Position Paper

Salvatore L. Ruggiero, DMD, MD, Clinical

Professor, Division of Oral and Maxillofacial

Surgery, Stony Brook School of Dental

Medicine, Hofstra North Shore-LIJ School

of Medicine, New York Center for Orthognathic

and Maxillofacial Surgery, Lake Success, N.Y.

Thomas B. Dodson, DMD, MPH, Professor

and Chair, University of Washington School of

Dentistry, Department of Oral and Maxillofacial

Surgery, Seattle, Wash.

Tara Aghaloo, DDS, MD, PhD, Professor,

Oral and Maxillofacial Surgery, Assistant Dean

for Clinical Research, UCLA School of Dentistry,

Los Angeles, Calif.

Eric R. Carlson, DMD, MD, EdM, Professor

and Kelly L. Krahwinkel Endowed Chairman,

Department of Oral and Maxillofacial Surgery,

University of Tennessee Graduate School of

Medicine, Knoxville, Tenn.

Brent B. Ward, DDS, MD, Chalmers J. Lyons

Professor of Oral and Maxillofacial Surgery,

Associate Professor of Dentistry, Chair of the

Department of Oral and Maxillofacial Surgery/

Hospital Dentistry in the School of Dentistry

and Associate Professor of Surgery for the

Medical School, University of Michigan

Hospital, Ann Arbor, Mich.

Deepak Kademani, DMD, MD, Chief of

Sta North Memorial Health, Fellowship

Director, Oral/Head and Neck Oncologic

and Reconstructive Surgery Attending Surgeon,

North Memorial Health and the University of

Minnesota. Private practice, Minnesota Oral

and Facial Surgery and Minnesota Head and

Neck Surgery, Minneapolis, Minn.

PAGE 1 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Abstract

Strategies for management of patients with, or at risk for,

medication-related osteonecrosis of the jaw (MRONJ) –

formerly referred to as bisphosphonate-related

osteonecrosis of the jaw (BRONJ) – were set forth

in the American Association of Oral and Maxillofacial

Surgeons (AAOMS) position papers in 2007, 2009

and 2014. The position papers were developed by a

committee appointed by the AAOMS Board of Trustees

and comprising clinicians with extensive experience in

caring for these patients, as well as clinical and basic

science researchers. The knowledge base and experience

in addressing MRONJ continues to evolve and expand,

necessitating modications and renements to the previous

position papers. Three members of the AAOMS

Committee on Oral, Head, and Neck Oncologic and

Reconstructive Surgery (COHNORS) and three authors

of the 2014 position paper were appointed to serve as a

working group to analyze the current literature and revise

the guidance as indicated to reect current knowledge in

this eld. This update contains revisions to diagnosis and

management strategies and highlights the current research

status. AAOMS maintains that it is vitally important for

this information to be disseminated to other relevant

healthcare professionals and organizations.

Introduction

Medications prescribed for dental and medical conditions

have potential side eects that warrant a risk-benet

discussion. Where therapeutic margins are wide and

complications are readily corrected, decisions are

implemented in a straightforward fashion. Where

therapeutic margins are wide but complications are

signicant, deciding to proceed with pharmacologic

treatment becomes more challenging. In most cases of

MRONJ, local therapies can be successful. The fact that

more complex treatment is required for a few patients

should not impact decision-making for all other patients

with osteonecrosis of the jaw. The medications associated

with MRONJ have proven to be safe and eective in

clinical trials and postmarketing analyses for most

Position Paper

American Association of Oral and Maxillofacial Surgeons

Medication-Related Osteonecrosis of the Jaw – 2022 Update

patients and should continue as a mainstay therapy when

indicated. Communicating the risks of MRONJ to patients

and providers is critical to ensure appropriate medical

management for the primary disease.

Undoubtedly, risk proles may change as new medications

come to market. In addition, our understanding of disease

pathophysiology, risk modiers and treatment strategies

will continue to evolve. It is of the utmost importance

that clinicians base their patient treatment decisions on

currently available scientic evidence.

Strategies for management of patients at risk for or with

MRONJ were set forth in AAOMS Position Papers in

2007,

2009

and 2014.

These position papers were

developed by a committee appointed by the AAOMS

Board of Trustees and comprised of clinicians with

extensive experience in caring for these patients as well as

clinical and basic science researchers. The knowledge base

and experience in addressing MRONJ continues to evolve

and expand, necessitating modications and renements to

the previously published position papers. A working group

comprised of three members of the AAOMS Committee

on Oral, Head, and Neck Oncologic and Reconstructive

Surgery and three authors of the 2014 paper convened

remotely in the fall of 2020 to appraise the current

literature and revise the guidelines as indicated to reect

the current knowledge in this eld. This update contains

revisions to the pathogenesis and management strategies

and highlights the current research status. AAOMS

maintains it is vitally important for this information to be

disseminated to other relevant healthcare professionals and

organizations.

Purpose

The purpose of this position paper is to provide updates

regarding:

1. Risk estimates of developing MRONJ.

2. Comparisons of the risks and benets of medications

related to osteonecrosis of the jaw in order to facilitate

medical decision-making for the treating physician,

dentist, dental specialist and patient with the

establishment of algorithms.

3. Guidance to clinicians regarding:

a. the dierential diagnosis of MRONJ in patients

with a history of exposure to antiresorptive

medications.

b. MRONJ prevention measures and management

strategies for patients with MRONJ based on the

disease stage.

PAGE 2 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Medications

Bisphosphonates (BPs) are antiresorptive medications

that are eective in managing cancer-related conditions,

including hypercalcemia of malignancy, spinal cord

compression and pathologic fractures (skeletal-related

events [SREs]) associated with bone metastases in the

context of solid tumors (such as breast, prostate and lung

cancers) and multiple myeloma.

4, 5, 6, 7, 8, 9, 10, 11, 12, 13

While

the potential for BPs to improve cancer-specic survival

remains controversial, these medications have had a

signicant positive eect on the quality of life for patients

with advanced cancer involving the skeleton and reducing

or preventing skeletal-related events.

Bisphosphonates also are used for the prevention of

osteoporosis-related fractures (fragility fractures) in

patients with osteoporosis and osteopenia.

14, 15, 16

BPs

administered orally – including alendronate (Fosamax),

risedronate (Actonel) or parenterally (zoledronic acid

[Reclast]), and ibandronate (Boniva) – can result in

a signicant reduction in vertebral and nonvertebral

fractures for patients with osteoporosis.

17, 18, 19, 20

Bisphosphonate therapy also is indicated for other

metabolic bone diseases such as Paget’s disease of bone

and osteogenesis imperfecta.

21, 22, 23

However, clinical trials

have not demonstrated the ecacy of bisphosphonate

therapy in the management of brous dysplasia.

Denosumab (DMB), a receptor activator of nuclear factor

kappa-B ligand (RANK-L), is an antiresorptive agent

that exists as a fully humanized antibody against RANK

ligand and inhibits osteoclast function and associated bone

resorption. When denosumab (Prolia) is administered

subcutaneously every six months, there is a signicant

reduction in the risk of vertebral, nonvertebral and hip

fractures in osteoporotic patients.

25, 26, 27, 28

Denosumab

(Xgeva) also is eective in reducing SREs related

to metastatic bone disease from solid tumors when

administered monthly.

29, 30, 31

RANK ligand inhibitors also have proven ecacy in

the treatment of giant cell tumors of bone and brous

dysplasia.

32, 33, 34, 35, 36

In contrast to BPs, RANK-L

Position Paper

PAGE 3 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

inhibitors do not bind to bone, and their eects on bone

remodeling are mostly diminished within six months of

treatment cessation.

Romosozumab is a new monoclonal antibody used

for fracture prevention in osteoporotic women.

Romosozumab, administered subcutaneously, works via

the Wnt pathway by binding to and inhibiting sclerostin,

resulting in increased bone formation and decreased bone

resorption.

MRONJ Case Denition

MRONJ should be distinguished from other forms of

osteonecrosis (ONJ) conditions and identied by history

and clinical exam. The clinical criteria required to establish

a diagnosis of MRONJ have remained unchanged from the

previous position paper.

The case denition of MRONJ includes all the following

elements:

1. Current or previous treatment with antiresorptive

therapy alone or in combination with immune

modulators or antiangiogenic medications.

2. Exposed bone or bone that can be probed through an

intraoral or extraoral stula(e) in the maxillofacial

region that has persisted for more than eight weeks.

3. No history of radiation therapy to the jaws or

metastatic disease to the jaws.

Staging

A staging system for MRONJ was introduced in the

2009 AAOMS position paper and then modied in the

2014 position paper to characterize more accurately all

aspects of the clinical presentation of MRONJ. Since

these modications, the AAOMS staging system has

continued to be a straightforward and relevant system to

properly stratify these patients. It has been adopted by

several professional societies and research organizations.

The staging system facilitates the creation of rational

treatment guidelines and guides data collection to assess

the prognosis and outcomes for MRONJ patients. While

AAOMS recognizes that dierent classication systems

are being used by other organizations,

the Association

considers the AAOMS system to be a useful and widely

implemented assessment tool guiding clinicians involved

in the care of MRONJ patients. AAOMS remains

concerned that overemphasizing variable radiographic

features often attributed to MRONJ may overestimate

the true disease frequency by including false positives

in the numerator (e.g., cases with radiographic ndings

suggestive of MRONJ), but these patients do not t the

criteria for the diagnosis of MRONJ. In the orthopedic

literature, the usefulness of a Stage 0 category has been

established for staging avascular necrosis (AVN) of the

femoral head when there is a suspicion of AVN in a patient

at risk, but the diagnostic information is not conclusive.

AAOMS believes the Stage 0 category for MRONJ is

analogous in principle and does account for the wide-

ranging radiographic presentation of MRONJ that exists

prior to overt bone exposure. Therefore, AAOMS has

decided to maintain the current classication system with

no modications.

Patients at-Risk

No apparent necrotic bone in asymptomatic patients who

have been treated with IV or oral antiresorptive therapy.

Stage 0 (Nonexposed Bone Variant)

Patients with no clinical evidence of necrotic bone but

who present with nonspecic symptoms or clinical and

radiographic ndings, such as:

Symptoms

• Odontalgia not explained by an odontogenic cause.

• Dull, aching bone pain in the jaw, which may radiate

to the temporomandibular joint region.

• Sinus pain, which may be associated with inammation

and thickening of the maxillary sinus wall.

• Altered neurosensory function.

Clinical Findings

• Loosening of teeth not explained by chronic periodontal

disease.

• Intraoral or extraoral swelling.

Radiographic Findings

• Alveolar bone loss or resorption not attributable

to chronic periodontal disease.

• Changes to trabecular pattern sclerotic bone and no new

bone in extraction sockets.

• Regions of osteosclerosis involving the alveolar bone

and/or the surrounding basilar bone.

• Thickening/obscuring of periodontal ligament

(thickening of the lamina dura, sclerosis and decreased

size of the periodontal ligament space).

These nonspecic ndings, which characterize this variant

of MRONJ without bone exposure, may occur in patients

with a prior history of Stage 1, 2 or 3 disease who have

been healed and have no clinical evidence of exposed

bone. Progression to Stage 1 disease has been reported

in up to 50 percent of patients with Stage 0 disease

and,

therefore, AAOMS deems it prudent to consider Stage 0

disease as a potential precursor to MRONJ.

Stage 1

Exposed and necrotic bone or stula that probes to the

bone in patients who are asymptomatic and have no

evidence of infection/inammation. These patients also

may present with radiographic ndings mentioned for

Stage 0 that are localized to the alveolar bone region.

Stage 2

Exposed and necrotic bone, or stula that probes to the

bone, with evidence of infection/inammation. These

patients are symptomatic. These patients also may present

with radiographic ndings mentioned for Stage 0 localized

to the alveolar bone region.

Stage 3

Exposed and necrotic bone or stulae that probes to the

bone, with evidence of infection, and one or more of the

following:

• Exposed necrotic bone extending beyond the region

of alveolar bone (i.e., inferior border and ramus in the

mandible, maxillary sinus and zygoma in the maxilla).

