J. Maxillofac. Oral Surg.
https://doi.org/10.1007/s12663-021-01680-4
REVIEW PAPER
Advances and Controversies in the Management
of Osteoradionecrosis After Head and Neck Cancer Treatment:
A Narrative Review
Radhu Raj1 • Aarya Haridasan Nair2 • Nitin Anand Krishnan2 •
Deepak Balasubramanian2 • Subramania Iyer2 • Krishnakumar Thankappan2
Received: 17 July 2021 / Accepted: 8 December 2021
Ó The Association of Oral and Maxillofacial Surgeons of India 2022
Abstract Osteoradionecrosis (ORN) is a painful and
debilitating serious late complication following treatment
for head and neck cancer (HNC) often requiring surgical
resection of the jaw and complex multidisciplinary man-
agement. An important aggravating factor for mandibular
ORN is surgical trauma, commonly dental extractions or
implant placement following head and neck radiotherapy.
The evidence on the treatment protocols ranges from
conservative management to more radical surgical strate-
gies including the use of hyperbaric oxygen therapy. The
available evidence on the preventive approaches for ORN
includes prophylactic dental care prior to radiotherapy, the
use of hyperbaric oxygen (HBO) treatment and prophy-
lactic antibiotics for post-radiotherapy extractions. How-
ever, the efficacy of hyperbaric oxygen therapy has been
questioned recently signifying poor understanding of the
pathophysiology of the condition and therapies targeting
the fibroatrophic process have become a focus of ORN
treatment. Implementing recent IMRT radiation techniques
has also shown evidence to reduce the incidence of ORN.
This review provides an insight into the variations in def-
inition and classification of the ORN, the controversies in
its pathophysiology and the advances in the prevention and
management.
& Krishnakumar Thankappan
drkrishnakumart@yahoo.co.in
1 controversial and highly varying from conservative man-
Department of Prosthodontics, Amrita School of Dentistry,
Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
2 antibiotics to radical surgical strategies due to lack in
Department of Head and Neck Surgery and Oncology,
Amrita Institute of Medical Sciences, Amrita Vishwa
Vidyapeetham, Kochi 682041, Kerala, India
Keywords Head and neck cancer
Oral cancer

Radiotherapy
Osteoradionecrosis
Intensity-modulated
radiotherapy
Introduction
Radiotherapy alone or in conjunction with chemotherapy
or as an adjuvant treatment after surgery is often the
treatment for head and neck cancer (HNC) [1]. The acute
side effects of HNC treatment involving radiotherapy are
commonly oral mucositis, dermatitis, salivary changes and
taste alterations, whereas the late toxicities in particular are
osteoradionecrosis, hypo-salivation and xerostomia, tris-
mus, radiation caries [2]. Among them, osteoradionecro-
sis (ORN) is a challenging clinical problem. ORN is most
common in patients treated with over 60 Grays (Gy) of
radiation, patients of advanced age, smokers, those cur-
rently using alcohol, and those with poor nutritional status
[3]. Medical comorbidities such as diabetes mellitus,
hypertension and collagen vascular diseases have also been
found to increase the risk of developing ORN [4]. Dental
patient risk factors include active periodontal disease and
extractions [5]. Evidence regarding the incidence and
prevalence of ORN varies, due to the non-uniformity in its
definition, inconsistencies in the length of follow-up
between studies and the scarce data available from
prospective studies [6]. The incidence of ORN in the
mandible is between 2 and 22% of cases, and it most often
affects the body [7]. The management of ORN has been
agement including prescribing mouthwash, analgesics and
evidence-based standard protocol [8]. The purpose of this
paper is to review the recent evidence regarding ORN and
123

to discuss the controversies in the diagnosis and manage-
ment of the condition.
