Fibrous Dysplasia and Medication-Related Osteonecrosis of ... · related bone pain and are frequently prescribed for this indication.2,17,18 The ﬁrst cases of bisphosphonate-related

PATHOLOGY

*Me

Minera

Nation

Institu

Michig

yCliMinera

Nation

Institu

zReof Den

New Y

xChCranio

Dental

Bethes

kAtHomeo

Institu

Health

Endoc

Health

Childre

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 and
other 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

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

http://www.fnih.org

mailto:[email protected]

http://dx.doi.org/10.1016/j.joms.2016.04.001

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).



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 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.



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.)


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.)



FIGURE 3 (cont’d). D, Panoramic radiograph displaying the region of the seriously decayed left maxillary third molar (arrow).


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.



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 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).



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.)


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.)



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 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).



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

References

1. Weinstein LS, Shenker A, Gejman PV, et al: Activating mutationsof the stimulatory G protein in the McCune-Albright syndrome.N Engl J Med 325:1688, 1991

2. Boyce AM, Collins MT: Fibrous dysplasia/McCune-Albright syn-drome, in Pagon RA, AdamMP, Ardinger HH, et al (eds): GeneRe-views�. Seattle, WA, University of Washington, 1993

3. Collins MT, Riminucci M, Bianco P: Fibrous dysplasia, in Rosen C(ed): Primer on the Metabolic Bone Diseases and Disorders ofMineral Metabolism (ed 8). Washington, DC, American Societyof Bone and Mineral Research, 2013, pp 786–793

4. Ito H, Waga S, Sakakura M: Fibrous dysplasia of the skull withincreased vascularity in the angiogram. Surg Neurol 23:408,1985

5. Hart ES, Kelly MH, Brillante B, et al: Onset, progression, andplateau of skeletal lesions in fibrous dysplasia and the relation-ship to functional outcome. J Bone Miner Res 22:1468, 2007

6. Akintoye SO, Boyce AM, Collins MT: Dental perspectives infibrous dysplasia and McCune-Albright syndrome. Oral SurgOral Med Oral Pathol Oral Radiol 116:e149, 2013

7. Lee J, FitzGibbon E, Chen Y, et al: Clinical guidelines for the man-agement of craniofacial fibrous dysplasia. Orphanet J Rare Dis7(suppl 1):S2, 2012

8. Riminucci M, Liu B, Corsi A, et al: The histopathology of fibrousdysplasia of bone in patients with activating mutations of the Gsalpha gene: Site-specific patterns and recurrent histological hall-marks. J Pathol 187:249, 1999

9. Papapoulos S: Bisphosphonates for postmenopausal osteo-porosis, in Rosen C (ed): Primer on the Metabolic BoneDiseases and Disorders of Mineral Metabolism (ed 8). Wash-ington, DC, American Society of Bone and Mineral Research,2013, pp 412–419

10. Wat WZ: Current perspectives on bisphosphonate treatment inPaget’s disease of bone. Ther Clin Risk Manag 10:977, 2014

11. Mhaskar R, Redzepovic J, Wheatley K, et al: Bisphosphonates inmultiple myeloma: A networkmeta-analysis. Cochrane DatabaseSyst Rev 5:CD003188, 2012

12. Biggin A, Munns CF: Osteogenesis imperfecta: diagnosis andtreatment. Curr Osteoporos Rep 12:279, 2014

13. Liens D, Delmas PD, Meunier PJ: Long-term effects of intrave-nous pamidronate in fibrous dysplasia of bone. Lancet 343:953, 1994

14. Chapurlat RD, Hugueny P, Delmas PD, et al: Treatment of fibrousdysplasia of bone with intravenous pamidronate: Long-termeffectiveness and evaluation of predictors of response to treat-ment. Bone 35:235, 2004

15. Plotkin H, Rauch F, Zeitlin L, et al: Effect of pamidronate treat-ment in children with polyostotic fibrous dysplasia of bone. JClin Endocrinol Metab 88:4569, 2003

16. Boyce AM, Kelly MH, Brillante BA, et al: A randomized, doubleblind, placebo-controlled trial of alendronate treatment forfibrous dysplasia of bone. J Clin Endocrinol Metab 99:4133,2014

17. Chapurlat RD: Medical therapy in adults with fibrous dysplasiaof bone. J Bone Miner Res 21(suppl 2):P114, 2006

18. Tessaris D, Matarazzo P, Lala R, et al: Odontoiatric perspec-tives and osteonecrosis of the jaw as a possible adverse ef-fect of bisphosphonates therapy in fibrous dysplasia andMcCune-Albright syndrome. J Pediatr Endocrinol Metab 29:333, 2016

19. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa)induced avascular necrosis of the jaws: A growing epidemic.J Oral Maxillofac Surg 61:1115, 2003

20. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis ofthe jaws associated with the use of bisphosphonates: A reviewof 63 cases. J Oral Maxillofac Surg 62:527, 2004