• Pathologic fracture.

• Extraoral stula.

• Oral antral/oral-nasal communication.

• Osteolysis extending to the inferior border of the

mandible or sinus oor.

Causality

It is important to understand that patients at risk for or with

established MRONJ also can present with other common

clinical conditions not to be confused with MRONJ.

Commonly misdiagnosed conditions may include but

are not limited to alveolar osteitis, sinusitis, gingivitis/

periodontitis, caries, periapical pathology, odontalgia,

atypical neuralgias, bro-osseous lesions, sarcoma,

chronic sclerosing osteomyelitis, and temporomandibular

joint (TMJ) disorders. It also is important to remember

that delayed healing, exposed bone or sequestra (i.e.,

osteonecrosis [ONJ]), can occur in patients not exposed

to antiresorptive agents.

Proving causality of any medication-related complication

is challenging from an epidemiologic perspective. It is

well-known that MRONJ is a rare entity, multifactorial

in nature, and patients with the same clinical presentation

exist who have not been exposed to an antiresorptive

medication. Studies have reported jaw necrosis in

antiresorptive naïve patients in which necrosis was linked

to bacterial, viral or fungal infections, trauma, smoking,

steroids, immunocompromised host, autoimmune diseases,

diabetes and chemotherapy.

43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,

55, 56, 57

Furthermore, patient populations – such as those

with osteogenesis imperfecta – have been treated with

antiresorptive agents without reports of MRONJ.

Many

patients receiving medications associated with MRONJ

have other comorbidities, which are likely exacerbating or

contributing factors. In combination, these confounding

variables make incidence and prevalence dicult to

estimate.

Clinical trials, while being the gold standard for ecacy

and safety data, are seldom powered to demonstrate

uncommon events. Prior to the discovery of MRONJ, large

randomized prospective trials of BPs with up to 10 years

of patient data did not reveal any jaw bone necrosis as a

complication.

17, 59

More recently, the HORIZON Pivotal

Fracture trial tested 3,889 randomized patients given

annual zoledronic acid versus placebo for three years; one

patient developed MRONJ in the intervention group and

one in the placebo group.

Extension of this trial for up to

six years resulted in one additional MRONJ patient in the

treatment group.

Extension to nice years resulted in no

additional conrmed cases of MRONJ.

Denitive causality, taken as a whole, remains a dicult

task to prove in general, let alone in individual patients

PAGE 4 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

PAGE 5 Medication-Related Osteonecrosis of the Jaw – 2022 Update

presenting with clinical symptoms. Clinicians should

be aware of these facts in decisions regarding treatment

recommendations.

Pathophysiology

Since the AAOMS position paper in 2014, signicant

knowledge has been gained regarding MRONJ

pathophysiology from both clinical and particularly

preclinical animal studies. It should be noted that animal

studies have a number of limitations, are most often using

supratherapeutic doses and likely do not truly mirror

the clinical environment. That said, they are critical in

understanding disease mechanisms and can serve as

one reference point to evidence-based clinical decision-

making.

Much debate persists among clinicians and researchers,

contributing to the various treatment protocols utilized

for patients today.

62, 63, 64, 65

Disease specicity unique

to the jaws has focused leading hypotheses to include

bone remodeling inhibition, inammation or infection,

angiogenesis inhibition, innate or acquired immune

dysfunction, as well as genetic predisposition.

3,65

Both

animal and human studies suggest that an antiresorptive

medication, coupled with inammation or infection, is

necessary and sucient to induce MRONJ. However, as

more knowledge is gained on the subject, it is becoming

increasingly apparent that MRONJ is multifactorial, and it

is likely that multiple hypotheses can explain the overall

pathophysiology of this disease.

3,65

Bone Remodeling Inhibition

The denition of MRONJ includes oral or parenteral

administration of antiresorptive medications, such that

bone remodeling suppression is a central hypothesis

in its pathophysiology. Antiresorptive medications,

including BPs and denosumab (DMB), have direct eects

on osteoclast formation, dierentiation or function. In

osteoporosis, BPs are a rst-line therapy to decrease bone

remodeling, increase bone mineral density, and decrease

vertebral and long bone fractures.

66,67

BPs, in higher doses,

also are utilized in primary bone malignancy and bone

metastases to decrease SREs, including hypercalcemia

of malignancy, reduce severe bone pain and improve

quality of life.

68, 69, 70, 71, 72

Although DMB has only been

approved for use since 2010, its use has increased

signicantly for both osteoporosis and malignancy

in the last decade. Prevalence of MRONJ with DMB

users is at least as high as BP users, likely due to its

increased potency to inhibit bone resorption.

30,73, 74, 75

This

is supported in the jaws as animal studies demonstrate

absent osteoclasts around the alveolar bone of DMB-

treated mice.

Human bone specimens also show an

increased number of nonfunctional osteoclasts surrounding

necrotic bone in BP-treated patients,

further reinforcing

bone remodeling inhibition as a leading hypothesis

in MRONJ pathophysiology. With the appearance of

MRONJ in DMB-treated patients, it becomes increasingly

apparent that the underlying pathophysiology involves

dysfunctional osteoclasts.

Animal studies evaluating withdrawal of BPs or DMB

further highlight the importance of bone remodeling

in MRONJ prevention and resolution. Rodents with

established ONJ failed to resolve when antiresorptives

were withdrawn. However, discontinuing DMB, but not

BPs, prior to tooth extraction successfully prevented

MRONJ development in rats.

78,79

Moreover, parathyroid

hormone, which acts directly on osteoblasts to induce

bone formation and indirectly increases osteoclastic bone

resorption and overall remodeling, has been shown to

prevent MRONJ and improve extraction socket healing

in rodents and preliminarily in patients.

80, 81, 82

This

observation provides further support for the central role

of osteoclast inhibition in MRONJ pathogenesis.

Inammation or Infection

Although most studies report tooth extraction as the

major inciting event for MRONJ development, it is clear

that most extracted teeth had pre-existing periodontal or

periapical disease.

3, 64, 83, 84

From this patient information,

animal models of inammation or infection were

developed to replicate clinical, radiographic and histologic

features of MRONJ.

85, 86, 87, 88

Presence of inammatory

cytokines, specically at the site of MRONJ, also

support the strong role of inammation.

As evidence of

increased systemic inammation and its contribution to

MRONJ development, mice with experimentally induced

rheumatoid arthritis demonstrated more severe MRONJ

with increased oral bone exposure, more pronounced

radiographic features, intense local inammatory inltrate

and larger areas of histologic necrosis.

Further support

for the inammatory etiology showed that removal of

the inammatory nidus in ligature-induced periodontitis

ameliorated MRONJ development in mice, demonstrating

Position Paper

PAGE 6 Medication-Related Osteonecrosis of the Jaw – 2022 Update

reduced inammation and prevention of disease

progression.

Moreover, transplantation of peripheral

blood mononuclear cells with anti-inammatory properties

reduced MRONJ prevalence by improving soft-tissue

healing, decreasing inammatory polymorphonuclear

cells and inammatory marker expression, as well as

enhancing vascularity.

These preclinical ndings conrm

the irrefutable role of inammation or infection in MRONJ

disease prevalence, severity and resolution.

The presence of bacteria on the exposed necrotic bone

also contributes to disease severity, where pain and signs

of infection dene Stage 2 MRONJ.

3, 93, 94

This is not

surprising since poor oral hygiene and biolm presence are

associated with MRONJ development,

95, 96

and oral health

maintenance and dental prophylaxis before initiating

antiresorptive therapy can decrease MRONJ prevalence.

97,

Importantly, clinical treatment protocols to reduce the

biolm and eradicate infection have emerged as important

alternatives to debridement and resection in patients who

may not be ideal surgical candidates.

Angiogenesis Inhibition

Osteonecrosis is traditionally dened as avascular necrosis

or aseptic necrosis, most commonly characterized as

osteocyte death after decreased blood ow to the femoral

head.

However, MRONJ is dened as necrotic bone

in the maxillofacial region after exposure to either

antiresorptive or antiangiogenic medications.

BPs such as

zoledronic acid directly inhibit angiogenesis in vitro and in

vivo

100, 101, 102, 103

and animal models demonstrate decreased

vascularity in sites of MRONJ and decreased microvessel

numbers during early stages of bone healing.

104

addition, angiogenesis normally seen during extraction

socket healing is inhibited by BPs, and both BPs and

DMB have been shown to decrease arterial area, venous

area and overall vascularity of periodontal tissues during

early and late MRONJ development.

105, 106

Importantly,

antiangiogenic medications, such as Vascular Endothelial

Growth Factor (VEGF) inhibitors, tyrosine kinase receptor

inhibitors and immunomodulatory drugs,

107, 108, 109

can be

associated with MRONJ. Moreover, patients with multiple

myeloma receiving both antiresorptive and antiangiogenic

medications, as shown in several studies,

110, 111, 112, 113, 114

have a higher MRONJ prevalence. Important aspects of

MRONJ treatment include determining disease margins,

which can be challenging as microvascular mucosal

abnormalities can be seen adjacent to frank MRONJ

lesions.

115

It is important to note that the incidence of

MRONJ in patients on antiangiogenics is much lower than

those taking antiresorptive medications.

Innate or Acquired Immune Dysfunction

Although animal studies conrm that an antiresorptive

medication—coupled with inammation or infection—

is necessary and sucient to produce MRONJ, not all

patients with dental infections develop the disease. It is

well-known that patients with medical comorbidities such

as diabetes or rheumatoid arthritis or immunocompromised

states are at signicantly higher risk for MRONJ with

or without exposure to antiresorptive agents.

3, 64, 114, 116

Patients with metastatic or primary bone malignancies

have a compromised immune system.

117

This also has

been conrmed with animal studies, where chemotherapy,

steroids and disease-modifying antirheumatic drugs

(DMARDs), combined with antiangiogenic medications

and an antiresorptive, increase MRONJ severity or

prevalence.

118, 119, 120

Moreover, higher rates of MRONJ

occur in patients with multiple myeloma who receive

multiple chemotherapeutic agents.

110,121

Replenishing the area of nonhealing MRONJ lesions with

mesenchymal stem cells (MSCs) to overcome immune

dysfunction is a potential area of therapeutic interest,

especially in patients who are immunocompromised.

A recent study showed altered numbers and patterns of

T-cells in human and rat MRONJ necrotic bone samples

as compared to healthy patients and non-MRONJ sites.

122

Preclinical studies also demonstrate healing or prevention

of MRONJ lesions after systemic infusion with adipose or

bone marrow-derived MSCs.

123, 124, 125

Genetic Factors

In the 2014 paper, the authors identied several reports

describing single-nucleotide polymorphisms (SNPs) that

were associated with the development of MRONJ. Most

of these SNPs were located within regions of the gene

associated with either bone turnover, collagen formation

or certain metabolic bone diseases. Indeed, increasing

evidence is available to support the role of SNPs with

MRONJ.

126, 127

Specic links to sirtuin-1 (SIRT1), a bone

remodeling regulator that promotes bone formation, may

be protective against MRONJ if upregulated.

128

SIRT1

also is involved in both reduction of inammation and

induction of angiogenesis, suggesting a role in several

Position Paper

PAGE 7 Medication-Related Osteonecrosis of the Jaw – 2022 Update

of the leading MRONJ hypotheses.

128

Other genes also

have been reported to increase MRONJ risk through

their role in angiogenesis, bone remodeling and immune

responses, including PPAR gamma, CYP2C8 and many

others.

129

Collectively, these studies suggest that MRONJ

is a multifactorial disease and that genetic factors may

play a role in its development.

130

Overall, however, current

studies document either a weak or no association between

genetic factors measured and risk for MRONJ.

131

determine predisposition, studies with larger sample sizes

should be performed, with genetic risks conrmed in both

BPs and DMB-treated patients who have breast or prostate

cancer metastases, multiple myeloma or osteoporosis.