Definition of ORN
There exists controversies in the literature regarding the
definition of ORN [9]. ORN is described as a necrotic
process of the bone that results from high-dose radiation
therapy that persists for 3 months or longer, slowly pro-
gresses and does not heal spontaneously. Importantly, it
must be unrelated to tumour occurrence [10]. Based on the
above common clinical presentation, ORN can be defined
as occurring when irradiated bone becomes devitalised and
exposed through the overlying skin or mucosa without
healing for 3 months, without recurrence of a tumour’ [11].
However, the timing of the bone exposure, and the defi-
nition of ‘devitalised’ bone varies in the literature con-
tributing to the lack of clarity in defining this post-
radiotherapy complication. Regarding the timing of the
exposed bone after radiation therapy, when few authors do
not rely on the time of exposure of bone as a predictive
factor, others recommend a 2 month period post-RT before
diagnosing ORN or even 3–6 months [11, 12]. ORN usu-
ally develops during the first 6–12 months after radio-
therapy; however, the risk remains for life [13].
Interestingly, the findings of the study by Berger and
Symington et al. reported two late presentations in their
study, one after 45 years of placement of radium implant,
and the other case 38 years after the last exposure to
external beam radiation therapy [14]. Also, with respect to
the role of devitalised bone in defining ORN, clinical
findings confirm the existence of underlying bony changes
although it presents with full mucosal coverage, misleading
the diagnosis clinically [15].
Staging of ORN
Regardless of several staging and classification systems
described in the literature, the first classification introduced
by Marx et al. in [16] is perhaps the most widely applied
and is based on response to treatment with hyper baric
oxygen therapy (HBOT). The mechanisms of action for
HBOT are thought to increase oxygen supply in hypoxic
tissues which in turn stimulates the proliferation of
fibroblasts, angiogenesis and collagen formation. HBOT
can have bactericidal as well as bacteriostatic effects.
Table 1 summarises the different staging systems proposed
and the basis of it.
Pathophysiology of ORN
The pathophysiology of ORN has not been fully under-
stood since its first reported occurrence in the early 1920s.
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J. Maxillofac. Oral Surg.
Watson and Scarborough later reported that the exposure to
radiotherapy above a critical dose; local injury; and
infection as the three crucial factors in the development of
ORN based on their clinical observations in the year 1939.
However, the initial experimental models of ORN to find
out the pathophysiology showed evidence of bacteria in
tissues 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 [17]. Meyer’s theory
published in 1971 proposed the radiation, trauma and
infection theory. His theory suggested that injury led to the
invasion of oral microbiological flora into the underlying
irradiated bone and became the foundation for the popular
use of antibiotics with surgery to treat ORN [18]. The
pathophysiological sequelae of ORN, according to
the hypoxic–hypocellular–hypovascular theory proposed
by Marx in the year 1983, stated the initial formation of
hypoxic hypocellular–hypovascular tissue following irra-
diation results in cellular death and breakdown of collagen
that exceeds cellular replication leading to a chronic non-
healing wound. These explanations of his landmark study
formed the cornerstone for the use of hyperbaric oxygen
(HBO) in the treatment of ORN.
Radiation-Induced Fibro-Atrophic Theory
Delanian et al. in 2004 suggested that ORN may not
actually be the result of hypoxia and hypovascularity, but
rather due to a radiation-induced fibro-atrophic process
secondary to altered bone turnover rate in the jaws. The
pathologic sequence is initiated by injury to the endothelial
cells following radiotherapy, either due to direct damage
by radiation and/or from indirect damage from radiation
generated reactive oxygen species or free radicals produce
chemotactic cytokines such as, tumour necrosis factor a
(TNF-a), platelet-derived growth factor, fibroblast growth
factor b, interleukins 1, 4 and 6, transforming growth factor
b1 (TGF-b1), and connective tissue growth factor. These
TNFs trigger an acute inflammatory response and results in
further release of reactive oxygen species from polymorphs
and other phagocytes. The following events lead to the
destruction of endothelial cells, along with vascular
thrombosis, leading to microvascular necrosis and local
ischaemia. This loss of the natural endothelial cell barrier
allows uninterrupted passage of various cytokines that
cause transformation of fibroblasts to myofibroblasts.
