morbidities; malnutrition
ORN, osteoradionecrosis; MRONJ, medica-
tion-related osteonecrosis of the jaw.
In line with previous studies, ORN was
found to occur predominantly in males in
the present study (79.7%). This can be
explained by the fact that men, given their
higher use of alcohol and tobacco, are at a
greater risk of developing head and neck
tumours and therefore the complications
associated with their treatment.
The patient-related risk factors for de-
veloping ORN or MRONJ are similar
(Table 3).13,14,25,26 The treatment-related
risk factors have their obvious differences.
Both MRONJ and ORN may remain
asymptomatic for prolonged periods.
Not uncommonly, these lesions will be-
come symptomatic with inflammation of
the surrounding tissues. Signs and symp-
toms may occur before the development of
bony exposure. ORN and MRONJ patients
may present with pain, tooth mobility,
mucosal swelling, erythema, ulceration,
malocclusion, dysphagia, trismus, pares-
thesia, or even anaesthesia of the associ-
ated branch of the trigeminal nerve. Some
patients may also present with symptoms
of altered sensation in the affected area
because the neurovascular bundle may
become compressed by the surrounding
inflammation.2,15,27
While MRONJ lesions may remain si-
lent until the occurrence of a triggering
event, such as an invasive dental proce-
dure, infection, or mechanical trauma to
the jawbone, ORN lesions seem to have
the tendency to develop spontaneously. In
the patient population presented here,
63.4% of the MRONJ lesions developed
after extraction compared to 31.9% of the
ORN lesions.
In the MRONJ group, the first com-
plaint was almost always bony exposure,
while this was the case in less than half of
the patients in the ORN group. In the other
patients in the ORN group, pain with or
Similarities and differences of ORN and MRONJ 1595
without extraoral fistulae was often the breach of the oral mucosa or cervicofacial
initial symptom triggering a medical visit; skin.31
even a pathological fracture could be the Marx’s classification system for ORN,
first complaint (Table 2). introduced in 1983, has three stages and is
The extent of the lesions varies. They based on the response to hyperbaric oxy-
can range from a non-healing extraction gen (HBO) therapy.26 Epstein et al. pub-
site to exposure and necrosis of large lished a classification in 1987 that also
sections of the jaw. Late stage ORN often involves the use of HBO. Neither of these
presents with intra- or extraoral fistulae, classifications is applicable for patients
complete devitalization of bone, and path- who are not undergoing HBO therapy,
ological fractures, occasionally leading to and they are therefore not ideal for clinical
life-threatening complications. In the evaluation.32–34 A third classification pro-
ORN group in this study, the clinical posed by Notani et al. grades ORN accord-
presentation was significantly more often ing to its anatomical extent.35 The most
complicated by skin fistulation (17.4%), recent classification, proposed by Lyons
nerve hypoesthesia (14.5%), or pathologi- et al., includes the extent of ORN and its
cal fractures of the jaw (29.0%) than in the symptoms in a four-stage classification
MRONJ group. (Table 4).36
While ORN lesions occur almost exclu- The definition of MRONJ was updated
sively in the mandible, MRONJ lesions in 2014 in an AAOMS position paper to
can occur in both the mandible and the (1) current or previous treatment with anti-
maxilla, with the mandible being most resorptive or anti-angiogenic agents; (2)
frequently affected. In this study, 68.9% exposed bone or bone that can be probed
of the MRONJ lesions and 91.3% of the through an intraoral or extraoral fistula in
ORN lesions were located in the mandible. the maxillofacial region that has persisted
This most likely occurs due to the restrict- for more than 8 weeks; and (3) no history
ed localized blood supply to the mandible of radiation therapy to the jaws or obvious
and the higher bone density in the mandi- metastatic disease to the jaws.2 The
ble. Also, in contrast to the mandible, the AAOMS has also suggested a revised
maxilla has a high number of anastomoses clinical staging system to describe the
and is usually restricted from the irradia- severity of MRONJ. The various stages
tion field.27–29 and suggested stage-specific treatment
For both MRONJ and ORN, the strategies are outlined in Table 5. Howev-
patient’s history and clinical examination er, the suggested stage-specific treatment
remain the most sensitive diagnostic tools. strategies are not evidence-based; in par-
Obtaining an accurate exposure history to ticular, stage 0 disease is not universally
the various anti-resorptive and anti-angio- accepted.2
genic medications or radiation therapy is Due to the non-specific findings on
always a critical first step. imaging, neither the diagnostic criteria
Marx defined ORN as ‘‘an area greater for ORN or MRONJ take radiological
than 1 cm of exposed bone in a field of features into account. Nevertheless, imag-
irradiation that had failed to show any ing certainly has the potential to signifi-
evidence of healing for at least 6 month- cantly contribute to the screening, initial
s’’.30 It is essential that the presence of diagnosis, treatment, and follow-up of
residual or recurrent tumour is excluded. these disease processes.2
However, it is now known that ORN can Panoramic radiographs are mostly used
be shown radiographically without any for follow-up and monitoring of patients
Table 4. The classification of ORN proposed by Lyons et al.37.
