C h e m i c a l an d R a d i a t i o n -

Associated Jaw Lesions

Temitope T. Omolehinwa, BDS, Sunday O. Akintoye, BDS, DDS, MS*

KEYWORDS
 Osteoradionecrosis  Medication-related osteonecrosis  Chemical  Radiation
 Recreational drug  Damage  Diseases  Necrosis

KEY POINTS
 The role of radiographic imaging in diagnosis of osteonecrotic lesions cannot be
overemphasized.
 Treatment options for jaw osteonecrosis include the use of local and systemic antibiotics,
pain medications, debriding, sequestrectomy, hyperbaric oxygen treatment, and use of
the antioxidants, tocopherol and Pentoxifylline. Surgical resection is usually a last resort,
when all other forms of therapy fail.
 The effects on the quality of life in patients with jaw osteonecrosis, makes it an important
area of research, especially to researchers interested in bone and tissue engineering.

INTRODUCTION

Bone is a unique connective tissue because it is functionally dynamic, consisting of

different cells that continuously interact together. Unlike other connective tissues
within the body, bone is physiologically mineralized. There is also an abundance of
osteoprogenitor cells that reside within the bone microenvironment that can be acti-
vated to form different cell types.1 The ability of bone to constantly remodel plays a
vital role in the maintenance of mineral homeostasis, as old bone is removed by the
activities of osteoclasts and new bone matrix is deposited by osteoblasts. Essentially,
external and internal insults from radiation, drugs, or other chemical insults can induce
a pathologic process that disrupts the bone microenvironment, turnover, and homeo-
stasis. The outcome is dysregulation of the bone healing process that can potentially
lead to loss of bone tissue, as in osteonecrosis.

This work was supported in part by the grants K22CA169089 and R21DE022826 (awarded to
S.O. Akintoye) by United States Department of Health and Human Services/National Institutes
of Health, Bethesda, MD.
Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Robert
Schattner Center Room 211, 240 South 40th Street, Philadelphia, PA 19104, USA
* Corresponding author.
E-mail address: [email protected]

Dent Clin N Am 60 (2016) 265–277

http://dx.doi.org/10.1016/j.cden.2015.08.009 dental.theclinics.com
0011-8532/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
266 Omolehinwa & Akintoye

Osteonecrosis is characterized by tissue dehiscence, chronic bone devitalization,

hypocellularity, and osteolysis. The term osteonecrosis is often used interchangeably
with ischemic necrosis, avascular necrosis, or aseptic necrosis, but there are different
types of osteonecrosis. Depending on the etiologic agent, osteonecrosis can occur in
any bone including the orofacial, appendicular, and axial bones. Osteonecrosis may or
may not be associated with exposed bone with delayed healing. Specifically, the
femoral head and mandible are highly susceptible to osteonecrosis. In the orofacial
region, jaw osteonecrosis can lead to significant loss of bone tissue, tooth loss, and
facial disfigurement. The unfortunate outcomes are significant morbidity, debility,
and diminished quality of life.2 The high susceptibility of the femoral bone to osteonec-
rosis is associated with a variety of factors that include alcohol abuse and steroid ther-
apy. However, jaw osteonecrosis is much more associated with complications of
radiation therapy, and long-term therapy with bone antiresorptives used to control
skeletal events of cancer metastasis and osteoporosis.3,4 In a randomized controlled
study that assessed 792 cases of osteonecrosis in general, 76% of the cases occurred
in the hip, and 4.4% occurred in the jaw mainly as a result of bisphosphonate thera-
pies. The remaining cases were associated with the wrist, knee, foot, or ankle.5
Several pathophysiologic theories have been proposed for osteonecrosis based on
correlations of clinical signs with histologic and radiologic analyses. Although many
of these theories have not been conclusively established, radiographic imaging has
played a major role in the diagnosis, management, and follow-up assessment of
osteonecrosis. Even more importantly is the increasing use of the combination of func-
tional imaging with planar images to fully understand the metabolic changes that lead
to osteonecrosis.6