These characteristic myofibroblasts have high rates of
proliferation, secretes abnormal extracellular matrix prod-
ucts and possess a reduced ability to degrade such unusual
cellular components. This imbalance between synthesis
and degradation of fibroblasts in irradiated tissue is obvious
in bone structures too. The combination of destruction of
J. Maxillofac. Oral Surg.

Table 1 Classification systems of Osteoradionecrosis

Author, Year Based on Classification

Marx, 1983 Response to hyperbaric
oxygen therapy (HBOT)
Epstein, 1987 Imaging and clinical findings
(sub-category
A) pathologic fracture
B) no pathologic fracture)
Kagan and Imaging and clinical findings
Schwartz, 2002
Notani, 2003 Imaging and clinical findings
Lyons, 2014 Extent of the condition and its
management
Stage I: exposed alveolar bone without pathological fracture which responds to HBOT
Stage II: disease does not respond to HBOT, and requires sequestrectomy and saucerization
Stage III: pathologic fracture, orocutaneous fistula, radiographic evidence of resorption to
inferior border and requires resection and reconstruction with free tissue
Stage I: resolved or healed orn
Stage II: chronic ([ 3 months), persistent, non-progressive ORN
Stage III: progressive, active ORN
Stage I: superficial involvement of the mandible only
Stage II: localised involvement of the mandible
Stage III: diffuse involvement of the mandible
Stage I: ORN confined to alveolar bone
Stage II: ORN limited to alveolar bone and/or the mandible above level of mandibular
canal
Stage III: ORN extended to mandible under level of mandibular canal with skin fistula or
pathological fracture
Stage I. \ 2.5 cm length of bone affected (damaged or exposed); asymptomatic. Medical
Treatment only
Stage II. [ 2.5 cm length of bone; asymptomatic, including pathological fracture or
involvement of inferior dental nerve or both. Medical treatment only unless there is dental
sepsis or obviously loose, necrotic bone
Stage III. [ 2.5 cm length of bone; symptomatic, but with no other features despite
medical treatment. Consider debridement of loose or necrotic bone, and local pedicled
flap
Stage IV. 2.5 cm length of bone; pathological fracture, involvement of inferior dental
nerve, or orocutaneous fistula, or a combination. Reconstruction with free flap if patient’s
overall condition allows

osteoblasts after irradiation coupled with excessive prolif-
eration of myofibroblasts results in a reduction in bony
matrix and its replacement with fibrous tissues. Micro-ra-
diographic analysis of bone in ORN suggests four possible
mechanisms of bony destruction: progressive resorption of
osteoclasts mediated by macrophages that are unaccom-
panied by osteogenesis; increased rate of periosteocytic
lysis, extensive demineralisation that is secondary to
external stimuli such as salivary secretion and bacterial
products; and accelerated bony ageing. Ultimately, the
myofibroblasts undergo apoptosis. Remarkably, even dec-
ades after radiotherapy, the bone remains paucicellular,
poorly vascularised, and fibrosed. To condense, the theory
of radiation-induced fibrosis proposed the activation and
dysregulation of fibroblastic activity that leads to atrophic
tissue within a previously irradiated area that leads to ORN
[19].
In 2004, Assael et al. proposed that ORN also occurs by
the same mechanism as other types of osteonecrosis (e.g.