Risk factors for MRONJ

Medication-related Risk Factors

To estimate the risk for medications associated with

MRONJ, the primary parameter to be considered is the

therapeutic indication for treatment (e.g., malignancy

or osteoporosis/osteopenia). The data suggest that

antiresorptive medications (i.e., BPs and DMB) are

associated with an increased risk for developing MRONJ.

The risk of MRONJ is considerably higher in the

malignancy group (<5%) than in the osteoporosis group

(<0.05%). Current data are insucient to identify other

medications as risk factors for developing MRONJ.

MRONJ risk among cancer patients

For estimating the risk for MRONJ among patients

exposed to a medication, the risk for MRONJ in patients

not exposed to antiresorptive medications must be

estimated (Table 1). The risk for MRONJ among cancer

patients enrolled in clinical trials and assigned to placebo

groups ranges from 0 percent to 0.7 percent.

132, 133, 134, 135, 136,

137, 138

a. Among cancer patients exposed to zoledronate,

the cumulative risk of MRONJ clusters in the low

single digits, <5 percent, and ranges from 0 percent

to 18 percent.

113,132,133,137, 138, 139, 140, 141, 142, 143, 144

The

wide variation in estimates may be explained by

the varying durations of follow-up, one to 10 years,

reported in the various studies. The risk of MRONJ

among cancer patients exposed to zoledronate

ranges between 2-10 times higher than cancer

patients treated with placebo.

b. Among cancer patients exposed to DMB, the

risk of MRONJ ranges from 0 percent to 6.9

percent, with most studies reporting rates <5

percent.

113,134,135,138,141,142,144,145

The risk for MRONJ

among cancer patients exposed to DMB is

comparable to the risk of MRONJ in cancer patients

exposed to zoledronate.

135,141,142,144,145

Since the 2014 update, investigators have implicated

numerous families of medications as risk factors for

MRONJ.

146, 147, 148, 149

These medications include tyrosine

kinase inhibitors (TKIs) such as sunitinib, monoclonal

antibodies (bevacizumab), fusion proteins (aibercept),

mTOR inhibitors (everolimus), radiopharmaceuticals

(radium 223), selective estrogen receptor modulators

(raloxifene) and immunosuppressants (methotrexate and

corticosteroids).

When compared to antiresorptive medications, the

level of evidence supporting other medication families

as risk factors for MRONJ is level 5 (e.g., isolated

case reports or mini-case series [<5 cases]).

146, 147, 148,

149

Given that the poly-pharmaceutical management of

cancer patients combined with the fact that cancer and

immunosuppression are risk factors for MRONJ without

exposure to antiresorptive agents, AAOMS believes that

identifying a single medication as being the etiologic agent

for MRONJ seems unlikely in case reports or mini-case

series. Further controlled prospective studies will be

required to measure the risk of MRONJ associated with

non-antiresorptive agents.

MRONJ Risk Among Osteoporosis Patients

Most dentists and oral and maxillofacial surgeons evaluate

patients in their practices exposed to antiresorptive therapy

for management of osteoporosis (Table 1).

a. Risk for MRONJ among osteoporotic patients

exposed to BPs.

The risk of MRONJ among study subjects assigned

to placebo groups enrolled in osteoporosis clinical

trials ranged from 0 percent to 0.02 percent.

26,150,151

Among study subjects treated with BPs, the risk

of MRONJ is 0.02 percent to 0.05 percent.

37,75,152

Among patients exposed to IV zoledronate,

the risk for MRONJ is estimated to be ≤0.02%

(≤ 2 per 10,000). For patients exposed to oral

bisphosphonates, MRONJ risk is estimated to be

≤0.05% (≤ 5 per 10,000).

Position Paper

PAGE 8 Medication-Related Osteonecrosis of the Jaw – 2022 Update

b. MRONJ risk among osteoporotic patients exposed

to RANK-L inhibitors.

After 10 years of follow-up, among patients

exposed to DMB, the risk for MRONJ was reported

to be 0.3 percent, almost an order of magnitude

higher than for BPs.

153

c. The risk for MRONJ when exposed to

romosozumab (0.03 percent to 0.05 percent) is

comparable to alendronate (0.05 percent).

37,151

In the

placebo group, there were no cases of MRONJ.

151

It will be important to continue to monitor

romosozumab to assess its role as a risk factor for

MRONJ.

The risk for MRONJ among osteoporosis patients

treated with BPs ranges from 0.02 percent to

0.05 percent and overlaps the risk for MRONJ

of patients enrolled in placebo groups (0 percent

to 0.02 percent). The risk for MRONJ among

patients treated with denosumab, however, has a

larger range—from 0.04 percent to 0.3 percent.

As such, additional research will be needed to

better estimate the risk of MRONJ among patients

receiving denosumab. The risk of MRONJ for

patients exposed to romosozumab (0.03 percent

to 0.05 percent) more closely aligns with the risk

associated with BPs.

37,151

However, given its recent

introduction as a therapeutic agent, additional

research will be needed to rene its association and

risk estimate for MRONJ.

Based on this current review of data, the risk of developing

MRONJ among osteoporotic patients exposed to BPs,

DMB and romosozumab is low. The occurrence of cases

seen is best explained by a rare event among a large

number of patients, 5.1 million over the age of 55, exposed

to these drugs.

154

MRONJ Risk Among Patients

with Nonmalignant Bone Disease

a. AAOMS identied two studies where DMB was

used to manage aggressive giant cell tumors of

bone.

155, 156

The risk of developing MRONJ in

the two studies was broad and ranged from 0.7

percent to 5 percent. This is comparable to the

risks of developing MRONJ in subjects treated

with DMB for malignancies (range = 0 percent

to 6.9 percent). Additional studies will be needed

to conrm the risk estimate for MRONJ among

patients with nonmalignant bone disease treated

with antiresorptives.

b. There are very limited data describing the

occurrence of MRONJ in the pediatric population

for osteogenesis imperfecta and other conditions. In

a systematic review estimating the risk of MRONJ

among children with osteogenesis imperfecta, there

were no cases of MRONJ identied in a sample

of 486 subjects treated for 4.5 to 6.8 years.

157

In a

dierent systematic review that estimated the risk

for MRONJ among those under the age of 24 for

several conditions treated using BPs, no cases of

MRONJ were reported.

158

The overall quality of

the studies included in both systematic reviews was

limited by small sample sizes or lack of MRONJ-

related risk factors.

Duration of Medication Therapy

as a Risk Factor for MRONJ

Regardless of indications for therapy, the duration of

antiresorptive therapy is a risk factor for developing

MRONJ. Among cancer patients exposed to zoledronate

or DMB (n = 5,723), the risk of developing MRONJ

was, respectively, 0.5 percent and 0.8 percent at 1 year,

1.0 percent and 1.8 percent at 2 years, and 1.3 percent

and 1.8 percent at 3 years.

141

In a study by Saad et al.,

the investigators combined three-blinded phase 3 trials

and found similar results, including a plateau after two

years for patients exposed to DMB.

In a more recent

systematic review by Ng et al., the risk of MRONJ among

cancer patients treated with zoledronate, was 1.6 percent

to 4 percent after two years of treatment and 3.8 percent

to 18 percent with more than two years of treatment.

145

Likewise, for DMB, the risks for developing MRONJ

were 1.9 percent and 6.9 percent with <24 months and >24

months of exposure, respectively.

145

For patients receiving bisphosphonate therapy to manage

osteoporosis, data regarding duration are mixed. Early on,

the prevalence of MRONJ was reported as increasing over

time from near 0 percent at baseline to 0.21 percent after

four or more years of BP exposure based on retrospective

analysis.

152,159

More recent data from a large prospective,

randomized placebo controlled trial demonstrate no

signicant increase in MRONJ in patients treated for up

to nine years.

18,60,61

In addition, there are no postmarketing

Position Paper

PAGE 9 Medication-Related Osteonecrosis of the Jaw – 2022 Update

data or general clinical experience to support an MRONJ

prevalence of 0.21 percent in any osteoporosis-treated

group. Therefore, while duration may be a risk factor, the

overall risk remains low.

Local Factors

Dentoalveolar Operations

Dentoalveolar operations are the most common identiable

predisposing factor for developing MRONJ. Several

studies report that among patients with MRONJ, tooth

extraction is cited as a predisposing event ranging from

62 percent to 82 percent.

5,75,160

While this information is

important, it is not what most patients or clinicians want to

know. Most providers and patients want an answer to the

following clinical question: “Among patients exposed to

antiresorptive medications, what is the risk for developing

MRONJ following tooth extraction (or other dentoalveolar

procedures such as implant placement or periodontal

procedures)?” Current estimates for the risk of MRONJ

among osteoporotic patients exposed to BPs following

tooth extraction range from 0 percent to 0.15 percent.

161,162

For osteoporotic patients exposed to DMB, the risk for

MRONJ following tooth extraction was 1 percent.

163

For cancer patients exposed to BPs, the risk of developing

MRONJ after tooth extraction ranges from 1.6 percent

to 14.8 percent.

164, 165, 166

In a small case series, n = 61

subjects having 102 extractions, the risk for MRONJ

after tooth extraction was 13.1 percent.

167

In a systematic

review by Gaudin et al., the risk for MRONJ after tooth

extraction (n = 564) was estimated to be 3.2 percent.

162

While the estimates for developing MRONJ in high-risk

patients undergoing tooth extraction vary, they cluster

between 1 percent and 5 percent, similar to estimates of

osteoradionecrosis following tooth extraction in irradiated

patients.

The risk of developing MRONJ among patients who

have been exposed to antiresorptive medications for

other dentoalveolar operations such as dental implant

placement and endodontic or periodontal procedures is

unknown.

168

The risk for MRONJ after implant placement

among patients treated with DMB has been reported to

be 0.5 percent.

163

Absent better data, AAOMS cautions

the use of these procedures in cancer patients exposed to

antiresorptive therapies and recommends osteoporosis

patients be informed of potential risks, albeit low,

including development of MRONJ, early and late implant

failure all of which have been described in case reports and

clinical trials.

Anatomic Factors

Limited new information regarding anatomic risk factors

for MRONJ is available. MRONJ is more likely to appear

in the mandible (75 percent) than the maxilla (25 percent)

but can appear in both jaws (4.5 percent).

5,75

Denture use

was associated with an increased risk for MRONJ among

cancer patients exposed to zoledronate (OR = 4.9; 95

percent CI = 1.2 to 20.1).

169

In a study by Vahtsevanos et

al., using a sample of 1,621 cancer patients treated with

intravenous zoledronate, ibandronate or pamidronate, there

was a twofold increased risk for MRONJ among denture

wearers.

170

Concomitant Oral Disease

Preexisting inammatory dental disease such as

periodontal disease or periapical pathology is cited as a

risk factor.

75,168

Among cancer patients with MRONJ, the

preexisting inammatory dental disease was a risk factor

among 50 percent of the cases.

5,165

Given that a common treatment of inammatory dental

disease is tooth extraction, pre-existing dental disease may

confound the relationship between tooth extraction and

risk for MRONJ. Tooth extraction may expose MRONJ

as opposed to being the precipitating event. It would be

valuable to see an estimate of the association between

tooth extraction and MRONJ adjusted for pre-existing

inammatory dental disease.

After tooth extraction and periodontal disease, the next

most common risk factor is reported as “spontaneous”

MRONJ with no identiable dental risk factor.

168

Demographic and Systemic Factors

and Other Medications

Age and sex are variably reported as risk factors

for MRONJ.

5, 165, 169, 170, 171

The higher prevalence of

MRONJ in the female population is likely a reection

of the underlying disease for which the agents are being

prescribed (e.g., osteoporosis, breast cancer).

As noted previously, those under the age of 24 treated

with antiresorptives for benign bone diseases have not

demonstrated any risk for MRONJ even after an extended

Position Paper

PAGE 10 Medication-Related Osteonecrosis of the Jaw – 2022 Update

duration of therapy. The overall quality of the studies

included even in systematic reviews is based on small

sample sizes and the lack of other MRONJ-related risk

factors. The risk of developing MRONJ in the pediatric

population requires continued surveillance.