TYPES OF OSTEONECROSIS
Osteoradionecrosis
Osteoradionecrosis (ORN) of the jaw is defined as nonhealing bony exposure and ne-
crosis that starts with a breach in the oral mucosa, and persists for at least 3 months, in
a patient who has undergone previous radiation therapy. The necrosis, however, must
be evidently different from a recurrent, vestigial, or metastatic tumor.7,8 This definition,
however, does not include cases of ORN in which the oral mucosa is intact, but osteo-
necrotic changes can be observed by diagnostic imaging.9 ORN is a chronic condition
that can last for months or even years after the initial radiation therapy. The incidence
of ORN can range from 2.6% to 22.0%10 and it develops when the radiation dose
exceeds 50 Gy. Specifically, radiation doses between 50 and 70 Gy have been impli-
cated in the etiology of ORN.11 Within the orofacial complex, the mandible is
commonly affected because the mandible is usually in the line of radiation delivery
and it is believed that the mandible is less vascularized than the maxilla.12,13 Radiation
also affects teeth secondarily, due to pronounced xerostomia noted in patients
receiving radiation therapy (Fig. 1). The extensive carious lesions can be readily noted
on bitewing radiographs, as demonstrated in Figs. 2 and 3.
Pathogenesis
Osteoradionecrosis was first described in 1926.14 It was not until 1970 that a triad of
radiation, trauma, and infection was proposed as the mechanistic process in ORN.
However, this theory was later replaced in 1983 by another proposal that radiation
causes development of hypoxic-hypocellular-hypovascular tissue (3H theory),15
when it was reported that microorganisms do not play any causative but rather a
contaminant role in ORN. It was also reported that trauma mainly creates a portal of
entry for microorganisms to invade the radiation-suppressed bone. The 3H theory
 Chemical and Radiation-Associated Jaw Lesions 267

Fig. 1. Intraoral photograph of a patient who received radiation therapy for oral cancer.
Note the several complications of radiation therapy that include extensive caries involving
multiple surfaces as well as the incisal edges (arrowheads). The chalky white appearance
of teeth is characteristic of radiation caries. Also note the angular cheilitis due to
radiation-induced xerostomia (arrow).

of ORN takes into account that several tissues from exterior to interior are damaged by
radiation, ranging from the skin or mucosa to periosteum, bone, and finally endothe-
lium within the bone marrow compartment.16 So the combination of tissue fibrosis,
vascular and cellular damage induces a hypoxic environment within the radiated tis-
sue.16 The 3H theory was quickly followed by development of hyperbaric oxygen
(HBO) therapy protocols to prevent and treat ORN, but this had only modest effective-
ness, and HBO therapy is limited because it is contraindicated in patients with meta-
static cancer.3,4,17
The radiation-induced fibroatrophic process is another mechanism associated with
radiation damage more commonly to the superficial structures. This is associated with
the activity of reactive oxygen species that cause damage to fibroblasts, endothelium,

Fig. 2. Right premolar bitewing radiograph of a patient who received radiation therapy for
head and neck cancer. Note the extensive carious lesions and failing restorations.
268 Omolehinwa & Akintoye

Fig. 3. Left premolar bitewing of the same patient as in Fig. 2 with evidence of extensive
dental caries due to a combination of decreased salivation and increased biofilm.

and bone cells, eventually causing tissue and bone necrosis (Fig. 4). However, the
direct application of this theory to deep-seated radiation damage within the bone is
yet to be conclusively clarified.16 Another proposed pathophysiologic hypothesis is
that ORN can be precipitated by a combination of dysregulated turnover, osteoclast

Fig. 4. Osteoradionecrosis of the mandible. This patient received radiation therapy for head
and neck cancer. The panoramic radiographs before radiation therapy (A) show intact and
well-corticated outline of the mandible. However, the patient developed left mandibular os-
teoradionecrosis (B, red arrow) after undergoing postirradiation extraction of the left
mandibular premolars.
 Chemical and Radiation-Associated Jaw Lesions 269

depletion, local tissue injury, and infection.11 As all these theories do not conclusively
define the pathophysiological process of ORN, more research is still needed to further
our understanding of ORN pathogenesis.

