INTRODUCTION

Tumors of the head and neck are heterogeneous group of neoplasms that display a
wide range of biologic behaviour. Among head and neck tumors, oral cancer constitutes an
important as well as separate entity. The global incidence of oral cancer is 5,00,000 cases per
year with mortality of 2,70,000 cases. The incidence of oral cancer in India is 40 % among
all cancer and about 1,00,000 patients suffer from oral cancer in any year. Oral cancer is
responsible for 7% of all cancer deaths in males while it is 3 % in females.
The management of head and neck cancer includes surgery, radiotherapy and
chemotherapy. Despite advances in surgical reconstructive techniques, 66.66 % patients
require adjuvant therapy in the form of radiotherapy or chemo-radiotherapy to control locoregional spread.
Radiation therapy is one of the major treatment modalities for the management of
head and neck malignancies :1. As primary therapy for many early stage malignancies
2. As an adjuvant therapy following surgical resection
3. As palliative therapy in conjunction with concurrent chemotherapy for late stage and
unresectable head and neck malignancies.
Radiotherapy, however, has significant limitations in the form of acute and late
toxicity. Acute toxicity, such as moist desquamation, skin erythema, loss of taste, and
especially mucositis, are often debilitating but resolve with time. Late toxicity, such as
myelitis, skin fibrosis, however, can be more problematic, because they may be a lifelong
problem for cancer patients.
Long term and most serious side effect of radiotherapy is osteoradionecrosis and is
anticipated to be an important clinical problem in future. Recently, new concepts are being
introduced to help outline new guidelines for treatment.
In this review etiology, pathophysiology, clinical features, treatment modalities
including hyperbaric oxygen therapy will be discussed.

SYNONYMS

1. Radiation Osteitis.
4

2.
3.
4.
5.
6.
7.
8.

Radio-osteonecrosis.
Radiation osteomyelitis.
Osteomyelitis of irradiated bone.
Osteonecrosis.
Radio-osteomyelitis.
Septic osteoradionecrosis.
Post-radiotherapy osteonecrosis.26

HISTORICAL BACKGROUND

In 1922, Regaud published the first report about osteoradionecrosis of jaws after
radiotherapy.26
In 1926, further description of osteoradionecrosis by Ewing under the name radiation
osteitis .29
6

James Ewing

In 1938, Watson and Scarborough described radiation osteitis as being caused by

radiation, trauma, and infection. It was believed that trauma to the soft tissue overlying bone
in the oral cavity permitted bacteria to enter into the underlying demineralized bone, leading
to osteomyelitis.26
In 1940, Scientist (primarily neurophysiologists) began to study the effects of direct
current and electromagnetic fields on living organisms and organ systems. In 1960, external
voltage was found to stimulate bone growth and in 1970, electromagnetic energy was
applied to bone healing problems. During this period it was also discovered that an
electromagnetic field could alter cell-membrane permeability.44

Meyer J.

In 1970, Meyer classified osteoradionecrosis as one special type of osteomyelitis.

Meyer suggested that injury provided the opening for invasion of oral microbial flora into the
7

underlying irradiated bone Meyers theory lasted for a decade and became the foundation for
the popular use of antibiotics with surgery to treat osteoradionecrosis.23
In 1971, Titterington related osteoradionecrosis to osteomyelitis provided one of its
first definitions and used the term osteomyelitis of irradiated bone. 38
In 1972, Daly challenged the role of trauma in osteoradionecrosis.45
In 1975, Mainous advocated the use of hyperbaric oxygen therapy (HBO) for late
radiation tissue injury. Mainous and Hart reported their use of HBO as adjunctive therapy to
surgical treatment of refractory osteoradionecrosis in 14 patients and reported successful
results.17
In 1979, Davis et al reported that 19 out of 23 patients treated with adjunctive HBO
remained in remission for 2 years of follow-up.19
In 1981, Mansfield et al reported that 11 of 12 patients with refractory
osteoradionecrosis responded favourably to HBO.21

Robert Marx

In 1983, Robert Marx proposed the hypoxic-hypocellular - hypovascular theory as a

new way of understanding the pathophysiology of osteoradionecrosis. The sequence

suggested by this study of Marx is as follows: (a) Radiation; (b) Formation of hypoxichypocellular-hypovascular tissue; (c) Tissue breakdown (cell death and collagen lysis exceed
synthesis and cell replication), d) chronic non-healing wound (a wound in which metabolic
demands exceed supply). These explanations formed the cornerstone for the use of hyperbaric
oxygen (HBO) in the treatment of osteoradionecrosis.76
In 1985, Kraut reported three cases in which HBO was used successfully as a
prophylactic measure before and after dental extraction to prevent the development of
osteoradionecrosis.56
More recently, the utility of HBO in the treatment of osteoradionecrosis has been called into
question by a number of authors.
In 1992, Harris introduced the use of Ultrasound as one of the modes to treat
osteoradionecrosis.10
In 1993, Werner-Wasik reported a case of radiation induced fibrosis following
radiotherapy for breast cancer, in which pentoxyphyllin was used14.
In 1994, Delanian advocated the use of copper or zinc superoxide dismutase to
successfully treat the radiation induced fibrosis.21
In 1998, Delanian reported a case radiation induced fibrosis which was treated by
combination of Pentoxyphylline and vit-E.21
In 1998, Marx gave the 30/10 protocol which was employed in the treatment of
established osteoradionecrosis. After 30 HBO treatments which provide sufficient
angiogenesis, surgical management can be staged according to the extent of improvement
achieved after HBO and the size of sequestrum or area of osteolysis. By using the Marx
protocols in the treatment of osteoradionecrosis, more than 95 per cent of patients were
successfully cured of their disease with predictable, functional and aesthetically acceptable
outcomes.18
9

In 2004, Delanian and Lefaix put forward a new theory named Radiation-induced
fibrosis that accounts for the damage to normal tissues, including bone after radiotherapy.
It was introduced when recent advances in cellular and molecular biology explained the
progression of microscopically observed osteoradionecrosis.35

10

DEFINITIONS

11

Marx defined osteoradionecrosis as An area of exposed bone greater than 1cm in a field of
irradiation that had failed to show any evidence of healing for atleast six months. 76
Beumer et al defined osteoradionecrosis as An exposure of bone of the maxilla or mandible
within the radiation treatment volume persisting for more than 3 months or longer.27
Morton and Simpson defined osteoradionecrosis as A loss of soft tissue integrity and
exposure of radiation damaged bone.27
Marx and Johnson defined osteoradionecrosis as An exposure of nonvital irradiated bone,
which fails to heal without intervention.27
Epstein et al defined osteoradionecrosis as An ulceration or necrosis of the mucous
membrane (In the absence of recurrent or metastatic disease), with exposure of necrotic bone
for more than 3 months27
Widmark et al defined osteoradionecrosis as, A non healing mucous or cutaneous ulcer
with denuded bone, lasting for more than 3 months.27
Koka et al defined osteoradionecrosis as A persistent ulceration with exposure of
devitalised bone, cellulitis, fistula and a pathologic mandibular fracture. Patients tumor free at
primary site27
Harris defined osteoradionecrosis as An exposed irradiated bone that has failed to heal over
period of 3 months in the absence of local tumor.27
Mirante et al defined osteoradionecrosis as A loss of viable bone resulting from radiation
therapy.27
Van Merkesteyn et al defined osteoradionecrosis as A Bone and soft tissue necrosis of six
months duration excluding radiation- induced periodontal breakdown.27

12

Most accepted definition Wong, Wood and Mcheani has defined osteoradionecrosis as, A slow-healing radiationinduced ischemic necrosis of bone with associated soft tissue necrosis of variable extent
occurring in the absence of local primary tumor necrosis, recurrence, or metastatic disease.70

13

CLASSIFICATIONS

14

Coffins Classification (1983)

A)

Minor - The minor form was considered to be a series of small sequestra

which separate spontaneously after varying periods of weeks or months. These small
areas can be seen clinically but cannot be demonstrated radiologically.
B) Major -The major form was defined when necrosis occurs of such an extent as to
involve the entire thickness of the jaw, and a pathological fracture is inevitable. This
form can obviously be seen radiologically, and is extremely rare in the maxilla (only 1
case in this series).56

Marx Classification of osteoradionecrosis (1983)

Type I
Develops shortly after radiation, due to synergistic effects of surgical trauma and radiation
injury.
Type II Develops years after radiation and follows a trauma, rarely occurs 2 years after treatment
commonly occurs after 6 years.
Due to progressive endartritis and vascular effusion.
Type III
Occurs spontaneously without preceding a traumatic event. Usually occurs between 6 months
and 3 years after radiation.76

Marxs staging system(1983) Stage I - osteoradionecrosis treatment involves primary HBO therapy, regardless of prior
treatment. The patient is given 30 HBO dives, followed by re-evaluation and restaging. If the
15

wound shows clinical improvement (granulation tissue, re-mucosalization), the patient

completes a full course of 60 dives with the goal of producing a full mucosal cover. If there is
no clinical improvement by 30 dives, the patient is categorized as a non-responder to Stage I
and is advanced to Stage II.
Stage II - osteoradionecrosis treatment involves a combination of trans-oral debridement or
sequestrectomy, with a primary mucosal repair, followed by additional HBO therapy. If
healing progresses without complication, the patient completes a total of 60 dives. If the
wound breaks down, with recurrent bone exposure, the patient is identified as a nonresponder and is advanced to Stage III treatment.
Stage III- osteoradionecrosis treatment involves a definitive surgical extirpation of all the
diseased bone, primary wound closure, and external fixation followed by additional HBO
therapy (20 dives). Ten weeks after resection of diseased bone, a staged reconstruction is
performed with autogenous cancellous bone packed into a freeze-dried allogenic bone carrier.
Additional post-operative HBO (10 dives) is then administered for completion of this
protocol.40

Morton and Simpsons Classification (1986)

A) Minor - Consisted of ulceration with exposed bone and a history of bony spicules
which healed spontaneously over a period of months.
16

B) Moderate - Consisted of exposed bone and small sequestra limited in nature and
healing spontaneously with conservative treatment within 6 to 12 months
C) Major- Consisted of large areas of exposed bone, with formation of large sequestra,
possible fracture and sinus formation. These cases often progressed rapidly, lasting in
excess of one year and often requiring radical treatment.67

Epsteins Stages of Post-radiation osteoradionecrosis (1987)

Stage I - Resolved healed osteoradionecrosis
Ia - No pathologic fracture
Ib - Pathologic fracture
StageII - Chronic persistent and non-progressive osteoradionecrosis
IIa - No pathologic fracture
IIb - Pathologic fracture
Stage III Active progressive osteoradionecrosis
IIIa -No pathologic fracture
IIIb -Pathologic fracture56

Late radiation mandibular morbidity according to the Late Effects of Normal Tissue
(LENT) /Somatic Objective Management Analytic scale (1995)

Subjective

Grade 1
Occasional

Grade 2
Intermittent

Grade 3
and Persistent
17

Grade 4
and Refractory and

Pain

and minimal

Mastication

tolerable

intense

Difficulty with solids

Difficulty

Denture use
Trismus

Excruciating

with

soft foods
Noted

but Loose denture

Inability

unmeasurable

use Inadequate

dentures
Preventing

Objective

to

oral

intake

normal

eating

Difficulty eating

< 2 cm

_2 cm or limited

Fracture

1-2 cm opening

Sequestration

<_0.5 cm opening

Exposed

0.5-1 cm opening

bone
Trismus
Managemen

Occasional

nonnarcotic

Pain

Regular nonnarcotic

Surgical
intervention or

Antibiotics

Debridement,

Exposed
bone

Regular narcotic

Resection

HBO2
Soft diet

Resection
Liquid

Trismus and

antibiotics,

mastication

muscle
meds.

Analytic
18

diet,
NG
relaxant gastrostomy

tube,

Mandibular
radiograph

Panograph

Osteoporosis
Questionable

(radioluscent)

changes or

osteosclerosis

none

(radiodense)

Sequestra

Fracture

x-ray/CT
Assessment
of

necrosis

progression

Claymans Classification (1997)

Type-I Here bone lysis occurs under intact gingiva or mucosa.
Type-II More aggressive type, called radiation osteomyelitis, when the soft tissues break
down, exposing the bone to saliva, occurring secondary contamination.54

Late radiation bone toxicity according to the Radiation Therapy Oncology Group
scoring criteria (1998)

Grade

Bone morbidity

None

Asymptomatic; no growth retardation; reduced bone density

19

Moderate pain or tenderness; growth retardation; irregular bone sclerosis

Severe pain or tenderness; complete arrest of bone growth; dense bone sclerosis

Necrosis; spontaneous fracture

Death directly related to radiation late effects

Store and Boysens (2000)

Stage
0
I
II
III

Criteria
Mucosal defects only
Radiological evidence of necrotic bone with intact mucosa
Positive radiographic findings with denuded bone intraorally
Clinically exposed radio-necrotic bone, verified by imaging techniques, along with
skin fistulas and infection

Kagan and Schwartzs staging (2002)

Stage I It is defined as minimal soft tissue ulceration and limited exposed cortical bone.
These patients are treated with conservative management.
Stage II
It is defined as localized involvement of the mandibular cortex and underlying
medullary bone.
Stage II
It is divided into 2 groups.
Stage IIa
It has minimal soft tissue ulceration.
Stage IIb

20

It is defined based on the presence of an oro-cutaneous fistula and mild soft tissue
necrosis.
Again, the majority resolve with conservative management or minor surgical procedures.