Corticosteroids are associated with an increased risk for

MRONJ.

5,168,171

There are concerns that corticosteroids

increase the risk for MRONJ when given in conjunction

with antiresporptive agents.

Comorbid conditions are inconsistently reported to be

associated with an increased risk for MRONJ, including

anemia (hemoglobin < 10 g/dL) and diabetes.

5,171

Cancer

type also is variably reported as a risk factor.

170,172

Tobacco use is variably reported as a risk factor for

MRONJ. In a case-control study, tobacco use approached

statistical signicance as a risk factor for MRONJ in

cancer patients (OR = 3.0; 95 percent CI = 0.8 to 10.4).

169

In a more recent case-controlled study, tobacco use was

not associated with ONJ in a sample of cancer patients

exposed to zolendronate.

171

Vahtsevanos did not report an

association between tobacco use and MRONJ.

170

In brief, after chemotherapy and corticosteroid exposure,

the next most reported comorbidity is “no comorbidity.”

168

In summary, the current literature rearms that the risk

of MRONJ is signicantly greater in cancer patients

receiving antiresorptive therapy compared to patients

receiving antiresorptive therapy for osteoporosis.

Moreover, the risk of MRONJ in osteoporosis patients

receiving antiresorptive therapy continues to be very low

regardless of drug type (BPs, DMB, romoszumab) or

dosing schedule.

Management Strategies

Treatment Goals

The major goals of treatment for patients at risk of

developing or who have established MRONJ are:

• Prevention of MRONJ (see section MRONJ risk

among cancer patients below).

• Prioritization and support of continued oncologic

treatment in patients receiving antiresorptive therapy

alone or in combination with immune modulators or

antiangiogenic medications:

○ Oncology patients benet from the therapeutic

eect of antiresorptive therapy by controlling bone

pain and reducing the incidence of other SREs.

• Prioritization and support of continued bone health and

the prevention of fragility fractures:

○ Patients with osteoporosis, osteopenia and other

metabolic bone diseases benet from antiresorptive

therapy by signicantly reducing the risk of fragility

fractures and other skeletal-related events.

• Preservation of quality of life through:

○ Patient education and reassurance.

○ Control of pain.

○ Control of secondary infection.

○ Prevention of extension of lesion and development

of new areas of necrosis.

Prevention of MRONJ

Numerous studies demonstrate potentially modiable

factors for reducing the risk of MRONJ, including

performing high-risk surgical procedures prior to initiating

therapy,

95,173, 174, 175

using preoperative and postoperative

antibiotics and antimicrobial mouth rinses,

174,176, 177, 178, 179, 180

primarily closing extractions sites,

176, 177, 178

and maintaining

good oral hygiene.

95,166,176,177,181

Maximizing overall patient

health is always indicated, such as smoking cessation and

diabetes optimization. Although no individual strategy nor

collection of strategies eliminates all MRONJ risks, these

preventive procedures are recommended.

The prevention of MRONJ begins with the realization

that patients receiving antiresorptive therapies may have

altered osseous wound-healing capacity, which may also

be a risk for developing MRONJ. Similar to other common

preventive strategies in medicine and dentistry, healthcare

providers need to recognize the importance of coordinated

dental care and pretreatment management in minimizing

the risk of MRONJ. This requires a continuous eort

to educate patients, dentists and medical professionals

about the real risks associated with these therapies and

clinical prevention paradigms that can mitigate MRONJ

development.

AAOMS re-emphasizes the importance of a

multidisciplinary approach to the treatment of patients

who are receiving antiresorptive therapies. This may also

Position Paper

PAGE 11 Medication-Related Osteonecrosis of the Jaw – 2022 Update

apply to other immune modulators or targeted therapies

taken alone or in combination with antiresorptives. This

approach includes consultation with an appropriate dental

professional when it is determined a patient would benet

from these therapies.

Optimization of Oral Health

The 2014 AAOMS position paper identied valid

prophylactic treatment strategies that reduce the

incidence of MRONJ. The ecacies of these strategies

remain validated by subsequent studies that demonstrate

the importance of pretreatment dental screening and

regimented dental surveillance. There is a robust level of

support for early screening and initiation of appropriate

dental care prior to the initiation of antiresorptive

therapy.

38,182, 183, 184, 185, 186

These preventive management strategies not only decrease

the risk for MRONJ but accrue the benets that all patients

enjoy with optimum oral health.

186, 187, 188, 189, 190, 191, 192, 193

In a prospective study of prostate cancer patients with

bone metastasis, instituting a more regimented dental

health surveillance system resulted in a 2.5-fold reduction

in relative risk compared to symptomatically driven

dental treatment.

186

In a systematic review aimed at

identifying prevention strategies associated with tooth

extractions in patients at risk for MRONJ, no randomized

clinical trials were reported.

194

However, there are

many animal studies that demonstrate that periodontal

or periapical inammation plays a key role in creating

a local environment that supports the development of

bone necrosis in the context of systemic antiresorptive

therapy.

85,91,195,196

Treatment planning for patients at risk of developing

MRONJ should include a thorough examination of the

oral cavity and a radiographic assessment when indicated.

It is important to identify both acute infection and sites of

potential infection to prevent future sequelae that could

be exacerbated once drug therapies begin. Considerations

during the clinical and radiographic assessment include

patient motivation, patient education regarding dental care,

uoride application, chlorhexidine rinses, tooth mobility,

periodontal disease, presence of root fragments, caries,

periapical pathology, edentulism and denture stability.

197

An additional benet of early dental consultation, when the

use of antiresorptive therapy is being considered, is that

the patient is informed of the risk associated with these

drug therapies and the risk incurred by not undergoing

recommended dental preventive measures before

consenting to treatment.

Cessation of At-Risk Medication Therapy (Drug

Holiday) Prior to Tooth Extraction or Other

Procedures that Involve Osseous Injury (e.g.,

Dental Implant Placement, Periodontal or Apical

Endodontic Treatment)

The clinical practice of antiresorptive drug holidays to

mitigate MRONJ risk in patients undergoing dentoalveolar

surgery was controversial at the time of the previous

AAOMS position paper in 2014 and remained the case

in 2021. While the practice of a drug holiday has been

accepted and recommended by several international

professional societies,

3,38,182,183,198

the evidence to support or

refute such positions remains inconclusive. The diculty

in establishing or refuting the ecacy of drug holidays is

due to the rarity of MRONJ in these patient populations.

Therefore, since few events are reported, randomized-

controlled trials provide insucient data to create sound

treatment protocols. In a 2020 systematic review that

studied the ecacy of antiresorptive drug holiday in

preventing MRONJ, a variety of papers were identied

with diering conclusions suggesting that a high level of

evidence for supporting or refuting the use of a holiday is

missing.

199

The historical use of a drug holiday was intended to

decrease the prevalence of MRONJ subsequent to the

performance of high-risk surgical procedures. The

concern regarding this practice is the loss of ecacy of

antiresorptive therapy with the development of SREs and

fragility fractures. Among others, factors for consideration

may include disease-related risk (cancer vs. osteoporosis),

drug-dosing frequency, duration of therapy, comorbidities,

other medications (especially chemotherapy, steroids

or antiangiogenics), degree of underlying infection/

inammation and extent of surgery to be performed.

Of note, the working group was unable to reach a

consensus regarding a recommendation on drug

holidays and was evenly split between oering drug

holidays to patients on a case-by-case basis using prior

recommendations and those who never recommend drug

holidays, believing that the risks of potential deleterious

eects of suspending antiresorptive therapy may outweigh

a benet.

Position Paper

PAGE 12 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

A special concern should be considered for suspending

RANKL inhibitors in osteoporosis patients. Several studies

have demonstrated a rebound increase in bone resorption

following the discontinuation of DMB, resulting in an

increased risk of multilevel vertebral fractures.

200, 201, 202

DMB is to be suspended, the timing and duration of the

holiday should be optimized in order to minimize this

risk. The planned dentoalveolar surgery can be completed

3-4 months following the last dose of DMB when the

level of osteoclast inhibition is waning. It can then be

reinstituted 6-8 weeks postsurgery. This management

strategy minimizes the length of the drug holiday while

maintaining a favorable environment for bone healing.

Bone Turnover Markers

Since the 2014 AAOMS position paper, there has been a

shift away from bone turnover markers. No biomarkers

are validated for clinical decision-making, and continued

research and prospective studies are required before these

markers can be considered ecacious tools in estimating

MRONJ risk.

Other Biomarkers

Biomarkers related to angiogenesis, VEGF activity,

endocrine function and PTH have more recently been

described.

203, 204, 205

These markers remain at an exploratory

stage and are not yet validated for clinical decision-

making.

Prevention Strategies

Patients scheduled to initiate

antiresorptive treatment for cancer therapy

The treatment objective for this group of patients is

to minimize the risk of developing MRONJ (Table

2). Although a small percentage of patients receiving

antiresorptives develop osteonecrosis of the jaw

spontaneously, the majority of aected patients

experience this complication following dentoalveolar

surgery.

5,112,165,206,207

Therefore, if systemic conditions

permit, initiation of antiresorptive therapy should be

delayed until dental health is optimized.

173,208

This decision

must be made in conjunction with the treating physician

and dentist and other specialists involved in the care of

the patient. There is widespread consensus that optimizing

dental health prior to initiating therapy is ecacious and

of paramount importance.

38,185,186,209

Medical oncologists

should educate their patients about the importance of

dental health and the ecacy of prophylactic dental

treatment in the prevention of MRONJ. Similar to patients

who are to receive radiation therapy, optimizing the

dental health in patients receiving antiresorptives or other

therapies that can compromise bone healing is essential.

The pretreatment evaluation of dental health must extend

beyond a review of systems and include a physical and

radiographic exam. Therefore, a comprehensive dental

examination performed by a dental health professional

would be a prudent approach for all patients prior to

receiving antiresorptive therapy for malignant disease. This

level of dental health assessment is most appropriately

performed by a dental health professional.

The importance of minimizing the burden of dental

infection and inammation prior to dentoalveolar surgery

in this cohort of patients with an elevated MRONJ risk

cannot be over-emphasized. Nonrestorable teeth and those

with a poor prognosis should be extracted. Other necessary

elective dentoalveolar surgery also should be completed at

this time. It remains advisable that antiresorptive therapy

should be delayed, if systemic conditions permit, until the

surgical site(s) have mucosalized or until there is adequate

osseous healing. Dental prophylaxis, caries control,

conservative restorative dentistry and nonoperative

endodontic therapy are critical to maintaining functionally

sound teeth. This level of care must be continued on a

frequent and indenite basis.

185

The posterior lingual plate region is a common site for

trauma and mucosal irritation in denture wearers.

5,75,170

Therefore, patients with full or partial dentures should be

examined for areas of mucosal trauma, especially along

the lingual ange region. It also is critical that patients

be educated as to the importance of dental hygiene and

regular dental evaluations, and specically instructed to

report any pain, swelling or exposed bone.

Patients scheduled to initiate

antiresorptive treatment for osteoporosis

Patients who are scheduled to receive antiresorptive

therapy for the prevention of fragility fractures assume a

signicantly lower risk of MRONJ. Therefore, the urgency

and the timing of optimizing the dental health are not as

crucial. However, at the initiation of treatment, it would

be prudent to educate patients regarding the potential risks

PAGE 13 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

of MRONJ. The importance of optimizing dental health

throughout this treatment period and beyond cannot be

underestimated.

It is not uncommon for patients to seek the consultation of

an oral and maxillofacial surgeon in guiding their decision

about starting or continuing antiresorptive therapy. In this

scenario, the consulting oral and maxillofacial surgeon

should use this opportunity to place the risks and benets

into the proper perspective. More specically, patients

should be reminded of the benets associated with

antiresorptive therapies in preventing fragility fractures

and an acknowledgment of the rare occurrence of MRONJ.

The initial enthusiasm and attention associated with the

discovery of MRONJ have had unintended consequences.

