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PATHOLOGY
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Fibrous Dysplasia andMedication-Related Osteonecrosis of
the JawTarek Metwally, BS,* Andrea Burke, DMD, MD,y Jeffrey Y. Tsai, DMD,z
Michael T. Collins, MD,x and Alison M. Boyce, MDk
Purpose: Osteonecrosis of the jaw (ONJ) is an established side effect of intravenous bisphosphonates andother antiresorptive medications. Although bisphosphonates are frequently prescribed for patients withthe skeletal disorder fibrous dysplasia (FD), there are no reports of ONJ in this population. This has led
some to conclude that patientswith FD are at low risk for the development of bisphosphonate-related ONJ.
Patients andMethods: Patients were evaluated as part of a longstanding FD natural history study at the
National Institutes of Health.
Results: Of 76 patients with FD who were treated with bisphosphonates, 4 developed ONJ (5.4%).
Three patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients
had features known to be associated with ONJ in the general population, including long-term high-dose
intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical
procedures.
Conclusions: These cases establish ONJ as a potential complication of bisphosphonate treatment in pa-
tients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests
that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in
prescribing bisphosphonates to patients with FD and should do so only for established indications.
Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial
Surgeons
J Oral Maxillofac Surg -:1-17, 2016
dical Research Scholar, Section on Skeletal Disorders and
l Homeostasis, Craniofacial and Skeletal Diseases Branch,
al Institute of Dental and Craniofacial Research, National
tes of Health, Bethesda, MD; Dental Student, University of
an School of Dentistry, Ann Arbor, MI.
nical Research Fellow, Section on Skeletal Disorders and
l Homeostasis, Craniofacial and Skeletal Diseases Branch,
al Institute of Dental and Craniofacial Research, National
tes of Health, Bethesda, MD.
sident, Department of Oral and Maxillofacial Surgery, School
tal Medicine, University at Buffalo, The State University of
ork, Buffalo, NY.
ief, Section on Skeletal Disorders and Mineral Homeostasis,
facial and Skeletal Diseases Branch, National Institute of
and Craniofacial Research, National Institutes of Health,
da, MD.
tending Physician, Section on Skeletal Disorders and Mineral
stasis, Craniofacial and Skeletal Diseases Branch, National
te of Dental and Craniofacial Research, National Institutes of
, Bethesda, MD; Adjunct Assistant Professor, Division of
rinology and Diabetes, and Attending Physician, Bone
Program, Division of Orthopaedics and Sports Medicine,
n’s National Health System, Washington, DC.
This research was supported by the Intramural Research Program
of the National Institute of Dental and Craniofacial Research,
National Institutes of Health (NIH) and the NIH Medical Research
Scholars Program, a public-and-private partnership supported jointly
by the NIH and generous contributions to the Foundation for the
NIH from the Doris Duke Charitable Foundation, the American Asso-
ciation for Dental Research, the Howard Hughes Medical Institute,
the Colgate-Palmolive Company, alumni of student research pro-
grams, and other individual supporters. For a complete list, please
visit the foundation Web site (http://www.fnih.org).
Dr. Tsai discloses stock ownership in Johnson & Johnson. All
other authors did not report any relevant financial relationship(s)
with a commercial interest.
Address correspondence and reprint requests to Dr Boyce:
National Institutes of Health, 30 Convent Drive, Room 228, MSC
4320, Bethesda, MD 20892-4320; e-mail: [email protected]
Received March 7 2016
Accepted April 1 2016
Published by Elsevier Inc on behalf of the American Association of Oral andMaxil-
lofacial Surgeons
0278-2391/16/30032-5
http://dx.doi.org/10.1016/j.joms.2016.04.001
1
FIGURE 1. Case 1, clinical images. A, Technetium-99 bone scinti-gram shows multiple areas of increased uptake consistent withfibrous dysplasia involving the skull, ribs, pelvis, and lower extrem-ities (arrowheads). (Fig 1 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac
Surg 2016.
