AristeidisChronopoulos ,TheodoraZarra ,MichaelEhrenfeld andSvenOtto fi ndings.Aconcisereview Osteoradionecrosisofthejaws:de fi nition,epidemiology,stagingandclinicalandradiological CONCISEREVIEW

Osteoradionecrosis of the jaws: de finition, epidemiology, staging and clinical and radiological findings. A concise review

Aristeidis Chronopoulos

, Theodora Zarra

, Michael Ehrenfeld

and Sven Otto

1Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany;²Department of Endodontology, Dental School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Osteoradionecrosis (ORN) of the jaws is a pernicious complication of radiation therapy for head and neck tumours. This article aims to provide an update on data related to the definition, epidemiology, staging, and clinical and radiological findings of ORN of the jaws. Using certain keywords, an electronic search was conducted spanning the period from Jan- uary 1922 to April 2014 to identify the available related investigations. Pooled data were then analysed. ORN is described as exposed irradiated bone that fails to heal over a period of 3 months without evidence of persisting or recur- rent tumour. The prevalence of ORN varies in the literature. Several staging or scoring systems of ORN have been pro- posed. Clinical findings include ulceration or necrosis of the mucosa with exposure of necrotic bone. Radiological findings are not evident in the early stages of ORN. Furthermore ORN may not be apparent in imaging even when the disease is advanced. Taking into account the severity of ORN and the difficulties in diagnosing it early and accurately, the clinician should be aware of this complex entity in order to prevent its appearance or the development of more sev- ere complications.

Key words: Clinical findings, epidemiology, jaw, osteoradionecrosis, radiation therapy

INTRODUCTION

Osteoradionecrosis (ORN) is a pernicious complica- tion of radiotherapy in head and neck cancer. It was first described by Regaud

in 1922 and is still a clini- cal challenge. According to the most recent literature, ORN of the jaws is defined as exposed irradiated bone that fails to heal over a period of 3 months without any evidence of persisting or recurrent tumour

. The mechanism of pathogenesis is still under investigation. However, the most frequently reported reason is radiation arteritis. Radiation arteri- tis leads to the development of a hypocellular, hypo- vascular and hypoxic environment, which results in a pathological outcome

.

The purpose of this paper is to explore the current theories on the definition and staging systems of ORN of the jaws. In addition, the epidemiology and the clin- ical and radiological findings of ORN of the jaws, are critically reviewed based on the available literature.

Finally, critical issues and considerations are discussed and pathways for future research are proposed.

METHODS

An electronic search of three databases (PubMed, Sco- pus and the Cochrane Library) was performed using the keywords ‘osteoradionecrosis’, ‘radiotherapy’, ‘os- teonecrosis’, ‘osteoradionecrosis’ and ‘mandible’, ‘os- teoradionecrosis’ and ‘jaw’, ‘osteoradionecrosis’ and

‘radiotherapy’, ‘osteoradionecrosis’ and ‘staging’, ‘os- teoradionecrosis’ and ‘clinical findings’, ‘osteora- dionecrosis’ and ‘radiological findings’, to identify literature published in English and German between January 1922 and April 2014 (Table 1). Abstracts were obtained for all the titles identified during the electronic search. Two reviewers (A.C. and T.Z.) independently screened titles and abstracts to elimi- nate articles that were completely off-topic. No other exclusion criteria were utilised. Following exclusion of

doi: 10.1111/idj.12318

the articles irrelevant to the topic and the removal of duplicating papers, the remaining articles were care- fully reviewed and their findings were critically anal- ysed.

RESULTS Definition

Several attempts have been made in order to define ORN. Ewing

was the first to use the term ‘radiation osteitis’ to describe changes in bone after radiother- apy. In the following years, several terms were used to name these changes in bone, such as radiation osteitis, ORN and avascular bone necrosis

. In 1974, Guttenberg

proposed the term ‘septic ORN of the mandible’ to describe the stage of necrosis when irra- diated bone becomes superficially infected, ending up with a high risk of involvement of deeper structures.

In 1983, Marx

defined ORN as ‘an area >1 cm of exposed bone in a field of irradiation that failed to show any evidence of healing for at least 6 months’.

Marx also reported that superficial contamination and no interstitial infection was present. In 1987, Marx and Johnson

suggested the definition of ORN as: ‘The exposure of nonviable bone which fails to heal without intervention’. Epstein et al.

defined ORN as ‘an ulcer- ation or necrosis of the mucous membrane, with expo- sure of necrotic bone for more than 3 months’.

Widmark et al.

described ORN as ‘a non-healing mucosal or cutaneous ulcer with denuded bone, last- ing for more than 3 months’. Both Widmark and Marx excluded from their definition conditions with necrotic bone for which the mucosa and skin were intact. Store and Boysen

reported that exposed bone is sporadically present; radiological findings are evi- dent in all cases of ORN. In 1997, Wong et al.

defined ORN as ‘a slow-healing radiation-induced ischemic necrosis of variable extent occurring in the absence of local primary tumor necrosis, recurrence or metastatic disease’.

According to the literature published in the last 15 years, ORN of the jaws is defined as exposed irra- diated bone that fails to heal over a period of

3 months without evidence of persisting or recurrent tumour

. At the time of diagnosis, the necrosis might involve the bone superficially or deeply. It might be a process that progresses slowly or an active progressive state that can lead to a pathological frac- ture

.