Stage III
It is classified based on full thickness involvement of the bone, including the inferior
border. Pathological fracture may also be present. All require surgical intervention,
including bone and/or soft-tissue replacement.12

Notani et als Classification (2003)

This classification is quickly applicable to all cases of mandibular osteoradionecrosis
(osteoradionecrosis) after clinical examination and orthopantogram.

Notani class Clinical features

I

Osteoradionecrosis confined to dentoalveolar bone.

II

Osteoradionecrosis limited to dentoalveolar bone or mandible above the

III

inferior dental canal, or both

Osteoradionecrosis involving the mandible below the inferior dental canal, or
pathological
fracture, or skin fistula
21

Bone toxicity according to the National Cancer Institute Common Terminology Criteria
(Version-IV, 2009)

Grade

Osteonecrosis of jaw

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Symptomatic; medical intervention indicated (e.g., topical agents); limiting

instrumental ADL

Severe symptoms; limiting self-care ADL; elective operative intervention indicated

Life-threatening consequences; urgent intervention indicated

Death

Classification of Bone exposuresBone exposures were classified according to Beumer et al.(1983)

I.
Bone exposure resulting from tumor necrosis where tumor death results in a
loss of soft tissue coverage.
Criteria - Bone exposure at the site of tumor either during or within a week of
II.

III.

completing radiotherapy.
Bone exposure as a consequence of tumor recurrence.
Criteria- In all cases surgical resection was undertaken as bone exposure was
noted to be the site of tumor recurrence.
Bone exposure resultant from oral surgical(surgical salvage operations) or
other dental interventions including prostetic dental treatment.
Criteria Extraction sites either before or after radiation persisted as areas of
necrotic bone exposure, sites of surgical salvage became areas of bony

22

exposure or definite reference to denture irritation as a apparent cause of

IV.

exposure.
Bone exposure de novowithout apparent cause aside from radiation exposure.
Criteria- A diagnosis of exclusion : no evidence of persistent recurrent cancer
that could account for exposure . No obvious source of trauma.33

23

RISK FACTORS

24

The existing articles in the literature fail to give an exact etiology for osteoradionecrosis. The
etiology of osteoradionecrosis is considered to be multifactorial. So these factors may
increase the risk of the patient for osteoradionecrosis. These risk factors are classified into 4
groups in the literature.

1. Patient related factors

2. Tumour-related factors
3. Treatment-related factors.
4. Miscellaneous factors

1.

Patient related factor

2.

Tumour-related factors

3.

Treatment-related factors

4.

Miscellaneous factors

A) Gender.
B) Age.
C) Race.
A) Site.
B) Histopathology.
C) Stage.
D) Size.
A) Radiotherapy setting.
B) Radiotherapy modality.
C) Radiotherapy dose.
D) Chemotherapy.
E) Surgery.
A) Active smoking.
B) Alcohol.
C) Inadequate oral hygiene
D) Steroids and anticoagulants
E) Dental diseases.
F) Body-mass index.
G) Secondary infection
H) Dental extraction
I) Nutritional status

1. Patient related factors A) Gender

25

Epstein, Wong and Stevensen Moore, Reuther, Schuster et al and

Chopra, Kamdar et al, in their studies found male predominance for the
occurrence of osteoradionecrosis. In their studies, they found that male to
female ratio was 1.6:1.

B) Age The literature shows wide variability in the age of the patients affected
by osteoradionecrosis. Epstein van der Meij et al and Chopra, Kamdar et
al found that severe osteoradionecrosis (Clinically exposed radionecrotic bone
along with skin fistulas and infection) was common in elderly patients.

C) Race
Literature reveals that the white race has the highest incidence for the
occurrence of osteoradionecrosis. Chopra, Kamdar et al in their study stated
that, 74% patients with osteoradionecrosis were whites. This may not have
significance in Indian scenario.

2. Tumour-related factors
A) Site
The oral cavity and oropharynx comprised the vast majority of primary
tumors leading to osteoradionecrosis of the jaws. Thosteoradionecrosis et al
revealed an almost equal incidence of floor of mouth and oropharyngeal
tumors, together comprising 66% of all lesions. However, Notani et al found
that tongue was the most common primary site, followed by the floor of mouth
and oropharynx. This suggests that the closer the presence of tumour to the
bone, higher is the incidence of osteoradionecrosis. 12,20

26

revealed that, Within the head and neck, oral cavity tumors, especially of the
tongue, oor of mouth, alveolar ridge, or retromolar region, are sites with the
highest risk of developing osteoradionecrosis after irradiation, owing to their
proximity to the mandible
While few studies69,70 stated that that tumor originating in the sinonasal
or

nasopharyngeal

areas

present

higher

risk

for

developing

osteoradionecrosis in the maxilla.

B) Histopathology
According to the histopathology, squamous cell carcinoma is more
prone to lead to the occurrence of osteoradionecrosis. Chopra et al stated that,
among all patients of osteoradionecrosis, 91% patients had squamous cell
carcinoma, 4% patients had osteosarcoma, 2% patients had adencarcinoma
and adenoid cystic carcinoma. This may attributed to the increased incidence
of Squamous cell carcinoma in oral cavity.

C) Stage
Literature shows that as the stage of carcinoma increases the risk for
development of osteoradionecrosis increases. Stage-IV carcinoma has higher
risk for developing osteoradionecrosis of the jaws. Chopra, Kamdar et al in
their study noted that incidence of osteoradionecrosis is 72% for stage IV
osteoradionecrosis.

For

osteoradionecrosis

patients

on

whom

stage

information was available, 80% had stage IV cancer, and 73% had T3T4

27

primary tumors. All except one T4a patient had stage II/III mandibular
osteoradionecrosis.

D) SizeBedwinek et al , Curi and Dib, Ranko and Weissman found that

larger tumours were associated with higher incidence of osteoradionecrosis
.However Reuther et al and Murrey, Daly and Zimmerman found no
correlation of development of osteoradionecrosis with the size of the tumor.
Hence site of the tumor is rather more relevant than the tumor size.

4. Treatment-related factors A) Radiotherapy settingLiterature reveals wide variation in the opinion regarding setting of
radiotherapy and occurrence of osteoradionecrosis. Curi and Dib stated that,
patients undergoing adjuvant radiotherapy had more risk for developing
osteoradionecrosis. Thorn et al stated that 10% of osteoradionecrosis in their
series were initiated by tumor surgery.
However, Chopra, Kamdar et al did not find any such correlation.
This may be due to the fact that higher osteoradionecrosis risk associated with
surgical procedure is similar to that which is associated with more aggressive
therapy of curative intent.
28

B) Radiotherapy Modality Several radiation delivery modalities present different levels of risk for
developing osteoradionecrosis of the jaws. Since the introduction of higher
energy radiotherapy in 1968, there is reduced incidence of osteoradionecrosis
of the jaws.27
Meyer noted that 5% of his patients treated with orthovoltage
developed osteoradionecrosis whereas only 1% to 1.5% developed it with the
use of supravoltage (cobalt 60).14
According to studies of Murray et al and Beumer et al, interstitial
radiotherapy (brachytherapy) is safer than external beam radiotherapy when
tumours are situated away from bone however, when the tumors are in the
immediate vicinity of the bone such as CA tongue and floor of the mouth, use
of brachytherapy is often associated with an exceedingly high incidence of
osteoradionecrosis. Obinata et al and Miura et al stated that the use of a
spacer to reduce the risk of developing osteoradionecrosis in such cases.24,47
Macdougall et al stated that the use of fast neutrons is now known to
cause very high rates of particularly severe osteoradionecrosis and soft tissue
necrosis, which is almost impossible to manage medically.67
Ben-David et al, Studer et al, Ahmed et al in their separate
studies,stated that advances in the delivery modality of radiotherapy, such as
3D-CRT or IMRT, have raised optimism in the probability of reducing the risk
of developing osteoradionecrosis. These modalities spared the parts of the
mandible, thereby reducing the risk of osteoradionecrosis.69,70

29

Eisbruch et al and Gomez et al, in their studies stated that there is no

reduced risk of osteoradionecrosis with the use of IMRT.92,95
Dijkema et al, Pow et al, Kam et al and Pacholke et al reported the
efficacy of 3D-CRT or IMRT in preventing xerostomia. 91,96 Hence it should be
pointed out that by preventing xerostomia, the risk of developing
osteoradionecrosis could be indirectly reduced, owing to the improvement of
oral health following the preservation of saliva production in the mouth.
Furthermore, optimal planning and simulation of irradiation fields will
help minimize irradiation of surrounding non-involved tissues.

C) Radiotherapy dose:
Associated risk of developing osteoradionecrosis increases with higher
RT doses. 19,20,45 Morrish et al, Bedwinek et al, Beumer et al, Tong et al, Oh
et al and Goldwaser et al reported higher incidence of osteoradionecrosis in
patients receiving doses higher than 65-75 Gy by almost 11 folds.23,32
Chopra et al stated that, among all patients of osteoradionecrosis, 47%
patients had received radiation dose more than 60 Gy while 53% patients
received radiation dose less than 60 Gy. There were no patients with stage III
mandibular osteoradionecrosis at a <60 Gy dose, and a higher incidence of
stage III disease was observed in the high-dose group.
Conventional radiotherapy is usually described as 1.8 to 2 Grays once daily,
5 days a week, over 4-8 weeks. Altered fractionation involves modification of
this schedule. Altered fractionation is divided into 2.
1. Hyperfractionation
30

2. Accelerated fractionation
Hyperfractionation involves increase in total dose and number of
fractions with smaller dose per fraction to enable better tumor control while
not increasing the late toxicity. Literature states conflicting data on the effects
of hyperfractionation on osteoradionecrosis risk.
Lyons et al proposed that, the incidence of osteoradionecrosis is
thought to be less common after hyperfractionated radiotherapy at 7280 Gy,
or moderately accelerated fractionated radiotherapy together with a boost of
6472 Gy.26
Mendenhall et al, in his study, described hyperfractionation which
involves delivering an increased total dose and number of fractions with
smaller dose per fraction to enable better tumor control while not increasing
the late toxicity associated with increased doses. ( ref 77 risk factors)

Glanzmann and Gratz and struder et al , in their different studies,

reported reduced incidence of osteoradionecrosis with the use of
hyperfractionation.53,28 However this was contradicted by the study of Niewald
et al. Who observed an increased risk of osteoradionecrosis with the use of
hyperfractionation. which was mainly attributed to reduced interfraction
interval.
Accelerated fractionation Accelerated fractionation is the shortening of treatment time in an
attempt to prevent tumor repopulation. When accelerated fractionation with
total dose reduction is used, there is reduction in osteoradionecrosis incidence.
Chart
31

The use of CHART (Continuous hyperfractionated accelerated radiotherapy) is

a relatively new introduction in the radiotherapy field, being applied since
1990. Pigott, Dischi and Saunders stated that there has been a significantly
significantly reduced incidence of post-radiation change in normal tissues
owing to low dose per fraction.27,75

D) Chemotherapy

Chemoradiotherapy (CRT) offers better locoregional control and overall

survival (ref risk 5,75) and is also used to eradicate micrometastases. Ref- risk 5,76
CRT has been shown to increase acute toxicity especially mucositis, but its
effect on late toxicity is less clearHowever

28,45

, Denis et al and Sharan et al

found an increased risk for late toxicity with the use of CRT.
Sader et al demonstrate a positive correlation between the incidence of the
osteonecrosis and the therapeutic intensity. They observe the complication
most commonly in patients treated with combined

radio / chemotherapy

before surgery.
Reuther observed earlier occurrences of osteoradionecrosis when CT was
used in combination with RT. Chemotherapy is likely to weaken the local
immune response by damaging the cellular immune system.
Chopra et al stated that, among all patients of osteoradionecrosis, 78%
patients had received chemotherapy along with radiotherapy while 22 % did
not receive chemotherapy but it failed to correlate significantly with severity

32

of mandibular osteoradionecrosis. Chemotherapy was concurrent in 97%

patients and induction chemotherapy was used in 8% patients.
Hehr et al suggested that when chemotherapy is added to radiotherapy
the incidence of osteoradionecrosis may be increased whereas the use of
intensity-modulated radiotherapy may reduce it.
Glanzmann and Gratz found no increased risk of osteoradionecrosis
when CT was added to the RT regimen. Nabil and Saman also found no
correlation between the CRT and development of osteoradionecrosis.