2 FIBROUS DYSPLASIA AND MRONJ
Fibrous dysplasia/McCune-Albright syndrome (FD/
MAS; OMIM 174800) is a genetic disorder arising
from somatic activating mutations in GNAS, which
codes for the signaling protein Gsa.1 This mutation
leads to constitutive receptor activation, resulting in
increased Gsa signaling and dysregulated cyclic aden-
osine monophosphateproduction.2 In the skeleton,
GNAS mutations lead to increased proliferation andimpaired differentiation of skeletal progenitor cells,
resulting in the formation of FD lesions that are highly
vascular and prone to expansion, deformity, fracture,
and pain.3,4 FD can affect 1 bone (monostotic) or
multiple bones (polyostotic) and can occur in
isolation or in combination with caf�e-au-lait skin
macules and hyperfunctioning endocrinopathies,
including precocious puberty, hyperthyroidism,growth hormone excess, hypercortisolism, and renal
phosphate wasting. The combination of FD and at
least 1 extraskeletal feature is considered MAS.2 FD
can affect any area of the skeleton and occurs
frequently in the craniofacial area.5 Morbidity in the
skull relates primarily to FD expansion, resulting in
facial asymmetry and, less commonly, functional defi-
cits, including malocclusion, dental anomalies, andvision and hearing impairment.6,7
The mainstay of treatment for FD is surgical, and
there are no medical therapies capable of altering
the disease course. Antiresorptive therapy with bi-
sphosphonates has been advocated as a potential
treatment because of high levels of osteoclastogene-
sis present in FD tissue and the established role of
bisphosphonates in inhibiting osteoclast function.8
Bisphosphonates inhibit bone resorption by incor-
porating into the hydroxyapatite crystal and inhibit-
ing osteoclast function when they are taken up by
active osteoclasts. This group of drugs is used to
treat conditions of excessive bone resorption, such
as osteoporosis,9 Paget disease,10 malignancies
with skeletal metastases,11 and other skeletal disor-
ders such as osteogenesis imperfecta.12 The role ofthese medications in the management of FD has
not been fully elucidated. Early case reports and
small series described subjective improvements
in pain and variable effects on the radiographic
appearance of FD lesions13-15; however, a placebo-
controlled trial of the oral bisphosphonate alendro-
nate showed no effects on pain or FD lesion
appearance.16 Currently, there is little evidence tosupport an effect of bisphosphonates on FD quality
or lesion expansion; however, intravenous formula-
tions are generally considered beneficial for FD-
related bone pain and are frequently prescribed for
this indication.2,17,18
The first cases of bisphosphonate-related osteonec-
rosis of the jaws (ONJ) were reported in 2003 by
Marx19 and 2004 by Ruggiero et al.20 Since that time,
FIGURE 1 (cont’d). B, Photograph depicting asymmetric expansion of the right mandible (arrow). Note the caf�e-au-lait macule involving thejaw, shoulder, and neck with characteristic features, including jagged ‘‘coast of Maine’’ borders and location in relation to the midline of thebody (dashed lines). (Fig 1 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
METWALLY ET AL 3
other antiresorptive (denosumab) and anticancer
(ie, sirolimus, bevacizumab) medications have been
implicated in jaw necrosis; as of 2015, the American
Association of Oral and Maxillofacial Surgeons’ Special
Committee has relabeled this diagnosis asmedication-
related osteonecrosis of the jaws.21 Despite the
frequent use of bisphosphonates in patients with FD,
there are no reports in the literature describing ONJ.This has led to postulation that patients with FD might
be at lower risk for ONJ compared with the general
population of patients treated with bisphospho-
nates.18 This article describes 4 patients in the Na-
tional Institutes of Health (NIH) FD/MAS natural
history study who developed ONJ subsequent to bi-
sphosphonate treatment.
Patients and Methods
The patients in this report were evaluated at the NIH
Clinical Center as part of a longstanding FD/MAS natu-
ral history study. All patients gave informed consent,
and the protocol was approved by the institutional re-view board of the National Institute of Dental and
Craniofacial Research of the NIH. This study followed
the Declaration of Helsinki on medical protocol
and ethics.
