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British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Review
Osteoradionecrosis of the jaws: current understanding
of its pathophysiology and treatment
Andrew Lyons a,∗ , Naseem Ghazali b
aDepartment of Oral & Maxillofacial Surgery, 23rd Floor Guy’s Tower, London SE1 9RT, United Kingdom
bMaxillofacial Unit, Guy’s, King’s & St Thomas Schools of Medicine and Dentistry,
King’s College Hospital, Denmark Hill, United Kingdom

Accepted 12 April 2008

Available online 17 June 2008

Abstract

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent
implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of
hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has
not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells
in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors.
New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to
reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It
has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.
© 2008 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Osteoradionecrosis; Radiation; Mandible; Pathophysiology; Radiation-induced fibrosis; Pentoxiphylline

Introduction ORN is recognised, it is irreversible and extremely difficult

In 1922, Regaud published what was arguably the first
report about osteoradionecrosis (ORN) of the jaws after
radiotherapy.1 During the past 80 years, this condition has
persisted as a consequence of radiotherapy for head and
neck cancer in an appreciable minority of patients. Since
then several theories have been propounded to explain its
cause including the release of histamine, the theory of radi-
ation, trauma, and infection2 and, until recently, the most
widely accepted theory of hypoxia, hypovascularity, and
hypocellularity.3 There is a general consensus, however,
about the clinical presentations of ORN, which are pain,
drainage, and fistulation of the mucosa or skin that is related
to exposed bone in an area that has been irradiated. Once
∗ Corresponding author.
to treat. We explore recommendations and current theories
about its aetiology, pathogenesis, and treatment.
Background
Terminology and definition
Various terms and definitions of ORN are given in
Tables 1 and 2. Perhaps the most widely used definition
of ORN that affects the jaws is based on clinical presen-
tation and observation: irradiated bone becomes devitalised
and exposed through the overlying skin or mucosa without
healing for 3 months, without recurrence of tumour.4
Although widely used, this definition is far from perfect,
and can be criticised for two reasons; the duration of the

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654 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Table 1 inconsistencies in the length of follow-up between studies,