Stage Description
ORN staging and treatment strategies
1  <2.5 cm length of bone affected (damaged or exposed); asymptomatic
 Medical treatment only
2  >2.5 cm length of bone affected; asymptomatic, including pathological
fracture or involvement of the inferior dental nerve, or both
 Medical treatment only unless there is dental sepsis or obviously loose,
necrotic bone
3  >2.5 cm length of bone affected; symptomatic, but with no other features
despite medical treatment
 Consider debridement of loose or necrotic bone and local pedicled flap
4  >2.5 cm length of bone affected; pathological fracture, involvement of the
inferior dental nerve, or orocutaneous fistula, or a combination
 Reconstruction with a free flap if the patient’s overall condition allows
ORN, osteoradionecrosis.
1596 Grisar et al.

Table 5. American Association of Oral and Maxillofacial Surgeons staging and treatment strategies for MRONJ.
MRONJ staging
At risk category No apparent necrotic bone in patients who have been treated with
either oral or IV bisphosphonates
Stage 0 No clinical evidence of necrotic bone, but non-specific clinical
findings, radiographic changes, and symptoms
Stage 1 Exposed and necrotic bone, or a fistula that probes to bone, in
patients who are asymptomatic and have no evidence of infection
Stage 2 Exposed and necrotic bone, or a fistula that probes to bone,
associated with infection as evidenced by pain and erythema in
the region of the exposed bone, with or without purulent drainage
Stage 3 Exposed and necrotic bone or a fistula that probes to bone in
patients with pain, infection, and one or more of the following:
exposed and necrotic bone extending beyond the region of
alveolar bone (i.e., inferior border and ramus in the mandible,
maxillary sinus and zygoma in the maxilla) resulting in
pathological fracture, extraoral fistula, oral antral/oral nasal
communication, or osteolysis extending to the inferior border of
the mandible or sinus floor
MRONJ, medication-related osteonecrosis of the jaw; IV, intravenous.
Treatment strategies
No treatment indicated; patient education
Systemic management, including the use of
pain medication and antibiotics
Antibacterial mouth rinse, clinical follow-
up on a quarterly basis, patient education,
and review of indications for continued
bisphosphonate therapy
Symptomatic treatment with oral
antibiotics, oral antibacterial mouth rinse,
pain control, debridement to relieve soft
tissue irritation, and infection control
Antibacterial mouth rinse, antibiotic therapy
and pain control, and surgical debridement
or resection for longer term palliation of
infection and pain

who are at risk of osteonecrosis. However,
it must be kept in mind that injury will not
be visible on X-ray until a decrease in
bone density of approximately 30–50%
has occurred.37
Cone beam computed tomography
(CBCT), computed tomography (CT),
and magnetic resonance imaging (MRI)
allow for a more extensive analysis of the
jaws, making it possible to assess the
extent of injury more accurately. CBCT,
CT, and MRI are also very helpful in
differentiating osteonecrosis from other
possible causes of osteolysis. CBCT and
CT are useful in providing detailed infor-
mation for both cortical and trabecular
bone. Meanwhile, MRI is useful in detect-
ing the involvement of the soft tissues.