Epidemiology

The prevalence of ORN varies widely in the literature (Table 2)

and ranges from 0.4% to 56%

. ORN usually affects patients over 55 years of age

. However, the most fre- quently reported prevalence rate is 5–15%

. In up to 20% of patients with persistent ORN which does not respond to aggressive treatment, bone dam- age is reported to be caused by recurrent disease or a second primary tumour

.

Staging

Several staging or scoring systems of ORN have been proposed (Table 3)

. These systems are based on response to hyperbaric oxygen (HBO) ther- apy, degree of bone damage, clinical–radiological find- ings, duration of bone exposure and treatment required.

Coffin

divided cases of ORN into two groups:

minor and major. Morton and Simpson

subdivided ORN into three groups – ‘minor’, ‘moderate’ and

‘major’. In 1983, Marx

proposed a three-stage sys- tem for ORN. According to his protocol, patients are categorised as Stage I if they exhibit exposed bone in a field of radiation that has failed to heal for at least 6 months and do not have a pathological fracture, cutaneous fistula or osteolysis to the inferior border.

In Stage I, all patients receive 30 sessions of HBO at 2.4 atmospheres absolute for 90 minutes at depth.

Patients who respond to HBO alone (Stage I respon- der) demonstrate a softening of the radiated tissues and spontaneous sequestration of exposed bone with formation of granulation tissue. Each Stage I respon- der undergoes an additional 10 HBO sessions and then the tissues are allowed to heal completely. Stage II patients are those who do not respond to the 30 sessions of HBO. This group is characterised by a large amount of non-viable bone that makes resorp- tion and sequestration from HBO-induced angiogene- sis alone impossible. Consequently, careful surgical debridement is required. Stage II patients undergo transoral resection with limited soft-tissue reflection.

In particular, surgical treatment includes extraction of involved dentition and a non-continuity bone resec- tion to clinically bleeding bone. Wound flaps are closed primarily and the patient is given 10 postsurgi- cal sessions of HBO. Tissues that heal without Table 1 Example of electronic search strategy in

PubMed

Search strategy Results

Osteoradionecrosis 1,980

Radiotherapy 286,652

Osteonecrosis 15,087

Osteoradionecrosis and mandible 636

Osteoradionecrosis and jaw 738

Osteoradionecrosis and radiotherapy 1,332

Osteoradionecrosis and staging 76

Osteoradionecrosis and clinical findings 177 Osteoradionecrosis and radiological findings 30

complication are treated with a prosthesis when required, similarly to Stage I responders. Stage III patients are characterised by having a large quantity of non-viable bone and/or soft tissue unable to be managed by HBO-induced angiogenesis alone or HBO combined with local sequestrectomy. In addition to 30 presurgical HBO treatments, each Stage III patient requires a continuity resection, stabilisation and 10 postsurgical sessions of HBO, and are sched- uled for later (usually 3 months) reconstruction (Stage III-R). Stage III patients are therefore those who fail to respond to Stage I and Stage II treatment and those who initially present with a pathological fracture, cutaneous fistula or osteolysis to the inferior bor- der

.

Epstein et al.

suggested a new staging system for ORN with three tiers based on clinical findings.

Glanzmann and Gratz

proposed a system based on the duration of bone exposure and necessity of treat- ment. Clayman

introduced a classification of ORN related to the integrity of the overlying mucosa.

According to this classification, type I includes cases of ORN in which bone lysis occurs under intact gin- giva or mucosa. Type II includes more aggressive cases of ORN in which soft tissues break down and

the bone is exposed to saliva, causing secondary con- tamination. This is defined as radiation osteomyelitis.

Type I cases heal with conservative therapy; type II cases do not. In 2000, Store and Boysen

introduced a new classification of ORN that is based on the pres- ence or absence of clinical and radiological signs.

The most recently designed staging systems are these of Schwartz and Kagan

and Notani et al.

The system of Schwartz and Kagan

is based on clin- ical and radiological findings. Notani et al.

divided the cases into three grades based on the extent of the ORN lesion. Grade I is defined as ORN confined to the alveolar bone. Grade II is defined as ORN limited to the alveolar bone and/or the mandible above the level of the mandibular alveolar canal. In Grade III the ORN extends to the mandible under the level of the mandibular alveolar canal and a skin fistula and/

or a pathological fracture is present.

Clinical findings

Clinical signs and symptoms of ORN include ulcera- tion or necrosis of the mucosa with exposure of necrotic bone for longer than 3 months, pain, trismus and suppuration in the area (Figure 1a)

. Table 2 Incidence of osteoradionecrosis (ORN) in different studies

Study Year Period Total number

of patients

Prevalence of ORN (%)