FIGURE 1 (cont’d). C, Three-dimensional computed tomogram displays facial asymmetry with multiple expansile lesions particularlyaffecting the right side of the skull. D, Axial computed tomogram shows extensive craniofacial fibrous dysplasia exhibiting the characteristic‘‘ground-glass’’ appearance with multiple areas of radiolucency. Note the left maxilla and alveolar ridge with extensive fibrous dysplasiainvolvement encasing the left maxillary first and second molars (arrow; American Dental Association teeth 14 and 15).
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
4 FIBROUS DYSPLASIA AND MRONJ
FIGURE 2. Case 1, dental images. A, Preoperative panoramic radiograph taken before extraction of the left maxillary second molar and3 months before initial presentation of osteonecrosis. The left maxillary first and second molars are located within fibrous dysplasia bone (ar-rows). B, Periapical radiograph taken before extraction of the left maxillary second molar (American Dental Association tooth 15). Note theperiodontal and endodontic lesion associated with the right maxillary second molar (arrowhead). (Fig 2 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
METWALLY ET AL 5
Results
Of 146 patients with FD seen at the NIH, 76 (46%)
had received treatment with bisphosphonates for
management of bone pain. Four patients developed
ONJ subsequent to bisphosphonate treatment, and
these patients are described in detail.
CASE 1
A 47-year-old woman presented with pain and cold
sensitivity 3 months after extraction of the left maxil-
lary second molar. The patient had a history of FD/
MAS manifested by severe bony involvement in the
craniofacial region, thorax, and femur; caf�e-au-lait
FIGURE 2 (cont’d). C, Panoramic radiograph taken 4 months after extraction of the left maxillary second molar shows bone resorption andosteosclerosis of the lesion (arrow). D, Gutta percha points within the persistent fistula.
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
6 FIBROUS DYSPLASIA AND MRONJ
macules; and MAS-associated growth hormone excess
(Fig 1). Her history was noteworthy for numerous
craniofacial surgeries, including bilateral optic nerve
decompressions and multiple maxillary and mandib-
ular recontouring procedures. Her clinical course
was complicated by severe FD-related bone pain unre-sponsive to over-the-counter analgesics and amitripty-
line. At 36 years of age, 11 years before her current
presentation, the patient was placed on bisphospho-
nates for pain management, including a 3-year course
of pamidronate 180 mg every 3 months from 36 to
39 years of age, followed by a 6-year course of zole-
dronic acid 4 mg every 3 months from 39 to 45 years
of age.
The patient had an extensive dental history with
numerous restorative, endodontic, and periodontal
procedures. One year before presentation, the pa-tient’s general dentist observed gingival swelling
around the left maxillary first and second molars
(American Dental Association [ADA] teeth 14 and 15,
respectively) and diagnosed a distal endodontic and
periodontal lesion with a probing depth of 12 mm;
FIGURE 3. Case 2, clinical and dental images. A, Technetium-99bone scan highlighting areas of increased radiotracer uptake inbone (arrowheads) affected by fibrous dysplasia in the skull andbilateral femurs, humeri, and fibulas. (Fig 3 continued onnext page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac
Surg 2016.
METWALLY ET AL 7
she was noted to have generalized mild chronic peri-
odontitis with localized aggressive periodontitis at
the left maxillary molars and purulent exudate from
the site. Of note, the left maxilla and alveolar ridge
had extensive FD involvement. The patient was
referred to a periodontist and was treated with scaling
and root planing, gingivectomy, and oral antibiotics.
One year later, the patient reported lingering pain inthe left maxillary second molar; her general dentist
observed periapical radiolucency and prescribed a 1-
week course of penicillin V. The patient was evaluated
by an endodontist who determined that the left maxil-
lary secondmolar was non-restorable secondary to the
persistent endodontic and periodontal lesion (Fig 2B),
and extraction was recommended. The patient was
referred to an oral andmaxillofacial surgeon for extrac-tion of the left maxillary second molar. Three months
after extraction, the patient returned to her oral and
maxillofacial surgeon with complaints of cold sensi-
tivity, severe pain, and a nonhealing extraction site.
Given her history of bisphosphonate treatment in
combination with symptomatic, exposed bone that
had been present for longer than 8 weeks, she was
diagnosed with stage 2 osteonecrosis (ONJ) of theleft posterior maxilla. Radiographically, the left maxil-
lary alveolar ridge was noted to have bone resorption
and osteosclerotic areas within the FD lesion (Fig 2A).