Bone scans can reveal abnormal local-
ized activity in the jaws compared with the
surrounding region. Bone scans could be
used as a screening test to detect subclini-
cal osteonecrosis in patients who are at risk
of developing osteonecrosis.38 Hybrid sin-
gle photon emission computed tomogra-
phy (SPECT)/CT may significantly
increase the diagnostic certainty of ana-
tomical localization by combining func-
tional information derived from SPECT
imaging with anatomical information de-
rived from CT imaging.39
More important than the treatment of
osteonecrosis of the jaw are dental pre-
ventive measures prior to, during, and
after treatment with IV bisphosphonates,
denosumab, or radiation. Preventive
measures include oral hygiene instruc-
tions, a thorough regular clinical and
radiographic dental assessment, dental
prophylaxis, caries control, and the
identification and atraumatic extraction
of non-restorable teeth or teeth with a
poor prognosis. Tooth extractions should
ideally be performed between 14 and 21
days prior to initiating therapy with ra-
diation or anti-resorptive medication.
Surgical wounds should have a full soft
tissue closure before parenteral anti-re-
sorptive medication is started. Full or
partial dentures should be checked for
pressure areas and adjusted if necessary
in order to avoid mucosal trauma.2,40
Some guidelines also advocate an oral
evaluation, either before starting or at an
early stage of oral bisphosphonate thera-
py, especially in the absence of appropri-
ate dental care or good oral hygiene.41
Ripamonti et al. found a significant de-
crease in incidence of MRONJ in cancer
patients receiving bisphosphonate therapy
when preventive measures were taken.42
Dentoalveolar surgery and the place-
ment of dental implants should be avoided
in asymptomatic patients receiving IV
bisphosphonates for cancer. However,
according to the AAOMS position paper
on MRONJ (revised in 2014), elective
dentoalveolar surgery is not contraindi-
cated in patients receiving oral bispho-
sphonates for osteoporosis, even though
these patients are also at risk of developing
MRONJ, especially when the duration of
the therapy exceeds 4 years.2,43
Frequent patient follow-up is required
to ensure optimal oral health. As bone
healing may be compromised, dental
extractions should be avoided whenever
possible and maximum conservative treat-
ment, including endodontic treatment,
should be performed instead.
For both ORN and MRONJ, the rapid
initiation of treatment is of paramount
importance. Bast et al. showed that
ORN, although complex, was still easier
to treat than MRONJ. After long-term
antibiotherapy and in some cases surgical
procedures, more than 80% of the patients
suffering from ORN recovered fully,
while only 50% of the patients in the
MRONJ population made a full recover-
y.44 In the patient population included in
the present study, a significant difference
was found with regard to the choice of
treatment. While in the MRONJ popula-
tion all patients were treated conservative-
ly (61.3%) or with sequestrectomy
(38.7%), a major part of the ORN popula-
tion (37.7%) needed broad resection and
major reconstructive surgery with a free
fibula flap. This higher percentage may be
explained by the frequent occurrence of
severe complications with ORN, such
as pathological fractures and extraoral
fistulae.
The conventional treatment of ORN in
the early stages of the disease consists of
conservative measures such as anti-
biotherapy, debridement, and irrigation,
while surgical resection and reconstruc-
tion are reserved for more advanced cases.