Mean irradiation dose

Watson and Scarborough²⁰ 1938 1930–1937 1,819 12.9

Martin and Sugarbaker²¹ 1940 103 25

MacComb²² 1962 1952–1959 251 37.1

MacDougall et al.²³ 1963 364 5

Grant and Fletcher²⁴ 1966 1954–1962 176 37.5 10,000*

Rahn and Drane²⁵ 1967 1960–1962 120 44.2

Rankow and Weissman²⁶ 1971 176 6.3 5,000*

Wang²⁷ 1972 262 5.8

Cheng and Wang²⁸ 1974 76 17.1 2,500*

Marciani and Plezia²⁹ 1974 220 10.5

Bedwinek et al.³⁰ 1976 1966–1971 381 14.2 7,000*

Murray et al.³¹ 1980 1966–1975 653 21.1 5,000*

Morrish et al.¹⁹ 1981 1971–1977 100 22 7,500*

Epstein et al.³² 1987 1977–1984 1,000 2.7 6,000*

Withers et al.³³ 1995 1976–1985 676 4.7 65^†

Turner et al.³⁴ 1996 1980–1987 333 5.9 55^†

Thorn et al.¹⁶ 2000 1992–1998 80 74 60^†

Storey et al.³⁵ 2001 1965–1995 83 6 60^†

Reuther et al.³⁶ 2003 1969–1999 830 8.2 60^†

Oh et al.³⁷ 2004 1989–2004 81 4.9 52.6^†

Studer et al.³⁸ 2004 1980–1998 268 12.5 60^†

Ben-David et al.³⁹ 2007 1996–2005 176 0 65^†

Jham et al.⁴⁰ 2008 2003–2005 207 5.5 58.9^†

Katsura et al.⁴¹ 2008 1996–2003 39 15 60.7^†

Gomez et al.⁴² 2009 2000–2006 35 5 60^†

Lee et al.⁴³ 2009 1990–2000 198 6.6 60^†

Stenson et al.⁴⁴ 2010 1994–2008 27 18.4 62^†

Gomez et al.⁴⁵ 2011 2000–2007 168 1.2 67.9^†

Monnier et al.¹⁷ 2011 2000–2007 73 40 66^†

Crombie et al.⁴⁶ 2012 2000–2007 54 36 69.7^†

Niewald et al.⁴⁷ 2013 1993–2001 99 12 72

Tsai et al.⁴⁸ 2013 2000–2008 402 7.5 70^†

*Radiation dose given in rads.

†Radiation dose given in Grays (Gy).

Neurological symptoms, such as pain, dysaesthesia or anaesthesia, as well as fetor oris, dysgeusia and food impaction in the area, are also usually present. Expo- sure of rough and irregular bone can result in physical irritation of adjacent tissues. Progression of ORN may lead to pathological fractures, intra-oral or extra-oral fistulae and local or systemic infection. Difficulties in mouth opening, mastication and speech frequently arise

. In patients treated with external beam

radiation therapy (EBRT), osseous alterations usually appear in the body of the mandible (premolar and molar regions), whereas in those managed with brachytherapy, the lingual or buccal surfaces are affected

.

The diagnosis of septic ORN appears to be easier.

Marked pain is the primary symptom. A thorough clinical examination will reveal intra- or extra-oral draining fistulae, ulcerations of the mucous Table 3 Classification systems of osteoradionecrosis (ORN)

Study Stages Description of stages Basis of stage

Coffin⁵⁵ 2 Minor A series of small sequestra which separate spontaneously after varying periods of weeks or months. These areas cannot be demonstrated radiologically

Clinical and radiological findings

Major Necrosis occurring to an extent that involves the entire thickness of the jaw, and a pathological fracture is inevitable. This form can be obviously seen radiologically

Marx² 3 Stage I Exposed alveolar bone without pathologic fracture, which responds to HBO therapy

Response to HBO therapy Stage II Disease does not respond to HBO therapy, and requires sequestrectomy and

saucerisation

Stage III Full-thickness bone damage or pathological fracture, usually requires complete resection and reconstruction with free tissue

Morton and Simpson⁵⁶

3 Minor Ulceration with exposed bone and a history of bony spicules that healed spontaneously over a period of months

Clinical findings and response to treatment Moderate Exposed bone and small sequestra limited in nature and healing spontaneously

with conservative treatment within 6–12 months

Major Large areas of exposed bone, with formation of large sequestra, possible fracture and sinus formation. These cases often require radical treatment Epstein

et al.³²

3 Stage I Ia Ib

Resolved, healed No pathological fracture Pathological fracture

Disease progression

Stage II IIa IIb

Chronic, persistent non-progressive No pathological fracture Pathological fracture Stage III

IIIa IIIb

Active, progressive No pathological fracture Pathological fracture Glanzmann

and Gratz⁵⁷

5 Stage 1 Bone exposure without signs of infection and persisting for at least 3 months Duration of bone exposure and treatment necessity

Stage 2 Bone exposure with signs of infection or sequester and without the signs of Grades 3–5

Stage 3 Bone necrosis treated with mandibular resection with a satisfactory result Stage 4 Bone necrosis with persisting problems despite mandibular resection Stage 5 Death from ORN

Clayman⁵⁴ 2 Type I Bone lysis occurs under intact gingiva or mucosa Clinical findings Type II A more aggressive type in which soft tissues break down, exposing the bone to

saliva, and causing secondary contamination Store and

Boysen¹¹

4 Stage 0 Mucosal defects only Combination of

radiological and clinical parameters

Stage 1 Radiological evidence of necrotic bone with intact mucosa Stage 2 Positive radiological findings with denuded bone intra-orally

Stage 3 Clinically exposed radionecrotic bone, verified by imaging techniques, along with skin fistulae and infection

Schwartz and Kagan⁵⁸

3 Stage I Minimal soft-tissue ulceration and limited exposed cortical bone. Patients are treated with conservative management

Imaging and clinical findings

Stage II IIa IIb

Localised involvement of the mandibular cortex and underlying medullary bone

Minimal soft tissue ulceration

Presence of an oro-cutaneous fistula and mild soft-tissue necrosis Stage III Full-thickness involvement of the bone, including the inferior border.