Of note, the patient had discontinued zoledronic acid
2 years before undergoing extraction and received 1
additional dose of zoledronic acid 2 weeks before
her ONJ diagnosis. After her ONJ diagnosis, local
debridement was performed 3 times during the nextyear. She was treated with oral cephalexin. Cultures
obtained on 2 occasions did not exhibit a predominant
species. Ten months after her ONJ diagnosis, the
maxillary left first molar (ADA tooth 14) was found
to be mobile and showed periodontal compromise
(Fig 2C). This tooth was surgically extracted, and the
area was debrided. Postoperatively, oral hygiene was
stressed, and the patient was prescribed fluoridatedtoothpaste and triannual dental prophylaxis. Two
months after extraction of the left maxillary first molar,
the patient reported improved healing and some soft
tissue coverage. One year after extraction of the left
maxillary first molar, the patient presented with pain
and discomfort; a panoramic radiograph showed a
persistent fistula (Fig 2D). The patient received ceph-
alexin and reported pain relief. Two years later, the pa-tient again presented with pain and swelling. An
intraoral examination disclosed moderate erythema
of the mucosa around the lesion with no discharge.
Two days later, the patient underwent an incision
and drainage. At that time, she was placed on a long-
term course of oral antibiotics; however, compliance
has been intermittent, and 5 years after her initial diag-
nosis, she continues to have active ONJ.
FIGURE3 (cont’d). B, Clinical photograph depicting facial dysmorphism resulting frommild vertical dystopia and diffuse expansion of maxil-lary and mandibular fibrous dysplasia. C, Three-dimensional computed tomographic reconstruction visualizes diffuse craniofacial involvementwith fibrous dysplasia. (Fig 3 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
8 FIBROUS DYSPLASIA AND MRONJ
FIGURE 3 (cont’d). D, Panoramic radiograph displaying the region of the seriously decayed left maxillary third molar (arrow).
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
METWALLY ET AL 9
CASE 2
A 23-year-old man with intellectual disability and
FD/MAS presented for routine dental consultation.
His disease burden included extensive polyostotic
FD involving the skull, proximal humerus, bilateral
ribs, and femurs (Fig 3). Additional features of MASincluded neonatal hypercortisolism treated with bilat-
eral adrenalectomy, hyperthyroidism treatedwith total
thyroidectomy, and pancreatic intraductal papillary
mucinous neoplasms treated with pancreatoduode-
nectomy. His clinical course was complicated by post-
operative right-side vision loss after a prophylactic
right optic nerve decompression at 5 years of age.
He has a history of severe FD-related bone pain treatedwith zoledronic acid 4 mg every 3 months from 18 to
23 years of age.
The patient’s complex dental history included or-
thodontic treatment to correct his malocclusion,
FIGURE 4. Case 2, intraoral photographs. A, B, Photographs of the antedental caries and stagnant plaque after removal of the patient’s braces annext page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 20
starting with a palatal expander 1 year before his cur-rent presentation. During orthodontic treatment, the
patient sustained a traumatic fracture of the maxillary
left lateral incisor. The family requested that the or-
thodontic appliance be removed owing to difficulty
in maintaining oral hygiene. When the appliance
was removed, extensive decay was noted on all the
maxillary and mandibular anterior teeth (Figs 4A,B).
During a routine dental consult at the NIH, a 3- to4-mm circular area of exposed bone was noted on
the left palate adjacent to the left maxillary second
and third molars (ADA teeth 15 and 16; Fig 4C).
Remarkably, the area of exposed bone was in an
area of FD, but did not occur in an area that had
been covered by the palatal expander. In addition,
the left maxillary third molar was decayed to the
gingival margin, and numerous caries were notedthroughout the dentition. Neither the patient nor
rior maxillary and mandibular teeth, respectively, illustrate rampantd the fractured maxillary left lateral incisor. (Fig 4 continued on
16.
FIGURE 4 (cont’d). C, An area of exposed bone is visible on the left palate adjacent to the left maxillary second and third molars (arrow).D, Photograph of the site of osteonecrosis covered by granulation tissue (arrow) at the patient’s follow-up appointment 3 years after its initialdocumentation.