bisphosphonate-related osteonecrosis) and results from
decreased osteoclastic bone resorption [20]. It has always
appeared unusual that technetium, gallium and indium
scans nearly showed sharply increased uptake in osteora-
dionecrosis, suggestive of an increased (not decreased)
bone turnover rate, inflammation, and infection. Another
striking clinical finding is the increased subperiosteal bone
deposition resulting in increased thickness of the jaw in the
radiated zone indicating altered remodelling suggestive of
increased bone turnover rate. Also, sequestrum formation is
severely delayed in ORN and only occurs when very dense
surrounding new bone appears to cut off the central core
vascular supply. Therefore, bone grafting of the affected
site with a vascularised free flap, seems to do well when the
soft tissue bed. Hence, in addition to the concept of
hypovascularity, hypocellularity, and hypoxia theory of
Marx et al., the selective suppression of osteoclasts in
radiated bone is also a detrimental event in osteora-
dionecrosis. Radiation dose, portals, voltage, host immune
response, concomitant therapy, cardiovascular disease,
diabetes, atherosclerotic heart disease, cytotoxic drugs,
cancer stage, surgical method, bisphosphonates, nutrition,
endocrine response, or other yet unknown alterations of
bone physiology may all play a part in the development of
osteoradionecrosis.

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Clinical and Radiological Findings of ORN
ORN most often affects the mandible, particularly the
posterior mandible, than maxilla or any other bones of head
and neck region due to its compact and dense nature. It
presents clinically as painful and denuded bone with
purulent drainage and/or possible fistula formation [10, 21].
The majority of cases occur in the first years after treatment
for Head and Neck Cancer, with increasing yearly inci-
dence for several years after treatment [22, 23]. An
Orthopantomogram x-ray (OPG) is the most frequently
used imaging method for the diagnosis of ORN and is
usually supplemented with other extra-oral or intraoral
radiographs. In an OPG, ORN is depicted as an undefined
radiolucency, without sclerotic demarcation, which sur-
rounds necrotic zone. However, radiopaque areas can also
be identified when bone sequestra are formed. To be visible
in an OPT, a substantial alteration in mineral content and
extensive involvement of bone is required and this only
occurs in later stages of ORN [6]. Ardran et al. noted that a
30% loss of bone mineral content is necessary before any
radiographic change can be seen [24]. Computer tomog-
raphy (CT) image shows bony abnormalities, such as focal
lytic areas, cortical interruptions and loss of the spongiosa
trabeculation, resulting in soft tissue thickening on the
symptomatic side, clinically. These changes may be mis-
interpreted as a recurrent tumour [25]. In MRI with
gadolinium administration, an abnormal marrow signal,
cortical destruction and slight-to-mild irregular enhance-
ment are also confirmed [26]. MRI has the advantage of
excellent tissue contrast and high spatial resolution [27].
Treatment modalities of ORN
The management of ORN has been controversial and
highly variable between centres ranging from local
debridement and sequestrectomy may be offered for grade
II ORN, and resection is usually reserved for late-stage
grade III ORN [7].
Efficacy of Hyperbaric Oxygen Therapy (HBOT)
The use of hyperbaric oxygen (HBO) in damaged irradi-
ated tissue improves vascularity and fibroblastic cellular
density, thus limiting the amount of nonviable tissue to be
removed surgically, thereby enhancing wound healing. The
therapeutic value of HBO was observed firstly 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 fibrob-
lasts, and synthesis of collagen [28], whereas the findings
of the recent papers suggest that cellular radiogenic effects
in bone occur earlier than the already known vascular
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J. Maxillofac. Oral Surg.
alterations. This hypothesis challenges the well-accepted
‘‘three-H concept’’ (hypoxia, hypocellularity, hypovascu-
larity) of Marx et al. [29].
