Lip Teh 2005
OSTEORADIONECROSIS
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Definition: condition in which irradiated bone becomes devitalized and exposed
through the overlying skin or mucosa, persisting without healing for 3 months
unrelated to tumor recurrence
Affects the mandibular bone more frequently than any other bone in the head and
neck.
Anatomy
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A bone with a tenuous blood supply that is mechanically stressed is much more
susceptible to the development of osteoradionecrosis.
The craniofacial skeleton receives its blood supply in three distinct manners
1. direct muscular attachments
2. periosteal perforators,
3. intramedullary vessels.
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Most of craniofacial skeleton receive its blood supply through nutrient vessels from
the periosteum and muscular attachments
The mandible has different dominant blood supply according to various regions in
the bone itself.
1. posterior segment (condyle process and neck, coronoid, angle, and upper ramus
a. abundant blood supply from the surrounding musculature, either from
direct muscular attachments or through muscular perforators penetrating
the periosteum.
b. This area is typically less susceptible to radiation induced ischemia.
2. anterior segment of the mandible
a. primary nutrient source for the body, parasymphyseal, and symphyseal
regions is intramedullary, the inferior alveolar artery.
b. There is a second, far less significant blood supply from small periosteal
perforators in this region.
c. More susceptible to osteoradionecrosis
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In a study by Bras, et. al. on mandible resected during the course of treatment
for osteoradionecrosis, radiation induced obliteration of the inferior alveolar
artery was consistently found and was felt to be a dominant factor.
Histology
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7 histological features of radiation (early to late)
1.
2.
3.
4.
5.
6.
hyperemia
inflammation
thrombosis
hypocellularity
hypovascularity
fibrosis
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7. endarteritis
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2 essential mechanisms of damage
1. direct DNA damage to rapidly dividing cells
a. tumorogenesis long term
b. damage to skin stem cells – fibroblast lineage = reduced healing
c. damage to skin appendages – dry skin = prone to cracking
2. endarteritis
Pathophysiology
 Concepts of the pathogenesis of ORN have undergone change over the last decade.
Initially ORN was considered primarily an infection - irradiated bone was
traumatised and became infected.
 Common traumatic events which breached the overlying mucosa and thus allowed
ingress of bacteria were biopsies, cancer surgery, tooth extraction and denture
irritation.
 Hence treatment of ORN followed the classical principles of infection management;
removal of the cause, debridement, drainage and antibiotics.
 Current opinion:
1. it is rare at radiation therapy doses of less than 60 Gy
2. it is more common when brachytherapy is used
3. the mandible is more frequently affected than the maxilla or any other
bones of the head and neck
4. dental extractions, surgery, or trauma frequently precede the onset of
osteoradionecrosis
5. osteoradionecrosis is an issue of impaired wound healing rather than
infection, though secondary infection may be present.
Marx 3H Principle
 This concept was challenged by Marx in the early 1980s. He presented the view
that ORN was primarily a non-healing wound secondary to endarteritis.
1) hypovascular
2) hypoxia
3) hypocellular
 The effect of irradiation on the bone was to decrease the vascularity and cellularity
of both the hard and soft tissues.
 The tissues became hypoxic and when challenged by a traumatic insult were unable
metabolically and nutritionally to respond to the injury.
 In the hypoxic, injured tissues, macrophages are not stimulated to re-organize the
wound, fibroblasts fail to lay down new collagen and a chronic non-healing wound
results.
 Micro-organisms are essentially surface contaminants, and an effect rather than the
cause. Thus treatment should be aimed at reversing the hypoxia and increasing the
vascularity and cellularity of the tissue
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This sequence is
(1) radiation,
(2) hypoxic-hypovascular-hypocellular tissue,
(3) tissue breakdown in which cellular death and collagen lysis exceed synthesis and
cellular replication, and
(4) finally, the progression to non- healing wound in which the energy, oxygen, and
metabolic demands clearly exceed the supply.
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ORN (1) is not a primary infection of bone, rather a homeostatic imbalance, (2)
microorganisms play surface contaminant role only, and (3) trauma does not
necessarily need to be an inciting factor.
