OralSurgery Enhanced CPD DO C

Vinod Patel

Michael Fenlon, Lucy Di Silvio and Mark McGurk

Osteoradionecrosis in the Current

Era of Radiation Treatment
Abstract: Osteoradionecrosis (ORN) is a late complication of radiotherapy treatment for head and neck cancer. In the past two decades
there have been significant changes in the mode by which radiation is delivered and it was assumed this would lead to a reduction, or even
elimination, of this complication. Paradoxically, ORN rates may have risen. This article provides a summary of the current understanding and
approach to ORN.
CPD/Clinical Relevance: Those who have had radiotherapy carry a life-long risk of developing osteoradionecrosis, and it is important that
the dental team are aware of this.
Dent Update 2022; 49: 64–67

Osteoradionecrosis (ORN) was first definition exists. In the UK, the most to occur via the 3H theory (hypoxia,
reported almost a century ago.1 To commonly accepted ORN description is ‘an hypocellularity and hypovascularity)
date, numerous approaches have been area of exposed bone present for longer proposed by Marx.4 This theory suggested
taken to prevent it from occurring or to than 2 months in a previously irradiated the depletion of oxygen, cellular content
treat it once established. This includes field, in the absence of recurrent tumour’ of the bone and vascular supply all
improvements in radiotherapy (RT) (Figure 1).2 The definition is incomplete combined over time to produce non-vital
delivery, pre-treatment dental assessment in that it ignores both maxillary ORN and patches of bone as a result of the inability
and continuing dental care. However, non-exposed ORN. A commonly used and to metabolize and repair the osseous
ORN continues to occur, in part due simple classification is one proposed by structure. More recently, this explanation
to a change in the profile of head and Notani et al3 (Table 1 and Figure 2). has been superseded by a newer theory
neck cancer (HNC) patients. This article termed ‘radiation-induced fibrosis’ (RIF).
Here, tissues that have received radiation
highlights some of the key changes Pathophysiology
occurring in the modern era that impact essentially develop fibrous scar-like
Understanding the pathophysiology of a tissue. This extends to the blood vessels
on the development of ORN.
disease is the key to developing effective walls and inevitably the lumen becomes
treatment strategies. Unfortunately, narrower. This process progresses over
Definition there is still debate about the processes time and leads to a reducing blood
Although ORN is a well-recognized underlying the development of ORN. In supply to the tissues, leading eventually
condition, no international agreed the UK, until recently, ORN was thought to atrophy and tissue necrosis. At present,
the latter explanation has primacy as
Vinod Patel, BDS (Hons), MOralSurg RCS Eng, FDSRCS, PhD, Consultant (Oral Surgery), drug medication to reduce fibrosis has a
Oral Surgery Department, Guy’s Dental Hospital, London. Michael Fenlon, MA, PhD, positive impact on ORN.
BDentSc, FDS, Professor of Prosthodontics/Honorary Consultant (Restorative Dentistry),
Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London. Lucy Di Risk factors
Silvio, PhD, Professor of Tissue Engineering. Centre for Clinical, Oral and Translational Several factors have been found to
Science, King’s College London. Mark McGurk, MD, FRCS, DLO, FDS, RCS, Professor/ increase the risk for developing ORN.5
Consultant (Oral and Maxillofacial Surgeon), Head and Neck Centre, Division of Surgical These risk factors can be divided into three
Interventional Sciences, University College London. broad categories, namely radiation, dental
email: vinod.patel@hotmail.co.uk and patient factors.
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Grade I ORN confined to the alveolar bone

Grade II ORN limited to the alveolar bone and/or the mandible above the level of
the mandibular alveolar canal
Grade III ORN that extends to the mandible under the level of the mandibular
alveolar canal, and ORN with a skin fistula and/or a pathological fracture
Table 1. The Notani classification for ORN.3

Figure 1. Intra-oral view of the edentulous

mandible with an area of exposed bone (ORN) in
the lower right posterior region on the crest. The
soft tissue margins are pink and non-inflamed
suggesting the ORN is currently stable and
non-infected.