When initially described, a “class eect” was observed,

suggesting that MRONJ rates for patients receiving

oncologic doses of BPs and those receiving osteoporotic

doses of BPs were similar. A plateau and a decline in

the use of BPs for osteoporosis was noted in 2006 and

is hypothesized to be associated with various safety

concerns, such as MRONJ. Patients are becoming

increasingly more reluctant to begin or comply with their

antiresorptive therapy. Current evidence also conrms an

increase in fragility fractures with signicant associated

morbidity. As one salient example, hip fracture rates in

the United States declined each year from 2002 to 2012

and then plateaued at levels higher than projected for

2013 to 2015, attributable to an “osteoporosis treatment

gap.”

210

Hip fracture carries signicant morbidity, with

only 40 percent to 60 percent of individuals recovering

their prefracture level of mobility and ability to perform

instrumental activities of daily living.

211

These data are

representative of a true health crisis. The documented

risk for developing MRONJ is low; however, the patient-

perceived risk is not. As such, patients are unwilling to

start or continue antiresorptive medical therapy. Patients

are irrationally denying themselves the tangible therapeutic

benet of antiresorptive therapy to minimize the risk of

fragility fractures in order to prevent a minuscule risk of

developing MRONJ.

It is clear the benet of fracture prevention outweighs

the risk of MRONJ development in osteoporotic

patients.

212

This benet is even more favorable in the

cancer population where bone-stabilizing medications

signicantly improve quality of life, and it is detrimental

when antiresorptives are withheld due to MRONJ safety

concerns.

Asymptomatic patients receiving

antiresorptive therapies for cancer

Maintaining good oral hygiene and dental care is of

paramount importance in preventing dental disease that

may require eventual extractions or other dentoalveolar

surgery. Procedures that involve direct osseous injury

should be avoided if possible. If a dentoalveolar surgical

procedure is unavoidable (e.g., fractured tooth, advanced

periodontal disease), patients should be informed of the

associated risks. The benet of a drug holiday remains

unsubstantiated in this setting. Nonrestorable teeth may be

treated by removal of the crowns and endodontic treatment

of the remaining roots.

213

Teeth may be extracted if

necessary. Placement of dental implants should be avoided

in the oncology patient receiving parenteral antiresorptive

therapy or antiangiogenic medications. Case series and

systematic reviews have reported necrosis associated with

antiresorptive therapy and implant placement.

194, 214, 215, 216

Asymptomatic patients receiving

antiresorptive therapy for osteoporosis

Since the 2014 position paper, epidemiologic data

regarding the risk of MRONJ in patients receiving

antiresorptive therapy for osteoporosis remain limited due

to the lack of sound prospective studies with sucient

power. Nevertheless, the risk for developing MRONJ is

between 0.02 percent and 0.04 percent for BPs and 0.3

percent for DMB. (see Table 1). Sound recommendations

based on strong clinical research design are still lacking

for patients taking oral BPs.

In general, elective dentoalveolar surgery does not appear

to be contraindicated in this group. Risk assessment for

the development of MRONJ in these patients includes the

above-stated data and the discussion above related to drug

holidays.

The placement of dental implants in the context of

antiresorptive therapy for osteoporosis continues to be an

area of research interest. Several systematic reviews have

acknowledged the lack of quality data and randomized

clinical trials. Some studies have recommended caution,

PAGE 14 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

especially with a longer duration of therapy or steroid

use.

194,216

For example, in their systematic review, Granate

et al.,

216

identied several studies that reported an elevated

MRONJ risk associated with implants placed in the

posterior jaw if the duration of bisphosphonate therapy

exceeded three years and if the patients were receiving

systemic corticosteroids. In contrast to these studies,

systematic reviews by Gelazius et al., and Stavropoulos et

al., reported no increase in risk.

214,217

A recent retrospective

propensity-matched cohort study of 44,900 patients

reported a decreased risk of ONJ in osteoporosis patients

receiving implants compared to matched controls who did

not have implants. Of note, 9,738 patients had a history of

BP use, and the results for implants was in contrast to risk

increase for patients who underwent tooth extraction.

218

Reports of implant-related (MRONJ) necrosis can be

divided into the early (implant surgery-triggered) or late

(implant presence-triggered) category.

215,219,220

In these

reviews, the majority of the implant-related necrosis were

not related to the initial implant surgery but occurred

late (>12 months) and often at sites where implants

were placed prior to the initiation of bisphosphonate

therapy. The common presentation was an en bloc failure,

where the osseointegration of the implants is maintained

within the sequestrum.

220,221

This has been recognized

as a separate pattern of failure that is distinct from the

common peri-implantitis failure and considered by some

to be pathognomonic of MRONJ. Although there are no

prospective studies or systematic reviews pertaining to

implant-related necrosis associated with RANKL inhibitors

or other targeted therapies, AAOMS considers this to have

a similar level of risk.

In summary, robust data do not exist, and available data

are conicting. Therefore, AAOMS suggests that if dental

implants are placed, informed consent should be provided

to include the low risk of MRONJ, as well as early and

late implant failure. These patients should be placed on a

regular long-term recall schedule.

Treatment Strategies

AAOMS has developed a series of treatment algorithms

to streamline the evaluation (Figure 1) and management

strategies (Figure 2, Figure 3, Figure 4) for patients with

MRONJ. These strategies are based on a current review of

nonoperative and operative therapies and their associated

outcomes. Emphasis is placed on both nonoperative and

operative management being acceptable for all stages of

disease based on surgical judgment and patient factors in a

shared decision-making model.

Nonoperative therapy

The ecacy of nonoperative therapies in the management

of MRONJ is documented in the literature and provides

a useful adjunct to the spectrum of management

strategies that also include operative treatment (Figure

2). Nonoperative strategies can be useful in all stages,

especially where signicant comorbidities preclude

operative treatment. They may also result in stabilization

of disease or cure in earlier stages. The goal of both

operative and nonoperative therapies remains the same:

curative therapy and quality-of-life improvement.

Nonoperative therapy heavily focuses on patient education,

reassurance, control of pain and control of secondary

infection to allow for sequestration of the exposed,

necrotic bone.

3,63

Decisions on operative versus nonoperative therapy should

be patient-specic and tailored to individual needs. The

risk versus benet ratio (including quality of life with their

current symptomology), ability to perform good wound

care to prevent infection and disease spread, morbidity

from a major surgical procedure, as well as oral function

or dental rehabilitation after marginal or segmental

resection should be considered. Radiographic imaging is

of utmost importance in the evaluation of MRONJ lesions.

Three-dimensional imaging can identify forming or fully

formed sequestra and potentially decrease the invasiveness

of a surgical procedure. Maintenance of maxillary or

mandibular integrity is desirable, as the reconstruction of

surgical defects in this population can be challenging.

63,222

Stage 1 patients can be managed with chlorhexidine

wound care and improved oral hygiene to remove the

biolm from the necrotic bone surface.

Surgery may not

be indicated in the absence of disease progression, with

patient adequate quality of life.

63, 223

Stage 2 patients may

struggle with local wound care and may require antibiotics

for symptom control. Those patients who remain refractory

to nonoperative treatment or those patients who cannot

maintain adequate hygiene may benet from operative

therapy. In the presence of developing or established bony

sequestra, nonoperative therapy may be indicated to allow

for ultimate sequestrectomy. Exfoliation of the exposed,

necrotic bone will often result in disease resolution.

63,224,225

PAGE 15 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Therefore, for those patients with Stage 2 or 3 diseases

who are poor surgical candidates, nonoperative therapies

may be indicated (Figure 2).

There is little evidence to suggest that the use of adjunctive

therapies, such as hyperbaric oxygen or ozone therapy,

can lead to MRONJ resolution. Larger studies and

controlled trials have yet to demonstrate the ecacy of

the aforementioned treatments.

226, 227, 228, 229

Therefore, these

therapies should not be recommended as a mainstay of

treatment at this time.

The use of vitamin E and pentoxifylline as an adjunct to

standard MRONJ therapies have been reported only in case

studies. A randomized, prospective, placebo-controlled

trial of vitamin E and pentoxifylline is underway and

will provide additional information about this treatment

modality. Teriparatide, one of the few anabolic agents used

for the treatment of osteoporosis, also has shown promise

as an adjunct for the treatment of MRONJ in osteoporotic

patients.

230

Operative therapy

While nonoperative therapy continues to be a treatment

option for MRONJ, operative therapy is increasingly

reported as a viable option with high success rates for all

stages of the disease (Figures 3 and 4). Numerous reports

have identied high success rates associated with resection

of MRONJ lesions.

231, 232, 233, 234, 235, 236, 237

Importantly, one

must consider that MRONJ may progress over time, albeit

in an unpredictable manner.

238

Furthermore, adopting a

nonoperative approach to MRONJ does not uniformly

result in sequestration of the exposed necrotic bone with

disease resolution.

239

Thus, operative intervention should

be explored and presented as a treatment option in an

attempt to reduce the progression of disease with the

recognition that early surgical intervention can predict

benecial patient outcomes.

240

Segmental or marginal resection of the mandible and

partial maxillectomy are eective methods to control

MRONJ.

231, 232, 233, 234, 235, 236, 237, 238,241

This approach can be

applied to patients with all stages of MRONJ, including

Stage 1 disease.

169

These resections require margins

beyond the borders of the necrotic bone to an area of

vital, bleeding bone. Additional reports have identied

success when surgical resection of MRONJ was performed

by experienced surgeons.

242,243

Consistent with surgical

principles, control of comorbid conditions is paramount

in managing MRONJ.

241

Physiologically compromised

patients, such as those with an increasing burden of

distant metastatic disease, may not respond favorably to

resection of their osteonecrotic jaw and may occasionally

develop refractory disease.

241

Finally, surgical resection for

MRONJ in patients with metastatic cancer may identify

metastases in the jaw specimen, albeit in a minority of

patients.

Active clinical and radiographic surveillance is critical in

the nonoperative management of patients with Stage 1, 2

and 3 diseases to monitor for signs of disease progression.

In patients who demonstrate the failure of nonoperative

therapy, early operative intervention is recommended.

In patients with a progressive clinical or radiographic

disease or more advanced disease at presentation, surgical

resection of MRONJ should be performed without rst

instituting prolonged nonoperative measures. MRONJ

represents a complex wound whereby operative therapy

can be performed in a timely fashion.

241,244

Although

controversy between operative and nonoperative therapies

exist, operative treatment of patients has demonstrated

maintenance of mucosal coverage, improved quality of life

and expedient resumption of antiresorptive therapy for all

stages of MRONJ disease.

245

The benet of drug holidays

for the operative intervention of MRONJ has not been

substantiated.

Future Research

AAOMS realizes that MRONJ is a complex disease

process with a multifactorial etiology for which many

questions remain unanswered. Continued preclinical

and clinical data are required, especially in the form of

prospective studies. Continued research eorts and the

outcomes that result should be considered the foundation

upon which recommendations are developed that will

guide patients and providers. While the data supporting

the conclusion that antiresorptives represent genuine

risk factors are robust, this is not the case for other

classications of medications (e.g., antiangiogenics,

corticosteroids, immune modulators). Published studies

have reported a relationship of certain dosing practices

(e.g., transition from BPs to DMB) or a synergistic eect

between antiresorptive medications and antiangiogenic

medication with a risk of MRONJ. These associations,

however, are based on case reports and small case series.

It also has been hypothesized that the total exposure to an

PAGE 16 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

antiresorptive medication is a risk factor for developing

MRONJ. However, this has been dicult to demonstrate,

possibly as a result of not having a good measure of

exposure other than years of treatment. Similar to the

cancer risk associated with tobacco use (e.g., pack/years),

the antiresorptive exposure risk MRONJ may be better

dened as a cumulative dose load (e.g., mg equivalent

of BP/years of exposure) that would account for risk

associated with dierent medications and dosing schedules

over time. Dose-reduction protocols and individualized

strategies for antiresorptive therapy in long-term cancer

survivors with a metastatic bone disease are being

explored. It remains to be determined if these protocols

will reduce the risk of MRONJ in this patient cohort.