E) Surgery
Literature states that ablative surgeries such as bone resection or osteotomy
before radiotherapy is associated with the development of osteoradionecrosis
in the development of healing bone. 17,20,43,45
Marx and Johnson found that 8.9% of patients, in their series of 536
osteoradionecrosis cases, were directly caused by the ablative surgery before
radiation.
Thorn et al stated that 10% of osteoradionecrosis in their series were initiated
by tumor surgery.
Celik et al, Lee et al, Wang et al, Nam et al and Store and Boysen stated
that specic procedures, such as mandibulotomy and mandibulectomy have
been considered to cause an increased risk of developing osteoradionecrosis
after radiation.
Chopra et al stated that, among all patients of osteoradionecrosis, 72%
patients had undergone surgery while 28% patients did not undergo surgery.

33

Surgical tumor management did not correlate with severity of mandibular

osteoradionecrosis.

5. Miscellaneous factors
A) Active smoking
Thorn et al, Katsura et al and Kluth et al considered tobacco
smoking as a risk factor for osteoradionecrosis although the mode of action is
unexplainable.Furthermore, smoking

probably potentiates the risk when

combined with other negative factors, such as poor oral hygiene. The
vasoconstriction which occurs owing to smoking will lead to chronic ischemic
insult which in turn will.Chopra et al revealed that 35% of all patients with
osteoradionecrosis were smokers. However, Marx found that 83% of his
osteoradionecrosis patients continued their earlier smoking habits. Thorn et al
found that 89% of their osteoradionecrosis patients continued their earlier
smoking habits.

B) Alcohol
Alcohol consumption during and after radiotherapy is one of the risk
factors for developing osteoradionecrosis. Kluth et al confirmed that there
was significantly higher incidence of osteoradionecrosis with those who used

34

alcohol during and after radiation. While its mode of action is unexplained yet,
it probably potentiates the combined effects of other risk factors such as, poor
oral hygiene. Chopra et al revealed that 76 % of all patients who had
osteoradionecrosis were alcoholic.

C) Inadequate oral hygieneIntraoral tissues are damaged by irradiation, which causes mucositis
and xerostomia. These conditions, in combination with poor dental care or
poorly fitting prosthesis, will give rise to odontogenic and periodontal
infections. This again can lead to osteoradionecrosis. Chopra et al revealed
that 23% of all patients who had osteoradionecrosis had good oral hygiene
while 18% patients had fair and 59% patients had poor oral hygiene. Kastura
et al stated that oral health conditions predisposing to osteoradionecrosis are:
periodontal pocket depth >5 mm, dental plaque score >40%, alveolar bone
loss level >60%, and grade 3 radiographic periodontal status.

D) Steroids and anticoagulants

In the study Goldwaser et al.it was demonstrated that 54% of nonosteoradionecrosis patients compared with 28% of the osteoradionecrosis
patients took steroids before or after radiation therapy. On multivariate
analysis, steroid use before or after radiation reduced the risk of
osteoradionecrosis by 96%. Their anti-inflammatory effects may inhibit the
initial inflammatory phase of osteoradionecrosis, thereby preventing
progression to thrombosis, atrophy, and necrosis.
35

Similarly, use of anticoagulant also reduces the risk for developing

osteoradionecrosis. This may be attributed to the fact that these drugs prevent
thrombosis, thereby preserving microvascular blood supply to the irradiated
tissues.

E) Dental disease
There is a well established association between dental disease and
osteoradionecrosis.
Radiotherapy directly affects the supporting structures of the teeth, the
gingiva, periodontal ligament and bone
Galler et al. reported three cases of osteoradionecrosis which developed from
periodontal disease activity, but the incidence could be much higher.
Murray et al. showed a positive association between dental disease present
before radiation therapy and subsequent necrosis of the mandible (p=0.09),
leading to a recommendation that significant disease be eradicated before
irradiation of oral tissues.

F) Body mass index -

In the study of Goldwaser et al. the body mass index (BMI) of patients who
developed osteoradionecrosis averaged 23.02 while the BMI of those who did not
averaged 25.13. On multivariate analysis, for every one point increase in BMI,
osteoradionecrosis risk decreased by 27%. This study suggests that a higher BMI at
36

any level protects against osteoradionecrosis, but not significantly so in the obese
range.

G) Secondary infectionAlthough osteoradionecrosis is primary problem of wound healing secondary

infection can also be associated. Chopra et al, in their study found that secondary
infection

in

post-radiotherapy

phase

correlated

with

stage-III

mandibular

osteoradionecrosis. Thus, secondary infection in the post treatment period predicted

severity with strong significance.

H) Dental extractionDentoalveolar surgery, in particular dental extractions after radiotherapy, are wellestablished predisposing factors to osteoradionecrosis; the documented incidence of
osteoradionecrosis 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. The
risk of developing osteoradionecrosis after extractions are higher in posterior
mandibular teeth with roots that lie below the mylohyoid line, and when an atraumatic
extraction was not possible.

37

Irreparable teeth due to caries, periodontal disease or root lesions can cause infection
of the bone and progression to osteoradionecrosis because of low vascular patency
and the inability of the mechanisms of repair in irradiated tissues.The irradiated
patients present alterations in the salivary glands and in the dental structure, which
predispose to progressive periodontal attachment loss, rampant caries and fungal and
bacterial infections. These patients can also present fibrosis, resulting in trismus and
consequently difficulties in adequate oral care.
Several authors consider removal of diseased teeth, especially in the
postirradiation period, a main risk factor in the development of osteoradionecrosis but
few studies have shown increased risk for osteoradionecrosis development when
exodontias were executed before radiation treatment and others show similar results
when dental extractions were compared before and after radiotherapy.11,28
Chopra et al stated that 63% of all patients who underwent pre-radiotherapy dental
extraction had osteoradionecrosis .while occurrence was less, upto 42%, in patients
who underwent postradiotherapy dental extraction. It was notable that 2 of every 3
patients who had pre-RT extractions did not develop stage III disease and a similar
percentage of patients who did not have the extractions, did. Conversely, post-RT
extractions appeared to portend severe mandibular osteoradionecrosis, with 60% of
these patients developing stage III disease. Both these relationships did not achieve
significance.
Thorn et al , Marx and Johnson and Beumer et al reported that most of the
osteoradionecrosis cases were developed directly owing to a dental cause, such as
tooth extraction due to dental caries or periodontal disease.

38

Nabil and Saman stated that, when a patient undergoes radiotherapy for head and
neck cancer, the general risk is 2%, but the risk would be higher (6.88%) among the
subset of this population that undergoes post-radiation tooth extraction.

H) Nutritional status
The nutritional status of the patient can also influence the progression of osteoradionecrosis.
(paradigm shifts Jacobson ) Poor nutritional status affects wound healing thereby, increasing
the risk of osteoradionecrosis.

39

PATHOPHYSIOLOGY

The pathophysiology of osteoradionecrosis is not very clear till today. However, the literature
reveals three theories being put forward since 1970. These theories are as mentioned below
1. Meyers radiation, trauma and infection theory
2. Marxs hypoxic-hypocellular-hypovascular theory
3.

Delanians radiation-induced fibroatrophic theory.

The first evidence in the literature on the pathophysiology of osteoradionecrosis was by

Watson and Scarborough. They reported three crucial factors in the development of
osteoradionecrosis based purely on clinical observations.
1. An exposure to radiotherapy above a critical dose.
2. Local injury.
3. Infection.

40

Their study showed evidence of bacteria in tissues affected by osteoradionecrosis 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.
They stated that trauma to the soft tissue overlying the bone in the oral cavity permitted
bacteria to enter into the underlying demineralised bone leading to osteomyelitis. However
this concept did not gain the popularity. In 1970, in an excellent monograph on infectious
disease of the jaws, Mayer defined the classic triad of osteoradionecrosis as radiation, trauma
and infection .Thus, rekindling the Watson and Scarboroughs concept.

Meyers radiation, trauma and infection theory:

Radiation

Trauma

Infection
Meyers theory
Mayer portrayed that the trauma provided the opening for invasion of oral
microbiological flora into the underlying irradiated bone. Most common sources of trauma
were tooth removal and sharp bony ridges. He also described that there is loss of resistance to
41

the bacteria in the irradiated bone thereby leading to relatively rapid progression of infection.
Soon radiation osteomyelitis sets in and spreads throughout the bone, which cannot wall off
the infection. However he did not demonstrate spread of osteomyelitis and microorganisms
throughout the bone through cultures or tissue sections, neither did he demonstrate septic
destruction in such avascular tissue which were the shortcomings of this theory. Other
authors agreed and referred to osteoradionecrosis as secondary infection after trauma to
devitalised bone, and even as radiation-induced osteomyelitis. Meyers theory lasted for a
decade and became the foundation for the popular use of antibiotics with surgery to treat
osteoradionecrosis.

Marxs hypoxic-hypocellular-hypovascular theory:

Robert E Marx in his landmark study noted that there was no injury before the onset
of osteoradionecrosis in 35% of his cases .Similarly, Daly and Drane have reported 39%
incidence of osteoradionecrosis not associated with any specific trauma. Marx also found
that the microbiological profile of osteoradionecrosis was different from that of osteomyelitis.
Microbiological investigation of bone affected by osteoradionecrosis showed various
microbes on its surface, which were possibly contaminants. 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.

42

Marx concluded that: osteoradionecrosis is not a primary infection of irradiated

bone, but a complex metabolic and homeostatic deficiency of tissue that is created by
radiation-induced cellular injury; micro-organisms play only a contaminating role in
osteoradionecrosis; and trauma may or may not be an initiating factor.
The pathophysiological sequence suggested by Marx is given below,
Irradiation
Formation of hypoxic-hypocellular-hypovascular tissue

Breakdown of tissue (cellular death and breakdown of collagen that exceeds cellular
replication and synthesis) driven by persistent hypoxia that can cause a chronic non-healing
wound (a wound in which metabolic demands exceed supply).
Chronic non-healing wound

Delanians radiation-induced fibroatrophic theoryRadiation-induced fibrosis is a new theory that accounts for the damage to normal
tissues, including bone, after radiotherapy. It was introduced in 2004 when recent advances
in cellular and molecular biology explained the progression of microscopically observed
osteoradionecrosis.
The histopathological phases of the development of osteoradionecrosis closely reflect
those seen in chronic healing of traumatic wounds.
Three distinct phases are seen:
1. The initial prefibrotic phase in which changes in endothelial cells predominate
together with the acute inflammatory response.
2. The constitutive organised phase in which abnormal fibroblastic activity
predominates, and there is disorganisation of the extracellular matrix.

43

3. The late fibroatrophic phase, when attempted tissue remodelling occurs with the
formation of fragile healed tissues that carry a serious inherent risk of late reactivated
inflammation in the event of local injury.
The theory of radiation-induced fibrosis suggests that the key event in the
progression of osteoradionecrosis is the activation 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. The destruction of endothelial cells, coupled
with vascular thrombosis, lead to necrosis of microvessels, local ischaemia, and tissue
loss. Loss of the natural endothelial 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 (PDGF), fibroblast growth factor (FGF), interleukins (IL) 1, 4 & 6, transforming
growth factor (TGF), and connective tissue growth factor (CTGF), result in unregulated
fibroblastic activation and the myofibroblast phenotype persists. 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. The mandible is thought to be predisposed to the development of
osteoradionecrosis. This is principally the result of fibrosis that causes the obliteration of

44

the inferior alveolar artery together with the failure of the facial artery to jointly form a
supply.

