Pharmacologic Modalities in

t h e Tre a t m e n t o f
Osteoradionecrosis of the J aw
James Anthony McCaul, PhD, FRCS(OMFS), FRCS, FDSRCPSa,b,*

KEYWORDS
 Osteoradionecrosis  Radiation-induced fibroatrophy  Pentoxifylline  Tocopherol  Clodronate

KEY POINTS
 Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head and
neck surgical practice.
 Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic mo-
dalities to manage this disorder.
 These treatment regimens may allow medical management to replace major reconstructive surgery
for some patients who have already undergone chemoradiotherapy or combined modality therapy
for head and neck cancer.

INTRODUCTION PATHOGENESIS
Osteoradionecrosis (ORN) of the jaws was first Four hypotheses have been described for the
described in the 1920s and remains the most development of ORN. Watson and Scarborough6
problematic complication occurring after the use first described the sequence of radiation exposure,
of radiotherapy to treat head and neck cancer.1 local injury, and infection as a possible cause, and
The condition has been defined as exposed and this hypothesis was further popularized by Meyer.7
necrotic bone associated with ulcerated or Later Marx8 described the “Three-H” hypo-
necrotic soft tissue that persists for greater than thesis: wherein the area shows a hypocellular, hyp-
3 months in an area that has been previously irra- oxic, and hypovascular state. This condition is
diated, and is not caused by tumor recurrence.2 thought to be consequent to microvasculature
According to the current medical literature, ap- damage, resulting in endarteritis, thrombosis, and
proximately 20.0% (range, 0.9%–35.0%) of vessel obliteration.
patients have radiotherapy as part of their head A more recently described hypothesis is that
and neck cancer treatment.3 This incidence may of suppression of osteoclast mediated bone turn-
be declining.4 The condition affects the mandible over, wherein irradiation-induced loss of osteoclast
most frequently, and diagnosis depends on clinical function results in the clinical features described
features, including a history of exposure to greater earlier. This idea is supported by the evidence
than 50 Gy of ionizing radiation. Symptoms include from antiresorptive therapy–related osteonecrosis
pain, trismus, and dysesthesia. Clinical signs of the jaws, which occurs after administration of bi-
include ulceration and/or necrosis of the oral mu- sphosphonates and other antiresorptive agents in
oralmaxsurgery.theclinics.com

cosa, exposure of underlying bone, malodor, some patients.

a b
Maxillofacial/Head and Neck Surgery, The Royal Marsden Hospital, London, UK; UK RCS/BAOMS/Saving
Faces Maxillofacial Surgical Specialty Lead for Research, London, UK
* Maxillofacial/Head and Neck Surgery, The Royal Marsden Hospital, London, UK.
E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 26 (2014) 247–252

based on enhanced understanding of the cellular cytokine release, including tumor necrosis factor
and molecular biology of the histopathologic fea- a (TNF-a); fibroblast growth factor b; platelet-
tures seen in ORN. Earlier, in 1998, the first report derived growth factor; interleukin (IL) 1, 2, and 4;
emerged of bone healing in a patient with ORN of connective tissue growth factor; and transforming
the sternum after receiving radiotherapy for carci- growth factor b1 (TGF-b1). This process produces
noma of the breast 29 years previously treated a predominance of the myofibroblast phenotype,
with pharmacologic therapy based upon this with attendant high rates of cellular proliferation
new hypothesis. With this hypothesis, bone and and release of abnormal extracellular matrix
soft tissue damage is proposed to be caused by (ECM) components.13 These myofibroblasts also
radiation-induced fibrosis, and this has been demonstrate impaired ability to breakdown the
summarized by Lyons and Ghazali.11 Three abnormal ECM. This is shown diagrammatically
phases of tissue injury are described, which in Fig. 1. This fibroblast process is similarly
mirror those in healing of chronic traumatic described in fibrotic processes in the lungs and
wounds12: the initial predominantly acute inflam- liver after tissue injury of various types.14
matory phase with endothelial changes, a second Ionizing radiation produces osteoblast cell death
phase of abnormal fibroblast activity with extra- and prevents repopulation of this cellular com-
cellular matrix disruption, and a third late fibroa- ponent of bone. Together with excess myofibro-
trophic phase. At this late phase, the healed blast proliferation and abnormal ECM formation, a
tissues are friable and undergo late reactivation reduction in bony hard tissue matrix and an excess
of the acute inflammatory response after injury. of fibrous tissue is described. Four possible me-
In the proposed fibroatrophic mechanism, the chanisms of bony destruction are suggested by
key event in ORN progression is described as Delanian and colleagues15 in an article describ-
activation and dysregulation of fibroblast activity, ing microradiographic analysis of ORN bone.
resulting in tissue atrophy and fibrosis. These mechanisms are progressive macrophage-
Radiation-induced endothelial injury initiates mediated osteoclast loss with no accompanying