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
10 FIBROUS DYSPLASIA AND MRONJ
his family was aware of the lesion or the carious
tooth, and the patient denied pain or sensitivity. No
erythema or purulence was associated with the
exposed bone. Based on his history of bisphospho-
nate treatment and the duration of exposed bone,
the patient was diagnosed with stage 1 ONJ. Because
of more pressing medical issues, the patient did not
return for follow-up until 3 years later. At that time,necrotic bone was still noted to be present (Fig
4D), as was the carious left maxillary third molar
(Fig 3D). The patient was referred to a tertiary care
center near his home for treatment and is being
closely monitored.
CASE 3
A 57-year-old man with FD/MAS presented for
dental clearance before orthopedic surgery. The pa-
tient had severe FD involving the lower extremitiesand pelvis, caf�e-au-lait macules, and renal phosphate
wasting. He had a history of multiple pathologic frac-
tures requiring orthopedic surgeries. Eleven years
before his current presentation, the patient received
a 2-year course of bisphosphonates from 46 to 48 years
of age for treatment of FD-related bone pain. He was
initially treated with zoledronic acid 6 mg every
6 months for the first year and transitioned to 4 mg
every 3 months for the subsequent year.
The patient’s dental care had been sporadic owing to
financial issues and dental phobia. Seven months
before his current presentation, he underwent a preop-erative dental evaluation in preparation for a planned
total femur replacement. The general dentist observed
carious root tips, generalized caries, and a horizontal
partial bony impacted left mandibular first molar
(Fig 5A). Ten teeth were recommended for extraction,
but the patient elected to limit extraction to the left
mandibular first and second molars (ADA teeth 18
and 19) and left mandibular first premolar (ADA tooth21). After extraction, the patient was prescribed a daily
chlorhexidine rinse.At a follow-upevaluation2months
later, the patient elected to have the right maxillary
secondmolar (ADA tooth 2) and leftmaxillary first, sec-
ond, and third molars (ADA teeth 14 to 16) extracted.
At a follow-up evaluation 2 months later, planned
restorative work on the right maxillary first molar
FIGURE5. Case 3, dental images.A, Panoramic radiograph depicting the poor state of dentition before dental treatment. B, Panoramic radio-graph taken 6 months after extractions and restorative treatment.
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
METWALLY ET AL 11
and right maxillary first premolar was performed. Dur-
ing the restorative appointment, the dentist noted a
cariogenic pulp exposure on the right mandibular first
molar (ADA tooth 30), and this toothwas subsequently
extracted, as were the left maxillary lateral incisor(ADA tooth 10) and left mandibular first molar (ADA
tooth 17; Fig 5B). Two weeks after the extractions,
the patient presented to the dental clinic with
pain and discomfort because of impacted food in the
bilateral extraction sites; the sites were irrigated and
the patient was instructed to continue home irriga-
tion. At a follow-up evaluation 3 months later, the in-
traoral examination showed exposed bone in the
lingual mandible bilaterally (3 � 3 mm on the leftand 3� 2mm on the right side; Figs 6A,B). The patient
was asymptomatic and subsequently diagnosed with
stage 1 ONJ. The patient was placed on chlorhexidine
rinses with close observation.
FIGURE 6. Case 3, intraoral photographs. Photographs were taken 2 weeks after initial presentation of osteonecrosis of the jaw. A, Rightposterior mandible with exposed bone along the lingual alveolar ridge (arrow; image is reflected in mirror). B, Patient’s left mandibular lingualalveolus, reflected in mirror. Area of exposed bone is present along the posterior mylohyoid ridge (arrow).
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
12 FIBROUS DYSPLASIA AND MRONJ
CASE 4
A 57-year-old woman with FD/MAS presented for
routine dental consultation. The patient had polyos-
totic FD affecting the craniofacial region, ribs,
femurs, and tibias (Fig 7A). MAS-related endocrinopa-thies included precocious puberty and hyperthyroid-
ism after thyroidectomy for poorly differentiated
clear cell carcinoma. Because of chronic FD-related
bone pain, the patient was prescribed a course of bi-
sphosphonates, which included pamidronate 60 mg
every 3 months from 36 to 39 years of age, followed
by zoledronic acid 4 mg every 6 months from 39 to
49 years of age.