Until recently, tissue hypoxia, hypovascu-
larity, and hypocellularity were postulated
as the primary causes for the development
of ORN. Marx suggested the following
pathophysiological sequence: (1) irradia-
tion, (2) formation of hypoxic–hypocellu-
lar–hypovascular tissue, (3) tissue
breakdown (collagen lysis and cellular
death), causing (4) a chronic non-healing
wound in which metabolic demands

exceed supply.7 This led to the use of HBO
for the treatment and prevention of com-
plications associated with radiotherapy in
the head and neck. However, as yet, HBO
as an adjunctive therapy to conventional
treatment has not been proven to yield
significantly favourable results compared
to conventional treatment alone. Recently,
the ‘fibro-atrophic theory’ has emerged,
which offers an alternative explanation
for the onset of the tissue damage that
occurs after radiotherapy. The fibro-atro-
phic theory suggests that the activation and
dysregulation of fibroblastic activity leads
to atrophic tissue within a previously irra-
diated area, resulting in ORN.36 This new
theory has prompted the development of
new therapeutic regimens composed of
pentoxifylline and tocopherol (vitamin
E).45,46 Pentoxifylline exerts an anti-tu-
mour necrosis factor alpha (TNF-a) effect,
increases erythrocyte flexibility, vasodi-
lates, inhibits inflammatory reactions in
vivo, inhibits human dermal fibroblast pro-
liferation and extracellular matrix (ECM)
production, and increases collagenase ac-
tivity in vitro.45 Tocopherol is a scavenger
of reactive oxygen species. Pentoxifylline
and tocopherol combined have been shown
to have a synergistic effect on the regres-
sion of ORN.47 Pentoxifylline and vitamin
E have been used to great effect in treating
small areas of ORN, with visual and symp-
tomatic resolution of the condition.14,15,27
Larger areas might be stabilized, but they
will not resolve with this treatment.27 Clo-
nodrate, a first-generation non-aminobi-
sphosphonate, has been described as
effective when combined with pentoxifyl-
line and tocopherol for refractory ORN.48
In the case of MRONJ, the entire jaw
bone has been exposed to bisphosphonates
and their effects. Due to the systemic
nature of the condition, the treatment of
patients with established MRONJ is gen-
erally more difficult than the treatment of
patients with established ORN. As a result,
patients with MRONJ usually do not re-
spond well to surgical interventions and
therefore these should be postponed when-
ever possible. In the unusual case an ex-
tended surgical resection is necessary,
both the clinician and the patient must
be aware of the potential for failure of
the reconstruction Plate.2 The various
clinical stages and stage-specific treatment
strategies for MRONJ that are suggested
by the AAOMS are outlined in Table 5.
A promising and relatively novel mode
of treatment that is used in the study
institution in Leuven, Belgium, is the
use of autologous platelet concentrates
for the treatment and prevention of
MRONJ. In a systematic review of the
Similarities and differences of ORN and MRONJ
literature, Del Fabbro et al. concluded that
the adjunctive use of autologous platelet
concentrates in MRONJ significantly re-
duced the recurrence of osteonecrosis with
respect to control.49 However, due to the
limited sample size, prospective compar-
ative studies with a larger sample size are
needed to confirm these findings.
Although treatment with HBO for
osteonecrosis has long been associated
solely with the treatment of ORN, recent
studies have suggested the possibility of
using HBO in the treatment of MRONJ.
However, a randomized controlled trial of
HBO as an adjunct to surgery and anti-
biotics showed no statistically significant
difference between the control group and
the HBO-treated group with regard to time
to complete gingival coverage.42 Other
reported non-surgical treatment modali-
ties in MRONJ include low-level laser
therapy, parathyroid hormone (teripara-
tide), and bone morphogenetic protein,
but more research and controlled trials
are needed to establish the efficacy of
these treatment strategies.50–55
In conclusion, both MRONJ and ORN
are significant complications. Although
the incidence of ORN is declining as
radiation therapy techniques improve
and since dental workup and optimized
oral hygiene has become routine before
radiation treatment is started, the inci-
dence of MRONJ is increasing due to
the increased use of bisphosphonates
and other anti-resorptive medications.
There is no conclusive agreement as to
the underlying pathophysiology of ORN
or MRONJ. These two distinct pathophys-
iological entities share some similarities,
but differ in patient population character-
istics, clinical course, and treatment. Pa-
tient history and clinical examination
remain the most sensitive diagnostic tools,
although imaging has certainly proven its
worth in the follow-up of patients and in
evaluating extensive pathology. While the
AAOMS classification of MRONJ is
adopted widely, there is still no consensus
on the classification of ORN lesions.
Prevention is key for both ORN and
MRONJ, but there are some important
differences regarding their treatment. In
advanced or refractory cases, surgical
treatment, including microvascular recon-
struction techniques for bone and soft tis-
sue, remains the only available option. The
management of ORN and MRONJ remains
a major challenge for the dental and oro-
maxillofacial professional community.
Funding
No funding.
1597
Competing interests
No conflicts of interest.
Ethical approval
Ethical approval was obtained from the
Ethic Committee of UZ Leuven (number
S58693).
Patient consent
Not applicable.
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Address:
Koenraad Grisar
Department of Oral and Maxillofacial
Surgery
University Hospitals Leuven
Kapucijnenvoer 33
3000 Leuven
Belgium
Tel: +32 499384684
E-mail: koenraadgrisar@gmail.com