Fig. 1. Activation and dysregulation of fibroblast activity. (Modified from Delanian S, Lefaix JL. The radiation-
induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol
2004;73(2):119–31.)
 Pharmacologic Treatment of ORN 249

osteogenesis; periosteocytic lysis; extensive de- debridement. Later work by Marx described bac-
mineralization; and accelerated bone aging. teria as a superinfection rather than as being
Therefore, after radiotherapy, bone has reduced involved in pathogenesis, but nonetheless antibi-
numbers of viable cells, is poorly vascularized, and otic therapy in acute episodes of pyogenic in-
is fibrosed compared with normal healthy bone. fection in ORN, guided by microbiologic samples
Apoptosis of the myofibroblast component re- and culture and sensitivity assays, remains a
duces cellularity further.14 This tissue is then at cornerstone of treatment.
risk of the development of ORN after any physical
or chemical trauma, which induces the late acute
Hyperbaric Oxygen Therapy
inflammatory response described earlier. Fig. 2
summarizes this process. Hyperbaric oxygen therapy is still widely used for
ORN prevention and management, although this
PHARMACOLOGIC AGENTS IN ORN practice has had recent challenges.5,16,17 In the
MANAGEMENT United Kingdom, the Medicines and Healthcare
Products Regulatory Agency considers hyperbaric
The initial infection-based hypothesis resulted in oxygen a medicinal product, and therefore inspect
treatment based on antibiotic therapy and surgical trials involving this modality (eg, the HOPON

Fig. 2. The ionizing radiation–induced fibroatrophic process. (Modified from Lyons A, Ghazali N. Osteoradionec-
rosis of the jaws: current understanding of its pathophysiology and treatment. Br J Oral Maxillofac Surg
2008;46(8):653–60.)
250 McCaul

trial; Professor Richard Shaw, personal com- and single-agent therapy, and also that rebound
munication). This modality is discussed elsewhere tissue injury can occur if treatment is too short
in this issue. (<3 months).
Delanian and colleagues18,19 have described
Pentoxifylline and Tocopherol 2 phase II trials of combined therapy for ORN of
Pentoxifylline the mandible. In the first, 18 consecutive patients
Pentoxifylline is a methylxanthine derivative that were treated with pentoxifylline and tocopherol.
has multiple effects considered advantageous in Each had at least 13.4 mm of exposed mandibular
ORN management, including vascular dilatation bone and all had been prescribed pentoxifylline,
and increased erythrocyte flexibility effects, both 400 mg twice daily and tocopherol, 1000 IU orally
of which enhance blood flow. Furthermore, pen- for 6 to 24 months.18 The worst affected cases
toxifylline has anti–TNF-a activity and is thought (n 5 8) were also given clodronate, 1600 mg daily
to reduce the cytokine cascade driving the ORN for 5 days per week. The second trial,19 published
process. It has also been shown to reduce prolifer- in 2011, reported on 54 patients who received ra-
ation of dermal fibroblasts and limit ECM produc- diation for head and neck cancer a mean of 5 years
tion by these cells. In vitro experiments have also before the onset of ORN. In this report, the term
shown promotion of collagenase activity in these PENTOCLO was coined for the treatment regimen
cells.18 including all 3 agents. This treatment regimen had
evolved to combined pentoxifylline and tocopherol
Tocopherol as described earlier, with clodronate, 1600 mg
Tocopherol is a fat-soluble vitamin (vitamin E) and given 5 days per week, and prednisone, 20 mg
is a weak antioxidant agent. Therefore, tocopherol with ciprofloxacin given on the other 2 days. This
is capable of scavenging reactive oxygen species study showed that prolonged treatment (16 
involved in the pathogenesis of ORN, wherein they 9 months) was safe and well tolerated. All patients
induce cell membrane peroxidation among other in the study experienced improvement, with an
deleterious effects. Tocopherol also shows partial exponential progressive and significant reduction
inhibition of TGF-b1 and an antifibrotic effect in exposed bone (P<.0001). A total of 36 patients
mediated by procollagen genes.11 underwent spontaneous sequestrectomy during
the course of treatment. All patients in this series
Clodronate were shown to experience complete recovery in
This agent is a first-generation, nonnitrogenous bi- a median time of 9 months. The investigators
sphosphonate approved for use in osteoporosis, concluded that the treatment is safe and effective,
hyperparathyroidism, hypercalcemia of malig- and recommended that a randomized controlled
nancy, and multiple myeloma. Clodronate reduces trial be conducted.
bone resorption through reducing osteoclast In a retrospective series of 12 patients treated
numbers and activity. It is also known to reduce in- with pentoxifylline and tocopherol without clo-
flammatory cytokines IL-1b, IL-6, and TNF-a. dronate, McLeod and colleagues1 show more
Although bisphosphonates are clearly implicated modest treatment outcomes. These patients
in antiresorptive therapy–related osteonecrosis of were treated for a mean of 14.8 months (range,
the jaws, clodronate has been used in French 4.0–46.0 months). One patient stopped treatment
studies of severe ORN cases and been described because of side effects to pentoxifylline, and 3 re-
as effective (see next section).18,19 Notably and ported difficulty in swallowing the large pentoxifyl-
uniquely among this group of agents, clodronate line tablets, and resorted to crushing them, against
also has been shown to act on osteoblasts to in- pharmaceutical advice. Epstein scoring showed
crease bone formation20 and reduce fibroblast that 5 patients improved, 5 were unchanged,
proliferation.21 and 2 had become worse. Three patients deterio-
rated and subsequently underwent resection and
Pentoxifylline and Tocopherol Combined
composite free flap reconstruction surgery. These
Therapy With or Without Clodronate
authors acknowledge that they did not use clodro-
Experiments in vitro and animal studies have been nate for any of the cases in this short retrospective
unable to show that either pentoxifylline or tocoph- series.
erol alone can reduce reactive oxygen species. The Bradford Teaching Hospitals series reports
Combination therapy with these agents has been on 18 patients with ORN after radiotherapy
described in several radiation-associated tissue or chemoradiotherapy administered as part of
injury studies, including small placebo-controlled head and neck cancer therapy (McCaul and
randomized trials.22,23 These reports show benefit colleagues, unpublished data, 2014). These pro-
for combination therapy over placebo treatment spectively followed patients all received
 Pharmacologic Treatment of ORN 251