246

AAOMS acknowledges the challenge of elucidating

potential risks associated with non-antiresorptive therapies,

alone or in combination with antiresorptive medications,

and therefore considers it imperative that research eorts

continue in the form of prospective studies.

A review of the current literature also failed to provide

sound data in the form of randomized, controlled trials

that would establish the eectiveness of biomarkers

and drug holidays or validate a risk relationship with

genetic markers and MRONJ. Until these relationships

are established or refuted, AAOMS considers it prudent

to recognize that these factors may play a role in the

development and management of MRONJ.

PAGE 17 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Table 1

MRONJ Disease Frequency Grouped by Disease Status vs Medication*

Indications for

treatment

Medication

Study

design

Placebo Zoledronate Oral BPs Denosumab Romosozumab

Malignancy

Coleman (2020)

138

0.2% (2,218)* 5% (2,241) RCT†

O’Carrigan, et al.

(2017)

137

0.7% (6,788) 0.4% (6,788)

Systematic

review

O’Carrigan et al.

(2017)

137

0% (3,060) 1% (3,078)

Systematic

review

Macherey, et al.

(2017)

136

0.7% (818) 1.5% (808)

Systematic

review

Gnant, et al.

(2015)

246

0% (903) 0% (900) RCT

Coleman, et al.

(2014)

133

0% (1,679) 1.7% (1,681) RCT

Valachis, et al.

(2013)

132

0% (3,039) 0.52% (4,774)

Systemic

review

Boquete-Castro, et

al. (2016)

135

0.1% 1.14% 1.7%

Systematic

review

Coleman (2020)

138

0.2% (2,218) 5.4% (2,214) RCT

Gnant, et al.

(2015)

134

0% (1,709) 0% (1,711) RCT

Raje, et al. (2018)

113

2.8% (82) 4.1% (850) RCT

Himelstein

(2017)

140

1.5% (1,822) RCT

Henry (2014)

141

1.1% (786) 0.8% (792) RCT

Yang, et al.

(2019)

247

2% (8,525)

Systematic

review

Peddi, et al.

(2013)

142

1.3% (2,846) 1.8% (2,885)

Systematic

review

Ng, et al. (2021)

145

1.6-4%‡

3.8-18%§

1.9%‡

6.9%§

Systematic

review

Wang, et al.

(2014)

144

1.4% (1,013) 2% (1,020)

Systematic

review

(continued on following page)

PAGE 18 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

(continued from previous page)

Indications for

treatment

Medications

Study

design

Placebo Zoledronate Oral BPs Denosumab Romosozumab

Osteoporosis

Papapoulos, et al.

(2012)

0% (3,383) 0.04% (4,549) RCT

Grbic, et al.

(2010)

150

0.02% (4,945) 0.02% (5,864)

Systematic

review

Cosman, et al.

(2016)

151

0% (3,322) RCT

Saag, et al. (2017)

0.05% (2,047) RCT

Bone, et al.

(2017)

153

0.3% (2,343)

10-yr f/u

RCT

Hallmer, et al.

(2018)

0.043%

Population

study

(50,000)

Non-malignant

bone disease

Chawla, et al.

(2019)

156

5% (532)

Prospective

case series

Rutkowski

155

0.7% (138)

Retrospective

case series

*Sample size in parentheses

†‡Randomized clinical trial

‡ <2 years of followup

§ >2 years of followup

PAGE 19 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Table 2

MRONJ Prevention Strategies

Pretherapy (nonmalignant disease)

• Educate patient about the potential risks associated

with long-term ART.*

• Optimization of dental health can occur concurrent

with ART.

Pretherapy (malignant disease)

• Educate patients about the higher risk of MRONJ

and the importance of regimented dental care.

• Optimization of the dental health prior to the initiation

of ART if systemic conditions permit (extraction of

nonrestorable teeth or teeth with a poor prognosis).

During antiresorptive therapy

(nonmalignant disease)

• No alteration of operative plan for most patients.

• Considerations include drug schedule, duration of

therapy, comorbidities, other medications (especially

chemotherapy, steroids or antiangiogenics), degree of

underlying infection/inammation and extent of surgery

to be performed. Drug holidays are controversial.

• BTM† are not a useful tool to assess MRONJ risk.

During antiresorptive therapy/targeted

therapies (malignant disease)

• Educate patients about the higher MRONJ risk in the

setting of malignant disease.

• Educate the patient about the importance of regimented

dental care and prevention.

• Avoid dentoalveolar surgery if possible.

• Consider root retention techniques to avoid extractions.

• Dental implants are contraindicated.

• Drug holidays are controversial.

*Antiresorptive therapies

† Bone turnover markers (CTX)

PAGE 20 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Figure 1

PAGE 21 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Figure 2

PAGE 22 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Figure 3

PAGE 23 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

Figure 4

PAGE 24 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

References

1. American Association of Oral and Maxillofacial Surgeons position

paper on bisphosphonate-related osteonecrosis of the jaws. J Oral

Maxillofac Surg. 65:369, 2007.

2. Ruggiero SL, Dodson TB, Assael LA, et al. American

Association of Oral and Maxillofacial Surgeons position paper

on bisphosphonate-related osteonecrosis of the jaw - 2009 update.

J Oral Maxillofac Surg. 67, 2009, Supp 1.

3. Ruggiero SL, Dodson TB, Fantasia J, et al: American Association

of Oral and Maxillofacial Surgeons position paper on medication-

related osteonecrosis of the jaw–2014 update. J Oral Maxillofac

Surg. 72:1938, 2014.

4. Saad F, Gleason DM, Murray R, et al: Zoledronic acid prostate

cancer study G. A randomized, placebo-controlled trial of

zoledronic acid in patients with hormone-refractory metastatic

prostate carcinoma. J Natl Cancer Inst. 94:1458, 2002.

5. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors,

and outcomes of osteonecrosis of the jaw: Integrated analysis from

three blinded active-controlled phase III trials in cancer patients

with bone metastases. Ann Oncol. 23:1341, 2012.

6. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid

versus placebo in the treatment of skeletal metastases in patients

with lung cancer and other solid tumors: A phase III, double-blind,

randomized trial–the zoledronic acid lung cancer and other solid

tumors study group. J Clin Oncol. 21:3150, 2003.

7. Hortobagyi GN, Theriault RL, Porter L, et al. Ecacy of

pamidronate in reducing skeletal complications in patients with

breast cancer and lytic bone metastases. Protocol 19 Aredia Breast

Cancer Study Group. N Engl J Med. 335:1785, 1996.

8. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term

prevention of skeletal complications of metastatic breast cancer

with pamidronate. Protocol 19 Aredia Breast Cancer Study Group.

J Clin Oncol. 16:2038, 1998.

9. Berenson JR, Lichtenstein A, Porter L, et al. Ecacy of

pamidronate in reducing skeletal events in patients with advanced

multiple myeloma. Myeloma Aredia Study Group. N Engl J Med.

334:488, 1996.

10. Berenson JR, Lichtenstein A, Porter L, et al: Long-term

pamidronate treatment of advanced multiple myeloma patients

reduces skeletal events. Myeloma Aredia Study Group. J Clin

Oncol. 16:593, 1998.

11. Berenson JR, Hillner BE, Kyle RA, et al. American Society of

Clinical Oncology Bisphosphonates Expert Panel. American

Society of Clinical Oncology clinical practice guidelines: The role

of bisphosphonates in multiple myeloma. J Clin Oncol. 20:3719,

2002.

12. Stopeck A, Brufsky A, Kennedy L, et al. Cost-eectiveness of

denosumab for the prevention of skeletal-related events in patients

with solid tumors and bone metastases in the United States. J Med

Econ. 23:37, 2020.

13. Jeon HL, Oh IS, Baek YH, et al. Zoledronic acid and skeletal-

related events in patients with bone metastatic cancer or multiple

myeloma. J Bone Miner Metab. 38:254, 2020.

14. Delmas PD. The use of bisphosphonates in the treatment

of osteoporosis. Curr Opin Rheumatol. 17:462, 2005.

15. Watts NB. Bisphosphonate treatment of osteoporosis. Clin Geriatr

Med. 19:395, 2003.

16. Gossiel F, Paggiosi MA, Naylor KE, et al. The eect of

bisphosphonates on bone turnover and bone balance in

postmenopausal women with osteoporosis: The T-score bone

marker approach in the TRIO study. Bone. 131:115158, 2020.

17. Black DM, Cummings SR, Karpf DB, et al. Randomized trial

of eect of alendronate on risk of fracture in women with existing

vertebral fractures. Fracture Intervention Trial Research Group.

Lancet. 348:1535, 1996.

18. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic

acid for treatment of postmenopausal osteoporosis. N Engl J Med.

356:1809, 2007.

19. Nakamura T, Fukunaga M, Nakano T, et al. Ecacy and safety

of once-yearly zoledronic acid in Japanese patients with primary

osteoporosis: Two-year results from a randomized placebo-

controlled double-blind study (ZOledroNate treatment in ecacy

to osteoporosis; ZONE study). Osteoporos Int. 28:389, 2017.

20. Cranney A, Wells G, Willan A, et al. Meta-analyses of therapies

for postmenopausal osteoporosis. II. Meta-analysis of alendronate

for the treatment of postmenopausal women. Endocr Rev. 23:508,

2002.

21. Delmas PD, Meunier PJ. The management of Paget’s disease of

bone. N Engl J Med. 336:558, 1997.

22. Letocha AD, Cintas HL, Troendle JF, et al. Controlled trial

of pamidronate in children with types III and IV osteogenesis

imperfecta conrms vertebral gains but not short-term functional

improvement. J Bone Miner Res. 20:977, 2005.

23. Florenzano P, Pan KS, Brown SM, et al. Age-related changes

and eects of bisphosphonates on bone turnover and disease

progression in brous dysplasia of bone. J Bone Miner Res.

34:653, 2019.

24. Boyce AM, Kelly MH, Brillante BA, et al. A randomized, double

blind, placebo-controlled trial of alendronate treatment for brous

dysplasia of bone. J Clin Endocrinol Metab. 99:4133, 2014.

PAGE 25 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

25. Cummings SR, San Martin J, McClung MR, et al. Denosumab

for prevention of fractures in postmenopausal women with

osteoporosis. N Engl J Med. 361:756, 2009.

26. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of

denosumab exposure in women with postmenopausal osteoporosis:

Results from the rst two years of the FREEDOM extension.

J Bone Miner Res. 27:694, 2012.

27. Kanis JA, Harvey NC, Lorentzon M, et al. Combining fracture

outcomes in phase 3 trials of osteoporosis: An analysis of the

eects of denosumab in postmenopausal women. Osteoporos Int.

32:165, 2021.

28. Miller PD, Pannacciulli N, Malouf-Sierra J, et al. Ecacy and

safety of denosumab vs. bisphosphonates in postmenopausal

women previously treated with oral bisphosphonates. Osteoporos

Int. 31:181, 2020.

29. Terpos E, Raje N, Croucher P, et al. Denosumab compared with

zoledronic acid on PFS in multiple myeloma: Exploratory results

of an international phase 3 study. Blood Adv. 5:725, 2021.

30. Fizazi K, Carducci M, Smith M, et al. Denosumab versus

zoledronic acid for treatment of bone metastases in men with

castration-resistant prostate cancer: A randomized, double-blind

study. Lancet. 377:813, 2011.

31. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with

zoledronic acid for the treatment of bone metastases in patients

with advanced breast cancer: A randomized, double-blind study.

J Clin Oncol. 28:5132, 2010.

32. Chawla S, Henshaw R, Seeger L, et al. Safety and ecacy of

denosumab for adults and skeletally mature adolescents with giant

cell tumour of bone: Interim analysis of an open-label, parallel-

group, phase 2 study. Lancet Oncol. 14:901, 2013.

33. Bredell M, Rordorf T, Kroiss S, et al. Denosumab as a treatment

alternative for central giant cell granuloma: A long-term

retrospective cohort study. J Oral Maxillofac Surg. 76:775, 2018.

