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Current Management of Osteoradionecrosis of Jaw in Head and Neck Cancer

Article · July 2019

DOI: 10.6696/IJHNS.201906_3(2).0003

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International Journal of Head and Neck Science 3(2): 92-98, 2019
DOI:10.6696/IJHNS.201906_3(2).0003
Review Article

Current Management of Osteoradionecrosis of Jaw in

Head and Neck Cancer
Lisa Alice Hwang, Chi-Hua Chang, Wei-Chun Tai, Wei-Chia Su
Department of Oral and Maxillofacial Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

Background: Osteoradionecrosis (ORN) of jaw is one of the most challenging sequela of radiation
therapy in head and neck cancer. It is characterized by bone tissue necrosis and failure to heal. ORN either
stabilizes or gradually worsens and is notoriously difficult to manage. The variations in definition and
classification of the condition affect the estimations of incidence and also the treatment strategies.
Methods: A literature review.
Results: Theories of pathophysiology of ORN including radiation-induced osteomyelitis, hypoxic, and
hypovascular theory had been proposed. The treatment of ORN has included local wound debridement,
antibiotic therapy, administration of hyperbaric oxygenation and radical surgical procedures. Currently
the role of hyperbaric oxygenation therapy (HBOT) in ORN is yet to be determined and more trials are
ongoing. Recently, the new method of pentoxifylline-tocopherol-clodronate combination in late stage
ORN was proposed according to the new “fibroatrophic theory,” and had shown some promising results.
Prevention strategies include dental evaluation before treatment and the improvement radiation planning
techniques.
Conclusions: Controversy around the ideal treatment of the ORN of jaw persists. The pentoxifylline-
tocopherol-clodronate combinations have shown some promising results in late stage ORN. However, it
demands greater evidence from more randomized clinical trials.
Key words: head and neck cancer, osteoradionecrosis, radio-osteomyelitis, radiation osteitis, oral surgery

Introduction as “a non-healing mucosal or cutaneous ulcer with

Osteoradionecrosis (ORN) of jaw is one of the
most challenging sequela of radiation therapy in head
and neck cancer. Historically, ORN has been described
as radio-osteomyelitis, radiation osteodysplasia, ra-
dio-osteonecrosis, radiation osteitis, and radiation ne-
crosis.1,2 In 1926, Eiving was the first to use the term
“radiation osteitis,”1 as the bone necrosis secondary
to radiation. In 1974, Guttenberg proposed the term
“septic ORN of the mandible” to describe when irra-
diated bone becomes necrotic and superficially infect-
ed, ending up with a high risk of involvement of deep-
er structures.2 In 1989, Widmark et al. described ORN
denuded bone, lasting for more than three months.”3
In 1997, Wong et al. defined ORN as “a slow-healing
radiation-induced ischemic necrosis of variable extent
occurring in the absence of local primary tumor ne-
crosis, recurrence or metastatic disease.”4 According
to the published articles in past 20 years, ORN of jaw
is defined as exposed irradiated bone that fails to heal
over a period of three months without any evidence of
persisting or recurrent tumors.5,6
Theories and Pathophysiologies
The earlier studies had accepted that ORN re-

Received: April 14, 2019; Accepted: April 22, 2019.

Corresponding author: Wei-Chia Su, DDS, Department of Oral and Maxillofacial Surgery, Kaohsiung Chang Gung Memorial Hospital, No.
123, Dapi Rd., Niaosong Dist., Kaohsiung City 833, Taiwan. Tel: +886-9-75369075, E-mail: Zahn9@cgmh.org.tw