Terms used to describe osteoradionecrosis and limited data from prospective studies.
Radiation osteitis 4
ORN affects the mandible more often than the maxilla
Radio-osteonecrosis 5
2
or any other bones of the head and neck.12 Its incidence in
Radiation osteomyelitis
Osteomyelitis of irradiated bone 6 the mandible is between 2% and 22% of cases, and it most
Osteonecrosis 7 often affects the body.10 It is rare after radiation of less than
Radio-osteomyelitis 8 60 Gy, but more common when brachytherapy is used (the
Septic osteoradionecrosis 9
mandible must be in the area of treatment to be at risk).12
Post-radiotherapy osteonecrosis 10
However, the incidence of ORN is thought to be less common
after hyperfractionated radiotherapy at 72–80 Gy, or moder-
bone’s exposure to radiation, and the definition of “devi- ately accelerated fractionated radiotherapy together with a
talised” bone.5 Some studies have not commented on the boost of 64–72 Gy. Recent reports have suggested that when
length of exposure, while others have suggested a period chemotherapy is added to radiotherapy the incidence of ORN
of up to 6 months.4,6–9 With a short period of observa- may be increased13,14 whereas the use of intensity-modulated
tion, simple radionecrosis of the mucosa with no underlying radiotherapy may reduce it.15
necrotic bone can be mistaken for ORN. The observation Factors that are thought to affect the development of ORN
period should also take into account the time taken for include size and site of the tumour, dose of radiation and
complete healing after any operation or extraction, which type of mandibular resection, injury, or dental extractions:
can take up to four weeks. Conversely, a period of passive infection; immune deficiencies; and malnutrition. Many
observation of less than 6 months is difficult to justify in patients with oral cancer have other serious diseases and have
clinical practice because some earlier intervention is often often had a long history of alcohol and tobacco misuse.16
necessary.5 These, combined with poor nutrition and unsatisfactory oral
Regaud noted the absence of a clear line of demarcation hygiene, place such patients at high risk of developing
between devitalised and vital bone.1 Attempts to clarify this ORN.
ambiguity have led to calls for ORN to be defined by radio- Dental disease and dentoalveolar surgery, in particular
logical evidence of bony necrosis within the radiation field,10 dental extractions after radiotherapy, are well-established
or through histological examination of necrotic bone at the predisposing factors to ORN; the documented incidence of
time of eventual resection.11 ORN after extractions is about 5%. Its incidence is three times
higher in dentate than in edentulous patients, mainly as a
result of injury from extractions and infection from periodon-
Epidemiology and risk factors for the development of
tal disease.17–20 The risk of developing ORN after extractions
osteoradionecrosis
is higher in posterior mandibular teeth with roots that lie
below the mylohyoid line, and when an atraumatic extraction
Analysis of epidemiological studies of ORN does not provide
was not possible.21
accurate data about incidence and prevalence of ORN in the
jaws because of the lack of agreement about its definition,
Clinical range of osteoradionecrosis and its staging
Table 2
Definitions of osteoradionecrosis Early ORN may be asymptomatic even though the its
main features of exposed devitalised bone through ulcer-
First author Reference No Definition
6
ated mucosa or skin can be seen clearly. Pain is a common
Beumer “When bone in the radiation field was
symptom and some patients have presented with intractable
exposed for at least 2 months in the
absence of local neoplastic disease” pain. Other associated symptoms include dysaesthesia, hal-
Marx 8 “An area greater than 1 cm of itosis, dysgeusia, and food impaction in the area of exposed
exposed bone in a field of irradiation sequestra.22,23 In severe cases, patients can present with fis-
that had failed to show any evidence tulation from the oral mucosa or skin, complete devitalisation
of healing for at least 6 months”
9 of bone, and pathological fractures.
Hutchinson “An area of exposed bone (mandible)
present for longer than 2 months in a The interval between radiotherapy and the onset of ORN
previously irradiated field, in the can vary, but most occur between 4 months and 2 years.
absence of recurrent tumour” ORN usually develops during the first 6 to 12 months after
Epstein 7 “an ulceration of the mucous radiotherapy, however, the risk remains for life, albeit to a
membrane with exposure of necrotic
lesser degree.24 It may present much earlier after a local
bone”
Harris 4 “Irradiated bone becomes devitalised traumatic event. Epstein et al. reported that ORN usually
and exposed through the overlying presented about 4.5 months after radiotherapy in cases asso-
skin or mucosa, persisting without ciated with dental or surgical injury,23 but in most it may
healing for 3 months in the absence present after follow-up of the incidence studies. Berger and
of tumour recurrence”
Symington reported two late presentations, one 45 years after
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660
a radium implant, and the other 38 years after external beam
treatment.25
Over the years, many staging systems have been pro-
posed to aid treatment and provide classifications for
research.8,10,12,23,26 The classifications were based on vari-
ous criteria, including the presence of: soft tissue dehiscence
necrotic bone, the amount of necrotic bone oro-cutaneous fis-
tulae and pathological fracture. The Wilford Hall hyperbaric
oxygen ORN protocol proposed by Marx stages ORN in its
response to his HBO treatment protocols.8 The late effects
on normal tissue (LENT) and subjective, objective, manage-
ment and analytic (SOMA) scales proposed by the Radiation
Therapy Oncology Group are scoring systems to stage the
late complications of radiation, and may also be used to stage
ORN.27
Theories of the pathophysiology of
osteoradionecrosis: a critical appraisal
Watson and Scarborough reported three crucial factors in
the development of ORN based purely on clinical observa-
tions; exposure to radiotherapy above a critical dose; local
injury; and infection.28 Early experimental models of the
pathophysiology of ORN showed evidence of bacteria in tis-
sues affected by ORN, and documented microscopic tissue
changes, namely thickening of arterial and arteriolar walls,
loss of osteocytes and osteoblasts, and the filling of bony
cavities with inflammatory cells.29
This gained popularity when Meyer proposed his radia-
tion, trauma and infection theory.2 He suggested that injury
provided the opening for invasion of oral microbiologi-
cal flora into the underlying irradiated bone. Other authors