RADIATION

Generation of free
radical oxygen
species (ROS)
Injured endothelial
cells
ROSmediated
cytokine
production
Microvessel
necrosis

FIBROBLAST

Osteoblasts

MYOFIBROBLAST

Osteocytes
Osteoclasts

Vascular thrombosis
45

INF

PDG
F

Tissue loss

TRAUMA

Irreversible damage
to DNA, bone cell
necrosis

FRAGILE,
PAUCICELLULAR
TISSUE REPLACED BY
ABNORMAL
MYOFIBROBLAST

OSTEORADIONECROSIS

Radiation-induced fibroatrophic theory

46

IL-1, IL-4,
IL-6
FG
F

TGF1

Dysregulati
on of

FIBRO
SIS

MICROBIOLOGY

osteoradionecrosis was earlier attributed to secondary infection in the traumatized

irradiated tissue following the non-healing wounds and exposed bone.
Marx stated in 1983 that infection associated with osteoradionecrosis was only
superficial and secondary, and that the microorganisms found in resections were surface
contaminants. The statement was based on a study that failed to describe microorganisms in
the medullary parts of the resections.
Store and Olsen demonstrated the existence of a diverse microbiota of the medullary
parts of the mandible visualized by scanning and transmission electron microscopy and by
DNA_DNA hybridization in a checkerboard assay. The detection of anaerobes indicates that
infection might play an important role in the pathogenesis of osteoradionecrosis. They found
47

polymicrobial bacterial infection in deep medullary bone of osteoradionecrosis where rods,

spirochetes and cocci were present and rods were the predominant.
Store et al (2005) found Porphyromonas gingivalis to be the predominant organism
in most of their material and also found Actinomyces species to be present in all of the
samples.
In a study involving 31 patients, Hansen et al suggested that Actinomyces species
play a significant role in development of osteoradionecrosis as they were found in 20 of their
patients. In another report they also found a relationship between the presence of
Actinomyces species and an unfavourable treatment outcome.
Nason

and

Chole

described

formation

of

biofilm

in

association

with

osteoradionecrosis of the temporal bone after external beam radiation. Phylogenetic analysis
of complex bacterial communities in biofilms relies on the sequences of housekeeping genes
in bacteria, like the 16S rRNA gene, and includes both the cultivable and not-yet cultivable
segment of the bacterial flora. By using modern molecular techniques, studies have shown
the breadth of microbial diversity of the whole gastrointestinal tract in health and disease, and
it has been discovered that as much as 50% of the oral and 80% of the intestinal indigenous
bacterial flora consist of uncultured phylotypes.
Jorn A. Aas et al detected 59 predominant species such as Firmicutes,
Actinobacteria, Proteobacteria, Fusobacteria, Spirochaetes, and Bacteroidetes. Out of these,
27% could not be cultivated. The predominant species detected from radionecrotic mandibles
were Campylobacter gracilis, Streptococcus intermedius, Peptostreptococcus sp. oral clone
FG014, uncultured bacterium clone RL178, Fusobacterium nucleatum, and Prevotella spp.
In reviewing 60 patients suffering from osteoradionecrosis and osteomyelitis,
Calhoun et al reported the most commonly found bacteria to be, Streptococcus sp.,

48

Bacteroides sp., Lactobacillus sp., Eubacterium sp. and Klebsiella sp. Only four cultures
were positive for Actinomyces.

Kjetil Pedersen (2006) found that there was a high bacterial diversity associated
with osteoradionecrosis. Bacteria that dominate the bacterial flora are mainly of oral origin.
Known periodontal pathogens such as Treponema spp. and Porphyromonas gingivalis were
well represented.
Detection of all members of the complex bacterial communities is necessary to better
understand the role of infection in the pathogenesis of osteoradionecrosis. Further studies on
bacterial flora associated with osteoradionecrosis are required, which may contribute to a
more precise use of antibiotics.

49

CLINICAL FEATURES

IncidenceAnalysis of epidemiological studies of osteoradionecrosis does not provide accurate

data about incidence and prevalence of osteoradionecrosis in the jaws because of the lack of
agreement about its definition, inconsistencies in the length of follow-up between studies and
limited data from prospective studies. According to Clayman, the incidence of
osteoradionecrosis was 10.31 % before 1968 and 6.28 % after that. Reuther et al reported
the incidence of osteoradionecrosis from 0.95 % to 35 %. According to Beumer et al and
Murray et al, incidence of osteoradionecrosis is 3 times higher in dentate patient compared
to edentulous patient because of injury from extractions and infection from periodontal
diseases.54
50

The wide range may be the result of differences in the study population and length of
observation.

Ageosteoradionecrosis can occur at any age of life. Chopra and Kamdar et al found
52% of patients to be less than 54 years. But incidence is higher in young patients because of
injury from extractions and infection from periodontal diseases after undergoing radiotherapy,
while it is less in older patients because of absence of these factors. However, the severity of
osteoradionecrosis occurring in elderly patients was more compared to younger patients.43

SiteLiterature shows, strong predisposition of the mandible to osteoradionecrosis relative

to the maxilla or any other bone in head and neck region. According to literature, it is 2.6 %
to 10.4% for mandible, while according to Store and Boyson, it is 2% -22% for mandible.
However, according to Beumer et al, it is 2% - 11% for maxilla.65

Clinical presentationUsually it is asymptomatic

1. Pain.
2. Swelling.
3. Non resolving painful mucosal ulcer with exposure of necrotic bone: Initial
breakdown of buccal mucosa followed by facial skin. Exposed bone with a grey to
51

yellow colour. The exposed bone often has rough surface texture. It abrades adjacent
soft tissues and causes further discomfort. Sequestration is slow because of inhibition
of osteoblastic and osteoclastic mechanisms.
4. The tissues surrounding the bone may be indurated.
5. Trismus
6. Dysesthesia
7. Xerostomia
8. Dysguesia
9. Food impaction.
10. Fetor oris
11. Malocclusion.
12. Talengectasia.
13. Orocutaneous fistula.
14. Elevated temperature.
15. Missing hair follicles.
16. Surface texture changes- Cutaneous flaking and keratinisation.
17. surface colour changes,
18. Pathologic fracture in severe cases.
19. Deep cellulitis of face and neck.
Pain and evidence of exposed bone are the chief clinical features, while trismus, fetor oris
and elevated body temperature are usually present during the initial period although acute
infection is usually not present.

In 1987, Marx and Johnson found the following physical diagnostic signs to correlate
with increased degrees of radiation tissue injuries.

1.
2.
3.
4.
5.
6.

Induration of tissues
Mucosal radiation telangiectesias
Loss of facial hair growth
Cutaneous atrophy
Profoundness of xerostomia
Profoundness of taste loss

52

INVESTIGATIONS

53

There are two methods of investigation as far as osteoradionecrosis is concerned.

1. Radiographic investigations
2. Histopathological investigation

1. Radiographic investigations
The presence of osteoradionecrosis cannot always be diagnosed radiographically and
often clinically obvious signs of exposed necrotic may not be accompanied by significant
radiologic changes.
In skeletally mature patients, radiation therapy impairs osteoblast function, resulting in
decreased matrix production. This is manifested radiographically as osteopenia and is
typically seen 1 year after irradiation.
Vascular damage may contribute to late radiation-induced changes including bone
atrophy. Attempts at osseous repair result in the deposition of new bone on ischemic
trabeculae. Radiographs obtained at this stage will reveal heterogeneous bone density
with punctate areas of increased density, osteopenia, and coarse trabeculation.

Plain film Radiography

Radiologic features include ill-defined cortical destruction without sequestration. Absence
of soft-tissue mass aids in distinguishing osteoradionecrosis from neoplastic recurrence.
1. Orthopantomogram(OPG):
In panoramic radiograph of mandible with osteoradionecrosis, there can be ill-defined
cortical destruction without sequestration. Radiography may also demonstrate

54

Pathologic fracture.

Disorganization and coarsening of trabecular architecture

Cortical irregularity

Heterogenous bone density.

A. Periphery - The periphery is ill defined and similar that in osteomyelitis. If the
lesion reaches inferior border of the mandible, irregular resorption of this bony
cortex often occurs.
B. Internal structure A range of bone formation to bone destruction occurs, with
a balance heavily toward more bone formation, giving the affected bone an
overall sclerotic or radiopaque appearance. Bone pattern is granular. Scattered
regions of radiolucency may be seen, with or without central sequestra.
Maxillary bone can also be very sclerotic and have areas of bone resorption.
C. Effects on surrounding structures
Inflammatory periosteal new bone formation is uncommon, possibly because of
the deleterious effects of radiation on potential osteoblasts in the periosteum. In
very rare cases the periosteum appears to have been stimulated to produce bone,
resulting in new bone formation on the outer cortex in an unusual shape. The
most common effect on surrounding bone is stimulation of sclerosis.

55

2. Lateral Oblique radiographOblique radiograph of the mandible shows osseous destruction of the mandibular body
(arrows) with associated sclerosis.

56

Special radiographic investigations -

1. Computer tomography (CT):

57

Computed tomography plays an important role in diagnosis of osteoradionecrosis

since it is hard tissue lesion. Anterior-posterior and supero-inferior extent of the
osteolytic lesion is best judged with CT scans compared to plain film radiography.
Moreover, plain radiographs often fail to correlate with the clinical signs of
mandibular osteoradionecrosis including areas of denuded bone, while clinical signs
are well correlated with CT.
Hence from diagnostic purpose to the surgical intervention, CT is recommended
as far as osteoradionecrosis is concerned.

1. Cortical destruction and loss of spongiosa trabeculation on the symptomatic side.

(Predominantly seen in the body of the mandible)
2. Sclerosis.
3. Sequestration
4. Soft tissue thickening on the symptomatic side.
5. Subtle fractures, alterations in bone architecture, and dystrophic soft-tissue
calcification.
6. Central necrosis (loss of cancellous bone)
As the bony abnormalities in mandibular osteoradionecrosis are often
associated with a soft tissue mass, CT differentiation from tumor recurrence can be
difficult. The association with cortical defects distant from the position of the original
tumor (buccal surface or opposite side of mandible) should evoke the possibility of
mandibular osteoradionecrosis.

58

In conclusion, we have found that panoramic radiography is suitable for monitoring

mandibular osteoradionecrosis, but for diagnostic problems or surgical
intervention CT is recommended.45
2.

Magnetic resonance images (MRI):

On MRI, there is development of new heterogeneous signal within the marrow of an

irradiated area (intermediate or low T1 signal, intermediate or high T2 signal). Adjacent
muscles may appear oedematous and show intense enhancement, which can be difficult to
differentiate from recurrent tumor if bone changes are not visible on CT.

T1 : high signal intensity

T2 : intermediate signal intensity.

3. Positron emission tomography (PET):

59

PET scan is helpful to differentiate between osteoradionecrosis and recurrent

tumour.

4. Radionuclide bone scanning:

Radionuclide bone scanning with technetium methylene diphosphonate
(99mTc-MDP) can identify pathophysiologic changes in bone earlier than
conventional radiography because scan changes reflect osteoblastic activity and good
blood flow.
A) Technetium bone scans- Technetium bone scans is also being used to monitor
improvements in tissue viability, before, during and after radiotherapy.
B) Gallium-67 citrate (GA-67)- Gallium-67 citrate localises in bone, tumours and
inflammatory lesions. Gallium scans have been used in osteoradionecrosis, with
variable findings, consistent with the fact that osteoradionecrosis is not
necessarily associated with inflammation within bone. Thus, gallium uptake may
not be of diagnostic value for osteoradionecrosis.

5. Infrared spectroscopy (NIRS)

Recognised non invasive method, used largely to monitor cerebral tissue
oxygenation and ischaemic changes in neonates. It has been used as an investigation
method for osteoradionecrosis in retrospective studies, and shows a reduction of the
amount of deoxygenated haemoglobin at sites of osteoradionecrosis, confirming that
it is a hypovascular, hypoxic tissue with decreased metabolic rate subtracting little.

60

Histologic investigations
The histological findings noted by Marx showed endothelial death, hyalinisation and
thrombosis of vessels with a fibrotic periosteum.
Bone osteoblasts and osteocytes were deficient, with fibrosis of the marrow spaces. Mucosa
and skin also become fibrotic, with markedly diminished cellularity and vascularity of the
connective tissue. The overall result was a composite tissue, which is hypovascular and
hypocellular and was proven to be hypoxic compared with non-irradiated tissue by direct
measurement.

61

DIAGNOSTIC CRITERIA

62

In 1997, Wong JK, Wood RE, McLean M. have given diagnostic criteria for
osteoradionecrosis which seem to be agreed by the majority of the authors:
1.

The affected site should have been previously irradiated;

2.

There should be absence of recurrent tumour on the affected site;

3.

Mucosal breakdown or failure to heal should occur, resulting in bone exposure

(except in cases of bones that lie within thick soft tissue integuments, such as the
pelvis or femur, or rarely in cases of a pathological fracture of the mandible after
irradiation);

4.

The overlying bone should be dead, usually due to a hypoxic necrosis;

5.

Cellulitis, fistulation, or pathologic fracture need not be present to be considered as

osteoradionecrosis.

Osteoradionecrosis usually develops after 3-6 months having bone exposure at least for 3
months.

63

MANAGEMENT

64

Preventive Management-

Radiotherapy regimes such as accelerated fractionation and hyperfractionation,

improve local control but at the expense of increased local complications. Newer protocols
such as 3D conformational radiation therapy and intensity modulated radiotherapy are able to
maximize delivery to treatment areas and minimize dose to surrounding normal
tissue. Nevertheless, preventive measures should be put in place to help to reduce the
incidence and severity of osteoradionecrosis. These measures should be applied both before
and after the radiotherapy.

Multidisciplinary approach:
As soon as head and neck malignancy is diagnosed, the patient should be reviewed
within a multidisciplinary team. This team should include a dentist who is sufficiently
experienced in dealing with oral cancer patients. If such a person is not available within the
team and the patient is likely to receive radiotherapy, then a referral must be sought.