Radiotherapy factors
Intensity modulated radiation treatment
(IMRT) is a novel delivery system ideally
suited to HNC owing to its ability to target
tumours, considering the complex anatomy
of this region. RT beams are divided into
many small beamlets with varying intensity.
These are spun around the patient with
careful precision so that interacting beams
deposit the energy at high density only at
the tumour site. The surrounding tissues
are also irradiated, but to a lesser degree.
Owing to its precision, it was anticipated
that the introduction of IMRT would lead
to a reduction, or even an elimination
of serious RT-induced complications.
Unfortunately, this has not been the case
because it is apparent that the multi-beam
IMRT actually incorporates more of the jaws
than traditional techniques.6
The dose of radiation received by the
bone is also important. There is no absolute
threshold dose after which ORN will
develop. However, it is generally accepted
the risk commences above 40 Gray (Gy).7
Established areas of ORN have consistently
received >50Gy8–11 even using the new
radiation delivery systems.
What has changed in the past two
decades is the realization that combining
chemotherapy with radiation provides
a substantial increase in survival,13 but it
comes at the cost of an increased risk of
complications in general, including ORN.5,12
This combination is used in advanced
disease, and extensively in oropharyngeal
January 2022
Figure 2. Dental panoramic tomograph showing bilateral mandibular ORN in the edentulous molar
region. The lower right side is limited to the dento-alveolar segment (Notani I) (red arrow), while the
left side shows a pathological fracture (Notani III) (blue arrow) and extension of ORN into the body of
the mandible (green arrows).
cancer (OPC). This may be one of the
reasons why those in this tumour group
have seen a rise in ORN. The relevance of
this association is that OPC is numerically
the fastest growing cancer in head and neck
specifically due to human papilloma virus
(HPV) and is projected to be responsible for
35–50% of head and neck cancers within
the next decade.13,14
Dental factors
The dentition in irradiated HNC patients
is considered the main risk factor for
developing ORN as teeth are a natural
portal for oral bacteria to access the
underlying bone. Historically, HNC
patients have been stereotyped as
having detrimental lifestyle habits, such
as excess smoking and alcohol drinking,
together with irregular dental attendance
and a neglected dentition. The situation
is compounded after RT by an oral
environment parched by xerostomia,
with limited access due to trismus and,
because of difficulty in swallowing, to eat
frequently (as often as 4 hourly) using
high calorific liquid food supplements. The
combination fosters dental decay, notably
root decay, commonly termed radiation
caries. This perfect storm of events has
led to the mandatory requirement for all
HNC patients to have a dental assessment
prior to radiation treatment.15–17 However,
there is no agreement on what constitutes
‘dental fitness’. The pre-treatment screening
has reduced the risk of ORN, but it has not
eliminated it. As mentioned previously, the
rise of HPV-related OPC has provided a new
clinical challenge. These patients do not
have the typical lifestyle factors associated
with oral cancer, nor have the typical
dental status.18,19 They are an upwardly
mobile and younger population with a
much better dentition and can afford
complex dental restorations.18,19
In the era preceding IMRT, a systematic
review suggested the incidence of ORN after
tooth extraction in irradiated patients to be
7%.20 By taking prophylactic antibiotics or
hyperbaric oxygen therapy (HBOT) there
was a suggestion that ORN rates fell to
4–6%.20 This has been eclipsed by a recent
prospective randomized trial that showed
no advantage for HBOT or antibiotics.21 In
contrast, results from drugs that reduce
fibrosis (pentoxifylline and tocopherol)
point towards an ORN rate of only 1.2% or
0.26% per dental extraction.22
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Patient factors
Some HNC sub-sites that are in close
proximity to the mandible are inevitably
associated with ORN .This applies to the
oral cavity and the oropharynx,9 whereas
for nasopharyngeal or sinonasal cancers,
the beam of radiation falls on the maxilla.23
Unfortunately, the risk of ORN is not limited
to these two sites, as occasionally, unusual
areas fall victim to this disease. A recent
mini-case series reported ORN in the hyoid
and temporal bones, even with the use
of IMRT.24
A substantial change that has
become evident has been the dynamic
shift towards the increased number of
young male patients with HPV-associated
OPC. In addition, ORN tends to affect
the male population by a factor of 3:1,25
and at a relatively early age of 55 ± 10.1
years.26 Once again, these factors may
be influencing the skewed trend seen
regarding ORN and OPC. Another risk factor
is smoking.27 Patients who continued to
smoke during radiation treatment had a
32% increased risk of developing ORN.28
The association of alcohol to ORN is a little
more indistinct, but excessive consumption
may increase risk by 3.22 times.9
ORN management
The morbidity associated with ORN can
be significant, and there appears to be
an international consensus regarding
prevention and good practice.15 In
contrast, agreement on the management
of established ORN remains as fractious
as the pathogenesis of the disease, and
remains undecided. To date, no treatment
regimens have been able to guarantee
a cure, although each has claimed
continual success in the absence of
incisive large patient cohort prospective
randomized studies.
Antibiotics
Antibiotics are commonly used, but on their
own are not deemed to be an option for
cure. The disease progresses unrelentingly.
No one antibiotic carries advantage. The
empirical protocol that has been adopted
involves a broad-spectrum antimicrobial
in the acute phase, switching to low-dose
long-term antibiotic in the tetracycline
group to tackle chronic infection.
66 DentalUpdate
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Hyperbaric oxygen therapy
Mainous et al proposed the use of HBOT,29
but it was Marx’s endorsement that led
to its routine use in the 1980 to date.4 In
isolation, the results are poor, and the
recommendation is to use it as an adjunct
to surgery. The objective is to prime and
optimize the compromised surgical site
for healing. The principle of its use is to
oxygenate the hypoxic tissue by placing
the patient in a high oxygen pressure
chamber prior to the operation. Each visit,
often referred to as a ‘dive’, can last up to
90 minutes. In preparation for surgery, a
patient would be expected to undergo
30 consecutive daily dives, followed by a
further 10 after surgery. Understandably
this is impractical for the majority of
patients as HBOT facilities are few, and
patients have to relocate for periods of
treatment. HBOT has fallen out of favour in
the UK, although it is still used in the USA.
The lack of effect in a recent prospective
randomized trial seems to have invalidated
it use.21
Surgery
Surgery is still a viable management
option in the right circumstances and
varies from minimal procedures, such
as sequestrectomy, saucerization and
debridement to jaw resection and repair
with microvascular flaps. Successful
major reconstructive procedures open
the possibility for comprehensive dental
rehabilitation that may involve dental
implants, but is seldom achieved. The route
is strewn with complications that may
compromise the expected treatment plan.
Pentoxifylline–tocopherol–
clodronate
The RIF theory of ORN has allowed for a
novel pharmacological solution to ORN.30
A combination of three medications;
pentoxifylline, tocopherol (vitamin E) and
clodronate have shown promising results
in managing ORN.31–33 When all three
are used in conjunction, they are often
referred to as PENTOCLO (PENtoxifylline,
TOcopherol, CLOdronate).
Pentoxifylline was originally licensed
for treatment of peripheral vascular
disease. Consequently, the aims are to
encourage improved blood flow at the
irradiated site. The addition of clodronate,
a bisphosphonate, seems nonsensical
considering this group of drugs have been
implicated in osteonecrosis of the jaw.
However, when combined with PENTO, it
improves efficacy, leading to exfoliation
of sequestrum and new bone formation.31
Evidence continues to grow regarding the
value of this approach. A recent systematic
review concluded that the combination
of PENTO with or without clodronate is
effective for the treatment of mandibular
ORN.34 This drug combination is not a
panacea for ORN, and cases of gross ORN
remain a problem. Currently, most early
(Notani I) and moderate (Notani II) cases
of ORN will heal with this regimen. Notani
III cases are much more challenging, but
can respond to this regimen, but over a
protracted period of time (>12months).31,35
Treatment via PENTOCLO needs very
careful and individual management. Simply
prescribing the drugs will not produce a
satisfactory outcome. Treatment has to
be tailored to the individual and there are
limitations. Pentoxifylline is only available
in tablet form and some patients are tube
fed (nasogatric or percutaneous endoscopic
gastrotomy). Crushing the tablet can
increase side effects, such as gastric
irritation, and although a liquid preparation
has been developed, its efficacy in this
formulation is yet to be validated.36
The success of PENTO37 has led to its use
being extended to a prophylactic role when
extracting teeth for previously irradiated
patients. The results are promising.22 A trial
is in preparation to test whether the drug
combination taken prophylactically at the
time of RT will help avoid ORN, trismus
and dysphagia.
Miscellaneous treatments
Numerous other management strategies
have been employed such as piezosurgery
to debride limited areas of necrotic bone,38
platelet rich plasma,39 ultrasound therapy40
and laser treatment.41 They have not been
incorporated into routine or regular use for
the management of ORN.
Future challenges in ORN
The dental profession needs to appreciate
that, hidden in their patient group, there
will be an increasing number of patients
who have been successfully treated for
January 2022
11/01/2022 09:40