21. Ruggiero SL, Dodson TB, Fantasia J, et al: American Associationof Oral and Maxillofacial Surgeons position paper onmedication-related osteonecrosis of the jaw—2014 Update.J Oral Maxillofac Surg 72:1938, 2014

http://refhub.elsevier.com/S0278-2391(16)30032-5/sref1




































































METWALLY ET AL 17

22. Allen MR, Burr DB: The pathogenesis of bisphosphonate-relatedosteonecrosis of the jaw: So many hypotheses, so few data.J Oral Maxillofac Surg 67:61, 2009

23. Santini D, Vincenzi B, Galluzzo S, et al: Repeated intermittentlow-dose therapy with zoledronic acid induces an early, sus-tained, and long-lasting decrease of peripheral vascular endothe-lial growth factor levels in cancer patients. Clin Cancer Res 13:4482, 2007

24. Vincenzi B, Santini D, Dicuonzo G, et al: Zoledronic acid-relatedangiogenesis modifications and survival in advanced breast can-cer patients. J Interferon Cytokine Res 25:144, 2005

25. Lescaille G, Coudert AE, Baaroun V, et al: Clinical study evalu-ating the effect of bevacizumab on the severity of zoledronicacid-related osteonecrosis of the jaw in cancer patients. Bone58:103, 2014

26. Sivolella S, Lumachi F, Stellini E, et al: Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: An uncom-mon but potentially severe disease. Anticancer Res 33:1793,2013

27. Garetto LP, Chen J, Parr JA, et al: Remodeling dynamics of bonesupporting rigidly fixed titanium implants: A histomorphomet-ric comparison in four species including humans. ImplantDent 4:235, 1995

28. Han ZH, Palnitkar S, Rao DS, et al: Effects of ethnicity and age ormenopause on the remodeling and turnover of iliac bone: Impli-cations for mechanisms of bone loss. J Bone Miner Res 12:498,1997

29. Cheong S, Sun S, Kang B, et al: Bisphosphonate uptake in areasof tooth extraction or periapical disease. J Oral Maxillofac Surg72:2461, 2014

30. Ristow O, Gerngross C, Schwaiger M, et al: Is bone turnover ofjawbone and its possible over suppression by bisphosphonatesof etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg 72:903, 2014

31. Chapurlat RD, Delmas PD, Liens D, et al: Long-term effects ofintravenous pamidronate in fibrous dysplasia of bone. J BoneMiner Res 12:1746, 1997

32. Kuznetsov SA, Cherman N, Riminucci M, et al: Age-dependentdemise of GNAS-mutated skeletal stem cells and ‘‘normalization’’of fibrous dysplasia of bone. J Bone Miner Res 23:1731, 2008

33. King AE, Umland EM: Osteonecrosis of the jaw in patientsreceiving intravenous or oral bisphosphonates. Pharmaco-therapy 28:667, 2008

34. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw andbisphosphonates. N Engl J Med 353:99, 2005

35. Hoff AO, Toth BB, Altundag K, et al: Frequency and risk factorsassociated with osteonecrosis of the jaw in cancer patientstreated with intravenous bisphosphonates. J Bone Miner Res23:826, 2008

36. Bamias A, Kastritis E, Bamia C, et al: Osteonecrosis of the jaw incancer after treatment with bisphosphonates: Incidence andrisk factors. J Clin Oncol 23:8580, 2005

37. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate-inducedexposed bone (osteonecrosis/osteopetrosis) of the jaws: Riskfactors, recognition, prevention, and treatment. J Oral Maxillo-fac Surg 63:1567, 2005

38. Aghaloo T, Hazboun R, Tetradis S: Pathophysiology of osteonec-rosis of the jaws. Oral Maxillofac Surg Clin North Am 27:489,2015

39. Goodday RH: Preventive strategies for patients at risk ofmedication-related osteonecrosis of the jaw. Oral MaxillofacSurg Clin North Am 27:527, 2015

40. Denadai R, Raposo-Amaral CA, Marques FF, et al: Strategies forthe optimal individualized surgical management of craniofacialfibrous dysplasia [published online ahead of print September28, 2015]. Ann Plast Surg. PMID: 26418800.

41. Hellstein JW, Adler RA, Edwards B, et al: Managing the care of pa-tients receiving antiresorptive therapy for prevention and treat-ment of osteoporosis: Executive summary of recommendationsfrom the American Dental Association Council on ScientificAffairs. J Am Dent Assoc 142:1243, 2011

42. Khan AA, Morrison A, Hanley DA, et al: Diagnosis and manage-ment of osteonecrosis of the jaw: A systematic review and inter-national consensus. J Bone Miner Res 30:3, 2015






































































Documents

Fibrous Dysplasia and Medication-Related Osteonecrosis of ... · related bone pain and are frequently prescribed for this indication.2,17,18 The ﬁrst cases of bisphosphonate-related