Pathological fractures may also be present Notani

et al.⁵⁹

3 Stage I ORN confined to alveolar bone Clinical findings

Stage II ORN limited to the alveolar bone and/or mandible above the level of the inferior alveolar canal

Stage III ORN involving the mandible below the level of the inferior alveolar canal and/

or skin fistula and/or pathological fracture HBO, hyperbaric oxygen.

membrane, exposed devitalised bone, haemorrhage, cellulitis or pathological fractures. A biopsy is manda- tory for final diagnosis in order to exclude metastatic cancer

.

Radiological findings

Radiographs, computed tomography (CT) scans, mag- netic resonance imaging (MRI), Doppler ultrasound, nuclear medicine and near-infrared spectroscopy are often indicated in order to detect ORN

.

ORN is not usually detectable radiographically in early stages

. Imaging features are not correlated to the severity of ORN

. The described radio- graphic features range from normal appearance, to localised osteolytic areas, extensive osteolytic areas, sequestra and fracture (Figure 1b). Radioluncies indi- cating post extraction sockets will often remain visible for longer than 12 months (Figure 2a). The most defi- nitive radiographic alterations in early disease are increased radiodensity, as well as a mixed radio- opaque/radiolucent lesion in which radiolucent areas represent bone destruction (Figure 2b)

.

Orthopantomogram (OPT) is the most frequently used imaging method for the diagnosis of ORN and is usually supplemented with other extra-oral or intra- oral radiographs. In an OPT, ORN is depicted as an undefined radiolucency, without sclerotic demarca- tion, which surrounds necrotic zone. Radiopaque areas can be identified when bone sequestra are formed. In order to be visible in an OPT, a substantial alteration in mineral content and extensive involve- ment of bone is required and this only occurs in later stages of ORN

. Ardran

noted that a 30% loss of bone mineral content is necessary before any radio- graphic change can be seen.

CT

shows osseous abnormalities, such as focal lytic areas, cortical interruptions and loss of the spon- giosa trabeculation on the symptomatic side, fre- quently accompanied by soft-tissue thickening. Such a picture may cause difficulties in differential diagnosis between ORN and recurrent tumour

. In MRI with gadolinium administration, an abnormal marrow sig- nal, cortical destruction and slight-to-mild irregular enhancement is demonstrated

. MRI has the advantage of excellent tissue contrast and high spatial resolution

.

Bone scintigraphy permits estimation of the exten- sion and location of the lesion. It shows high sensitiv- ity (up to 100%) but low specificity (about 60%) for the diagnosis of ORN

. Scintigraphy using 99mTc-

(b)

Figure 1. A 69-year-old man presented with pain and a non-healing wound in the left lower jaw. The patient was an active smoker, suffered from pharynx cancer and had received radiotherapy (external beam radio-

therapy with standardfield sizes, conventional fractionation and mean dose 64 Gy) and chemotherapy. Clinically, exposed necrotic bone in the left lower jaw, inflammation, swelling and inferior alveolar nerve hypes- thesia was present (a). The orthopantomogram revealed pathologic frac-

ture of the left lower jaw (b). The patient was diagnosed with osteoradionecrosis of the lower jaw and was scheduled to be treated

surgically.

(a)

(b)

Figure 2. Orhtopantomograms of patients who have received radiother- apy (external beam radiotherapy with standardfield sizes, conventional

fractionation and mean dose 64 Gy) for oropharyngeal cancers. The patients underwent extractions of teeth of the lower jaw after completion

of radiotherapy. The orthopantomogram revealed radiolucencies indicat- ing post extraction sockets, which remained visible for longer than 12 months (a), as well as increased radiodensity with mixed radio-opa-

que/radiolucent lesions, where the radiolucent areas represent bone destruction (b).

marked diphosphonates (99mTc-MDP) allows highly sensitive depiction of mandibular lesions as a result of their altered phosphate metabolism. Pathophysiologi- cal changes in bone can be identified sooner when using 99mTc-MDP than when using conventional radiography because scan changes reflect osteoblastic activity and good blood flow

. Low spatial resolution and over-projection by soft tissues are the major dis- advantages of the method, which can be overcome with the use of single photon emission computed tomography (SPECT)

. Finally, positron emission tomography (PET), which is a promising method for pretherapeutic assessment of the spread of squa- mous cell carcinomas, has been advocated as being efficient for differentiating between ORN and tumour recurrence

.

Discussion and Conclusion

Irradiation of bone is the main prerequisite for devel- opment of ORN. A differential diagnosis is required to exclude recurrence of tumour and bisphosphonate- related osteonecrosis of the jaws. In contrast to the findings of Store and Boysen

, mucosal breakdown or failure of healing is necessary for the diagnosis of ORN

.

The duration of bone exposure is still a matter of controversy. Some authors did not state the period of time that bone was exposed

. Other authors recom- mended a 2-month period of exposed bone before diagnosis

, or even 3

to 6

months.

There are also cases in which a late diagnosis is pre- sent. Berger and Symington

reported two late pre- sentations: one 45 years after radium implant therapy; and the other 38 years after external beam treatment.

A very short waiting period can lead to over-diagno- sis as mucosal radionecrosis can occur without ORN.

Moreover, any surgery and/or extraction usually takes up to 1 month to heal. On the other hand, monitoring a trauma for a longer period (such as 6 months) is con- traindicated; intervention prior to this time is certainly needed. For the aforementioned reasons, in order to diagnose ORN, recent literature

indicates that bone exposure should be at least 3 months in duration.

The variability in prevalence of ORN can probably be attributed to differences in the study populations observation periods and existence of pretreatment dental assessment and dental management of cohorts.