HNC and, in particular, OPC. This group
have a good prospect of long-term survival.
They are usually treated exclusively by RT
or chemo-RT and their precarious dental
situation may not be immediately apparent
to the dentist. The pool of ‘at risk’ patients is
slowly building in the community. The time
will take its natural toll on the dentition,
inevitably accentuated by the effects of the
radiation. This population will seek access
to complex dental restorations, including
crowns, bridgework and dental implants. It
is unclear where the line should be drawn
as to what is safe in terms of inducing late
complications of RT. It may be prudent,
for the general dental practitioner when
treatment planning these cases to look two
decades in advance to prevent complex
problems evolving. Mass extractions prior
to RT is not the solution and personal
experience shows it is deeply resented42
by the patient and impacts on their quality
of life.43 A concerted effort is required by
both patient and dentist to maintain the
dentition. The burden of responsibility
will inevitably fall upon the primary care
practitioner who will be expected to
meet the patient’s routine dental needs.
It is this care that will help avoid ORN. It is
recognized that there is limited information,
training, support and funding provided to
the primary care practitioner to fulfil the
needs of these patients and this requires
addressing by the administrative arm of the
dental fraternity.
Compliance with Ethical Standards
Conflict of Interest: The authors declare that
they have no conflict of interest.
Informed Consent: Informed consent was
obtained from all individual participants
included in the article.
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