Newer evidence suggest that osteoclasts suffer radiation therapy-related effects
earlier than vascular alterations and that suppression of bone turnover via
osteoclasia is the true etiologic crux of osteoradionecrosis
a. high incidence of osteoradionecrosislike mandibular bone disease in
patients receiving bisphosphonate therapy for cancer-associated
hypercalcemia or metastatic osteolytic lesions
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ORN is, therefore, a problem of impaired and inadequate tissue turnover and
wound healing.
Incidence
 Prior to 1990, the incidence of osteoradionecrosis was approximately 15% after
conventionally fractionated irradiation dosed between 66 and 72 Gy.
 After 1990, the incidence of osteoradionecrosis was approximately 5% or less
after using either hyperfractionated radiation therapy at a dose of 72-80 Gy or
moderately accelerated fractionated radiation therapy with concomitant boost (6472 Gy)
Clinical
 Manifestations of ORN may include
1) Pain – usually earliest symptom
2) orocutaneous fistula
3) exposed necrotic bone
4) pathologic fracture
5) suppuration.
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Contributing factors:
1) dental hygiene
2) dental trauma
3) tumour location
 radiation therapy to the floor or mouth or oropharynx placed patients at
the greatest risk, followed distantly by oral cavity, unknown primary,
and salivary glands.
4) radiation dosage, delivery and fractionation
5) elapsed time since radiation
6) nutrition
7) alcohol and tobacco use,
8) concomitant surgery and chemotherapy.
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ORN is more commonly seen in the mandible than in the maxilla due
1) the relatively decreased vascularity and increased bone density of the mandible
2) the mandible often receives a greater dose of radiation than the maxilla
Types of ORN. (Marx)
 Type I is trauma-induced ORN - secondary to the synergistic effects of surgical
trauma and radiation closely coupled in time leading to devascularization of the
mandible.
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Type II (most common) – Trauma induced. Occurs years after radiation therapy.
Represents the progressive endarteritis and vascular occlusion of the nutrient vessels
in the bone, periosteum, and surrounding soft tissue with the absolute inability for
wound repair.
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Type III (spontaneous) - can occur anytime after radiotherapy but commonly
occurs 6 months to 2 years following radiotherapy, without any obvious preceding
surgical or traumatic event
Investigations
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Plain radiography of the mandible, such as OPG, depicts areas of local decalcification
or sclerosis.
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CT scanning and MRI may allow early diagnosis of ORN and better delineate the
extent of disease.
o
MRI depicts ORN with reduced bone marrow signal intensity on T1weighted images and increased signal intensity on T2-weighted images.
o
Absence of marrow signal on MRI can be used to identify significant
radiation injury in the mandible.
o
Panoramic radiography and CT scan images can be used to determine sites of
significant bone injury. Alteration in trabeculation, cortical thinning, and
sclerosis are common findings in sites of injury.
Treatment
Primary goals in the treatment osteoradionecrosis of the mandible:
1) elimination of the necrotic bone
2) improvement of the vascularity of the remaining radiation damaged tissues.
3) freedom from pain
4) retention or reconstruction of mandibular continuity
5) restoration of mandibular function including the ability to wear prosthodontic
appliances, if needed
6) maintenance of intact mucosa over the bone.
Conservative measures
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a. avoid irritants - alcohol, smoking, hot or cold foods, and all prosthodontic
appliances
b. course of systemic antibiotics (tetracycline)
c. oral rinses (saline solution or cholohexidine .2%)
d. analgesics.
Hyperbaric Oxygen
 HBO improves tissue healing by increasing the oxygen gradient in irradiated
tissues.
 In normal nonirradiated wounds, there is a central area of tissue injury
surrounded by tissue with normal perfusion, setting up a steep oxygen gradient
across the wound. Such gradients have been shown to be the physical–chemotactic
factor attracting macrophages to a wound.
 Lactate, iron and steep oxygen gradients stimulate macrophage-derived
angiogenesis factor and macrophage-derived growth factor, which in turn
promote capillary budding and collagen synthesis in wounds.
 However, in wounds with radiation tissue injury, which inevitably results in
diffuse damage, only shallow oxygen gradients are created.
 The stimulus for fibroplasia and angiogenesis is therefore lacking.
 HBO restores the steep oxygen gradient needed for wound healing.