34. Boyce AM. Denosumab: An emerging therapy in pediatric bone

Disorders. Curr Osteoporos Rep. 15:283, 2017.

35. de Castro LF, Burke AB, Wang HD, et al. Activation of RANK/

RANKL/OPG pathway is involved in the pathophysiology of

brous dysplasia and associated with disease burden. J Bone Miner

Res. 34:290, 2019.

36. Palmisano B, Spica E, Remoli C, et al. RANKL inhibition in

brous dysplasia of bone: A preclinical study in a mouse model of

the human disease. J Bone Miner Res. 34:2171, 2019.

37. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or

alendronate for fracture prevention in women with osteoporosis.

N Engl J Med. 377:1417, 2017.

38. Campisi G, Mauceri R, Bertoldo F, et al. Medication-related

osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian

consensus update 2020. Int J Environ Res Public Health. 17, 2020.

39. Steinberg ME, Hayken GD, Steinberg DR. A quantitative system

for staging avascular necrosis. J Bone Joint Surg Br. 77:34, 1995.

40. Fleisher KE, Welch G, Kottal S, et al. Predicting risk for

bisphosphonate-related osteonecrosis of the jaws: CTX versus

radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol

Endod. 110:509, 2010.

41. Fedele S, Porter SR, D’Aiuto F, et al. Nonexposed variant of

bisphosphonate-associated osteonecrosis of the jaw: A case series.

Am J Med. 123:1060, 2010.

42. Fleisher KE, Janal MN, Albstein N, et al. Comorbid conditions

are a risk for osteonecrosis of the jaw unrelated to antiresorptive

therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 127: 140,

2019.

43. Farah CS, Savage NW. Oral ulceration with bone sequestration.

Aust Dent J. 48:61, 2003.

44. Filippi A, Dreyer T, Bohle RM, et al. Sequestration of the alveolar

bone by invasive aspergillosis in acute myeloid leukemia. J Oral

Pathol Med. 26:437, 1997.

45. Friel P, Macintyre DR. Bone sequestration from lower 3rd molar

region. Br Dent J. 193:366, 2002.

46. Huang JS, Kok SH, Lee JJ, et al. Extensive maxillary sequestration

resulting from mucormycosis. Br J Oral Maxillofac Surg. 43:532,

2005.

47. Peters E, Daley T. American Academy of Oral and Maxillofacial

Pathology. Persistent painful ulcer of the posterior lingual

mandibular mucosa. J Contemp Dent Pract. 4:71, 2003.

48. Sonnier KE, Horning GM. Spontaneous bony exposure: A report

of 4 cases of idiopathic exposure and sequestration of alveolar

bone. J Periodontol. 68:758, 1997.

49. Peters E, Lovas GL, Wysocki GP. Lingual mandibular

sequestration and ulceration. Oral Surg Oral Med Oral Pathol.

75:739, 1993.

50. Nandakumar H, Shankaramba KB. Massive sequestration of the

upper jaw: A case report. Br J Oral Maxillofac Surg. 28:55, 1990.

51. Ramon Y, Oberman M, Horowitz I, Freedman. Extensive

maxillary sequestration resulting from rhinocerebral

mucormyocosis. 35:989, 1977.

52. Liao MT, Chien WC, Wang JC, et al. Increased risk of

bisphosphonate-related osteonecrosis of the jaw in patients with

Sjogren’s syndrome: Nationwide population-based cohort study.

BMJ Open. 9:e024655, 2019.

PAGE 26 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

53. Schwartz HC. Osteonecrosis of the jaws. A complication of cancer

chemotherapy. Head Neck Surg. 4:251, 1982.

54. Cooper JC. Tooth exfoliation and osteonecrosis of the jaw

following herpes zoster. Br Dent J. 143:297, 1977.

55. Schwartz O, Kvorning SA. Tooth exfoliation, osteonecrosis of the

jaw and neuralgia following herpes zoster of the trigeminal nerve.

Int J Oral Surg. 11:364, 1982.

56. Calhoun KH, Shapiro RD, Stiernberg CM, et al. Osteomyelitis of

the mandible. Arch Otolaryngol Head Neck Surg. 114:1157, 1988.

57. Koorbusch GF, Fotos P, Goll KT. Retrospective assessment

of osteomyelitis. Etiology, demographics, risk factors, and

management in 35 cases. Oral Surg Oral Med Oral Pathol. 74:149,

1992.

58. Maines E, Monti E, Doro F, et al. Children and adolescents treated

with neridronate for osteogenesis imperfecta show no evidence of

any osteonecrosis of the jaw. J Bone Miner Metab. 30:434, 2012.

59. Black DM, Schwartz AV, Ensrud KE, et al. Eects of continuing

or stopping alendronate after 5 years of treatment: The fracture

intervention trial long-term extension (FLEX): A randomized trial.

JAMA. 296:2927, 2006.

60. Black DM, Reid IR, Boonen S, et al. The eect of 3 versus 6

years of zoledronic acid treatment of osteoporosis: A randomized

extension to the HORIZON-Pivotal fracture trial (PFT). J Bone

Miner Res. 27:243, 2012.

61. Black DM, Reid IR, Cauley JA, et al. The eect of 6 versus 9 years

of zoledronic acid treatment in osteoporosis: A randomized second

extension to the HORIZON-Pivotal fracture trial (PFT). J Bone

Miner Res. 30:934, 2015.

62. Carlson ER, Fleisher KE, Ruggiero SL. Metastatic cancer

identied in osteonecrosis specimens of the jaws in patients

receiving intravenous bisphosphonate medications. J Oral

Maxillofac Surg. 71:2077, 2013.

63. Hadaya D, Soundia A, Freymiller E, et al. Nonsurgical

management of medication-related osteonecrosis of the jaws using

local wound care. J Oral Maxillofac Surg. 76:2332, 2018.

64. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-

induced exposed bone (osteonecrosis/osteopetrosis) of the jaws:

Risk factors, recognition, prevention, and treatment. J Oral

Maxillofac Surg. 63:1567, 2005.

65. Aghaloo T, Hazboun R, Tetradis S. Pathophysiology of

osteonecrosis of the jaws. Oral Maxillofac Surg Clin North Am.

27:489, 2015.

66. Johnston CB, Dagar M. Osteoporosis in older adults. Med Clin

North Am 104:873, 2020.

67. Black DM, Rosen CJ. Clinical practice. Postmenopausal

Osteoporosis. N Engl J Med. 374:254, 2016.

68. Schwartz E, Reichert Z, Van Poznak C. Pharmacologic

management of metastatic bone disease. Bone. 115735, 2020.

69. Coleman R. Bisphosphonates and breast cancer from cautious

palliation to saving lives. Bone. 140:115570, 2020.

70. Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside:

Elucidation of the OPG-RANK-RANKL pathway and the

development of denosumab. Nat Rev Drug Discov. 11:401, 2012.

71. Coleman RE, Major P, Lipton A, et a.: Predictive value of bone

resorption and formation markers in cancer patients with bone

metastases receiving the bisphosphonate zoledronic acid. J Clin

Oncol. 23:4925, 2005.

72. Stewart AF. Clinical practice. Hypercalcemia associated with

cancer. N Engl J Med. 352:373, 2005.

73. Benjamin B, Benjamin MA, Swe M, Sugathan S. Review

on the comparison of eectiveness between denosumab and

bisphosphonates in post-menopausal osteoporosis. Osteoporos

Sarcopenia. 2:77, 2016.

74. Limones A, Saez-Alcaide LM, Diaz-Parreno SA, et al. Medication-

related osteonecrosis of the jaws (MRONJ) in cancer patients

treated with denosumab vs.. zoledronic acid: A systematic review

and meta-analysis. Med Oral Patol Oral Cir Bucal. 25: e326, 2020.

75. Hallmer F, Andersson G, Gotrick B, et al. Prevalence, initiating

factor, and treatment outcome of medication-related osteonecrosis

of the jaw-a 4-year prospective study. Oral Surg Oral Med Oral

Pathol Oral Radiol. 126:477, 2018.

76. Soundia A, Hadaya D, Esfandi N, et al. Osteonecrosis of the jaws

(ONJ) in mice after extraction of teeth with periradicular disease.

Bone. 90:133, 2016.

77. Wehrhan F, Gross C, Creutzburg K, et al. Osteoclastic expression

of higher-level regulators NFATc1 and BCL6 in medication-related

osteonecrosis of the jaw secondary to bisphosphonate therapy: A

comparison with osteoradionecrosis and osteomyelitis. J Transl

Med. 17:69, 2019.

78. de Molon RS, Shimamoto H, Bezouglaia O, et al. OPG-Fc but not

zoledronic acid discontinuation reverses osteonecrosis of the jaws

(ONJ) in mice. J Bone Miner Res .30:1627, 2015.

79. Hadaya D, Soundia A, Gkouveris I, et al. Antiresorptive-type and

discontinuation-timing Aect ONJ burden. J Dent Res. 100:746,

2021.

PAGE 27 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

80. Kuroshima S, Entezami P, McCauley LK, Yamashita J. Early

eects of parathyroid hormone on bisphosphonate/steroid-

associated compromised osseous wound healing. Osteoporosis Int.

25:1141, 2014.

81. Dayisoylu EH, Senel FC, Ungor C, et al. The eects of adjunctive

parathyroid hormone injection on bisphosphonate-related

osteonecrosis of the jaws: An animal study. Int J Oral Maxillofac

Surg. 42:1475, 2013.

82. Chopra K, Malhan N. Teriparatide for the treatment of medication-

related osteonecrosis of the jaw. Am J Ther. 28: e469, 2021.

83. Ficarra G, Beninati F, Rubino I, et al. Osteonecrosis of the jaws

in periodontal patients with a history of bisphosphonates treatment.

J Clin Periodontol. 32:1123, 2005.

84. Thumbigere-Math V, Michalowicz BS, Hodges JS, et al.

Periodontal disease as a risk factor for bisphosphonate-related

osteonecrosis of the jaw. J Periodontol. 85:226, 2014.

85. Aghaloo TL, Kang B, Sung EC, et al. Periodontal disease and

bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone

Miner Res. 26:1871, 2011.

86. Kang B, Cheong S, Chaichanasakul T, et al. Periapical disease and

bisphosphonates induce osteonecrosis of the jaws in mice. J Bone

Miner Res. 28:1631, 2013.

87. Hadaya D, Soundia A, Gkouveris I, et al. Development of

medication-related osteonecrosis of the jaw after extraction of

teeth with experimental periapical disease. J Oral Maxillofac Surg.

77:71, 2019.

88. Aguirre JI, Akhter MP, Kimmel DB, et al. Oncologic doses of

zoledronic acid induce osteonecrosis of the jaw-like lesions in rice

rats (Oryzomys palustris) with periodontitis. J Bone Miner Res.

27:2130, 2012.

89. Soma T, Iwasaki R, Sato Y, et al. Tooth extraction in mice

administered zoledronate increases inammatory cytokine levels

and promotes osteonecrosis of the jaw. J Bone Miner Metab.

39:372, 2021

90. de Molon RS, Hsu C, Bezouglaia O, et al. Rheumatoid arthritis

Exacerbates the severity of osteonecrosis of the jaws (ONJ) in

mice. A randomized, prospective, controlled animal study. J Bone

Miner Res. 31:1596, 2016.

91. Kim T, Kim S, Song M, et al. Removal of pre-existing periodontal

inammatory condition before tooth extraction Ameliorates

medication-related osteonecrosis of the jaw-like lesion in mice.

Am J Pathol. 188:2318, 2018.

92. Kuroshima S, Nakajima K, Sasaki M, et al. Systemic

administration of quality and quantity-controlled PBMNCs reduces

bisphosphonate-related osteonecrosis of jaw-like lesions in mice.

Stem Cell Res Ther. 10:209, 2019.

93. Hansen T, Kunkel M, Weber A, James Kirkpatrick C.

Osteonecrosis of the jaws in patients treated with bisphosphonates

histomorphologic analysis in comparison with infected

osteoradionecrosis. J Oral Pathol Med. 35:155, 2006.