Risk factors and classification

Several risk factors predispose to ORN; these include poor oral health, smoking,
alcohol abuse, and most importantly, type and dose of radiation. Brachytherapy
and radiation doses greater than 50 Gy have been associated with higher incidence
of ORN. Additionally, any surgical manipulations of the irradiated area, including
dental extractions, pose a significant risk. Several different classifications of ORN
have been proposed, but one recently proposed combines clinical description, pres-
ence or absence of symptoms, and the treatment option for each of the different
stages of ORN (Table 1).9
Clinical presentation
Patients with ORN usually present with pain that is typically neuropathic in nature. Also
swelling may be accompanied by fever depending on the extent of the inflammatory
process. Follow-up clinical evaluation may reveal tissue breakdown and bone
necrosis that may be associated with paresthesia/anesthesia. If untreated, ORN espe-
cially in the mandible may result in pathologic fracture. Definitive diagnosis of ORN is a
combination of clinical, radiologic, and histologic evaluations.

Medication-Related Osteonecrosis of the Jaws

Medication-related osteonecrosis of the jaw (MRONJ) is a more recent class of jaw
osteonecrosis first described in 2003 in patients taking nitrogen-containing
bisphosphonates (nBPs).18 It is defined as exposed bone in the intraoral cavity persist-
ing for 8 weeks or more, in patients who have previously undergone, or are currently
undergoing treatment with antiresorptives and/or antiangiogenic agents and with no

Table 1
Classification of osteoradionecrosis

Length of Affected Bone/

Associated Structures Presence/Absence of
Stage (Damaged/Exposed) Symptoms Treatment
1 <2.5 cm Asymptomatic. Medication treatment only.
2 >2.5 cm Asymptomatic. Medication treatment only;
Includes pathologic fracture except for presence of
and/or involvement of dental sepsis and loose/
inferior dental nerve. necrotic bone.
3 >2.5 cm Symptomatic. Debridement of loose/
No other features of bone necrotic bone.
necrosis. However, Local pedicle flap.
symptoms persist despite
medication treatment.
4 >2.5 cm Symptomatic. Reconstruction with free
Pathologic fracture. flap, if patient’s overall
Involvement of inferior health allows.
alveolar nerve and/or
orocutaneous fistula.

Adapted from Lyons A, Osher J, Warner E, et al. Osteoradionecrosis: a review of current concepts in
defining the extent of the disease and a new classification proposal. Br J Oral Maxillofac Surg
2014;52(5):394; with permission.
270 Omolehinwa & Akintoye

previous history of radiation therapy to the jaw. This excludes primary or metastatic
cancer within the jaw region.18 However, this definition does not take into account
the nonexposed bone variant of the disease process, which makes up about a third
of all cases of MRONJ cases.19
The nBPs, especially the intravenous nBPs, such as zoledronic acid, were the first
group of drugs initially associated with MRONJ. The high efficacy of intravenous nBPs,
such as zoledronic acid and pamidronate, to control altered bone remodeling make
them highly favored for the treatment of skeletal events of cancer metastasis, Paget
disease, osteogenesis imperfecta, and hyperparathyroid jaw tumors, so it is under-
standable that nBPs were the first to be associated with osteonecrosis exclusive to
the jaws. Other medications also have been implicated in MRONJ; these include
another antiresorptive drug, denosumab, which acts as an inhibitor of receptor acti-
vator for NFkB ligand (RANKL), and antiangiogenic drugs like bevacizumab, an inhib-
itor of vascular endothelial growth factor, and sunitinib, a tyrosine kinase inhibitor.
Because of the vast array of medications associated with osteonecrosis of the jaw
(ONJ), the nomenclature for this disorder has evolved over the years from ONJ,
bisphosphonate osteonecrosis (BON), bisphosphonate-related osteonecrosis of the
jaw (BRONJ), and anti-resorptive osteonecrosis of the jaw (ARONJ) to the more recent
MRONJ.20 The incidence of MRONJ in patients taking intravenous nBPs ranges from
0% to 27.5%,19,20 and denosumab 1.7%.19 The relative risks of MRONJ occurring in
patients taking intravenous nBPs, denosumab, or bevacizumab are 0.7% to 6.7%,
0.7% to 1.9%, and 0.2% respectively.20 MRONJ affects the mandible and maxilla
at a ratio of 2:1,21 because the mandible is partly associated with a single vascular
supply from the inferior alveolar artery compared with the superior, inferior, and middle
arteries in the maxilla. Severe cases of MRONJ in the mandible can lead to pathologic
fracture, whereas in the maxilla it can result in oroantral fistulation.