agreed and referred to ORN as secondary infection after
injury to devitalised bone, and even as radiation-induced
osteomyelitis.30 Meyer’s theory lasted for a decade and
became the foundation for the popular use of antibiotics with
surgery to treat ORN.
After an in-depth study of Meyer’s hypothesis, Marx pro-
posed the hypoxic-hypocellular-hypovascular theory as a
new way of understanding the pathophysiology of ORN.3
He noted that there was no injury before the onset of ORN in
35% of his cases, and found that the microbiological profile
of ORN was different from that of osteomyelitis. Micro-
biological investigation of bone affected by ORN showed
various microbes on its surface, which were possibly contam-
inants. This contrasted sharply with cultures of long bones
with osteomyelitis and infected bone grafts, which consisted
primarily of one pathogen, usually a staphylococcal species.
He also found that composite irradiated tissues were more
hypoxic than those that had not been irradiated.
Marx concluded that: “ORN is not a primary infection
of irradiated bone, but a complex metabolic and homeo-
static deficiency of tissue that is created by radiation-induced
cellular injury; micro-organisms play only a contaminating
role in ORN; and trauma may or may not be an initiat-
655
ing factor”.5 The pathophysiological sequence suggested
by Marx is: irradiation; formation of hypoxic-hypocellular-
hypovascular tissue; and breakdown of tissue (cellular death
and breakdown of collagen that exceeds cellular replica-
tion and synthesis) driven by persistent hypoxia that can
cause a chronic non-healing wound (a wound in which
metabolic demands exceed supply)5 (Fig. 1). These explana-
tions formed the cornerstone for the use of hyperbaric oxygen
(HBO) in the treatment of ORN.
The therapeutic value of HBO was originally observed
in controlled in vivo experiments on burns in which daily
increases in the oxygen tensions in hypoxic tissues were
found to encourage capillary angiogenesis, proliferation of
fibroblasts, and synthesis of collagen.27 Furthermore,HBO
can also be bactericidal or bacteriostatic to many pathogens.31
Mainous et al. were probably the first to suggest the use of
HBO for the management of ORN.32 Since then it has been
advocated for preoperative and postoperative treatment in
high-risk patients having teeth extracted or other operations.
HBO has been used with conservative measures to pre-
vent the onset of ORN.33,34 Marx et al. compared HBO with
penicillin alone in a randomised trial to prevent the onset of
ORN after dental extraction. The HBO group had a lower
incidence of ORN than the penicillin alone group.33 How-
ever, subsequent studies24,35,36 showed an incidence of ORN
of less than 5% after careful radiotherapy after dental extrac-
tion without HBO. These are valid arguments for the use of
HBO to prevent ORN.
The results of HBO in treating established ORN are not
convincing. In Marx’s HBO protocol study, only 15% of
(60) patients responded to HBO alone; most had operations
if they did not respond to HBO, 14% had sequestrectomy,
and 70% major reconstruction.8 These results suggested that
HBO without aggressive surgical management was inade-
quate, and this was noted in subsequent studies of HBO in
ORN.23,37–40
For advanced presentations of ORN including patholog-
ical fracture, fistula, and complete devitalisation of bone,
segmental mandibular resection with free vascularised bone
grafting has become standard treatment as it is increasingly
clear that HBO alone is not beneficial.21 Maier et al. showed
that patients with advanced ORN who had debridement and
were given antibiotics were just as likely to recover as those
who were also given HBO.41 Taking this a step further, Gal
et al. showed that patients who had resection and reconstruc-
tion with a free osteocutaneous flap but without the use of
perioperative HBO had fewer complications that those who
had HBO.42
The widespread use of HBO for the treatment of mandibu-
lar ORN may be considered largely theoretical or anecdotal
because of the paucity of controlled trials and the lack of
any unified assessment of the improvement of symptoms.
Recently, a random, placebo-controlled, double-blind study
was conducted in France to assess the efficacy and safety
of HBO for the treatment of overt mandibular ORN.43 All
patients had at least one clinical and one radiological sign of
656 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660
Fig. 1. Pathophysiology of osteoradionecrosis according to Marx.
ORN, but those with fracture or bony erosion of the inferior
border were excluded. Sixty-eight patients were randomly
allocated to the HBO and placebo groups, but the trial was
terminated prematurely because it failed to show any ben-
efits of HBO over placebo in recovery (19% against 33%,
respectively); neither did it slow the progression of disease,
or relieve pain. The authors concluded that better recovery
rates seen in patients given a placebo were likely to be a
result of improvements in conservative treatments. However,
in this trial HBO was the only treatment and not an adjunct
to surgery as is more commonly utilized.
In a Cochrane Collaboration review of the use of HBO
in late radiation injury of tissue,44 no other unpublished ran-
dom trial into the treatment of ORN with HBO was found
apart from one further trial by Marx,45 which reported that
HBO improves bony healing and maintains bony volume after
non-vascularised reconstruction of hemimandibular defects
in irradiated areas. However, this is in a chapter in a text-
book, and the authors of the Cochrane review comment that
the description of the trial is sketchy.
The lack of significant results obtained with HBO in
tissues affected by ORN may be attributed to the flawed
conclusion that the late presentation and irreversible nature
of ORN is related to tissue hypoxia, particularly in areas
of necrotic hypovascular tissues. Beehner and Marx found
higher levels of oxygen tension in tissues affected by ORN
based on transcutaneous partial oxygen pressure (TcPO2 )
after treatment with HBO, which suggested that these tissues
were hypoxic before they were treated. However, Rudolph et
al. found comparable TcPO2 in irradiated and non-irradiated
skin,46 so the importance of actual tissue hypoxia in tissues
affected by ORN has not been proved, and is a real challenge
to Marx’s theory.
Contemporary understanding of the pathophysiology
of osteoradionecrosis: radiation-induced
fibroatrophic theory
Radiation-induced fibrosis is a new theory that accounts
for the damage to normal tissues, including bone, after
radiotherapy.47 It was introduced in 2004 when recent
advances in cellular and molecular biology explained the
progression of microscopically observed ORN.