Preventive measures prior to radiotherapy:

The patient should have a full dental evaluation. This should include radiographs to
show all the teeth as well as the jaws to check for unerupted teeth and any bony pathology. A
panoramic radiograph should be a minimum but ideally, periapical views of all the teeth
should be taken. All the teeth should be meticulously charted for caries and periodontal
pocketing. Each tooth should be given an individual prognosis and a treatment plan
completed and discussed with the patient. It is important to educate the patient regarding
meticulous oral hygiene and the need for lifelong regular follow up. The patient's motivation
and compliance should be taken into account when assessing which teeth can be salvaged and

65

which should be removed. All teeth should be cleaned and scaled. The patient should be
encouraged to rinse with a fluoride and antibacterial mouth wash on a regular basis and high
risk patients should have custom trays made to assist in regular fluoride treatment. Patients
with no teeth are easier to treat but should still have a baseline radiographic evaluation to
check for buried teeth. Dentures should be inspected for fitting to ensure minimal trauma to
the tissues.
The timing of extractions is controversial. However, 2-3 weeks prior to radiotherapy
is advised to ensure timely healing. The extractions should be carried out in a non-traumatic
manner with minimal damaged to the surrounding tissues. Recent studies have shown no
difference in the osteoradionecrosis rates in patients who had extractions prior to radiotherapy
or after radiotherapy, however it is still the policy in most institutions to remove unrestorable
teeth prior to radiotherapy. Teeth with questionable prognosis should be carefully discussed
with the patient.

Hygiene during radiotherapy:

During radiotherapy, the patient will experience mucositis and xerostomia. Regular
review with the dentist is essential to minimize discomfort. The xerostomia will cause
dryness of the mouth due to lack of saliva, which is essential to wash away debris and dilute
the plaque. Regular mouthwashes and meticulous oral hygiene is essential during this period.
A dry mouth will sometimes result in patients resorting to foodstuffs that are sloppy and
sticky and have more carbohydrate component which together with a low saliva flow rate
may lead to increased caries.

66

Other measures:
Patient medication should be reviewed as Biphosphonates, used in various conditions
such as osteoporosis, Paget's disease and metastatic breast disease have been shown to cause
osteonecrosis of the jaws. The exact mechanism is not known but is related to suppression of
osteoclastic activity. Paradoxically, biphosphonates have also been used in the treatment of
osteoradionecrosis, highlighting our incomplete understanding of the condition.

After radiotherapy:
The patient should be reviewed regularly to re-enforce oral care and look for signs of
dental disease or mucosal damage.

Therapeutic management
Nonsurgical management:
The initial approach to the treatment of osteoradionecrosis should be conservative,
with medication and local wound care only, since up to 60% of the cases resolve thereby.
This resolution rate may be over-estimated by including the figures of so called mild cases
of osteoradionecrosis. Conservative approaches have also been cited to be wasteful of
resources when ineffective, involving unacceptable amounts of time, effort and medication.
Oral hygiene is essential, including the use of 0.02% aqueous chlorhexidine
mouthwashes after meals and constant saline mouthwashes. Debris should be washed /
irrigated away and sequestra should be allowed to separate spontaneously or gently removed,
since any surgical interference may encourage extension of the necrotic process.

67

Pharmacologic treatments recommended for patients with osteonecrosis of the

jaw

Treatment

Dose and Schedule

Antibacterials
Penicillin VK

500 mg every 6 to 8 hours for 7 to 10

days, then bid for maintenance

Amoxicillin

500 mg every 8 hours for 7 to 10 days,

then bid for maintenance

Patients with penicillin allergy

Clindamycin

150 to 300 mg qid

Vibramycin

100 mg qd

Erythromycin

400 mg tid

ethylsuccinate

Azithromycin

500 mg PO _ 1 on day 1; 250 mg PO

qd on days 2 to 5

Antifungals (when required)

Nystatin oral suspension

5 to 15 mL qid or 100,000 IU/mL

Mycelex troches (clotrimazole)

10 mg tid 5_/day for 7 to 10 days

Fluconazole

200 mg initially, then 100 mg qd

Antivirals

Acyclovir

400 mg bid

Valacyclovir hydrochloride

500 mg to 2 g bid

68

Studies1. Curi and Dib advocate sequestrectomy when a sequestrum is identified by radiologic
techniques.
2. Galler et al. reported three cases of osteoradionecrosis which developed from
periodontal disease activity, and proposed the use of chlorexidine digluconate and
hyperbaric oxygen in the management of this condition.
3. In the study of Wong et al. (not including four patients who died with
osteoradionecrosis), 19 (69%) of 28 patients had lesions resolve, stabilize or improve,
avoiding surgery or HBO. Identical conservative strategies have been reported by
other studies to spare patients resection in 77% to 96% where complete resolution is
not achieved asymptomatically preserved function may still be acceptable especially
in patients with advancing age or those who wish to avoid surgery. Complete
resolution was experienced in 31% to 48% of patients.10,11,14

Analgesics and anti-inflammatory drugs are prescribed when the physicians judged it
necessary (increasing signs and symptoms of pain, discomfort, etc.). Removal of
sequestra facilitates secondary epithelialisation and healing. Complete healing of
osteonecrotic lesions after gentle or spontaneous removal of sequestra has been reported.
It is unreasonable to assume that sequestration alone contributes to complete recovery in
all cases, because not all sequestrating lesions resolved in the cases of Wong et al.
It appears that removal of sequestra does facilitate healing and is a guide to lesions that
tend to respond most favourably to nonsurgical / HBO treatment. Although
osteoradionecrosis is not primarily an infectious process and the tissues are hypovascular,
limiting the success of systemic antimicrobial agents, tetracyclines have been
recommended because of their selective uptake by bone. However, access to avascular

69

bone is questionable, making tetracycline inactive. Penicillin has also been used, because
of the involvement of oral bacteria in the superficial contamination. Metronidazole, 200
mg, three times daily or other broad spectrum antimicrobials, could be added in cases of
severe infection or where anaerobes are implicated. Antibiotics rarely, if ever, cure
osteoradionecrosis.
The use of packs over exposed bone has been popular in the past.
Zinc peroxide mixed with carboxymethylcellulose in hydrogen peroxide, and also the use
of 5% neomycin solution or acriflavine as alternatives.
Morton and Simpson recommended packs for covering small areas of exposed
bone and delicate granulation tissue following separation of sequestrum, and for keeping
necrotic bone cavities clean in patients who are not ready for definitive treatment. They
found BIPP (bismuth and iodoform paraffin paste) on ribbon gauze very satisfactory, as it
remains fairly soft and quite clean. An important management consideration is that most
patients understandably wish to avoid additional major jaw surgery.

Hyperbaric Oxygen Therapy

Hyperbaric oxygenation is defined as a treatment where the patients breathes oxygen in a
pressure chamber at 1.5 atmospheres or greater. The treatment may be delivered in a
monoplace chamber pressurized with oxygen or in a larger, multiplace chamber pressurized
with air, in which case the patient receives oxygen by mask, head tent, or endotracheal tube.
Hyperbaric oxygen (HBO) may have a significant role to play in the management of many
conditions, including radiation necrosis of bone and soft tissues.
Mainous et al. in 1973 were probably the first authors to suggest the use of HBO therapy for
the treatment of osteoradionecrosis.
HBO has revolutionized facial bone reconstruction in irradiated patients as it has made
outcomes predictable and functional. If it is given preoperatively according to six rigid
70

criteria, the success rates are more than 90%. The six criteria are: restoration of jaw
continuity, restoration of alveolar bone height, restoration of osseous bulk, restoration of arch
form, maintenance of bone, and restoration of facial contours.
Osteoradionecrosis should be regarded as a chronic wound in which necrosis is compounded
by hypoxia. Contamination by a variety of aerobic and anaerobic organisms leads to infection
which further enhances hypoxia and leads to further necrosis.
HBO breaks the vicious circle in the following manner:
1. By increasing tissue oxygenation through angiogenesis;
2. By controlling infection, predominantly through enhanced bacterial killing fungi
macrophages and the production of bactericidal free radicals;
3. By stimulating fibroblast replication and development of a collagen matrix (healing).
The reason why the osteoradionecrosis does not heal is because metabolic demands for repair
exceed the supply of oxygen and nutrition. The rationale for using HBO is that intermittent
elevation of tissue oxygen tension stimulates collagen synthesis and fibroblastic proliferation,
promote growth of new capillaries, and enhance the phagocytic ability of leucocytes. HBO
increases arterial blood oxygen tension level at least 3-fold compared with levels achieved
during breathing 100% at sea level. Oxygen is transferred from the blood to tissues by
diffusion, which depends on the oxygen tension gradient. Thus more oxygen is transported
into tissues under HBO therapy, even when the circulation is compromised but not totally
absent. It is also inhibitory to aerobic and anaerobic bacteria and inhibits bacterial toxin
formation. The daily elevation of oxygen tension in hypoxic bone and soft tissues result in the
ingrowth of capillaries, fibroblastic proliferation, collagen synthesis, capillary angiogenesis
and enhances mineralization of bone in fractures.
Uncomplicated irradiated tissue, after the usual dose of 6080 Gy for malignant tumours, has
a capillary density only 20%40% of that of non-irradiated tissue. HBO does not induce
supervascularization in non-irradiated, otherwise normal tissue and therefore cannot be

71

expected to accelerate healing in tissue in which the wound healing potential is not
compromised.

Marx protocol Marx introduced a protocol for the treatment of osteoradionecrosis that combines
HBO therapy (HBO) and surgery as its primary treatment modalities. He concluded that HBO
alone cannot heal osteoradionecrosis wounds, suggesting that HBO without aggressive
surgical management would not resolve the disease progress in most cases. The reasons
showed for the low success rate were:
(1) The degree of radiation tissue damage varies greatly between patients, even with identical
doses and fractions,
(2) HBO cannot resurrect dead bone,
(3) HBO cannot entirely reverse radiation injury. The use of HBO associated with surgery is
commonly described in the literature. It has concluded that only mild cases of
osteoradionecrosis can be cured with HBO and the severe cases will need surgery to remove
dead bone.
The target tissue in HBO application is not the necrotic bone, but the compromised
living tissue that is under great metabolic demands to simply remain viable. HBO is
adjunctive and not a stand alone therapy.
When used alone without surgically removing necrotic bone, success rates are not
greatly improved over local wound care or conservative therapy. HBO alone may arrest
osteoradionecrosis only to have it recur later. HBO stimulation may also produce exuberant
proliferation of granulation tissue, but this will be lost if the bone is dead.

72

Three reasons given by Marx as reasons HBO is unable alone to consistently resolve
osteoradionecrosis lesions also give us food for thought as to why nonsurgical / non-HBO
methods are successful in certain circumstances.
1. Individual radiation effects are highly variable. Some patients have a greater residual
and peripheral cellular pool after radiation.
2. Improvements in oxygen tensions with HBO are toward normal but do not reach those
levels. Healing nonetheless can progress in suboptimal oxygen tensions.
3. HBO cannot resurrect dead bone.
Some necrotic bone remains unresorbed because of hypovascularity. Sequestration
removes this unperfused tissue.
Gal et al. also suggested that HBO therapy does not revive dead bone or resuscitate
impaired bone and in advanced disease, will only delay more definitive therapy.
Postoperative HBO cannot be the treatment of choice if operation fails to treat
osteoradionecrosis. The purpose of hyperbaric therapy is to prepare the patient for surgical
debridement and appropriate grafting, not to try to rescue poor results following the
inappropriate use of surgery in the treatment of osteoradionecrosis. If HBO is not given until
after surgery, even if it begins the day after surgery, it will take a minimum of two weeks to
have any clinical effect, during which time the tissues are severely compromised by hypoxia.
To be effective, hyperbaric treatment must be given prior to surgery. HBO therapy is not
universally applicable.
McKenzie et al. reported 15% of 26 patients failed to complete HBO therapy because
of lack of funds, noncompliance, inconvenience, and claustrophobia. Maxymiw et al. say
that HBO is time-consuming and expensive. Marciani and Ownby regard funding and
availability of chambers as limitations to the general application of HBO. Epstein et al. say
that prophylactic HBO for post-radiation extractions would not be cost-effective.

73

The protocols usually consist of 2030 dives before and 10 after tooth removal, with
humidified pure oxygen administered at 2.0-2.5 atmospheres absolute pressure for 90120
min each session, once a day Protocol. A more specific protocol is not indicated. The pressure
range suggested likely relates at least in part to historical practice differences between
monoplace and multiplace hyperbaric chambers. In monoplace chambers not equipped for
breaks of air breathing, continuous oxygen administration is often performed at 2.0
atmospheres absolute to minimize risk of central nervous system oxygen toxicity.
Toxic effects are usually observed in the central nervous system and the main
contraindications against the employment of HBO are some drugs, non-treated
pneumothorax, neuritis, some forms of pulmonary disease, smokers emphysema, and active
viral infections. The only absolute contra-indications to HBO are: optic neuritis, and existing
neoplasia. Although HBO may stimulate malignant growth it is not contraindicated in
patients with treated neoplasia, HBO may be of use pre and postoperatively in the patient
with neoplasia both in primary and delayed reconstruction cases. Side effects of HBO are
uncommon but include transient myopia, seizures, and otic or pulmonary barotrauma, the
latter potentially leading to air embolism. Concern has been expressed that HBO may
exacerbate a variety of autoimmune and immunosuppressive disorders, and viraemia, but
there is little supporting evidence.