Pathogenesis
The pathophysiology of MRONJ is still unclear, but different investigators have proposed
several theories.22,23 These include a decrease in bone turnover, presence of infection
(especially Actinomyces species), inhibition of angiogenesis, and a dysregulation or
dysfunction of innate and acquired immunity.24 The infection theory is based on the
premise that a “complex biofilm” is present on the surface of exposed necrotic
bone.25 Definitive elucidation of MRONJ pathogenesis is hampered because the offend-
ing drugs have different mechanisms of action (Table 2) and nonoral bones are spared by
MRONJ. The role of bone mesenchymal stem cells (MSCs) also cannot be overlooked,
considering that jaw MSCs are phenotypically and functionally different from those of
axial and appendicular bones1 and they are disproportionately more sensitive to both
zoledronic acid and pamidronate, both of which are strongly associated with MRONJ.26

Risk factors and classification

The local risk factors that may predispose to MRONJ include trauma, overall poor dental
health, presence of tori or bony exostosis, and invasive dental procedures, such as
dental extractions and periodontal treatment. In addition, the systemic risk factors
include diabetes, smoking, alcohol, and an ongoing immunosuppressive therapy.28

Clinical presentation
Patients with MRONJ have variable clinical presentation depending on the clinical
course of the disease. This can vary from nonexposed bone to extensive bone loss
and pathologic fracture (Fig. 5). Therefore, a staging algorithm has been proposed
to aid not only in the diagnosis but also management of MRONJ (Table 3). A detailed
 Chemical and Radiation-Associated Jaw Lesions 271

Table 2
Implicated drugs in medication-related osteonecrosis of the jaw and their mechanisms of
action

Zoledronic Acid Denosumab Bevacizumab

Half-life Binds to bone: longer Does not bind to bone: Does not bind to bone:
half-life short half-life short half-life
(approximately 28 d) (approximately 20 d)
Mechanism Apoptosis of osteoclasts Prevents formation of Inhibits angiogenesis
osteoclasts
Target pathways/ Inhibits farnesyl Inhibits receptor Inhibits tyrosine kinase
transcription pyrophosphate activator of nuclear by binding to vascular
proteins through mevalonate factor kappa-B ligand endothelial growth
pathway factor
Effects on No effect on immune Tendency to cause Has effects on the
immune system immunosuppression immune system
system by action on B and
T cells
Clearance Clearance through Clearance through Clearance by
kidneys: nephrotoxic immunoglobulin pinocytosis with
(up to 12 y) pathway in binding to neonatal
reticuloendothelial Fc receptor27
system (within 6 mo)

history, clinical examination, and carefully selected radiographic imaging will aid in the
diagnosis of MRONJ (Figs. 6 and 7).

Recreational Drug–Induced Osteonecrosis

Chronic use of recreational or illicit drugs, such as cocaine, amphetamine, and meth-
amphetamine, are established independent risk factors for osteonecrosis, termed rec-
reational drug–induced osteonecrosis (RDIO).29–32 It is more common in the maxilla.29

Fig. 5. Exposed bone in the right mandibular posterior region in a patient with MRONJ.
(Courtesy of Arthur Kuperstein, DDS, and Mel Mupparapu, DMD, University of Pennsylvania
School of Dental Medicine, Philadelphia, PA.)
272 Omolehinwa & Akintoye

Table 3
Clinical staging of medication-related osteonecrosis of the jaw

Clinical Staging Presentation

Stage 0 Nonspecific odontogenic symptoms in patients with a history of
antiresorptive treatments.
Stage 1 Asymptomatic bony exposure.
Stage 2 Bony exposure, pain, and infection, well contained in the dentoalveolar
area.
Stage 3 Stage 2 disease symptoms extending beyond the alveolar area. Includes
pathologic fractures, oroantral communication, maxillary sinusitis, sinuses,
and fistula.