The patient’s dental history was defined by sporadic
dental care, including multiple restorative procedures
and extractions. Seven months before presentation,
the right maxillary first molar and second premolar
(ADA teeth 3 and 4, respectively) were deemed non-
restorable and were extracted by the patient’s home
providers. At examination at the NIH, a 2-mm nonheal-
ing bony defect of the right maxillary alveolar ridgeand potential radiographic fistula were noted (Figs
7B,D). Of note, FD was present in the bilateral maxilla,
including in the region of the extractions (Fig 7C). The
patient was asymptomatic and denied pain or sensi-
tivity and was subsequently diagnosed with stage 1
METWALLY ET AL 13
ONJ. The patient reported that her home dentist never
mentioned the exposed bone and 1.5 years later re-
ported that the right maxillary wound had healed
without complication. Approximately 1 year after
her visit to the NIH, the patient also recounted that
the left maxillary canine and first premolar (ADA teeth
11 and 12) were extracted because of mobility and
marked decay. Three months after this extraction,the patient denied complications, stating that her
wounds had completely healed and that a removable
partial denture had been fabricated.
FIGURE 7. Case 4, clinical, dental, and intraoral images. A,Technetium-99 bone scan highlighting areas of increased radio-tracer uptake in bone (arrowheads) affected by fibrous dysplasiain the skull, ribs, femur, and tibia. (Fig 7 continued on nextpage.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac
Surg 2016.
Discussion
ONJ is an established complication of bisphos-
phonate use and appears to occur uncommonly in
association with FD/MAS. To the authors’ knowl-
edge, these cases are the only reports of
bisphosphonate-associated ONJ in patients treated
for FD, and cases 1, 2, and 4 are the only reportedinstances of ONJ occurring in FD bone. In the
NIH cohort of 76 patients treated with bispho-
sphonates, this represents a 5.4% prevalence of
bisphosphonate-related ONJ. Although this cohort
is not sufficiently large to draw conclusions regarding
prevalence in the general FD population, these cases
establish that, contrary to previous thinking, patients
with FD are at risk for the development ofbisphosphonate-related ONJ and should be coun-
seled and monitored accordingly.
The pathophysiology of bisphosphonate-relatedONJ
in FD and other disorders is not well understood. One
proposed mechanism includes inhibition of angiogen-
esis resulting in an interruption of the vascular supply
to the jaws.21,22 This is supported by studies showing
antiangiogenic properties of bisphosphonates23,24 andincreasing evidence of a potential association
between ONJ and other antiangiogenic agents, such
as tyrosine kinase inhibitors and an anti–vascular
endothelial growth factor monoclonal antibody.25,26
FD bone is highly vascular,7 and it is unknownwhether
inhibition of angiogenesis is a contributory factor in the
development of ONJ in patients with FD.
Another commonly cited hypothesis links thepathophysiology of bisphosphonate-related ONJ to
suppression of osteoclastic bone resorption and re-
modeling.21,22 This could explain the predominant
localization of ONJ to the jaws, where intracortical
remodeling rates are believed to be increased
compared with other skeletal sites,27,28 although it
should be noted that more recent studies have
challenged this paradigm.29,30 High bone turnoverand increased osteoclastogenesis are characteristic
of FD lesions.3 The effects of bisphosphonates on
osteoclast activity within FD lesions have not been
fully elucidated; however, 1 study reported no
FIGURE 7 (cont’d). B, Panoramic radiograph taken at initial presentation, with the arrow pointing to the region of extraction 7 monthspreviously. (Fig 7 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
14 FIBROUS DYSPLASIA AND MRONJ
detectable effect on histomorphometric indices,
including resorption parameters, in biopsy speci-mens of patients treated with pamidronate.15 This
is consistent with long-term studies that did not
find a consistent effect of bisphosphonate treatment
on FD lesion size or radiographic appearance.16,31
Therefore, the potential role of suppression of bone
remodeling or resorption in the development of
these patients’ ONJ is unclear.