The literature reports numerous factors which are associated with the risk of ORN development and also affect its prevalence. Total radiation dose, brachytherapy, fractionation, poor oral hygiene, alco- hol, tobacco use, dental extractions, tumour size and location, staging and chemotherapy have been high- lighted

.

The late onset of ORN can be attributed to the late occurrence of oropharyngeal cancers (OPCs) and their complications (mean age of patients over 60 years).

This can be explained by the fact that oral tissues tend to undergo prolonged exposure to potential carcinogens with advancing age. In addition, aging cells may be more susceptible to DNA damage. ORN is predomi- nant in the mandible (the ratio between ORN in the mandible and ORN in the maxilla is 24:1)

. The rea- son for this could be that the mandible has a restricted localised blood supply, which is often completely within the radiation field, whereas the maxilla has many anastomoses located outside the area of irradia- tion. Furthermore, mandibular bone density is different from maxillary bone density, and the mandible absorbs a higher amount of radiation during radiotherapy.

The prevalence of ORN has decreased since the 1990s

. Recent studies have shown a decrease in the prevalence of ORN to levels lower than 5%. Accord- ing to Clayman

, the application of megavoltage therapy resulted in a significant reduction of the over- all prevalence of ORN from 11.8% before 1968 to 5.4% after this time. Wahl

described similar results and noted a prevalence of ORN of 3% during the period 1997 to 2006. Lee et al.

found that the fre- quency of ORN was 6.6% among 198 patients with either oral cavity or OPCs treated with radiation between 1990 and 2000. The overall reduction of ORN can be attributed to the advent of megavoltage radiotherapy, improved dental-preventive care and improved radiation techniques, including three-dimen- sional conformal radiotherapy (3D-CRT) and inten- sity-modulated radiotherapy (IMRT)

.

Marx’s staging system

is based on the use of, and response to, HBO. The advantages of this protocol include selection of patients who are able to respond to less aggressive treatments, use of minimal levels of HBO, resolution of the disease and preparation of patients’ tissues for reconstruction without further HBO

.

Even though Marx’s staging system is the one still used by surgeons, it has been used less frequently from the mid-1990s to date. The reasons for this are that HBO is nowadays recommended for use as adju- vant therapy, its effectiveness has been questioned and most cases of ORN can be managed successfully with- out HBO according to the most recent literature

. The staging system of Epstein et al.

is an improve- ment, but it is focussed on the presence or absence of a pathological fracture

.

The classification system of Notani et al.

seems to

be more accurate as it is based on: (i) the presence or

absence of clinical and radiological signs, in contrast

to other systems that are non-specific and are partly

based on patients’ subjective interpretation; and (ii)

pretreatment evaluation, not on treatment response or

refractoriness. It is also simple and easily recalled

. (For review see Chronopoulos

.)

During the past 80 years, a number of theories about the origin of ORN have been proposed. Despite the controversy, the majority of authors agree that prereq- uisites for the diagnosis of ORN are: (i) previous irradi- ation of the affected bone; (ii) absence of recurrent tumour; (iii) presence of mucosal breakdown or failure of healing, resulting in bone exposure; and (iv) ‘necro- sis’ of the overlying bone. The presence of pathological fracture, fistula formation or cellulitis is not necessary for the diagnosis. Mandibular ORN is predominant over maxillary ORN. ORN can lead to pain, fracture and sequestration of the bone, as well as to fistulae.

Although the prevalence of ORN has decreased to levels lower than 5%, it still remains a pernicious com- plication of radiotherapy and a challenge to the clini- cian because of difficulty in its management. Owing to the severity of ORN and the difficulties in its early and accurate diagnosis and treatment, increased awareness of this complex entity among clinicians is desirable, with the aim to prevent its appearance or the develop- ment of severe complications. Further research is required in order to clarify its complex etiology, and guide new treatment strategies.

Acknowledgements

This review is included in the doctoral thesis of the first author, entitled ‘Clinical presentation and risk factors of osteoradionecrosis’.

Patient data were anonymised and de-identified before analysis. The clinical photograph and three radiographs were derived from the archive of the Department of Oral and Maxillofacial Surgery in Munich (LMU).

Conflicts of interest

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. There was no funding received for this study.

REFERENCES

1. Regaud C. Sur la sensibilite du tissu osseux normal vis-a-vis des rayons X et gamma et sur la mecanisme de l’osteoradionecrose.

CR Soc Boil 1922 87: 629–932.

2. Marx RE. Osteoradionecrosis; a new concept of its pathophysi- ology. J Oral Maxillofac Surg 1983 41: 283–288.

3. Marx RE, Johnson RP. Studies in the radiobiology of osteora- dionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol 1987 64: 379–390.

4. Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg 2005 13: 217–221.

5. Marx RE. A new concept in the treatment of osteoradionecro- sis. J Oral Maxillofac Surg 1983 41: 351–357.

6. Ewing J. Radiation osteitis. Acta Radiol 1926 6: 399–412.

7. Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat Rev 2002 28:

65–74.

8. Guttenberg SA. Osteoradionecrosis of the jaw. Am J Surg 1974 127: 326–332.

9. Epstein JB, Rea G, Wong FL et al. Osteonecrosis-study of the relationship of dental extractions in patients receiving radiother- apy. Head Neck Surg 1987 10: 48–54.

10. Widmark G, Sagne S, Heikel P. Osteoradionecrosis of the jaws.

Int J Oral Maxillofac Surg 1989 18: 302–306.

