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REVIEW

CURRENT
OPINION Modern management of osteoradionecrosis
Blake S. Raggio a and Ryan Winters b

Purpose of review
Despite recent advances in radiotherapy, osteoradionecrosis (ORN) remains a common and difficult
complication of radiation therapy in head and neck cancer patients. Available treatment options are
complementary to its complex pathophysiology and the currently available theories of ORN development.
The efficacy of hyperbaric oxygen therapy has recently been questioned, and therapies targeting the
fibroatrophic process have become a focus of ORN treatment. The objective of this review is to evaluate
the literature regarding ORN of the mandible, with a focus on available treatment options.
Recent findings
The recently proposed fibroatrophic theory has challenged the traditional hypovascular-hypoxic-hypocellular
theory as the mechanism of ORN. Medical management targeting this fibroatrophic process offers
promising results, but has yet to be confirmed with robust clinical trials. The routine use of hyperbaric
oxygen therapy is not substantiated in the literature, but may be justified for select patients. Systemic
steroids may also have a role, though data are limited.
Summary
The fibroatrophic process has gained acceptance as a main mechanism of ORN. No gold standard
treatment or consensus guidelines exist, though a combination of therapeutic strategies should be
considered, taking into account the severity of disease and individual patient characteristics.
Keywords
hyperbaric oxygen, jaw, mandible, osteoradionecrosis, radiation necrosis

INTRODUCTION Clinical presentation

Osteoradionecrosis (ORN), a common late sequela of
radiation therapy in head and neck cancer (HNC)
patients, is a challenging clinical problem. Treatment
of ORN correlates with the severity of disease, and
ranges from conservative therapy (antibiotics and
meticulous oral care) to extensive surgical resection
and free flap reconstruction. With the efficacy of
hyperbaric oxygen therapy (HBOT) recently being
questioned, medical treatment options targeting the
newly proposed fibroatrophic theory have become a
&
main focus of study [1,2 ]. The objective of this review
is to evaluate the available literature regarding ORN of
the mandible, with a particular focus on available
treatment options and the fibroatrophic theory.
ORN of the head and neck most often affects the
mandible and presents clinically as painful and
denuded bone with purulent drainage and/or possi-
ble fistula formation [3,4]. The majority of cases
&& &
occur in the first years after treatment [5 ,6 ], with
increasing yearly incidence for several years after
&&
treatment [7 ].
Radiographic presentation
The diagnosis of ORN is a clinical one; however,
imaging can be used to detect early ORN when
presenting symptoms are nonspecific. When the
clinical presentation is consistent with ORN (i.e.
bone exposure, fistula formation), imaging with

REVIEW
Definition of osteoradionecrosis
ORN describes a necrotic process of the bone that
results from high-dose radiation therapy, persists
for 3 months or longer, slowly progresses and does
not heal spontaneously. Importantly, it must be
unrelated to tumour occurrence [3].
a
Tulane University Medical Center, Department of Otolaryngology and
b
Ochsner Health System New Orleans, Department of Otolaryngology,
New Orleans, LA, USA
Correspondence to Ryan Winters, MD, Ochsner Health System, Depart-
ment of Otolaryngology, 1514 Jefferson Hwy, New Orleans, LA 70121,
USA. E-mail: Ryan.winters@ochsner.org
Curr Opin Otolaryngol Head Neck Surg 2018, 26:000–000
DOI:10.1097/MOO.0000000000000459

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KEY POINTS
 Although the pathophysiology of ORN remains unclear,
Marx’s vascular insufficiency theory and Delanian’s
fibroatrophic process predominate as the main
mechanisms of ORN.
 Currently, there is no gold standard treatment of ORN
and no widely accepted guidelines exist.
 The roles of hyperbaric oxygen therapy and medical
management are yet to be confirmed in robust
clinical trials.
 Surgical resection should be reserved for advanced
disease in patients whose symptoms persist despite
conservative measures.
radiographs, computed tomography scans, MRI or
scintigraphy is warranted to assess the extent of
disease. Radiographic features vary among normal
appearance, osteolytic regions, sequestra and frac-
&
ture [8,9 ]. When tumour recurrence is in doubt, PET
scan may be warranted [10].
Classification systems
Despite the numerous staging and classification
&&
systems described in the literature [11–15,16 ],
the initial classification introduced by Marx in
1983 [17] is perhaps the most widely utilized and
is predicated on staging ORN based on response to
treatment with HBOT. These classifications, how-
ever, have not yet been fully validated in clinical
practice, and modifications are continuing to be
proposed to enhance reliability and consistency of
&&
future studies [18 ].