Adapted from Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxil-
lofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update.
J Oral Maxillofac Surg 2014;72(10):1938; with permission.

The incidence of RDIO is unknown because many addicts do not seek medical care.
Additionally, most illicit drug addicts are also heavy smokers and may be abusing
alcohol or other prescription drugs, which also heightens their predisposition to osteo-
necrosis.31 The pathogenesis of RDIO is multifactorial. Although several recreational
drugs have been implicated, cocaine in particular induces vascular constriction that
results in local ischemia of the adjacent soft and hard tissues.33 It has been proposed
that the combined effect of chemical irritation from additives to the recreational drug,
trauma, and superimposed microbial infection accentuate the necrotic process that
leads to bone destruction.32 Therefore, excessive bone destruction caused by nasal
inhalation or snorting of a recreational drug like cocaine initially starts as ulceration
of mucosal tissue that progressively leads to osteocartilaginous necrosis. If uncon-
trolled, the nasal septum and palate become perforated, consequently leading to oro-
nasal and oroantral fistulations.30,34 Specifically, cocaine-induced midline destructive
lesion (CIMDL) has been used to describe extensive destruction caused by cocaine
addiction to the oronasal structures, including the hard palate.32 This extensive osteo-
necrosis of the bony structures is one of the hallmarks used to identify CIMDL in the
assessment of human skeletal remains by medical examiners and forensic scientists.
If the addicted individual seeks treatment early, which often does not happen, RDIO
can be controlled before extensive bone destruction occurs by discontinuation of
the offending recreational drug.

Fig. 6. Panoramic reconstruction of the mandible and maxilla CBCT image of a patient with
MRONJ (arrow points to the area of osteonecrosis). (Courtesy of Arthur Kuperstein, DDS, Mel
Mupparapu, DMD, University of Pennsylvania School of Dental Medicine, Philadelphia, PA.)
 Chemical and Radiation-Associated Jaw Lesions 273

Fig. 7. Same patient as in Figs. 5 and 6. CBCT 3-dimensional reconstruction of the facial skel-
eton showing the separated osteonecrotic alveolar portion of the mandible (arrowheads).
(Courtesy of Arthur Kuperstein, DDS, and Mel Mupparapu, DMD, University of Pennsylvania
School of Dental Medicine, Philadelphia, PA.)

Steroid-Induced Osteonecrosis
Steroid-induced osteonecrosis, also referred to as aseptic, ischemic, or avascular ne-
crosis, develops as a result of long-term administration of corticosteroids. It is more
common in the appendicular bones, such as the femur or humerus rather than the
jaw35,36 and it is not induced by trauma or external insults, so it is a form of atraumatic
osteonecrosis. Corticosteroids affect multiple organs and systems, have immunosup-
pressive effects, and can disrupt bone homeostasis.36 Long-term use of corticoste-
roids of more than 20 mg per day can result in osteopenia and eventually
osteoporosis. To further complicate the situation, the patient may need to be placed
on bisphosphonate therapy to control dysregulated bone remodeling, consequently
resulting in the development of medication-induced osteonecrosis of the jaw. Smok-
ing, alcohol abuse, and comorbid conditions, such as osteoporosis and systemic
lupus erythematosus, predispose patients to steroid-induced osteonecrosis.37

HISTOLOGIC FEATURES OF OSTEONECROSIS

Definitive diagnosis of osteonecrosis is based on clinical, histologic, and radiological

findings. Histologically, vascular damage with hyperemia, inflammatory cells, and
osteoclastic activity are often seen at the early stages of osteonecrosis. Thereafter,
osteonecrosis displays regions of acellular marrow with loss of hematopoietic cells,
adipocytic infiltration suggestive of fatty marrow, and some regions of patchy calcifi-
cations within the marrow components due to osteoclastic activity. The bone is also
hypocellular with regions of empty lacunae devoid of osteocytic nuclei. There may
be attempts at healing demonstrated by reparative granulation tissue and some de-
gree of new osteoid deposition. Histologic features of osteonecrosis are similar in
the oral and nonoral bone and are independent of the bone type.