92 International Journal of Head and Neck Science 3(2) 2019


sulted from secondary infection due to local injury
of the devitalized bone, or radiation induced osteo-
myelitis. Meyer proposed the classic triad sequence
of pathogenesis as radiation, trauma, and infection.7
But further evidence suggested that micro-organism
appear to act more as surface contamination rather
than infective agents 8 and that spontaneous ORN
may occur without alveolar trauma such as dental ex-
tractions.8,9 In 1983, Marx’s8 noticed the radiation ef-
fects on the tissue level are endothelial death, hyalin-
ization, and thrombosis of vessels. Bone osteoblasts
and osteocytes become necrotic. Periosteum, mucosa,
and skin also become fibrotic, with markedly dimin-
ished cellularity and vascularity of the connective
tissue. He concluded that hypovascular-hypoxic-hy-
pocellular tissue was formed after radiation, and ORN
was resulted from the loss of reparative and synthetic
function that lead to chronic non-healing wounds
with metabolic demands outstripping supply due to
persistent hypoxia.8 In 2004, Delanian and Lefaix in-
troduced the “fibroatrophic theory” of ORN in which
radiation-induced fibrosis (RIF) of both soft and hard
tissue was thought to result in chronic non-healing
wounds in previously irradiated bone.10 Endothelial
cell injury occurs directly from radiation and indi-
rectly from the free radical or reactive oxygen species
(ROS) generation. The combination of reduced cellu-
larity, reduced vascularity and fibrosis leaves fragile
tissue prone to breakdown from simple trauma.
Evaluation and Incidence
ORN is more often reported in the mandible
in head and neck region, this may be attributed to
its lower blood supply and compact bone structure
compared with the maxilla.11,12 The risk of developing
ORN is three times higher in dentate patient than in
edentulous one, mainly as a result of injury from ex-
tractions and infection from periodontal disease.12 The
first step to evaluate a post treatment cancer patient’s
necrosis mandible should always exclude the possi-
bility cancer recurrence. Along with clinical evalu-
ation, image study is pivotal in diagnosing of ORN.
Orthopantomogram is a readily available, fast, and
convenient image to evaluate the state of bone demin-
eralization, periosteal thickening, bone sequestrum,
and fracture. However, radiological signs are delayed
compared to clinical signs, they are not observed
immediately but only after three to six months, as
radiological signs only become apparent after a sig-
International Journal of Head and Neck Science 3(2) 2019 93
Osteoradionecrosis of Jaw in Head and Neck Cancer
nificant degree of demineralization about 30 to 50%.13
Computed tomography (CT) scans can accurately
evaluate the extent and severity of osseous changes
along with soft tissue changes. Magnetic resonance
imaging (MRI) was used for depicting meticulous
marrow alterations. Dual-phase fluorodeoxy glucose
(FDG)-positron emission tomography (PET) has im-
proved the specificity in differentiating between ORN
and tumor recurrence compare the general FDG-
PET.14
The timing of developing ORN varied from a
few weeks following completion of therapy to the end
of the patient’s natural life. One study even described
ORN may occur up to 45 years after an initial course
of radiation therapy.15 According to literature, the in-
cidence of ORN reported varies from 1.2–44.2%,16-19
the most reported ORN rate was about 5.0–15.0%.17-19
In modern series, it was reported 4.0–8.0%.18,20 The
data had shown that the risk of developing ORN has
declined in recent years due to emergency of Intensi-
ty-Modulated Radiation Therapy (IMRT) which result
in less radiation exposure of the jaw bones,21,22 and
also the introduction of pre-radiotherapy (RT) dental
care.23,24 In Taiwan, the data was compatible with the
published results, a nationwide, population-based
retrospective study used the database of the National
Health Insurance Research Database (NHIRD) from
2000 to 2013 showed that the incidence of overall
ORN after head and neck RT was 2.22% (39/1,759),
and the incidence of post-extraction ORNJ was 5.17%
(27/522) during an average of 3.25 years.25
Classification
There are multiple staging systems for ORN
based on either clinical, radiological, or treatment
modalities as listed in Table 1. Schwartz and Kagan26
proposed the classification based on clinical and ra-
diological findings to classify the extend of necrotic
bone involvement. Notani et al.27 divided the cases
into three grades based on the extent of the ORN le-
sion related to alveolar canal. Glanzmann and Grätz28
classified ORN stages according to duration of bone
exposure and treatment necessity. Støre and Boysen29
divide the stages by combination of radiological and
clinical parameters. Most clinicians use the Notani’s
classification to describe a patient’s condition, as it is
intuitive through the view of orthopantomograph, but
this could be misleading that the mandible is the pri-
mary and exclusive site of ORN.
 Hwang et al.