Incidence
Historic series report an incidence of ORN ranging
from 2 to 22% [3]. Recent meta-analyses, however,
suggest a decreased rate (2–4%) of ORN over the past
few decades [19,20]. These findings were recently
confirmed in the largest cohort study (n ¼ 23 527)
to date investigating ORN in patients with HNC,
which reported an overall ORN incidence of 7%
&&
[5 ]. Advances in radiotherapy, particularly the
advent of intensity-modulated radiotherapy, and
oral healthcare are likely responsible for this
decreased rate of ORN seen in the modern era.
Risk factors
Main risk factors for ORN include oral cavity pri-
mary site, higher radiation dose (see radiotherapy
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technique below), poor periodontal status, post-
radiation extraction of teeth and trauma (i.e. extrac-
tions, surgery). Other postradiation sequelae
(xerostomia and trismus) and patient factors,
including older age, male sex, overall health and
tobacco or alcohol use, also influence the develop-
&& &
ment of ORN [1,3,4,5 ,21 ,22]. Concurrent chemo-
therapy seemingly has no clinically relevant
&&
influence on ORN development [5 ,11,23,24].
Protective factors
Preparing a comprehensive dental treatment plan
for patients undergoing radiation therapy is essen-
tial to help minimize risks for developing oral and
&
dental complications [25 ]. If a tooth is unlikely to
be restored, performing the extraction before treat-
ment might be safer than performing the extraction
&&
after treatment [5 ,19,23,26]. The use of prophylac-
tic HBOT or antibiotics for the prevention of pre or
postradiation extraction-induced ORN is not sup-
ported in the literature [27].
Steroid use, a well established risk factor for
osteonecrosis [28], may actually help prevent
ORN. Goldwaser et al. [29] in 2007 was the first to
show that steroid use before or after radiation can
reduce the risk of ORN (by 96% in their study), but
this study was underpowered (n ¼ 82) and hindered
by incomplete steroid usage data and inappropriate
&&
statistical methods. Similarly, Wang et al. [5 ] found
that systemic steroids reduced the risk of ORN by
nearly 30%. Despite these promising findings, pro-
spective studies are needed to clarify the usage and
timing of steroids in the prevention of ORN.
Radiation technique
Theoretically, intensity-modulated radiotherapy’s
(IMRT) ability to deliver precise radiation doses to
a tumour while minimizing the dose to surrounding
normal tissue should reduce adverse effects associ-
ated with radiation (i.e. ORN) as compared to con-
&
ventional radiation therapy [30 ]. A 2010 systematic
review of the literature demonstrated a slightly
lower prevalence of ORN with IMRT (5.2%) versus
conventional radiation therapy (7.3%); however,
the clinical significance of this difference is unclear
[31]. The low incidence of ORN associated with
IMRT has been confirmed in multiple studies
&
[32,33 ], but limited quality evidence makes it diffi-
cult to draw concise conclusions regarding IMRT’s
real benefit on ORN risk reduction as compared to
conventional radiation therapy [34]. Nevertheless,
IMRT has become the standard radiation therapy
treatment in patients with HNC due to its compara-
ble locoregional recurrence and overall survival
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versus conventional radiotherapy, with less fre-
&
quent trismus and xerostomia. [30 ]. When IMRT
is employed, minimizing the volumes of the man-
dible receiving more than 50 or more than 60 Gy can
&&
help decrease the incidence of ORN [7 ,34,35 ].
Pathophysiology
Early theories suggested that ORN was a manifesta-
tion of radiation-induced osteomyelitis (infection),
which formed the basis of managing ORN with anti-
biotic therapy [4]. In 1983, Marx challenged this
theory by proposing that radiation therapy causes
a series of events at the cellular and extracellular level
resulting in tissue hypovascularity, hypoxia and
hypocellularity. Ultimately, tissue breakdown occurs
and a chronic nonhealing wound develops. Marx’s
theory, with persistent hypoxia as one of the main
components of ORN, provides the grounds for the use
of HBOT [17]. At the turn of the century, Delanian
introduced the radiation-induced fibroatrophic the-
ory as the main mechanism of ORN. Delanian’s
theory proposed that radiation therapy causes acti-
vation and dysregulation of fibroblast activity result-
ing in fibrotic tissues prone to traumatic breakdown.