RADIOLOGIC FEATURES OF OSTEONECROSIS

Radiologic features of osteonecrosis must be correlated with histologic findings. A

good starting point for diagnosis of osteonecrosis is the use of plain film and pano-
ramic radiography (see Figs. 2–4), cone beam computerized tomography (CBCT)
(see Figs. 6 and 7), and conventional CT. Plain film radiographs will display mixed
radiolucent and radiopaque trabecular pattern. Depending on the cause of the osteo-
necrosis, there could be regions of osteolysis and sclerosis. Similarly, CT will display
altered trabeculation, cortical thinning, and sclerosis. Unfortunately, there needs to be
274 Omolehinwa & Akintoye

approximately 30% to 50% loss of bone mineral content for a bone lesion to be better
defined in a panoramic radiograph or CT.6
Other limits of panoramic radiograph and CT are that some of the radiographic fea-
tures are not specific to osteonecrosis; also, these imaging modalities cannot differen-
tiate necrotic bone from metastatic lesion, especially in oncology patients in whom this
may be a concern.38 Bone scintigraphy or bone scan provides better information
about the metabolic activities and pathophysiological changes in osteonecrosis
much earlier than panoramic radiographs, as osteonecrosis will display high uptake
of 99mTc-methylene diphosphonate in a bone scan. But a major diagnostic challenge
of using bone scintigraphy to diagnose osteonecrosis is its high signal sensitivity and
low specificity, as many dental disorders can present as osteonecrosis in a bone scan.
The additional use of the combinations of fluorodeoxyglucose/positron emission to-
mography (FDG/PET) and single photon emission computed tomography (SPECT)/CT
combination have also been shown to improve diagnostic accuracy because they pro-
vide functional and anatomic coregistration of the extent of the osteonecrosis.32,39–41
MRI can display osteonecrosis as decreased marrow signal intensity on T1-weighted
images and increased signal intensity on T2-weighted images. Interestingly, studies
using osteonecrosis of the hip samples have also shown that MRI findings correlate
well with histologic features of osteonecrosis.42 As MRI displays excellent visualization
of soft tissues, it may be useful in the diagnosis of osteonecrosis in the mandibular
condyle and around the temporomandibular joint complex where it may be clinically
impracticable to obtain biopsy samples.

SUMMARY

The role of radiographic imaging in diagnosis of osteonecrotic lesions cannot be over-

emphasized. However, there are limitations in the use of radiologic imaging only as the
standard of diagnosis without correlating the findings with other aspects of diagnosis:
clinical presentation and histologic findings. This is because most types of jaw osteo-
necrosis have similar radiographic presentations and cannot be differentiated from
other diseases affecting the jaw bone; for example, osteomyelitis and periapical
lesions.
Treatment options for jaw osteonecrosis include the use of local and systemic an-
tibiotics, pain medications, debriding, sequestrectomy, hyperbaric oxygen treatment,
and use of the antioxidants, tocopherol and Pentoxifylline.28 Surgical resection is usu-
ally a last resort, when all other forms of therapy fail.
The effects on the quality of life in patients with jaw osteonecrosis make it an impor-
tant area of research, especially to those interested in bone and tissue engineering. An
interesting area of ongoing research right now is the possible role of MSCs in possible
reconstruction of the defect caused by jaw osteonecrosis and the use of pharmaco-
logic compounds; for example, antisclerostin antibody in the prevention of the osteo-
necrotic process especially in patients with MRONJ.43–46

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