How to administer hyperbaric oxygen?

Hyperbaric oxygen is administered by placing the patient inside oxygen chambers.
Two types of chambers are commonly used for hyperbaric oxygen therapy.
1. Monoplace chambers.
2. Multiplace chambers.
In both these chambers facilities are provided for monitoring the various vital body
parameters like heart rate, blood pressure and blood oxygen levels etc. Facilities are provided
for intravenous administration of drugs and fluids.
74

Monoplace chamber:
Here 100% pressurised oxygen is utilized. Patient alone is placed in this type of
chamber. There is no space for attendants. The patient is placed alone inside this chamber.
This chamber is hence not useful in critically ill patients.

Multiplace chamber:
These chambers are pressurised with air. Patients inside this chamber are administered
100% oxygen via a face mask or hood. These chambers allow one or more attendants inside
them. This feature is advantageous in treating seriously ill patients. Regardless of the type of
chamber used the following factors must be considered:
1. The amount of pressure used.
2. Duration of the treatment.
3. How often the treatment is repeated.
To avoid oxygen toxicity the treatment duration should not exceed 120 minutes, the
safe range being 90120 minutes. The pressure used is about 2 atmospheres. When a patients
condition requires multiple hyperbaric oxygen treatments per day, a minimum duration of 6
hours between them is a must.
75

Mechanism of Action 1. Hyperoxygenation is achieved by first completely saturating the hemoglobin and then
by increasing the amount of oxygen dissolved in the plasma. This increases the distance of
oxygen diffuses away from the capillaries. This is three times higher than under normal
conditions.
2. Vasoconstriction Vasoconstriction caused by hyperbaric oxygen therapy does not reduce
oxygenation, on the contrary it has a beneficial effect of reducing edema in skin grafts and
flaps.
3. Anitmicrobial activity Hyperbaric oxygen therapy is bactericidal to obligate anaerobes.
It also increases the ability of polymorphs to kill bacteria. It is also known to inhibit and
inactivate the toxins released by clostridium welchi, thereby preventing gas gangrene.

76

4. Pressure effects Hyperbaric oxygen is used to reduce the size of gas bubble. Because of
this feature it is the treatment of choice in decompression sickness.
5. Neovascularisation
6. Fibroblastic proliferation
7. Improved functioning of osteoblasts and osteoclasts
8. Increased red cell deformability

Contraindications
Absolute contraindications:
1. Pneumothorax
2. Pulmonary damage

Relative contraindications:
1. Pulmonary bulla
2. Seizure disorder
3. Patients on high dose of steroids
4. Chronic obstructive pulmonary disorders
5. Recent myocardial infarction
6. Patients with claustrophobia

Complications
1. Middle ear barotrauma This can occur if the patient is unable to equalise the middle ear
pressure. This complication can be best avoided by the use of systemic and topical nasal
decongestants before proceeding with hyperbaric oxygen therapy. If this condition occurs
then myringotomy should be resorted to without hesitation.
2. Myopia This is temporary and reverses back to normal after cessation of treatment.
77

3. Pneumothorax This can occur if decompression occurs too rapidly or if the patient holds
the breath during decompression.
4. Oxygen induced seizures This complication is very rare. These patients should be given
vitamin E before treatment to protect against superoxide radicals. Oxygen induced seizures
can be stopped by allowing the patient to breath normal air. Oxygen induced seizures are not
known to cause permanent neurological sequelae.

Marx Miami university protocol for treatment of osteoradionecrosis

Stage I
30x (100% O2 for 90 mins at 2.4 ATA)
Examine exposed bone

No surgery
No antibiotics
Saline solution rinse only

Cutaneous fistula
Pathological fracture
Resorption of inferior border
of mandible

10x (100% O2 for 90 mins at 2.4 ATA)

(Stage I responder )

No response

78

Stage II
Surgery (Maintain inferior border of
mandible )
Response

10x (100% O2 for 90 mins at 2.4 ATA)

Healing without exposed bone

No response

(Stage II responder )
Stage III
Excision of nonviable bone
Fixation of mandibular segments
10x (100% O2 for 90 mins at 2.4 ATA)
Reconstruction after 3 months
No further HBO required

Ultrasound TherapyUltrasound has proved to be therapeutically valuable in many ways, including:

1.
2.
3.
4.
5.
6.
7.

Stimulation of tissue.
Regeneration
Increase blood flow in chronically ischaemic muscles
Protein synthesis in fibroblasts
Healing of ischemic varicose ulcers.
Tendon repair
Angiogenesis in full thickness excised incisions in the flank skin of adult rats and in
chick chorioallantoic membrane. Local stimulation of fracture repair in rabbits and
rabbits have also been evaluated. Ultrasound was also used in human tibial fractures,
in a prospective, randomised, double-blind evaluation. The results showed that the
treated group had a significant decrease in the time to clinical healing.

79

StudiesHarris was the first author to use therapeutic ultrasound for the treatment of
mandibular osteoradionecrosis. This was based on previous uses of ultrasound as a simple
means of promoting neovascularity and neocellularity in ischaemic tissues. 34
Telfah using near infrared spectroscopy has demonstrated that patients with
osteoradionecrosis who received ultrasound therapy showed significant improvements of the
metabolic activity (improvements of deoxyhaemoglobin concentrations).67
The methyxanthine derivative, pentoxifylline, used in the treatment of intermittent
claudication has been used with some success in radiation induced soft tissue injury but its
efficacy in osteoradionecrosis is unclear.

SURGICAL MANAGEMENTAdvanced, symptomatic cases, which have failed conservative measures, will require radical
surgery.

Preoperative work-up
Exclusion of local recurrence:
The first and most important step is to rule out a local recurrence of a malignancy
through a biopsy. Unfortunately, a recurrence will not be identified in 21% of cases until
pathologic examination of the sequestrectomy specimen has been completed. Therefore,
some believe that surgical treatment of osteoradionecrosis should be as radical as primary
tumor surgery.
A computed tomography scan or magnetic resonance imaging is performed to
preoperatively estimate the margins of bony resection. The definite extent of resection,
however, can only be determined intraoperatively with margins that demonstrate healthy,
bleeding bone.
80

PROTOCOL FOR DENTAL EXTRACTION

Diseased and at-risk teeth are described as those with caries extending into the pulp
chamber, those with periapical lesions, periodontal pockets over 4-5 mm, furcation
involvements of Grade 2 and mobility of Grade 2 or more. Extractions should be performed a
minimum of 2 weeks prior to the beginning of radiation therapy. Teeth that should be treated
are those within a field of radiation expected to exceed 50 Gy.
Irradiated head and neck cancer patients needing dental extractions may benefit from
HBO. HBO may also be indicated as a therapy prior to reconstruction of the mandible and
other facial structures. Treatment would usually consist of 20 dives prior to dental
extraction or reconstruction, followed by the primary closure or extraction and then 10 postoperative dives. (A dive is a term given to the period of time when the hyperbaric chamber
is slowly pressurized with air. Once at the correct pressure, the patient would begin breathing
100% oxygen.)
Daniel E. Jolly used this approach at The Ohio State University Medical Center,
Hyperbaric Medicine Unit. Patients were given 20 dives at 2.4 ATM of pure oxygen for 90
minutes (excluding pressurization and depressurization time) prior to dental extractions then
an additional 10 dives immediately following extraction of teeth. Utilizing this approach, the
author has treated more than two dozen patients in the last decade, and none have developed
osteoradionecrosis.45

Sequestrectomy Definition:

81

Sequestrectomy is the procedure which involves the removal of devitalized portions

of the bone that have been separated from the adjacent bone. 77
Although spontaneous sequestrectomy may occur in many cases, it is often necessary to
resort to operative procedures to lessen the suffering of the patient, especially if
complications develop. A sequestrectomy can be done if the radiographic and clinical
findings indicate some separation has occurred.

Procedure
This surgical procedure is performed under general anesthesia.
An intraoral approach is preferred because of skin and vascular damage resulting from the
irradiation. The incision is made over the alveolar ridge to expose the entire sequestrum.
Often it is necessary only to extend the already existing opening. The soft tissue is then
detached from the bone by blunt dissection, and the sequestrum is lifted out, unless it is partly
attached, in this case it should be separated by careful use of a sharp osteotome.
Any remaining necrotic bone should be removed with rongeurs. Generally granulation
tissue covers the bone from which the sequestrum has been separated. The wound should be
irrigated daily. Before discharge from the hospital the patient should be taught to use syringe
and saline solution to flush accumulated food from the defect.
Obwegeser (1962) stated that the delay until sequestration takes place frequently
leads to unnecessary loss bone, and he recommends early removal of necrotic bone. He found
the boundaries of necrotic bone by drilling the cortex until bleeding occurs. Osteotomy was
performed. This was in agreement with Meyer (1958) who recommended excision at least
1.5 cm in front of and behind the area of clinical and radiographic evidence of bone necrosis.

82

Resection with continuity defect Definition:

It is a procedure where some portion of the mandible is resected surgically leaving continuity
at the inferior border of mandible.77

Indication:
Surgical resection with continuity defect is indicated in osteoradionecrosis following
irradiation of the mandible. If waiting for sequestration is not desirable because of persistent
pain, infection or pathologic fracture, an ostectomy can be performed on the healthy part of
jaw. This prevents spread of infection and ensures better healing of the soft tissues, since
tissue more distant from irradiated field is likely to heal better.
Mostly intraoral approach is preferred because serious damage and impairment of the
skin circulation often occur due to the extraoral radiography, extraoral incision may result in
83

orofacial fistula.
Procedure:
This surgical procedure is performed under general anesthesia. The procedure can be
performed through either of the 2 approaches:
A] Extraoral approach.
B] Intraoral approach.

Extraoral approach:
This surgical procedure is performed under general anesthesia. The lower lip is split,
and a vertical incision is made up to the level of chin. The incision is then turned horizontally
about 1/2 inch below the lower border of the mandible. The horizontal arm of the incision is
extended up to the level of the angle of mandible. At the level of the angle of the mandible
the incision is turned upwards vertically and extended up to the level of the mastoid tip. Then
blunt dissection was performed deep down the bone, close to the mental foramen, there may
be bleeding because of the presence of neurovascular bundle. Vessels coming out of the
mental foramen are cauterised. The lower incisor is removed. The inner surface of the
mandible is slowly exposed by dissecting the oral mucosa. Using a gigli saw a vertical cut is
made in the mandible up to the level of mentum. This splits the mandible vertically. The
mandible is freed anterirorly from the muscles attached i.e.
-

Depressor labi inferioris

Depressor anguli oris
Platysma

The part of mandible to be resected is freed from the attachments to the oral mucosa
gently.The lateral surface of the mandible is freed from the attachments of masseter
muscle. The second osteotomy is made just below the level of condylar process. The whole

84

lesion of the mandible is freed and removed. The inner mucosal lining is reconstructed
using either the buccal mucosal flap or a tongue flap.
Recent work with microvascular surgery (Donoff and May in 1982)
employing rib grafts with their blood supply left intact and connected to the vascular supply
of the area holds great promise. As yet, an insufficient amount of data on this new technique
is available, but early results look promising.