In 1983, Marx’s presented the field-defining, Wilford
Hall protocol for HBO in the management of refractory
ORN in a retrospective series of 58 cases. Those retro-
spective cases included in the study had persistent ORN,
and conservative or surgical management, or both, had
failed. The observations of these retrospective series noted
the clinical success as being pain free, having mandibular
continuity, mucosal healing, and the ability to wear dental
prostheses and function normally. Later reports by Myers
and Marx detailed the successful treatment of 268 patients,
and others have also found similar success with the above-
mentioned protocol [30]. However, due to the logistic and
financial limitations of using so many hours of HBO, many
centres preferred a simplified protocol of 30 dives before
and 10 dives after the surgery [31]. Later, Marx reported a
further 104 patients who required mandibular reconstruc-
tion in tissue beds exposed to C 64 Gy radiotherapy using
mesh trays with free bone grafts and the intervention
comprised of 20 preoperative and 10 post-operative HBO
sessions. The results showed established bony continuity in
48 out of 52 patients for those with HBO compared with 34
of 52 without HBO. The largely outdated method of oro-
mandibular reconstruction, and the lacunae in the infor-
mation concerning the methodology of the trial makes the
data hard to evaluate.
The aforementioned ‘‘Wilfred-Hall Protocol’’ by Marx
consists of the three stages.
Stage I Thirty consecutive treatments. If the wound
showed no definitive clinical improvement, a further ten
exposures are indicated, to a full course of 40 exposures. If
there is failure to heal after 3 months, the condition is
advanced to the next stage.
Stage II The exposed bone is removed by alveolar
sequestrectomy and further 20 HBO treatments have to be
given to the affected patients, to a total of 60 exposures. If
wound dehiscence or failure to heal occurs, the patient is
advanced to the next stage.
Stage III The criteria for this category are failure of
Stage II, pathological fracture, orocutaneous fistula, or
radiographic evidence of resorption to the inferior border
of the mandible.
The need for evidence from randomised trials is essen-
tial due to the uncertainty of treatment outcome in many
affected patients. The optimum therapeutic use of HBO
remains poorly understood, and this is evident in the lack
of standardisation of HBO protocols used by both UK and
European chambers [8]. The protocols often deviate from
the ‘‘consensus’’ Marx protocol of 30 sessions before and
10 sessions after operation at 2.4 atmospheres for 90-min
sessions. Most British Hyperbaric Association (BHA)
J. Maxillofac. Oral Surg.
registered chambers only deviate from the Marx protocol in
the pressures used, for example a reduction to 2.2 atmo-
spheres, because of anecdotal evidence of fewer compli-
cations (transient myopia) at this pressure [32].
Shaw et.al in 2019 conducted the HOPON (Hyperbaric
Oxygen for the Prevention of Osteoradionecrosis) trial as
the evidence for using hyperbaric oxygen continued to be
poor. The purpose of this clinical trial was to assess the
benefit of hyperbaric oxygen in the prevention of osteora-
dionecrosis during surgery on the irradiated mandible. The
phase III, multi-centre, randomised controlled HOPON
trial employed an unblinded design, wherein the diagnosis
of osteoradionecrosis was assessed on anonymised clinical
photographs and radiographs by a blinded expert panel.
The included patients were randomised 1:1 to hyperbaric
oxygen arm (Marx protocol) the control arm; however,
both the groups received antibiotics and chlorhexidine
mouthwash. The primary objective was to assess the
occurrence of osteoradionecrosis at 6 months following
surgery and secondary objective assessed the time of onset
of ORN, acute symptoms and pain, quality of life, the
position of implants placed, their successful retention [8].
A total of 144 patients were randomised, and data from 100
patients were analysed. The incidence of ORN at 6 months
was 6.4% and 5.7% for the HBO and control groups,
respectively. Patients in the hyperbaric arm had fewer
acute symptoms but no significant differences in late pain
or quality of life. The authors concluded that the incidence
of ORN was low, making the recommendations for HBO in
dental extractions or implant placement in the irradiated
mandible unnecessary. The results of the study were in
contrast with a recently published Cochrane review and
previous trials and further reinforces the prevention of
unnecessary indication of HBO for dental extractions or
implant placement according to their results.