11. Store G, Boysen M. Mandibular osteoradionecrosis: clinical behavior and diagnostic aspects. Clin Otolaryngol 2000 25:

378–384.

12. Wong JK, Wood RE, McLean M. Conservative management of osteoradionecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 84: 16–21.

13. London SD, Park SS, Gampper TJ et al. Hyperbaric oxygen for the management of radionecrosis of bone and cartilage. Laryn- goscope 1998 108: 1291–1296.

14. Pitak-Arnnop P, Sader R, Dhanuthai K et al. Management of osteoradionecrosis of the jaws: an analysis of evidence. Eur J Surg Oncol 2008 34: 1123–1134.

15. Khojastepour L, Bronoosh P, Zeinalzade M. Mandibular bone changes induced by head and neck radiotherapy. Indian J Dent Res 2012 23: 774–777.

16. Thorn JJ, Hansen HS, Specht L et al. Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradia- tion. J Oral Maxillofac Surg 2000 58: 1088–1093.

17. Monnier Y, Broome M, Betz M et al. Mandibular osteora- dionecrosis in squamous cell carcinoma of the oral cavity and oropharynx: incidence and risk factors. Otolaryngol Head Neck Surg 2011 144: 726–732.

18. Chrcanovic BR, Reher P, Sousa AA et al. Osteoradionecrosis of the jaws–a current overview–part 1: Physiopathology and risk and predisposing factors. Oral Maxillofac Surg 2010 14: 3–16.

19. Morrish RB, Chan E, Silverman S et al. Osteoradionecrosis in patients irradiated for head and neck carcinoma. Cancer 1981 47: 1980–1983.

20. Watson WL, Scarborough JE. Osteoradionecrosis in intraoral cancer. Am J Roentgenol 1938 40: 524–534.

21. Martin HE, Sugarbaker EL. Cancer of the floor of the mouth.

Surg Gynecol Obstet 1940 71: 347–359.

22. MacComb WS. Necrosis in treatment of intraoral cancer by radiation therapy. Am J Roentgenol Radium Ther Nucl Med 1962 87: 431–440.

23. MacDougall JA, Evans AM, Lindsay RK. Osteoradionecrosis of the mandible and its treatments. Am J Surg 1963 106: 816– 818.

24. Grant BP, Fletcher GH. Analysis of complications following megavoltage therapy for squamous cell carcinomas of the ton- sillar area. Am J Roentgenol Radium Ther Nucl Med 1966 96:

28–36.

25. Rahn AO, Drane JB. Dental aspects of the problems, care and treatment of the irradiated oral cancer patient. J Am Dent Assoc 1967 74: 957–966.

26. Rankow RM, Weissman B. Osteoradionecrosis of the mandible.

Ann Otol Rhinol Laryngol 1971 80: 603–611.

27. Wang CC. Management and prognosis of squamous cell carci- noma of the tonsillar region. Radiology 1972 104: 667–671.

28. Cheng VST, Wang CC. Osteoradionecrosis of the mandible resulting from external megavoltage radiation therapy. Radiol- ogy 1974 112: 685–689.

29. Marciani RD, Plezia RA. Osteoradionecrosis of the mandible.

J Oral Surg 1974 32: 435–440.

30. Bedwinek JM, Shukovsky LJ, Fletcher GH et al. Osteora- dionecrosis in patients treated with definite radiotherapy for squamous cell carcinoma of the oral cavity and naso- and oropharynx. Radiology 1976 119: 665–667.

31. Murray CG, Herson J, Daly TE et al. Radiation necrosis of the mandible: a 10 year study. Part I. Factors influencing the onset of necrosis. Int J Radiat Oncol Biol Phys 1980 6: 543–548.

32. Epstein JB, Wong FLW, Stevenson-Moore P. Osteoradionecro- sis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 1987 45: 104–110.

33. Withers HR, Peters LJ, Taylor JM et al. Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil:

patterns of fractionation study of radiobiology. Int J Radiat Oncol Biol Phys 1995 33: 563–568.

34. Turner SL, Slevin NJ, Gupta NK et al. Radical external beam radiotherapy for 333 squamous carcinomas of the oral cavity– evaluation of late morbidity and a watch policy for the clini- cally negative neck. Radiother Oncol 1996 41: 21–29.

35. Storey MR, Garden AS, Morrison WH et al. Postoperative radiotherapy for malignant tumors of the submandibular gland.

Int J Radiat Oncol Biol Phys 2001 51: 952–958.

36. Reuther T, Schuster T, Mende U et al. 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 2003 32: 289–295.

37. Oh HK, Chambers MS, Garden AS et al. Risk of osteora- dionecrosis after extraction of impacted third molars in irradi- ated head and neck cancer patients. J Oral Maxillofac Surg 2004 62: 139–144.

38. Studer G, Gratz KW, Glanzmann C. Osteoradionecrosis of the mandibula in patients treated with different fractionations.

Strahlenther Onkol 2004 180: 233–240.

39. Ben-David MA, Diamante M, Radawski JD et al. Lack of oste- oradionecrosis of the mandible after intensity – modulated radiotherapy for head and neck cancer: likely contributions of both dental care and improved distributions. Int J Radiat Oncol Biol Phys 2007 68: 396–402.

40. Jham BC, Reis PM, Miranda EL et al. Oral health status of 207 head and neck cancer patients before, during and after radiotherapy. Clin Oral Investig 2008 12: 19–24.

41. Katsura K, Sasai K, Sato K et al. 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 2008 105: 731–738.

42. Gomez DR, Zhung JE, Gomez J et al. Intensity-modulated radiotherapy in postoperative treatment of oral cavity cancers.