The histopathological phases of the development of
ORN closely reflect those seen in chronic healing of trau-
matic wounds.48 Three distinct phases are seen: the initial
prefibrotic phase in which changes in endothelial cells pre-
dominate,together with the acute inflammatory response; the
constitutive organised phase in which abnormal fibroblas-
tic activity predominates, and there is disorganisation of the
extracellular matrix; and the late fibroatrophic phase, when
attempted tissue remodelling occurs with the formation of
fragile healed tissues that carry a serious inherent risk of late
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660
reactivated inflammation in the event of localinjury. Inter-
estingly, Marx had reached similar conclusions, but thought
that the driving force of the sequence of events was persistent
tissue hypoxia.
The theory of radiation-induced fibrosis suggests that
the key event in the progression of ORN is the activa-
tion and dysregulation of fibroblastic activity that leads to
atrophic tissue within a previously irradiated area. After
radiotherapy the endothelial cells are injured, both from direct
damage by radiation and from indirect damage by radiation-
generated reactive oxygen species or free radicals. Injured
endothelial cells produce chemotactic cytokines that trigger
an acute inflammatory response and then generate a further
release of reactive oxygen species from polymorphs and other
phagocytes.49 The destruction of endothelial cells, coupled
with vascular thrombosis, lead to necrosis of microvessels,
local ischaemia, and tissue loss. Loss of the natural endothe-
lial cell barrier allows seepage of various cytokines that cause
fibroblasts to become myofibroblasts.
The reactive oxygen species-mediated release of cytokines
such as tumour necrosis factor ␣ (TNF-␣), platelet-derived
growth factor, fibroblast growth factor ␤, interleukins 1,
4, and 6, transforming growth factor ␤1 (TGF-␤1), and
connective tissue growth factor, result in unregulated fibrob-
lastic activation and the myofibroblast phenotype persists.49
These myofibroblasts are characterised by unusually high
rates of proliferation, secretion of abnormal products of the
extracellular matrix, and a reduced ability to degrade such
components. Deregulation of the proliferation of fibroblasts
and metabolism are similar to those described in fibrosis of
the lungs and cirrhosis of the liver after attacks by viruses,
alcohol, and silica.50
The mandible is thought to be predisposed to the devel-
opment of ORN. This is principally the result of fibrosis
that causes the obliteration of the inferior alveolar artery
together with the failure of the facial artery to jointly form
a supply. The imbalance between synthesis and degrada-
tion in irradiated tissue is particularly dramatic in bone. The
combination of death of osteoblasts after irradiation, failure
of osteoblasts to repopulate, and excessive proliferation of
myofibroblasts, results in a reduction in bony matrix and its
replacement with fibrous tissues. Microradiographic anal-
ysis of bone in ORN suggests four possible mechanisms
of bony destruction: progressive resorption of osteoclasts
mediated by macrophages that are unaccompanied by osteo-
genesis; periosteocytic lysis, pathognomic of ORN; extensive
demineralisation that is secondary to external stimuli such
as saliva and bacterial products; and accelerated aging of
bone.51
Ultimately, the myofibroblasts undergo apoptosis and,
even decades after radiotherapy, the bone remains paucicel-
lular, poorly vascularised, and fibrosed.50 These irradiated
areas that have healed remain fragile, and may be subjected
to surges of late reactivated inflammation after any physic-
ochemical trauma so that they have a tendency to develop
ORN (Fig. 2).
657
To reverse changes in reactive oxygen species that pro-
duce radiation-induced fibrosis and ultimately ORN, new
therapeutic regimens have been developed.52 Pentoxifylline
is a methylxanthine derivative that exerts an anti-TNF␣
effect, increases erythrocyte flexibility, dilates blood vessels,
inhibits inflammatory reactions in vivo, inhibits proliferation
of human dermal fibroblasts and the production of extracel-
lular matrix, and increases collagenase activity in vitro. It
is given with tocopherol (vitamin E), which scavenges the
reactive oxygen species that were generated during oxidative
stress by protecting cell membranes against peroxidation of
lipids, partial inhibition of TGF-␤1, and expression of pro-
collagen genes, so reducing fibrosis. These two drugs act
synergistically as potent antifibrotic agents. In animal studies
neither drug alone was capable of reversing reactive oxygen
species.21
In a recent phase II clinical trial, 18 consecutive patients
who had had radiotherapy for head and neck cancer had
mandibular bone roughly 13.4 mm long exposed.53 Over 7
years all had been given daily pentoxifylline 800 mg com-
bined with vitamin E 1000 IU orally for 6–24 months. The
eight most seriously affected patients were also given clo-
dronate 1600 mg/day 5 days a week. Clodronate is a new
generation bisphosphonate that inhibits bone resorption by
reducing the number and activity of osteoclasts.54 When
an ORN-like disease of mandibular bone has been reported
in patients who had been given this treatment for cancer-
associated hypercalcaemia or metastatic osteolytic lesions,55
but unlike previous bisphosphonates clodronate has been
shown to act directly on osteoblastic cells by increasing for-
mation of bone56 and reducing proliferation of fibroblasts.57
All patients had improved at 6 months. Sixteen of the 18
recovered completely, 14 within 8 months. The remaining
two patients responded but not as well. This was not a
controlled prospectively randomised trial, but its results are
nevertheless dramatic.
New protocols for prevention and treatment of
osteoradionecrosis
Based on current understanding of the pathophysiology of
ORN, new protocols could be developed for its prevention
and treatment. Previously, patients who required multiple
dental extractions or extensive surgical extractions, or both,
might have been given HBO before and after operation.
Instead, all patients having dental extractions could be given
eight weeks of pentoxifylline 400 mg twice daily with toco-
pherol 1000 IU, starting a week before the procedure. If
ORN developed then they could be continued for a further 6
months with clodronate prescribed after 3 months if there has
been no appreciable response. The use of antibiotic prophy-
laxis before extractions, though commonplace, has not been
validated in any study to our knowledge. However, antimi-
crobial propylaxis could be incorporated into this protocol if
desired.
658 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Fig. 2. Radiation-induced Fibroatrophic Theory.