Hyperbaric Oxygen Therapy Versus Perioperative
Antibiotic Prophylaxis
Marx et al. found that there was a reduction in the inci-
dence of ORN while employing hyperbaric oxygen therapy
compared to the intervention with perioperative antibiotic
prophylaxis, with follow-up at six months although the
radiation doses for the included patients were not men-
tioned in the study. Whereas, the results of the study by
Schoen et al. in 2007 suggested that there was no reduction
in the incidence of ORN in the intervention arm employing
combined hyperbaric oxygen therapy and perioperative
antibiotics as compared to antibiotics alone, with a follow-
up period of one year from the time of prosthesis delivery
[33]. Additionally, the authors reported the results of
multiple quality of life questionnaires and clinical param-
eters with respect to oral status, functioning and other
satisfaction measures at pre-operative, as well as at the end
of six weeks, and 12 months following new denture
placement. Though the authors found emotional function-
ing and pain to be significantly higher at the end of six
weeks in the hyperbaric oxygen therapy group, there were
no significant differences between the two groups at the
end of 12 months.
Platelet-Rich Plasma (PRP)
It is an autologous blood product created by spinning
whole blood in a centrifuge to isolate a platelet-rich gel.
Platelets contain growth factors namely the platelet-derived
growth factor (PDGF), vascular endothelial growth factor
(VEGF) and transforming growth factor beta (TGFb). The
use of PRP gel has been already indicated for improving
the survival of bone grafts, in dental implantology, cos-
metic surgery and orthopaedic procedures. According to a
case report published by Scala et al. in 2010, an autologous
PRP gel was introduced into the ORN necrotic defect of a
44-year-old patient previously treated for squamous cell
carcinoma of the tongue. They reported that post-operative
two-year follow-up demonstrated by panoramic X-ray
showed regain of the mandibular bone continuity with a
complete repair of the necrotic defects. This case illustrated
an incident of successful regeneration of ORN critical-
sized defect of the mandible by autologous PRP gel [34].
Whereas Batstone et al. in 2012 found that there was no
reduction in the incidence of ORN despite the application
of PRP gel [35].
Pharmacological Management
The results of few earlier studies showed that advanced full
thickness ORN (Notani grade III), especially in the setting
of a pathological fracture or an orocutaneous fistula, has
traditionally been treated with surgical resection and vas-
cularized free flap reconstruction [36]. However, due to
concerns regarding operating within an irradiated field,
many patients can be unsuitable for resective and recon-
structive therapy, so conservative management and sup-
portive care remain a commonly adopted treatment for
ORN. In addition, many patients refuse further surgery.
Pentoxifylline and tocopherol were first used in the man-
agement of early ORN as the two agents directly coun-
teracted the proposed fibro-atrophic pathogenesis of ORN
[19]. Initial studies have shown good results with no sig-
nificant adverse effects from the medications. The role of
pentoxifylline and tocopherol in advanced ORN, where
patients are unsuitable for resection, has been reported by
Delanian et al. in 2004.
Pentoxifylline is a methylxanthine derivative that has
been found to act against some inflammatory mediators
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including TNF-alpha, increases erythrocyte flexibility,
dilates blood vessels, inhibits inflammatory reactions
in vivo, and increases collagenase activity in vitro. It is
given in combination with tocopherol, a vitamin E ana-
logue, 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 procollagen genes, in turn
reducing fibrosis37. Then, a first-generation non-nitroge-
nous bisphosphonate, clodronate, was also added in non-
responsive cases to promote osteogenesis and osteoblast
differentiation. The use of pentoxifylline, tocopherol and
clodronate together (PENTOCLO) in the management of
ORN was first proposed by Delanian and Lefaix. The
benefits of PENTOCLO were first described in a case of
sternal ORN in a female patient who had previously
underwent radiation therapy for the management of breast
cancer [38]. As a result, PENTOCLO was then successfully
used in 16 of 18 patients with mandibular ORN of the jaws,
not responding to conservative therapy. Among the
observed patients, four had stage III ORN with pathologi-
cal fractures. Although the paper did not discuss these more
advanced patients in significant detail, it appears that all the
patients had pathological fractures without ‘shifting’ or
without displacement [39]. A subsequent study by the same
author in 2011 evaluated the role of the PENTOCLO
protocol in the management of 54 patients [40]. Among
them, 36 patients were classified as having advanced ORN
(Epstein III with fistula, fracture, or osteitis). However, it
was unclear how many patients had fractures, and in the
conclusions, the authors advised that surgical management
should still be considered in patients with fractures without
displacement.