Intraoral approach
This surgical procedure is performed under general anesthesia. Technique is
developed and standardized by Meyer (1958) for either intraoral partial resection or total
disarticulation. This also has been reported by LaDow (1950), Marchetta, Sako and
Holyoke (1967), Friedlander, Mazzarella and Kisner (1979).
Procedure
This procedure is done under general anesthesia. An intraoral incision is started high
on the anterior border of the ramus and carried downward and forward along the alveolar
crest to the midline of the mandible. It then is extended labially deep into the mucogingival
sulcus and lingually just distal to the orifice of Whartons duct. The lateral alveolar mucosa is
stripped from the mandible with a broad periosteal elevator covered with gauze. After the
mental foramen is exposed, the neurovascular bundle is isolated, ligated and cut. The
stripping is continued to the inferior border of the body of mandible and then posteriorly to
line the insertion of the masseter muscle from the inferior border of the ramus. This will
cleanly expose the lateral aspect of the ramus.
The lingual aspect of the mandible is stripped in a similar manner to remove the
insertion of the mylohyoid, anterior belly of digastric and the medial pterigoid muscle and to

85

reflect the submandibular salivary gland with its enveloping fascia and medial surface of the
ramus is exposed up to the lingula.
With either an oscillating saw or Gigli saw brought under the mandible with right
angle gall bladder clamp, the mandible is sectioned just anterior to mental foramen.
Sometimes it is expeditious to place drill holes along the line of section and to complete the
actual sectioning with an osteotome. When instruments are being used, soft tissues must be
protected. If possible, it is wise to maintain the anterior curve of the mandible for esthetic
reasons. Bone wax must be applied if there is excessive bleeding.
The posterior portion may be exposed by turning the anterior body outward with bone
holding forceps which permits completion of the stripping of the lingual aspect of ramus. As
elevation of the lingual soft tissue attachments is advanced, the inferior alveolar
neurovascular bundle is encountered which, should be ligated and cut. If a partial resection of
the mandible will give an adequate margin beyond the area of known osteoradionecrosis, the
condylar and coronoid process may be preserved by sectioning the ramus horizontally with
the air drill along or combined with an osteotome. The segment of mandible thus excised is
easily lifted from its soft tissue bed. If a total disarticulation of the mandible is necessary,
stripping of the coronoid and condylar process should be completed. The insertions of lateral,
medial pterygoid, temporalis and masseter muscle should be detached with a periosteal
elevator. (Must be kept in contact with the underlying bone to avoid damage to internal
maxillary artery, vein and pterygoid plexus of veins).
Hemostasis is achieved by clamping and tying vessels, electroagulation and packing
with gelatine sponge. If there is infection or concern about formation of a hematoma, a rubber
drain may be placed for 24 to 36 hours and then remove. If the anterior part of the mandible
is removed completely, the detachment of the geniohyoid and genioglossus muscles may

86

allow the tonue to fall back and interfere with breathing. If necessary, silk suture should be
placed to pull the tongue.
Meyer (Between 1951 and 1981) performed more than 75 intraoral mandibulectomies
(Both partial resections and disarticulations) for osteoradionecrosis with no fatalities and
minimal morbidity from conditions such as orofacial fistulae, sloughing and nutritional
problems.

Resection of mandible without continuity defect

87

Resection of mandible with continuity defect (Bone defect after resection of the lesion.)

Resection of mandible with continuity defect (After bone plating)

Complications:
1.Bleeding
2. Cosmetic defects (gump deformity)
3. Inability to chew food

88

Reconstruction:
Goals of reconstruction :
Bony reconstruction of the jaws in cancer-related deformities presents several
unique problems that have historically produced low success rates and high morbidity. Large
spans of discontinuity, soft tissue deficiency, irradiated tissue and extreme scarring with bony
displacement are some of the more obvious problems. Particular goals of reconstruction are
to restore function of the jaw bone, especially with regard to food processing, swallowing and
intelligible speech production and to restore the appearance of the (lower) face.
Hyperbaric oxygen and delayed bone graft reconstruction :
Most authors feel that the availability of reconstructive microvascular surgery has
made Marx's algorithm of preoperative HBO followed by resection and delayed
nonvascularized bone graft reconstruction outdated and of questionable efficacy. However, if
microvascular expertise or instrumentation is not available, it has been stated that this 2-phase
bone healing concept can produce predictable reconstructions, although no data proving this
were presented. After 30 presurgical HBO treatments, a sequestrectomy is performed in
combination with bony stabilization with a reconstruction plate and immediate soft tissue
coverage using a myocutaneous flap. Routinely, the pectoralis major myocutaneous flap is
89

used, but latissimus dorsi, trapezius or sternocleidomastoid flaps may also be used to fit a
particular need. Postoperatively, each patient receives 10 HBO treatments and about three
months later bony reconstruction is performed using a nonvascularized posterior ilium bone
graft (cortical bone and cancellous bone marrow).

Microvascular free tissue transfer:

It has been generally accepted that wide radical resection of necrotic bone with
immediate free flap reconstruction is often the only and best option for the treatment of
advanced osteoradionecrosis. In addition, perioperative adjunctive HBO therapy is often
given, although it has not been conclusively proven to be of benefit. The key to successful
treatment in these advanced osteoradionecrosis cases is adequate and radical sequestrectomy
and replacement with healthy vascularized tissue with its pedicle outside the radiation field.
Furthermore, it should be realized that osteoradionecrosis affects surrounding soft tissue and
is not only a disease of the bone.
Several free flaps such as the scapula bone flap (in combination with either a
parascapular skin island or partial latissimus dorsi muscle), iliac crest flap or soft tissue only
flaps (rectus abdominis and latissimus dorsi myocutaneous flaps) have been used, but the
osteocutaneous fibula free flap is generally considered the workhorse flap. The fibula free
flap offers many advantages, especially if the defect involves the anterior mandibular arch. It
allows the surgical team: to obtain adequate length of bone up to 25 to 27 cm, to perform the
reconstructive procedure while doing the resection, to perform multiple osteotomies without
endangering its viability and to obtain a vascular pedicle up to 12 to 15 cm which is

90

important because identification of adequate recipient vessels may be difficult in these

patients with a heavily irradiated neck. Furthermore, the donor-site morbidity is generally
minimal and compared to the iliac crest flap. Sometimes, after radical osteoradionecrosis
resection composite through-and-through defects exist, which require a second free flap for
reconstruction of the external skin defect of the lower face or neck. As already mentioned,
recipient vessel identification and dissection in a previously operated and irradiated neck can
be tedious. It often requires more delicate dissections, sometimes with the aid of a
microscope. However, it is better to select vessels outside the irradiated field as the
superficial temporal or transverse cervical vessels or to select vessels from the opposite neck.
Although the cephalic turnover vein for venous anastomosis and the external carotid artery
for arterial anastomosis may be used if no native neck vessels are suitable, it may sometimes
be necessary to resort to interposition vein grafts.

91

Complications:
Surgical management of osteoradionecrosis patients is challenging and complex
because previous surgery and irradiation results in obliterated tissue planes and higher risk for
wound healing problems, respectively. In experienced hands partial or total free flap loss
which requires a second free flap or regional myocutaneous flap may range from 0% to 15%.
Local wound healing problems resulting in dehiscence, plate exposure or orocutaneous fistula
formation may occur in 8% to 43%. Most of these latter complications, however, can usually
be managed successfully with conservative treatment.
Tumor recurrence and survival:
Reported tumor recurrence rates after osteoradionecrosis reconstruction range
from 0% to as high as 25% with a follow-up time up to 62 months. Patient survival rates (not
necessarily disease free) usually are around 70% to 80% with a maximum follow-up of 62
months.

Functional and aesthetic outcome and dental rehabilitation:

92

Studies on outcome and dental rehabilitation after osteoradionecrosis are limited.

Very few patients after osteoradionecrosis reconstruction receive osseointegrated dental
implants. However, there is limited evidence that implants placed in the reconstructed areas
have success and survival rates comparable to those obtained in case of implants placed in
native bone. Cordeiro et al reported long-term functional and aesthetic results of 133 fibula
free flap reconstructions of which only 8 were osteoradionecrosis cases. A total of 45% of all
patients were able to have a normal diet, 45% had to use a soft diet and 5% were on a liquid
diet. Speech was normal or near-normal in 63% and aesthetics were good to excellent in 59%.
Interestingly, these results were better after reconstruction of hemi mandible defects
compared to central defects. Extensive composite defects after radical osteoradionecrosis
resection requiring double free flap reconstruction have a poorer long-term aesthetic and
functional outcome with a higher occurrence of speech, eating and oral incontinence
problems.

Treatment of osteoradionecrosis according to the clinical course of the disease.

1.

EARLY STAGE
No discomfort associated with the lesion, wich has been present for only a short period of
time
1. Periodic follow-up of the irradiated patient: every 3 months during the first year, and
then every 6 months.
2. Avoid oral mucosal irritants (smoking, alcohol, removable dentures).
3. Introduction of good oral hygiene.
4. Irrigation of the lesions with 0.2% chlorhexidine (3 times/day).

2.

5. Introduction of pentoxifylline (800 mg/day) + vitamin AND (1000 IU/day).

INTERMEDIATE STAGE
Appearance of pain that may or may not improve with antibiotic treatment
93

1. Continued observation of good oral hygiene.

2. Continued irrigation of the lesions with 0.2% chlorhexidine.
3. Antibiotic treatment: amoxicillin / clavulanic acid (875 mg/3 times a day) +
ciprofloxacin (500 mg twice daily), until disappearance of the pain.
4. If the pain and discomfort persist, scantly invasive oral surgery can be carried out,
3.

provided the lesion is small (0.5-1 cm) and does not invade neighboring structures.
ADVANCED STAGE
Complications appear in the form of trismus, cutaneous fistula or mandibular fracture
1. The above measures apply.
2. Ablative surgery to eliminate the osteolytic areas.
3. Posterior reconstructive surgery with bone grafts, vascularized flaps or free grafts.

94

RECENT ADVANCES

95

New treatments have 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 osteoradionecrosis 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 osteoradionecrosis.
New treatment possibilities have recently been proposed, though not all of them are
supported by the desirable level of scientific evidence. Tocopherol (vitamin E) protects the
cell membrane against peroxidation, and partially inhibits expression of the procollagen gene
and TGF-1.20
A synergic effect has been observed between pentoxyphylline and tocopherol in the
treatment of osteoradionecrosis. These are moreover accessible, well tolerated and safe drugs.
Delanian et al. in the context of prolonged treatment (mean=169 months) of 54 patients
with osteoradionecrosis involving a pentoxyphylline dose of 800mg/day and vitamin E 1000
IU/day (5days a week), recorded an 89% reduction in bone exposure after 12 months, and an
even greater reduction over longer periods of treatment.
Ultrasound has been suggested with the purpose of promoting angiogenesis, with a
direct vasodilatory effect, inducing the synthesis of proteins and cytokines, and stimulating
the production of nitrous oxide and prostaglandin E2 on the part of the osteoblasts and
fibroblasts.5

96

Likewise, techniques such as bone distraction have been proposed to repair previously
resected areas, inducing progressive expansion of quality bone and neovascularization
in the zone.19

In turn, the use of certain biomolecules has been suggested with the aim of directly inducing
osteogenesis and thus regenerating the affected areas. These molecules comprise bone
growth factors such as bFGF and morphogenetic proteins such as BMP-1 and RHBMP2.5

However, the studies have been carried out in animal models, without clinical trials or
acceptable levels of evidence. Of all the new therapeutic models, the application of
antioxidant agents has offered the best results to date, in the context of controlled clinical
trials. Of these antioxidant agents, pentoxifylline derived from methylxanthine produces an
anti-tumor necrosis factor alpha effect, facilitates microcirculation, and inhibits the
inflammatory mechanisms, fibroblast proliferation and the formation of extracellular matrix.20

97

CONCLUSION

98

Osteoradionecrosis of craniofacial skeleton is a sever complication of head and neck

radiotherapy, and may be acute or appear. Head and neck cancer patients continue to pose a
challenge for surgeons and oncologists. Prevention of osteoradionecrosis by regular followup and early diagnosis should be the goal of every health care professional managing patients
with head and neck cancer. Improved radiotherapy protocols, multidisciplinary preventive
care and reconstructive surgery can help to improve the quality of life of patients suffering
from osteoradionecrosis. Recent advances like surgical free tissue transfer should be
considered as treatment of choice for long established cases of osteoradionecrosis,
particularly with pathological fracture.
Head and neck cancer patients continue to pose a challenge for Oral surgeons.
osteoradionecrosis can be a cruel blow to patients and their families who have been enduring
radiotherapy for the treatment of cancer. Improved radiotherapy protocols, multidisciplinary
preventive care and reconstructive surgery can help to improve the quality of their lives.