Age-related changes in craniofacial FD also mightaffect the development of ONJ. The natural history
of FD lesions is to become established during early
childhood, expand during linear growth, and remain
relatively quiescent in adulthood.5 Craniofacial lesions
in older patients typically become less homogeneous
radiographically, developing discrete radiolucent
‘‘cystic’’-appearing areas over time.2 These findings
are mirrored histologically, with lesions in olderpatients showing fewer features characteristic of FD,
and in some cases exhibiting normal bone andmarrow
histology, complete with restoration of hematopoie-
sis.32 Decreased vascularity and bone turnover over
time might predispose older patients with FD to the
development of ONJ. However, the occurrence of
ONJ in FD bone in case 2, who presented at the rela-
tively young age of 23 years, argues against thispossibility.
The patients presented in this report had
multiple features known to be associated with
bisphosphonate-related ONJ in the general popula-
tion. ONJ occurs more commonly in conjunction
with nitrogen-containing bisphosphonates, in partic-
ular zoledronic acid, as opposed to lower potencynon–nitrogen-containing and oral formulations.33,34
Higher doses, intravenous formulations, duration of
treatment, and more frequent dosing intervals also
are correlated with increased risk.35,36 All patients
described in this report had frequent treatment with
zoledronic acid at high doses and over a long period.
In addition, all had concomitant periodontal and
endodontic infections and underwent dentoalveolarsurgical procedures, which also are established risk
factors for ONJ.37 The development of ONJ in these pa-
tients likely was the result of a combination of these
multiple risk factors.
Current ONJ treatment guidelines stress the need
for disease prevention with regular dental examina-
tions and professional prophylaxis before beginning
bisphosphonate and non-bisphosphonate antiresorp-tive or antiangiogenic medication regimens.38 Peri-
odontal surgical procedures are treated in the same
manner as oral and maxillofacial surgical proce-
dures.39 Evaluation and treatment for MAS-associated
endocrinopathies is an essential element of care in
patients with FD and should be performed before initi-
atingmedical or dental treatments. In active ONJ, treat-
ments can range from debridement of the necroticbone to aggressive resection of the affected area.38
Postoperative regrowth is common after conservative
debulking and recontouring surgeries in craniofacial
FD; therefore, if ONJ is treated surgically, then the
FD bone should be monitored to assess response to
FIGURE 7 (cont’d). C, Coronal computed tomogram showing characteristic homogenous ground-glass appearance of fibrous dysplasia inthe area of extraction (arrow). (Fig 7 continued on next page.)
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
METWALLY ET AL 15
surgery.40 As more patients with FD/MAS are treated
with bisphosphonates and antiosteoclastic drugs, it
is important to investigate ONJ and other long-term ef-
fects of these drugs to develop appropriate treatment
and monitoring guidelines.
These cases establish ONJ as a potential complica-tion of bisphosphonate treatment in patients with
FD/MAS. The presence of established risk factors for
ONJ in this group of patients with FD suggests that
high-risk patients could be identified before the devel-
opment of ONJ. Population studies are needed to iden-
tify additional FD-specific risk factors and to determine
the prevalence of bisphosphonate-related ONJ in pa-
tients with FD/MAS. Future studies investigating the
effect of bisphosphonates on histology, turnover, and
other morphometric indices could provide insights
into the pathophysiology of medication-related ONJin FD and other conditions. The identification of
this potential side effect also highlights the need to
be judicious in administering bisphosphonates to pa-
tients with FDwithout a clearly established indication.
The current literature does not support a beneficial
FIGURE7 (cont’d). D,Clinical photograph showing2-mmbonyexposureof the rightmaxillary alveolar ridge in theareaof extraction (arrow).
Metwally et al. Fibrous Dysplasia and MRONJ. J Oral Maxillofac Surg 2016.
16 FIBROUS DYSPLASIA AND MRONJ
effect of bisphosphonate treatment on FD beyond
the treatment of FD-related bone pain. Similar to
patients without FD, the development of ONJ can
be mitigated by 1) obtaining pretreatment dental
screening and initiation of appropriate dentalcare, 2) using the lowest dose and interval necessary
to maintain a therapeutic effect, and 3) using clinical
judgment for the use of alternative dosing schedules
or drug holidays in patients who require invasive
dental procedures.21,41,42
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