Fig. 3. (A) 62-year-old man underwent chemoradiotherapy for a T4,N3 right oropharynx squamous carcinoma.
This tumor exhibited complete response and was followed up according to protocol. (B) In November of 2010
he presented complaining of pain from the right lower third of his face and had exposed bone and pus discharg-
ing intraorally. No evidence was seen of new primary cancer at this site and the bone exposure persisted for more
than 3 months. He was managed initially with antibiotic therapy and local intraoral measures. He then
commenced pentoxifylline, 400 mg twice daily and tocopherol, 1000 IU daily. His ORN remained quiescent but
progressed. (C) Autosequestrectomy occurred after this time and his symptoms settled to a firm fibrous nonunion
with good function. He did not require surgical intervention. (D) The patient later developed a new primary can-
cer of the right lateral tongue, which required lip split mandibulotomy for access to resect and reconstruct, and
this healed without incident. (E) He remained on pentoxifylline and tocopherol throughout this process.

combined therapy with pentoxifylline and tocoph- two-thirds of which require radiotherapy or che-
erol only, and not clodronate for similar reasons moradiotherapy as part of treatment for cure.
as in the cases reported by McLeod and col-
leagues.1 Two patients could not tolerate therapy SUMMARY
and did not continue with the agents, and
16 continued with therapy. ORN resolved in 7 pa- Recent changes in understanding of the patho-
tients (44% of patients completing therapy); in genesis of ORN have led to the emergence of
3 with medical therapy alone and in 3 with medi- some exciting new pharmacologic therapies. Up-
cal therapy and surgical debridement. Three pa- take of these agents has been generally slow
tients received hyperbaric oxygen therapy as worldwide, despite the success of the Delanian
part of ORN management. In 1 patient, medical group18,19 in France, perhaps partly because of
therapy resulted in a symptom-free fibrous bony the previous acceptance that ORN of the mandible
union of the right body of the mandible (Fig. 3). is a surgical disease for which hyperbaric oxygen
No adverse events have been associated with therapy can be of utility. However, there is a clear
vitamin E and pentoxifylline therapy in the Brad- reluctance among surgeons who are faced with an
ford series. None of these patients have experi- increasing burden of antiresorptive agent–induced
enced progression on therapy, and none have osteonecrosis of the jaw to introduce clodronate
required major resection and reconstruction for into the therapeutic armamentarium for ORN.
ORN in the past 8 years. The Bradford center Clodronate seems to be unique among the bi-
treats 240 new head and neck cancers per year, sphosphonate group in that it can stimulate
252 McCaul

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