99

BIBLIOGRAPHY

100

1. Jansma J, Vissink A, Spijkervet FKL, Roodenburg JLN, Panders AK, Vermey A, Szab
BG, Gravenmade EJ (1992a) Protocol for the prevention and treatment of oral sequelae
resulting from head and neck radiation therapy. Cancer 70:2171-2180
2. Jansma J, Vissink A, Bouma J, Vermey A, Panders AK, Gravenmade EJ (1992b) A survey
of prevention and treatment regimens for oral sequelae resulting from head and neck
radiotherapy used in Dutch radiotherapy institutes. Int J Radiat Onc Biol Phys 24:359-367
3. Sulaiman F, Huryn JM, Zlotolow IM (2003) Dental extractions in irradiated head and neck
patient: a retrospective analysis of Memorial Sloan-Kettering Cancer Center protocols,
criteria and end results. J Oral Maxillofac Surg 61:11231131
4. Hutchinson IL (1996) Complications of radiotherapy in the head and neck: an orofacial
surgeon's view. In: Tobias JS, Thomas PRM (eds) Current radiation oncology. Arnold,
London, pp 144-177
5. Thosteoradionecrosis JJ, Hansen HS, Specht L, Bastholt L (2000) osteoradionecrosis of the
jaws: Clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg
58:10881093
6. Marx RE. Johnson RP (1987) Studies in the radiobiology of osteoradionecrosis and their
clinical significance. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 644:379-390
7. Katsura K, Sasai K, Sato K, Saito M, Hoshina H, Hayashi T (2008) Relationship between
oral health status and development of osteoradionecrosis of the mandible: a retrospective
longitudinal study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 105:731-738

101

8. Marx RE (1983a) osteoradionecrosis: a new concept of its pathophysiology. J Oral

Maxillofac Surg 41:283-288
9. Epstein JB, Wong FLW, Stevenson-Moore P (1987b) osteoradionecrosis: clinical
experience and a proposal for classification. J Oral Maxillofac Surg 45:104-110
10. Kluth EV, Jain PR, Stuchell RN, Frich JC Jr (1988) A study of factors contributing to the
development of osteoradionecrosis of the jaws. J Prosthet Dent 59:194-201
11. Reuther T, Schuster T, Mende U, Kbler A (2003) osteoradionecrosis of the jaws as a side
effect of radiotherapy of head and neck tumour patients A report of a thirty-year
retrospective review. Int J Oral Maxillofac Surg 32:289-295
12. Regaud C (1922a) Sur la necrose des os attent par un processus cancereux et traites par
les radiaions. Compt Rend Soc Biol 87:427
13. Ewing J (1926) Radiation osteitis. Acta Radiol 6:399-412
14. Meyer I (1970) Infectious diseases of the jaws. J Oral Surg 28:17-26
15. Titterington WP (1971) Osteomyelitis and osteoradionecrosis of the jaws. J Oral Med
26:716
16. Marx RE (1983b) A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac
Surg 41:351-357
17. Wong JK, Wood RE, McLean M (1997) Conservative management of osteoradionecrosis.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:16-21
18. Epstein JB, Wong FLW, Dickens A, Szasz I, Lepawsky M (1992) Bone and gallium scans
in postradiotherapy osteonecrosis of the jaw. Head Neck 14:288-292
19. Beumer J 3rd, Curtis T, Harrison RE (1979b) Radiation therapy of the oral cavity:
sequelae and management. Part 2. Head Neck Surg 1:392-400

102

20. Hutchinson IL, Colpe M, Delpy DT, Richardson CE, Harris M (1990) The investigation
of osteoradionecrosis of the mandible by near infrared spectroscopy. Br J Oral Maxillofac
Surg 28:150-154
21. Beumer J 3rd, Harrison R, Sanders B, Kurrasch M (1983a) Preradiation dental extractions
and the incidence of bone necrosis. Head Neck Surg 5:514-521
22. Harris M (1992) The conservative management of osteoradionecrosis of the mandible
with ultrasound therapy. Br J Oral Maxillofac Surg 30:313-318
23. Morrish RB Jr, Chan E, Silverman S Jr, Meyer J, Fu KK, Greenspan D (1981)
Osteonecrosis in patients irradiated for head and neck carcinoma. Cancer 47:1980-1983
24. Clayman L (1997) Clinical controversies in oral and maxillofacial surgery: part two.
Management of dental extractions in irradiated jaws: a protocol without hyperbaric oxygen
therapy. J Oral Maxillofac Surg 55:275281
25. Berger RP, Symington JM (1990) Long-term clinical manifestation of osteoradionecrosis
of the mandible: report of two cases. J Oral Maxillofac Surg 48:82-84
26. Lyons A, Ghazali N (2008) osteoradionecrosis of the jaws: current understanding of its
pathophysiology and treatment. Br J Oral Maxillofac Surg 46:653-660
27. Reher P (1999) Evidence for the use of ultrasound therapy for the management of
mandibular osteoradionecrosis. Doctorate Thesis, University of London
28. Murray CG, Daly TE, Zimmerman SO (1980a) The relationship between dental disease
and radiation necrosis of the mandible. Oral Surg Oral Med Oral Pathol 49:99104
29. Murray CG, Herson J, Daly TE, Zimmerman S (1980b) Radiation necrosis of the
mandible: a 10 year study. Part II. Dental factors; onset, duration and management of
necrosis. Int J Radiat Oncol Biol Phys 6:549553

103

30. Murray CG, Herson J, Daly TE, Zimmerman S (1980c) Radiation necrosis of the
mandible: a 10 year study. Part I. Factors influencing the onset of necrosis. Int J Radiat Oncol
Biol Phys 6:543548
31. Mainous EG, Hart GB (1975) Osteonecrosis of the mandible: treatment with hyperbaric
oxygen. Arch Otolaryngol 101,173-177
32. Bedwinek JM, Shukowsky LJ, Fletcher GH, Daley TE (1976) osteoradionecrosis in
patients treated with definitive radiotherapy for squamous cell carcinomas of the oral cavity
and naso- and oropharynx. Radiology 119:665-667
33. Van Merkesteyn JPR, Bakker DJ, Borgmeijer-Hoelen AMMJ (1995) Hyperbaric oxygen
treatment of osteoradionecrosis of the mandible: experience in 29 patients. Oral Surg Oral
Med Oral Patho1 Oral Radiol Endod 80:12-16
34. Curi MM, Dib LL (1997) Osteoradiadionecrosis of the jaws: a retrospective study of the
background factors and treatment in 104 cases. J Oral Maxillofac Surg 55:540-544
35. Granstrm G, Fagerberg-Mohlin B, Fomander J (1992a) Aspects on the management of
patients with osteoradionecrosis after therapy of head and neck cancer. XVIIIth Annual
Meeting of EUBS, pp 163-169
36. Daly TE, Drane JB, MacComb WS (1972) Management of problems of the teeth and jaw
in patients undergoing irradiation. Am J Surg 124:539-542
37. Coffin F (1983) The incidence and management of osteoradionecrosis of the jaws
following head and neck radiotherapy. Br J Radiol 56:851-857
38. Morton ME, Simpson W (1986) The management of osteoradionecrosis of the jaws. Br J
Oral Maxillofac Surg 24:332-341
39. Gowgiel JM (1960 Experimental radio-osteonecrosis of the jaws. J Dent Res 39:176197

104

40. Stevens MR, Marx RE (1981) Complete resolution of osteoradionecrosis with a new
protocol combining hyperbaric oxygen and resection. Scientific Abstracts session 63rd
Annual AAOMS Meeting.
41. Jereczek-Fossa BA, Orecchia R (2002) Radiotherapy-induced mandibular bone
complications. Cancer Treat Rev 28:65-74
42. Pasquier D, Hoelscher T, Schmutz J, Dische S, Mathieu D, Baumann M, Lartigau E
(2004) Hyperbaric oxygen therapy in the treatment of radio-induced lesions in normal tissues:
a literature review. Radiother Oncol 72:113
43. Mainous EG, Boyne PJ, Hart GB (1973) Elimination of sequestrum and healing of
osteoradionecrosis of the mandible after hyperbaric oxygen therapy: report of case. J Oral
Surg 31:336339
44. Assael LA (2004) New Foundations in Understanding Osteonecrosis of the Jaws. J Oral
Maxillofac Surg 62:125-126
45. Al-Nawas B, Duschner H, Grtz KA (2004) Early cellular alterations in bone after
radiation therapy and its relation to osteoradionecrosis. J Oral Maxillofac Surg 62:1045
46. Delanian S, Depondt J, Lefaix JL (2005) Major healing of refractory mandible
osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial.
Head Neck 27:114123
47. Store G, Eribe ERK, Olsen I (2005) DNA-DNA hybridization demonstrates multiple
bacteria in osteoradionecrosis. Int J Oral Maxillofac Surg 34:193-196
48. Delanian S, Lefaix JL (2004) The radiation-induced fibroatrophic process: Therapeutic
perspective via the antioxidant pathway. Radiother Oncol 73:119-131
49. Vozenin-Brotons MC, Milliat F, Sabourin JC, de Gouville AC, Franois A, Lasser P,
Morice P, Haie-Meder C, Lusinchi A, Antoun S, Bourhis J, Math D, Girinsky T, Aiqueperse

105

J (2003) Fibrogenic signals in patients with radiation enteritis are associated with increased
connective tissue growth factor expression. Int J Radiat Oncol Biol Phys 56:561572
50. Dambrain R (1993) The pathogenesis of osteoradionecrosis. Rev Stomatol Chir
Maxillofac 94:140147
51. Delanian S, Baillet F, Huart J, Lefaix JL, Maulard C, Housset M (1994) Successful
treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: clinical
trial. Radiother Oncol 32:1220
52. Riley P (1994) Free radicals in biology: oxidative stress and the effects of ionizing
radiation. Int J Radiat Biol 65:2733
53. Scully C, Epstein JB (1996) Oral health care for the cancer patient. Eur J Cancer B Oral
Oncol 32B:281-292
54. Meghji S (1992) Bone remodelling. Br Dent J 172:235-242
55. Jones SJ, Boyde A, Ali NN (1984) The resorption of biological and non biological
substrates by cultured avian and mammalian osteoclasts. J Anat Embriol 170:247-256
56. Beumer J 3rd, Curtis T, Harrison RE (1979a) Radiation therapy of the oral cavity:
sequelae and management, Part 1. Head Neck Surg 1:301-312
57. Store G, Boysen M (2000) Mandibular osteoradionecrosis: clinical behaviour and
diagnostic aspects. Clin Otolaryngol Allied Sci 25:378384
58. Epstein JB, Rea G, Wong FLW, Spinelli J, Stevenson-Moore P (1987a) Osteonecrosis:
Study of the relationship of dental extractions in patients receiving radiotherapy. Head Neck
Surg 10:48-54
59. Ardran G (1951) Bone destruction not demonstrable by radiography. Br J Radiol 24:107109

106

60. Fujita M, Harada K, Masaki N, Shimizutani K, Kim SW, Fujita N, Sakurai K, Fuchihata
H, Inoue T, Kozuka T (1991) MR imaging of osteoradionecrosis of the mandible following
radiotherapy for head and neck cancers. Nippon Acta Radiologic 51:892-900
61. Minn H, Aitasalo K, Happonen R-P (1993) Detection of cancer recurrence in irradiated
mandible using positron emission tomography. Eur Arch Oto Rhin Laryngol 250:312-315
62. Alexander JM (1976) Radionuclide bone scanning in the diagnosis of lesions of the
maxillofacial region. J Oral Surg 34:249-256
63. Weiner R (1990) The role of transferrin and other receptors in the mechanism of GA-67
localization. Nucl Med Biol 17:141-149
64. Matcher SJ, Cooper CE (1994) Absolute quantification of deoxyhaemoglobin
concentration in tissue using near infrared spectroscopy. Phys Med Biol 39:1295-1312
65. Beumer J 3rd, Brady FA (1978) Dental management of the irradiated patient. Int J Oral
Surg 73:208-220
66. Beumer J 3rd, Harrison R, Sanders B, Kurrasch M (1984) osteoradionecrosis:
Predisposing factors and outcomes of therapy. Head Neck Surg 64:819-827
67. MacDougall RH, Orr JA, Kerr GR, Duncan W (1990) Fast neuron treatment for
squamous cell carcinoma of the head and neck: final report of Edinburgh randomised trial. Br
Med J 301:1241-1242
68. Beumer J 3rd, Harrison R, Sanders B, Kurrasch M (1983b) Postradiation dental
extractions: a review of the literature and a report of 72 episodes. Head Neck Surg 6:581-586
69. Tong AC, Leung AC, Cheng JC, Sham J (1999) Incidence of complicated healing and
osteoradionecrosis following tooth extraction in patients receiving radiotherapy for treatment
of nasopharyngeal carcinoma. Aust Dent J 44:187-194

107

70. Oh HK, Chambers MS, Garden AS, Wong PF, Martin JW (2004) Risk of
osteoradionecrosis after extraction of impacted third molars in irradiated head and neck
cancer patients. J Oral Maxillofac Surg 62:139-144
71. Goldwaser BR, Chuang SK, Kaban LB, August M (2007) Risk factor assessment for the
development of osteoradionecrosis. J Oral Maxillofac Surg 65:2311-2316
72. Hehr T, Classen J, Welz S, Ganswindt U, Scheithauer H, Koitschev A, Bamberg M,
Budach W (2006) Hyperfractionated, accelerated chemoradiation with concurrent mitomycinC and cisplatin in locally advanced head and neck cancer, a phase I/II study. Radiother Oncol
80:3338
73. Studer G, Studer SP, Zwahlen RA, Huquenin P, Grtz KW, Ltolf UM, Glanzmann C
(2006) osteoradionecrosis of the mandible: minimized risk profile following intensitymodulated radiation therapy (IMRT). Strahlenther Onkol 182:283288
74. Johnson RP (1997) Discussion: osteoradionecrosis of the jaws: a retrospective study of
the background factors and treatment in 104 cases. J Oral Maxillofac Surg 556:545-546
75. Pigott KH, Dische S, Saunders MI (1993) The long-term outcome after radical
radiotherapy for advanced head and neck cancer. Clin Oncol 5:343-349
76. Marx RE: A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg

41:351, 1983.
77.AAOS-2010 workshop

108