Since its introduction, the fibroatrophic theory has
gained wide acceptance as the main mechanism of
ORN, which has opened the door to the use of anti-
oxidant and antifibrotic drugs as a primary treatment
&
option for ORN [36 ,37]. A more recent study has
focused on radiation-induced changes of the oral
mucosa on the microstructural level, the role of
which remains uncertain in the cascade of ORN
[38,39]. Overall, the definitive mechanism of ORN
pathogenesis is unclear; however, Marx’s hypoxia-
hypocellular-hypovascular theory and Delanian’s
radiation-induced fibroatrophic theory predominate
in the literature and seem to be complementary on
the complex pathophysiology of ORN [40].
Treatment
Conservative approaches
Conservative approaches in the management of
ORN, which include oral hygiene optimization
and antibiotic coverage, are generally reserved for
asymptomatic or mildly symptomatic patients with
early or moderate disease. Unfortunately, patients
treated solely with these conservative measures
experience full resolution of ORN in only 15% of
cases [41]. The risk of disease progression with this
observational approach has led some to recommend
early simple surgical intervention (i.e. sequestrec-
tomy or saucerization) to remove necrotic bone and
cover bony defects with local mucosal flaps [4].
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Modern management of osteoradionecrosis Raggio and Winters
Hyperbaric oxygen therapy
The mechanisms of action for HBOT are thought to
increase oxygen supply in hypoxic tissues and stim-
ulate fibroblast proliferation, angiogenesis and colla-
&
gen formation. HBOT can have bactericidal or
bacteriostatic effects as well [1]. Unfortunately, the
studies evaluating HBOT and its effect on ORN are
limited by heterogeneous designs and outcomes.
Contributing factors include wide variability in both
ORN classification systems and HBOT regimens
&
[2 ,42]. These shortcomings were first identified in
a 2010 systematic review by Peterson et al. [31] who
reported variable resolution rates of ORN with HBO
(ranging from 19 to 93%). In 2016, an updated
Cochrane review on the role of HBOT in ORN con-
cluded that the application of HBOT may be justified
in select patients; however, the evidence was gener-
ally of moderate quality and limited by small num-
bers of participants, poor reporting of methods and
results, and uncertainty as to the exact degree of
&&
improvement with HBOT [16 ]. The sole RCT evalu-
ating the effectiveness of HBO in ORN was termi-
nated early after HBOT failed to demonstrate any
beneficial effect over placebo after 1 year [43]. This
study was severely criticized, however, due to several
methodological and performance issues, including
its lack of a protocol HBO treatment, poor accuracy,
exclusion criteria and being underpowered (n ¼ 68)
[44–46]. To overcome these limitations, three pro-
spective multicentre RCTs are underway to investi-
gate the role of HBOT in the prevention and
&&
treatment of ORN: UK HOPON [18 ,47] Danish
DAHNCA21 [47] and Portuguese phase II trial [48].
Currently, these authors are leading a multicentre
randomized phase II study on ORN with a new ther-
apeutic protocol, including HBOT with or without
the association of tocopherol (TCP), pentoxifylline
(PTX) and clodronate (CLO). Institutional guidelines
cite the lack of prospective studies as a rationale for
avoiding routine use of HBOT, an expensive treat-
ment that should be reserved for select high-risk
patients with persistent ORN refractory to conserva-
&
tive and surgical treatment [49 ].
Medical treatment options
The introduction of Delanian’s fibroatrophic theory
as the main mechanism of ORN prompted the use of
the following antioxidant and antifibrotic drugs for
the treatment of ORN: PTX, TCP and CLO [37]. PTX
is a methylxanthine derivative with an in-vivo
established inhibitory effect on fibroblast prolifera-
tion and extracellular matrix production. The anti-
oxidant TCP (with vitamin E activity) is a free radical
scavenger and protects cell membranes against lipid
peroxidation. TCP’s antifibrotic activity is based on
downregulation of procollagen gene expression.
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Both PTX and TCP exhibit anti-inflammatory
actions by inhibiting tumour necrosis factor-alpha
and transforming growth factor-beta-1. CLO is a
first-generation bisphosphonate that inhibits bone
resorption by reducing osteoclast activity through
direct activation of osteoblasts. The stimulated oste-
oblast activity also increases bone synthesis and
& &
decreases proliferation of fibroblast [36 ,40,50].
The individual use of the above medications is
not supported, as there appears to be no effect on
the resolution of ORN when used alone [51,52].
Pentoxifylline and tocopherol
In 1998, Delanian was the first to clinically test the
combination of PTX/TCP [53]. Promising results
from this case report and a subsequent cohort study
(n ¼ 43) [54] led to the first randomized, double-
blind clinical trial (n ¼ 24) that tested the drug com-
bination. The results from this study showed sta-
tistically significant RIF regression in the treatment
group (PTX/TCP) when compared with the double
placebo group, without notable adverse effects.