 Irradiated tissue has a low PO2 of 5 - 15 mm Hg;
 HBPO increases this to 20 - 35 mm Hg
 Effect is to
a. Stimulate fibroblasts to proliferate and deposit collagen. Normally, the
hypoxic conditions do not allow the remaining fibroblasts to extrude
their intracellular procollagen; however, with the intermittent hyperoxic
conditions, a favorable environment exists for the collagen to be laid into
the tissue.
b. Stimulate angiogenesis - along this carefully formed collagenous
framework, capillary proliferation occurs gradually increasing the overall
vascularity in the tissue. This, in turn, allows for further fibroblast
proliferation and activity.
Indications
1) adjunctive treatment to surgery for patients with overt ORN
2) for prophylactic use for dental extractions in patients at risk for developing
ORN
 controversial – good results have been reported without HBO therapy.
Prevention with a high level of oral hygiene and more efficient radiation
technique seems to be adequate
Contraindications
1. untreated pneumothorax only absolute contraindication
2. seizure disorders - HBO exposure may potentiate seizures
3. upper respiratory tract infections and previous ear surgery
The Marx HBO protocol
1. 100% humidified oxygen
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2. 2.4 atmospheres absolute pressure
3. 90 minutes per treatment
4. 30 pre-treatment / 10 post treatment
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The rationale for the 10 post extraction sessions in this preventative protocol is to
reduce wound dehiscence through the promotion of collagen production at the
incision lines.
The 30/10 protocol is employed in the treatment of established osteoradionecrosis.
No surgery should be attempted before the first 30 HBO treatments have provided
sufficient angiogenesis to support surgical wounding.
After 30 treatments surgical management can be staged according to the extent of
improvement achieved after HBO and the size of sequestrum or area of osteolysis.
Unless HBO and surgery are combined in the management of ORN, the results are
not long lasting or satisfactory. Even though resection of stage three ORN seems
unduly aggressive, it has stood the test of time. By using the Marx protocols in the
treatment of ORN, more than 95 per cent of patients can be successfully cured of
their disease with predictable, functional and aesthetically acceptable outcomes.
Reconstruction
Challenging to restore mandibular continuity especially when considering
1) the proximity to oral contaminants
2) the compromised adjacent tissues,
3) the stress bearing requirements of a functional mandible.
The options of reconstruction include non-vascularized corticocancellous particulate
bone grafts or a vascularized flaps (pedicled or microvascular).
Before the use of hyperbaric oxygen to prepare the recipient bed for a graft, the use of
non-vascularized bone graft in irradiated beds showed a high failure rate -approaching
50%.
With the use of pre-reconstructive hyperbaric oxygen therapy under the Marx protocol,
however, the success rate has improved to approximately 90%.
Marx Stages of treatment
Stage I : HBO – 30 dives
Stage II : transoral debridement / sequestrectomy with attempts at primary mucosal
closure. If postoperative healing occurs, the patient undergoes an additional ten sessions
of HBO. In contrast, those patients showing evidence of wound dehiscence with bone
exposure advance to stage III.
Stage III : mandibular resection of the necrotic segment until the bone margins yield
viable bone, furthermore, for an orocutaneous fistula, the involved skin is excised
followed by closure.The segments of the mandible are stabilized either with an external
fixator or maxillomandibular fixation and the patient undergoes additional hyperbaric
oxygen therapy post operatively. For reconstructive purposes, Marx advocates waiting
ten weeks after resection stating this permits a graft to be placed into a sufficiently
vascular and cellular bed with intact mucosa. Prior to reconstruction an additional 20
dives were planned with ten dives post operatively.
Results: 15% resolved in stage I, 15% resolved during stage II, and the remainder (70%)
resolved in stage III.
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The Evidence
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Some evidence that HBOT
1. improves the probability of healing following hemimandibulectomy and
reconstruction of the mandible
2. improves the probability of achieving mucosal coverage and the restoration of
bony continuity with ORN
3. prevents the development of ORN following tooth extraction from a radiation
field;
4. reduces the risk of wound dehiscience following grafts and flaps in the head
and neck.
Although there was some trend toward secondary favourable outcomes in
neurological tissue, there was no evidence of benefit in important clinical
outcomes with established radiation brachial plexus lesions or cerebral tissue
injury.
Annane J Clin Oncol. 2004 Dec - Hyperbaric oxygen therapy for radionecrosis of
the jaw: a randomized, placebo-controlled, double-blind trial
o study was stopped for potentially worse outcomes in the HBO arm