Table 1. Different staging systems of osteoradionecrosis

Study Stages Basis of stage

Schwartz and Stage I: minimal soft-tissue ulceration and limited exposed cortical bone. Imaging and clinical
Kagan26 Patients are treated with conservative management. findings
Stage II: localized involvement of the mandibular cortex and underlying
medullary bone.
Stage III: full-thickness involvement of the bone, including the inferior border.
Pathological fractures may also be present.
Notani et al.27 Stage I: ORN confined to alveolar bone. Clinical findings
Stage II: ORN limited to the alveolar bone and/or mandible above the level of
the inferior alveolar canal.
Stage III: ORN involving the mandible below the level of the inferior alveolar
canal and/or skin fistula and/or pathological fracture.
Glanzmann and Stage 1: bone exposure without signs of infection and persisting for at least Duration of bone
Grätz28 three months. exposure and
Stage 2: bone exposure with signs of infection or sequester and without the treatment necessity
signs of grades 3–5.
Stage 3: bone necrosis treated with mandibular resection with a satisfactory
result.
Stage 4: bone necrosis with persisting problems despite mandibular resection.
Stage 5: death from ORN.
Støre and Stage 0: mucosal defects only. Combination of
Boysen29 Stage 1: radiological evidence of necrotic bone with intact mucosa. radiological and
Stage 2: positive radiological findings with denuded bone intra-orally. clinical parameters
Stage 3: clinically exposed radionecrotic bone, verified by imaging techniques,
along with skin fistulae and infection.
ORN: osteoradionecrosis.

Management of ORN hypoxic tissues and stimulate fibroblast proliferation,

Conservative treatment
Conservative treatment of ORN including oral
hygiene optimization and antibiotic coverage, are
generally indicated for asymptomatic or mildly symp-
tomatic patients with early or moderate disease (ex.,
Notani stage 1 or 2). Unfortunately, only 40–60%
of patients respond to conservative treatment.30,31 To
avoid further disease progression, some studies have
suggested sequestrectomy to remove portion of bone
that becomes separated from sound bone during the
process of necrosis, and cover the bone defect by mu-
cosal flap.32
Hyperbaric oxygenation therapy (HBOT)
HBOT is defined as a treatment where the pa-
tients breathe oxygen in a pressure chamber at 1.5
atmospheres or greater. The mechanisms of action
for HBOT are thought to increase oxygen supply in
angiogenesis, and collagen formation, wishing to
disrupt the hypovascular-hypoxic-hypocellular condi-
tion. In 2016, an updated Cochrane review on the role
of HBOT in ORN concluded that HBOT may provide
some help in soft tissue healing and dental extraction
sockets. However, the evidence was generally limited
by small numbers of participants, poor reporting of
methods, and the exact degree of improvement with
HBOT.33 One randomized control trial enrolled ORN
participants who were not responsive to two months
of conservative treatment and evaluate the effective-
ness of hyperbaric oxygenation (HBO) in ORN. This
study was terminated early at one year due to an im-
proved outcome in the placebo group compared with
HBOT (33 vs. 19%).34 More multicenter randomized
trials like Hyperbaric Oxygen for the Prevention of
Osteoradionecrosis (HOPON) and Hyperbaric Ox-
ygen Treatment of Mandibular Osteoradionecrosis
(DAHANCA-21) are ongoing to evaluate the benefit