Delanian concluded that 6 months of treatment
with combined PTX/TCP can significantly reduce
RIF [51]. Combination PTX/TCP may only be useful
in early stages of disease, however, as advanced
stages of disease treated with combination PTX/
TCP alone often progressed to worse stages of disease
[55]. Combination PTX/TCP may also serve a pro-
phylactic role by reducing the incidence of ORN
in irradiated patients requiring dental extractions,
though further research is required [56].
Pentoclo
Treatment of ORN with PTX/TCP and CLO (PEN-
TOCLO) was first clinically tested by Delanian in
2002 [57]. After promising findings from this case
report, Delanian reported data from 18 patients with
ORN, 10 of whom were treated with PTX/TCP, and
eight of which (the most advanced cases) were
treated with PENTOCLO. Treatment was well toler-
ated and complete recovery was observed in a
median time of 6 months [58]. In 2011, Delanian
published larger prospective cohort of 54 HNC
patients with refractory mandibular ORN (after sur-
gery and HBOT). All patients were treated with
PENTOCLO (in addition to prednisone and cipro-
floxacin). Treatment was well tolerated, and a com-
plete recovery in all cases occurred in a median of
9 months. Interestingly, sequestrectomy was per-
formed in 67% of patients, which the authors report
is often necessary and speeds the healing process.
The authors concluded long-term PENTOCLO treat-
ment is effective, well tolerated and curative for
refractory ORN [52]. These findings have since been
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duplicated by several studies as noted by review of
&
the literature by Lyons and Brennan [36 ]. Despite
the promising results of PENTOCLO in the treat-
ment of ORN, the true value of this medical strategy
is yet to be confirmed in a randomized clinical trial
setting. Patients’ resilience towards the long-term
treatment duration and its possible side effects must
&
also be considered [21 ,36 ,48].
Other potential treatment options for ORN have
been investigated with promising but limited data,
including hydrogen-rich saline [59], autologous
transplants of epithelium [60], recombinant human
parathyroid hormone [61], manganese porphyrin
[62] and tonsil-derived mesenchymal stem cells
[63]. Future research is warranted.
Surgery for advanced disease
For advanced ORN (those with fractures and fistu-
las), treatment hinges on surgical resection and
reconstruction with free tissue transfer [1]. The
extent of resection is generally determined by pres-
ence of bleeding at resected edges; however, the lack
of objective clinical criteria to judge the appropriate
amount of mandible resection remains an unre-
solved issue that likely contributes to the high rates
(25%) of recurrent ORN [64]. Even with adequate
resection (based on histopathological analysis),
ORN can recur, which may be due to factors other
than the presence of residual necrotic bone (i.e.
infection) at the resection margin [65]. According
to a recent systematic review by Lee et al. [66], the
fibula is the most reliable flap for reconstruction in
mandibular ORN, the design of which depends on
the available vascular pedicle and soft tissue defect
&&
[67 ]. Rarely, patients with large mandibular defects
may require a double free flap technique with an
obligatory fibula free flap [68]. Not surprisingly, the
risk of flap failure (10%) and postoperative compli-
cations (40%) in patient with ORN are significantly
increased compared with free flap reconstruction
in nonradiated patients [66]. Protocols now exist
&
to limit such complications [69 ]. The significant
financial burden associated with surgical resection
and reconstruction of advanced ORN should not be
ignored [70], nor should the disappointingly poor
health-related quality of life scores seen after man-
dibular surgery [71,72]. For the above reasons, the
surgeon is often reluctant to operate on these chal-
lenging cases, which may explain the decline in
complex reconstructions for ORN seen in recent
years [73]. Newly introduced ‘Exact resection plan-
ning’, which includes use of virtual guided resection
based on the radiotherapy dose information and
bone imaging, may help limit the morbidity associ-
ated with these disfiguring surgeries [74].
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Modern management of osteoradionecrosis Raggio and Winters
CONCLUSION
Currently, there is no gold standard treatment of
ORN and no widely accepted guidelines exist.
Although early-stage ORN can initially be treated
conservatively with antibiotics and meticulous oral
hygiene, any sign of progression requires early
surgical intervention with debridement and local
mucosal flaps to cover exposed bone. The role of
HBOT and medical management (antifibrotics, anti-
oxidants, steroids) is yet to be defined with robust
clinical trials, some of which are currently ongoing.
Extensive surgical resection with fibular free flap
should be reserved for patients with advanced dis-
ease who have persistent symptoms refractory to
conservative treatments.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
The authors have no conflicts of interest or financial
disclosures to report.
The authors have not published or submitted any related
papers from the same study.
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Volume 26  Number 00  Month 2018