Int J Radiat Oncol Biol Phys 2009 73: 1096–1103.

43. Ij Lee, Koom WS, Lee CG et al. Risk factors and dose-effect relationship for mandibular osteoradionecrosis in oral and oropharyngeal cancer patients. Int J Radiat Oncol Biol Phys 2009 75: 1084–1091.

44. Stenson KM, Kunnavakkam R, Cohen EE et al. Chemoradia- tion for patients with advanced oral cavity cancer. Laryngo- scope 2010 120: 93–99.

45. Gomez DR, Estilo CL, Wolden SL et al. Correlation of osteora- dionecrosis and dental events with dosimetric parameters in intensitymodulated radiation therapy for head-and-neck cancer.

Int J Radiat Oncol Biol Phys 2011 81: 207–213.

46. Crombie AK, Farah C, Tripcony L et al. Primary chemoradio- therapy for oral cavity squamous cell carcinoma. Oral Oncol 2012 48: 1014–1018.

47. Niewald M, Fleckenstein J, Mang K et al. Dental status, dental rehabilitation procedures, demographic and oncological data as potential risk factors for infected osteoradionecrosis of the

lower jaw after radiotherapy for oral neoplasms: a retrospective evaluation. Radiat Oncol 2013 8: 227.

48. Tsai CJ, Hofstede TM, Sturgis EM et al. Osteoradionecrosis and radiation dose to the mandible in patients with oropharyn- geal cancer. Int J Radiat Oncol Biol Phys 2013 85: 415–420.

49. Daly TE, Drane JB, MacComb WS. Management of problems of the teeth and jaw in patients undergoing irradiation. Am J Surg 1972 124: 539–542.

50. Gr€otz KA, Riesenbeck D, Brahm R et al. Chronic radiation effects on dental hard tissue (radiation caries). Classification and therapeutic strategies. Strahlenther Onkol 2001 177: 96– 104.

51. Almazrooa SA, Woo SB. Bisphosphonate and non-bisphospho- nate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc 2009 140: 864–875.

52. Mendenhall WM. Mandibular osteoradionecrosis. J Clin Oncol 2004 22: 4867–4868.

53. Hao SP, Chen HC, Wei FC et al. Systematic management of osteoradionecrosis in the head and neck cancer. Laryngoscope 1999 109: 1324–1327.

54. Clayman L. Management of dental extractions in irradiated jaws: a protocol without hyperbaric oxygen therapy. J Oral Maxillofac Surg 1997 55: 275–281.

55. Coffin F. The incidence and management of osteoradionecrosis of the jaws following head and neck radiotherapy. Br J Radiol 1983 56: 851–885.

56. Morton ME, Simpson W. The management of osteoradionecro- sis of the jaws. Br J Oral Maxillofac Surg 1986 24: 332–341.

57. Glanzmann C, Gratz KW. Radionecrosis of the mandibula: a retrospective analysis of the incidence and risk factors. Radio- ther Oncol 1995 36: 94–100.

58. Schwartz HC, Kagan AR. Osteoradionecrosis of the mandible:

scientific basis for clinical staging. Am J Clin Oncol 2002 25:

168–171.

59. Notani K, Yamazaki Y, Kitada H et al. Management of mandibular osteoradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy. Head Neck 2003 25: 181–186.

60. Peleg M, Lopez EA. The treatment of osteoradionecrosis of the mandible: the case for hyperbaric oxygen and bone graft recon- struction. J Oral Maxillofac Surg 2006 64: 956–960.

61. Baker SR. Management of osteoradionecrosis of the mandible with myocutaneous flaps. J Surg Oncol 1983 24: 282–289.

62. Nakatsuka T, Harii K, Yamada A et al. Surgical treatment of mandibular osteoradionecrosis: versatility of the scapular osteo- cutaneous flap. Scand J Plast Reconstr Hand Surg 1996 30:

291–298.

63. Shaha AR, Cordeiro PG, Hidalgo DA et al. Resection and immediate microvascular reconstruction in the management of osteoradionecrosis of the mandible. Head Neck 1997 19: 406– 411.

64. Oh HK, Chambers MS, Martin JW et al. Osteoradionecrosis of the mandible: treatment outcomes and factors influencing the progress of osteoradionecrosis. J Oral Maxillofac Surg 2009 67:

1378–1386.

65. Jacobson AS, Buchbinder D, Hu K et al. Paradigm shifts in the management of osteoradionecrosis of the mandible. Oral Oncol 2010 46: 795–801.

66. M€ucke T, Konen M, Wagenpfeil S et al. Low-dose preoperative chemoradiation therapy compared with surgery alone with or without postoperative radiotherapy in patients with head and neck carcinoma. Ann Surg Oncol 2011 18: 2739–2747.

67. M€ucke T, Koschinski J, Wagenpfeil S et al. Functional outcome after different oncological interventions in head and neck can- cer patients. J Cancer Res Clin Oncol 2011 138: 371–376.

68. Hermans R, Fossion E, Ioannides C et al. CT findings in osteo- radionecrosis of the mandible. Skeletal Radiol 1996 25: 31–36.

69. Miles DA. Imaging inflammatory disorders of the jaw: simple osteitis to generalised osteomyelitis. Oral Maxillofac Surg Clin North Am 1992 1: 207–221.

70. Niebel HH, Neeman EW. Dental aspects of osteoradionecrosis.

Oral Surg Oral Med Oral Pathol 1957 10: 1011–1024.