94 International Journal of Head and Neck Science 3(2) 2019


of HBOT in ORN patients.35,36 A lack of prospective
studies and high levels of evidence has been a bar-
rier to date for the widespread use of this expensive
treatment of HBOT. Another concern that HBO might
have cancer metastatic potential was raised by some
authors, but studies showed no evidence for persistent
changes in tumor microenvironment or tumor growth
promotion caused by hyperbaric oxygen exposure and
use of HBO in patients with malignancies is consid-
ered safe.37,38
Medical treatment
The introduction of Delanian’s fibroatrophic
theory of ORN has prompted the use of the following
antioxidant and antifibrotic drugs for the treatment of
ORN. This new adjunctive treatment in ORN is the
pentoxifylline (PTX)-tocopherol (TCP)-clodronate
(CLO) combination (PENTOCLO) to RIF and bone
destruction and to stimulate osteogenesis via the an-
tioxidant pathway. PTX, a methylxanthine derivative
acting on erythrocyte deformability and vasodilation
and also reducing blood viscosity, decreasing the
potential for platelet aggregation, and thrombus for-
mation. It has been used in peripheral arterial disease
to increase tissue oxygen levels. TCPs are organic
chemical compounds with several methylated phe-
nol groups, many of which have vitamin E activity.
Studies have shown synergism in the combination of
PTX and TCP to treat RIF.39 CLO, a first generation
oral bisphosphonate, exhibits clinical benefits in the
treatment of ORN. CLO reduce the number and the
activity of osteoclasts, and consequently inhibiting
bone resorption. CLO also has a direct activity on os-
teoblast cells, increasing bone synthesis, and decreas-
ing fibroblast proliferation, without antiangiogenic
properties.40 One phase II trial included refractory
ORN patients and they were given a daily combina-
tion of twice-daily 400 mg PTX (800 mg/day) plus
500 IU vitamin E (1,000 IU/day) and once-daily 1,600
mg/day CLO for five days a week, the results showed
improvement in reduction of exposed bone and all
54 participants experienced in complete recovery in
a median of nine months.40 Another study have pa-
tients receives daily dose of 800 mg of PTX, 1 g of
TCP, 1,600 mg of CLO five days a week and 20 mg
of prednisone on the other two days a week. After 12
months of this PENTOCLO treatment, they found
71.4% of patients showed radiological regression, and
all patients return to oral feeding and 57.1% no longer
International Journal of Head and Neck Science 3(2) 2019 95
Osteoradionecrosis of Jaw in Head and Neck Cancer
require analgesics.41 According to a meta-analysis in
2018, seven studies and total 211 patients were re-
viewed. In cases with failed therapy such as antibiot-
ics, HBOT, and surgical management, after receiving
PENTOCLO treatment, the estimated proportion of
full recovery of ORN was calculated to be 62.7%,
reduction in SOMA score was 86.5%, and exposed
bone reduction was 62.0%.42 Although studies have
shown promising results in the PENTOCLO treat-
ment, there is currently no consensus on the optimal
therapeutic doses of these drugs or the shortest treat-
ment span. However, treatment periods shorter than
12 months have been associated with rebound effects
in RIF,43 and treatments longer than two to three years
are unnecessary, although more advanced stages may
require longer treatment periods.40,41
Surgery
For advanced ORN resulting in fractures and
fistulas, treatment is usually surgical resection with
resection margin based on healthy bone edge, and
then reconstruction with local regional flaps like tem-
poralis muscle flap for the posterior oral cavity, and
the nasolabial flap for anterior exposures. For larger
bony defects, free tissue transfer is needed. In a sys-
tematic review of microvascular free flap reconstruc-
tion for mandibular ORN, the fibula free flap was the
most common and reliable “workhorse” flap used for
reconstruction.44 The problems associated with recon-
struction include vessel depletion for microvascular
reconstruction and the presence of fibrosed avascular
tissue that had resulted in a higher risk of failure rate
(10%) and post-operation complication rate (40%).44
Prevention
Head and neck cancer patients are recommended
to have dental evaluation before treatment and any
necessary extractions are carried out well in advance
of RT due to known risk of poor healing after RT
and the risk for development of ORN after dental
extraction.45 Meanwhile, dental extractions should
be performed with as little trauma as possible,46 and
the number of extraction greater than five teeth was
considered more risk of developing ORN.25 Systemic
antibiotic treatment and topical chlorhexidine 0.2%
rinses prescribed on the day of extraction and contin-
ued for seven days have shown effective in preventing
ORN following dental extractions in irradiated pa-
 Hwang et al.
tients.47 Currently, there was no consistent evidence in
support of HBO in prevention of ORN following high
risk surgical procedures to the irradiated mandible.46
Evidence has shown that the use of PTX and vitamin
E for the prophylaxis of ORN after dental extraction
reduces the incidence to 1.2%. As 5.0% is currently
the benchmark, this indicates that it is effective.48 Patient
should also be informed to quit tobacco and alcohol
consumption and reinforcement oral hygiene.
Conclusions
Currently, there is no gold standard treatment of
ORN and no widely accepted guidelines exist. Early
stage ORN may be treated by conservative treatment
of antibiotics and early debridement and repair with
local flap to cover exposed bone. Currently the role
of HBOT in ORN is yet to be determined, while trials
are ongoing. Some promising results had been shown
in medication of PENTOCLO in late stage ORN,
though dose and duration are still under studied.
Surgical resection and fibular flap reconstruction is
reserved in advanced stage ORN who were refractory
to other more conservative treatments.
Disclosure Statement
The authors report no conflicts of interest in this
work.
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