Surgical Management of ORN
In advanced ORN cases, surgical management is generally
considered the therapy of choice [41]. However, in several
severe ORN patients with extensive bone and soft tissue
defects, functional and aesthetic reconstruction represents a
huge challenge with an increased risk of post-operative
wound healing complications. Even by using a free flap
with bone segments and large soft tissue parts, the risk of
post-operative complications, including wound dehis-
cences, necrotic tissue and functional and aesthetic limi-
tations, is more prevalent. Furthermore, restoration of the
three-dimensional anatomical boundaries cannot be
ensured.
Outcome of Microvascular Free Flap Reconstruction
Microvascular free flaps (MVFF) are the current standard
of care for reconstruction of oral ablative defects [42].
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J. Maxillofac. Oral Surg.
Microvascular free flaps are commonly used for
mandibular reconstruction in ORN. When MVFF recon-
structions are contraindicated, regional pedicle flaps com-
bined with rigid fixation and autologous bone grafts are
commonly reported options that can provide satisfactory
functional and aesthetic outcomes [43]. Hirsch et al. in
2008 compared 305 consecutive patients who underwent
MVFF reconstruction for a variety of cancer-related ther-
apies. Among them, 21 patients who underwent surgery for
Marx stage III ORN involving the mandible were identified
and for purposes of comparison, patients who received
preoperative radiation therapy and underwent microvas-
cular reconstruction but did not have ORN were identified
and included in the test group. Similarly, matched patients
who never received preoperative radiotherapy served as
controls. Overall MVFF survival and complication rates
among patients with ORN versus control groups were the
same. Free tissue transfer is another viable option for the
management of advanced mandibular ORN [36].
Prevention of ORN
Prophylactic Dental Care
Preventive measures must be evaluated to reduce the
severity of ORN. Poor maintenance of oral hygiene has
been shown to increase the risk of osteoradionecrosis. The
fluoride gel application and use of high content fluoride
toothpaste reduced the incidence of ORN according to the
study by Hariot et al.[44]. Before commencement of radi-
ation therapy, a thorough dental examination is indicated.
The Marx protocol of 20 dives at 2.4 atmospheres for
90 min per dive before extraction and ten dives after
extraction has become the de facto The results of the sys-
tematic review by Nabil et al. in 2011 suggested that a total
ORN incidence of 7%, which was reduced to 6% in con-
junction with antibiotics, and 4% with prophylactic HBO
therapy. They concluded that prophylactic HBO therapy
was effective in reducing the risk of developing ORN after
post-radiation extractions. These conclusions were drawn
from a total of seven articles reporting on a combined 160
patients and 595 extractions.
The results of the review published by Peterson et al. in
2010 identified three studies that evaluated the use of HBO
therapy to a comparison group in those requiring dental
extractions, two retrospective cohort studies demonstrated
a similar prevalence of ORN in HBO versus non-HBO
groups, whereas the prospective trial by Marx et al. in
1985, the landmark study, showed a markedly elevated
complication rate in the non-HBO plus antibiotic versus
HBO groups. These findings led the authors to conclude
that only level III evidence supported the use of prophy-
lactic HBO therapy prior to post-radiotherapy dental
J. Maxillofac. Oral Surg.
extraction. Limited prevention studies regarding hard tissue
replacement in extraction sockets, post-operative antibi-
otics, and pre-radiation extraction of impacted third molars
were also reported; however, it was concluded that addi-
tional studies were required to evaluate these preventive
options. Medical treatment including pentoxifylline, toco-
pherol and clodronate has also been reported before and
after extraction.