71. Epstein JB, Wong FLW, Dickens A et al. Bone and gallium scans in postradiotherapy osteonecrosis of the jaw. Head Neck 1992 14: 288–292.

72. Ardran G. Bone destruction not demonstrable by radiography.

Br J Radiol 1951 24: 107–109.

73. Tobias JS, Thomas PRM. Current Radiation Oncology. Lon- don: Arnold; 1996. p. 144–177.

74. Fujita M, Harada K, Masaki N et al. MR imaging of osteora- dionecrosis of the mandible following radiotherapy for head and neck cancers. Nihon Igaku Hoshasen Gakkai Zasshi 1991 51: 892–900.

75. Rabin BM, Meyer JR, Berlin JW et al. Radiation-induced changes in the central nervous system and head and neck.

Radiographics 1996 16: 1055–1072.

76. Yoshioka H, Nakano T, Kandatsu S et al. MR imaging of radi- ation osteitis in the sacro-iliac joints. Magn Reson Imaging 2000 18: 125–128.

77. Bachmann G, Rossler R, Klett R et al. The role of magnetic res- onance imaging and scintigraphy in the diagnosis of pathologic changes of the mandible after radiation therapy. Int J Oral Maxillofac Surg 1996 25: 189–195.

78. Alexander JM. Radionuclide bone scanning in the diagnosis of lesions of the maxillofacial region. J Oral Surg 1976 34: 249– 256.

79. Minn H, Aitasalo K, Happonen RP. Detection of cancer recur- rence in irradiated mandible using positron emission tomogra- phy. Eur Arch Otorhinolaryngol 1993 250: 312–315.

80. Beumer J, 3rd, Curtis T, Harrison RE. Radiation therapy of the oral cavity: sequelae and management, part 2. Head Neck Surg 1979 1: 392–408.

81. Hutchinson IL, Colpe M, Delpy DT et al. The investigation of osteoradionecrosis of the mandible by near infrared spec- troscopy. Br J Oral Maxillofac Surg 1990 28: 150–154.

82. Beumer J, 3rd, Harrison R, Sanders B et al. Pre-radiation dental extractions and the incidence of bone necrosis. Head Neck Surg 1983 5: 514–521.

83. Harris M. The conservative management of osteoradionecrosis of the mandible with ultrasound therapy. Br J Oral Maxillofac Surg 1992 30: 313–318.

84. Berger RP, Symington JM. Long-term clinical manifestation of osteoradionecrosis of the mandible: report of two cases. J Oral Maxillofac Surg 1990 48: 82–84.

85. Kluth EV, Jain PR, Stuchell RN et al. A study of factors con- tributing the development of osteoradionecrosis of the jaws. J Prosthet Dent 1988 59: 194–201.

86. Jeremic B, Shibamoto Y, Milicic B et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000 18: 1458–1464.

87. Denis F, Garaud P, Bardet E et al. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003 55: 93–98.

88. Cooper JS, Pajak TF, Forastiere AA et al. Postoperative concur- rent radiotherapy and chemotherapy for high-risk squamous- cell carcinoma of the head and neck. N Engl J Med 2004 350:

1937–1944.

89. Budach V, Stuschke M, Budach W et al. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mito- mycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 2005 23: 1125– 1135.

90. Semrau R, Mueller RP, Stuetzer H et al. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head- and-neck cancer. Int J Radiat Oncol Biol Phys 2006 64: 1308– 1316.

91. Perrier M, Moeller P. Osteoradionecrosis. A review of the liter- ature. Schweiz Monatsschr Zahnmed 1994 104: 271–277.

92. Berger A, Bensadoun RJ. Normal tissue tolerance to external beam radiation therapy: the mandible. Cancer Radiother 2010 14: 295–300.

93. Wahl MJ. Osteoradionecrosis prevention myths. Int J Radiat Oncol Biol Phys 2006 64: 661–669.

94. Annane D, Depondt J, Aubert P et al. Hyperbaric oxygen ther- apy for radionecrosis of the jaw—a randomized, placebo-con- troled, double-blind trial from the ORN96 study group. J Clin Oncol 2004 22: 4893–4900.

95. Bessereau J, Annane D. Treatment of osteoradionecrosis of the jaw: the case against the use of hyperbaric oxygen. J Oral Max- illofac Surg 2010 68: 1907–1910.

96. Pitak-Arnnop P, Hemprich A, Dhanuthai K et al. A systematic review in 2008 did not show value of hyperbaric oxygen ther- apy for osteoradionecrosis. J Oral Maxillofac Surg 2010 68:

2644–2645.

97. Shaw RJ, Dhanda J. Hyperbaric oxygen in the management of late radiation injury to the head and neck. Part I: Treatment.

Br J Oral Maxillofac Surg 2011 49: 2–8.

98. Chronopoulos A. (2015). Clinical presentation and risk factors of osteoradionecrosis (Doctoral dissertation). Available from:

https://edoc.ub.uni-muenchen.de/18089/ and https://edoc.ub.uni- muenchen.de/18089/1/Chronopoulos_Aristeidis.pdf (Persistent Identifier URN: urn:nbn:de:bvb:19-180892). Accessed 15 April 2015.

Correspondence to:

Aristeidis Chronopoulos, DDS, Oral Surgeon, PhD, Panagiotou Kaisari 19, Kalamata 24133, Greece.

Emails: arisx8@hotmail.com,

ar.chronopoulos@gmail.com