Fig. 3. Protocol for patients who require dental extractions after radiotherapy.
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660
Patients with established ORN follow this regimen for 6
months; those who do not respond after 3 months are given
clodronate. Patients who would be excluded are those with
pathological fractures, or in whom pathological fracture seem
likely such as when free vascularised composite tissue trans-
fer is planned in the short term. Patients who would have
been given HBO before and after curettage or sequestrec-
tomy should be given pentoxifylline and tocopherol. These
treatments are based not on evidence from prospective ran-
dom control trials, but on what seems to be good retrospective
data in reports by Delanian et al.52 (Fig. 3).
The role of infection in ORN is not clear, particularly as
the transition between ORN and osteomyelitis is ambigu-
ous, but recent reports have suggested that bacteria may have
an important role in its pathogenesis.57,58 Although the suc-
cess of the pentoxifylline with tocopherol regimen seems
to be successful, it is appropriate to give a short course of
oral antibiotic for any extractions. Antibiotics should be used
only for established ORN when there is clinical evidence
of infection and frank pus, including discharging sinuses
or collections.43 Free tissue transfer has a role in severe,
extensive, and long-established ORN particularly with a
pathological fracture, but in patients who are deemed unfit for
extensive surgery the pentoxifylline-tocopherol-clodronate
regimen with the use of rigid fixation may be a viable treat-
ment.
Prospective random control trials are essential to define
these new treatments for ORN, but based on evidence of other
reports and trials with HBO there is perhaps no place for the
use of HBO in the treatment or prevention of ORN.
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