Owosho et al. conducted a study in 2016, to determine
the prevalence and correlation of various risk factors [ra-
diation dose, periodontal status, alcohol, and smoking] to
the development of ORN. The medical records of 1023
patients treated with IMRT for oral cavity cancer (OCC)
and oropharyngeal (OPC) were retrospectively reviewed to
identify risk factors among patients who developed ORN.
The result of their study suggested that higher radiation
dose, poor periodontal status and alcohol use are signifi-
cantly related to the risk of developing ORN [5].
Role of Intensity-Modulated Radiotherapy (IMRT) The
risk of osteoradionecrosis increases with higher total radi-
ation doses, short regimens using high doses per fraction,
large field sizes, and the delivery of radiotherapy through a
single field (15, 16). Recent advances in the delivery of
photon radiotherapy such as 3D conformal radiotherapy
(3D CRT) or intensity-modulated radiotherapy (IMRT)
have reduced the risk of osteoradionecrosis45,46 compared
to the previous conventional two-dimensional (2D) radio-
therapy that documented 5% to 20% higher risk of inci-
dence [47].
As mentioned earlier, with the advances in the delivery
of radiation therapy, such as intensity-modulated radiation
therapy (IMRT), there is a fall in the incidence of osteo-
radionecrosis as it uses increasing the conformality of the
high dose prescription to spare larger volumes of mandible
by improved conformality of the high prescription dose and
improved dose homogeneity. Thus, to date the best out-
comes with IMRT with regard to ORN appear to be when
the dose to organs at risk (mandible, oral cavity and par-
otid) are constrained, conventional fractionation is utilised,
and meticulous dental hygiene is applied[48]. The use of
more advanced, intensity-modulated proton therapy
(IMPT) theoretically allows delivery of highly conformal
and homogeneous dose deliveries to the target while
simultaneously sparing adjacent organs at risk to a greater
degree than is possible with IMRT. Proton therapy allows
energy to be contained at a specific depth within tissues,
with rapid energy fall off beyond that point (the Bragg
peak). The use of IMPT minimised excess irradiation of the
mandible and consequently reduced the risk of osteora-
dionecrosis as compared with IMRT for oropharyngeal
cancer[49]. However, further prospective studies with lar-
ger number of patients incorporating mandibular dose-
volume histogram analysis should be undertaken to clarify
the influence of radiation technique (IMRT or IMPT) on
the prevalence of and severity of osteoradionecrosis.
According to Clayman et al., the application of mega-
voltage therapy resulted in a significant reduction in the
overall prevalence of ORN from 11.8% before 1968 to
5.4% after this time [13]. Wahl et al. also described similar
results and noted a prevalence of ORN of 3% during the
period 1997 to 2006 [44]. Lee et al. found that the fre-
quency of ORN was 6.6% among 198 patients with either
oral cavity or OPCs treated with radiation between 1990
and 2000[50].
Conclusion
Effective management of any disease process initially
requires a timely diagnosis. Although there exists no gold
standard treatment or consensus, a combination of thera-
peutic strategies shall be considered, taking into account
the severity of disease and individual patient characteris-
tics. The available evidence shows clinical success with
conservative management of early stage ORN with
antibiotics and meticulous oral hygiene, and any sign of
progression requires early surgical intervention with
debridement and local mucosal flaps to cover exposed
bone. Extensive surgical resection with fibular free flap
may be considered for patients with advanced disease who
have persistent symptoms refractory to conservative treat-
ments. A better understanding of underlying pathophysi-
ology and risk factors will help to improve the prognosis
for those being treated for ORN. The role of HBOT and
medical management (antifibrotics, antioxidants, steroids)
is yet to be understood better.
Availability of Data and Materials This is a review article, and
hence, no data were collected.
Declarations
Conflict of interest All authors declare that they have no conflict of
interest.
Ethical Approval Being a literature review, no formal ethical
approval needed.
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