94. Mawardi H, Giro G, Kajiya M, et al. A role of oral bacteria in

bisphosphonate-induced osteonecrosis of the jaw. J Dent Res.

90:1339, 2011.

95. Vandone AM, Donadio M, Mozzati M, et al. Impact of dental care

in the prevention of bisphosphonate-associated osteonecrosis of the

jaw: A single-center clinical experience. Ann Oncol. 23:193, 2012.

96. Sedghizadeh PP, Kumar SK, Gorur A, et al. Microbial biolms in

osteomyelitis of the jaw and osteonecrosis of the jaw secondary to

bisphosphonate therapy. J Am Dent Assoc. 140:1259, 2009.

97. Francini F, Pascucci A, Francini E, et al. Osteonecrosis of the

jaw in patients with cancer who received zoledronic acid and

bevacizumab. J Am Dent Assoc. 142:506, 2011.

98. Migliorati CA, Schubert MM, Peterson DE, Seneda LM.

Bisphosphonate-associated osteonecrosis of mandibular and

maxillary bone: An emerging oral complication of supportive

cancer therapy. Cancer. 104:83, 2005.

99. Petek D, Hannouche D, Suva D. Osteonecrosis of the femoral

head: Pathophysiology and current concepts of treatment. EFORT

Open Rev. 4:85, 2019.

100. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic eects of

the bisphosphonate compound zoledronic acid. J Pharmacol Exp

Ther. 302:1055, 2002.

101. Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces

signicant and long-lasting modications of circulating angiogenic

factors in cancer patients. Clin Cancer Res. 9: 2893, 2003.

102. Ishtiaq S, Edwards S, Sankaralingam A, et al. The eect of

nitrogen containing bisphosphonates, zoledronate and alendronate,

on the production of pro-angiogenic factors by osteoblastic cells.

Cytokine. 71:154, 2015.

103. Kun-Darbois JD, Libouban H, Mabilleau G, et a.: Bone

mineralization and vascularization in bisphosphonate-related

osteonecrosis of the jaw: An experimental study in the rat. Clin

Oral Investig. 22:2997, 2018.

104. Gao SY, Lin RB, Huang SH, et al. PDGF-BB exhibited therapeutic

eects on rat model of bisphosphonate-related osteonecrosis

of the jaw by enhancing angiogenesis and osteogenesis. Bone.

144:115117, 2021.

105. Bi Y, Gao Y, Ehirchiou D, et al. Bisphosphonates cause

osteonecrosis of the jaw-like disease in mice. Am J Pathol.

177:280, 2010.

106. Gkouveris I, Hadaya D, Soundia A, et a.: Vasculature submucosal

changes at early stages of osteonecrosis of the jaw (ONJ). Bone.

123:234, 2019.

PAGE 28 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

107. Vallina C, Ramirez L, Torres J, et al. Osteonecrosis of the jaws

produced by sunitinib: A systematic review. Med Oral Patol Oral

Cir Bucal. 24:e326, 2019.

108. Gacche RN, Meshram RJ. Angiogenic factors as potential drug

target: Ecacy and limitations of anti-angiogenic therapy. Biochim

Biophys Acta. 1846(1):161, 2014.

109. Akita Y, Kuroshima S, Nakajima K, et al. Eect of anti-

angiogenesis induced by chemotherapeutic monotherapy,

chemotherapeutic/bisphosphonate combination therapy and

anti-VEGFA mAb therapy on tooth extraction socket healing

in mice. J Bone Miner Metab. 36:547, 2018.

110. Rugani P, Walter C, Kirnbauer B, et al. Prevalence of medication-

related osteonecrosis of the jaw in patients with breast cancer,

prostate cancer, and multiple myeloma. Dent J (Basel). 4:32, 2016.

111. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al.

Osteonecrosis of the jaw in patients with multiple myeloma treated

with bisphosphonates: Evidence of increased risk after treatment

with zoledronic acid. Haematologica. 91:968, 2006.

112. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw

in multiple myeloma patients: Clinical features and risk factors.

J Clin Oncol. 24:945, 2006.

113. Raje N, Terpos E, Willenbacher W, et al. Denosumab versus

zoledronic acid in bone disease treatment of newly diagnosed

multiple myeloma: An international, double-blind, double-dummy,

randomised, controlled, phase 3 study. Lancet Oncol. 19:370,

2018.

114. Filleul O, Crompot E, Saussez S. Bisphosphonate-induced

osteonecrosis of the jaw: A review of 2,400 patient cases. J Cancer

Res Clin Oncol. 136:1117, 2010.

115. Bastos P, Patel V, Festy F, et al. In-vivo imaging of the

microvasculature of the soft tissue margins of osteonecrotic jaw

lesions. Br Dent J. 223:699, 2017.

116. Zhang Q, Yu W, Lee S, et al. Bisphosphonate induces osteonecrosis

of the jaw in diabetic mice via NLRP3/Caspase-1Dependent IL-1

beta mechanism. J Bone Miner Res. 30:2300, 2015.

117. Kabilova TO, Kovtonyuk LV, Zonov EV, et al. Immunotherapy of

hepatocellular carcinoma with small double-stranded RNA. BMC

Cancer. 14:338, 2014.

118. Hayano H, Kuroshima S, Sasaki M, et al. Distinct

immunopathology in the early stages between dierent

antiresorptives-related osteonecrosis of the jaw-like lesions in

mice. Bone. 135:115308, 2020.

119. Rao NJ, Yu RQ, Wang JY, et al. Eect of periapical diseases in

development of MRONJ in immunocompromised mouse model.

Biomed Res Int. 2019:1271492, 2019.

120. Aghaloo TL, Tetradis S. Osteonecrosis of the jaw in the absence

of antiresorptive or antiangiogenic exposure: A series of 6 cases.

J Oral Maxillofac Surg. 75:129, 2017.

121. Bamias A, Kastritis E, Bamia C, et a.: Osteonecrosis of the jaw in

cancer after treatment with bisphosphonates: Incidence and risk

factors. J Clin Oncol. 23:8580, 2005.

122. Qu X, Wang Z, Zhou T, Shan L. Determination of the molecular

mechanism by which macrophages and gammadelta-T cells

contribute to ZOL-induced ONJ. Aging (Albany NY). 12: 20743,

2020.

123. Rodriguez-Lozano FJ, Onate-Sanchez R, Gonzalvez-Garcia M, et

al. Allogeneic bone marrow mesenchymal stem cell transplantation

in tooth extractions sites Ameliorates the incidence of osteonecrotic

jaw-like lesions in zoledronic acid-treated rats. J Clin Med. 9:1649,

2020.

124. Alonso-Rodriguez E, Gonzalez-Martin-Moro J, Cebrian-Carretero

JL, et al. Bisphosphonate-related osteonecrosis. Application of

adipose-derived stem cells in an experimental murine model. Med

Oral Patol Oral Cir Bucal. 24: e529, 2019.

125. Barba-Recreo P, Del Castillo Pardo de Vera JL, Georgiev-Hristov

T, et al. Adipose-derived stem cells and platelet-rich plasma for

preventive treatment of bisphosphonate-related osteonecrosis of

the jaw in a murine model. J Craniomaxillofac Surg. 43:1161,

2015.

126. Sarasquete ME, Garcia-Sanz R, Marin L, et al. Bisphosphonate-

related osteonecrosis of the jaw is associated with polymorphisms

of the cytochrome P450 CYP2C8 in multiple myeloma: A genome-

wide single nucleotide polymorphism analysis. Blood. 112:2709,

2008.

127. Yang G, Hamadeh IS, Katz J, et al. SIRT1/HERC4 Locus

associated with bisphosphonate-induced osteonecrosis of the jaw:

An Exome-wide association analysis. J Bone Miner Res. 33:91,

2018.

128. Yang G, Collins JM, Raee R, et al. SIRT1 gene SNP rs932658 is

associated with medication-related osteonecrosis of the jaw. J Bone

Miner Res. 36:347, 2021.

129. Lee KH, Kim SH, Kim CH, et a.: Identifying genetic variants

underlying medication-induced osteonecrosis of the jaw in cancer

and osteoporosis: A case control study. J Transl Med. 17: 381,

2019.

130. Kastritis E, Melea P, Bagratuni T, et a.: Genetic factors related with

early onset of osteonecrosis of the jaw in patients with multiple

myeloma under zoledronic acid therapy. Leuk Lymphoma.

58:2304, 2017.

131. Guo Z, Cui W, Que L, et al. Pharmacogenetics of medication-

related osteonecrosis of the jaw: A systematic review and meta-

analysis. Int J Oral Maxillofac Surg. 49:298, 2020.

PAGE 29 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

132. Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with

zoledronic acid in patients with breast cancer: A systematic review

and meta-analysis. Oncologist. 18:353, 2013.

133. Coleman R, Cameron D, Dodwell D, et al. Adjuvant zoledronic

acid in patients with early breast cancer: Final ecacy analysis

of the AZURE (BIG 01/04) randomised open-label phase 3 trial.

Lancet Oncol. 15:997, 2014.

134. Gnant M, Pfeiler G, Dubsky PC et al. Adjuvant denosumab in

breast cancer (ABCSG-18): A multicentre, randomised, double

blind, placebo-controlled trial. Lancet. 386:433, 2015.

135. Boquete-Castro A, Gomez-Moreno G, Calvo-Guirado JL, et al:

Denosumab and osteonecrosis of the jaw. A systematic analysis of

events reported in clinical trials. Clin Oral Implants Res. 27: 367,

2016.

136. Macherey S, Monsef I, Jahn F, et al. Bisphosphonates for advanced

prostate cancer. Cochrane Database Syst Rev. 12: CD006250,

2017.

137. O’Carrigan B, Wong MH, Willson ML, et a.: Bisphosphonates and

other bone agents for breast cancer. Cochrane Database Syst Rev.

10:CD003474, 2017.

138. Coleman R, Finkelstein DM, Barrios C, et al. Adjuvant denosumab

in early breast cancer (D-CARE): An international, multicentre,

randomised, controlled, phase 3 trial. Lancet Oncol. 21:60, 2020.

139. Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid

versus intravenous zoledronic acid in treatment of bone metastases

from breast cancer: A randomised, open label, noninferiority phase

3 trial. Lancet Oncol. 15:114, 2014.

140. Himelstein AL, Foster JC, Khatcheressian JL, et al. Eect of

longer-Interval vs standard dosing of zoledronic acid on skeletal

events in patients with bone metastases: A randomized clinical

trial. JAMA. 317:48, 2017.

141. Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related

events in a randomized phase 3 study of denosumab versus

zoledronic acid in patients with advanced cancer: An analysis of

data from patients with solid tumors. Support Care Cancer. 22:

679, 2014.

142. Peddi P, Lopez-Olivo MA, Pratt GF, Suarez-Almazor ME.

Denosumab in patients with cancer and skeletal metastases: A

systematic review and meta-analysis. Cancer Treat Rev. 39: 97,

2013.

143. Jackson GH, Morgan GJ, Davies FE, et al. Osteonecrosis of the

jaw and renal safety in patients with newly diagnosed multiple

myeloma: Medical Research Council Myeloma IX Study results.

Br J Haematol. 166:109, 2014.

144. Wang X, Yang KH, Wanyan P, Tian JH. Comparison of the

ecacy and safety of denosumab versus bisphosphonates in

breast cancer and bone metastases treatment: A meta-analysis of

randomized controlled trials. Oncol Lett. 7: 1997, 2014.

145. Ng TL, Tu MM, Ibrahim MFK, et al. Long-term impact

of bone-modifying agents for the treatment of bone metastases:

A systematic review. Support Care Cancer. 29:925, 2021.

146. Fusco V, Santini D, Armento G, et al. Osteonecrosis of jaw beyond

antiresorptive (bone-targeted) agents: New horizons in oncology.

Expert Opin Drug Saf. 15:925, 2016.

147. Nicolatou-Galitis O, Kouri M, Papadopoulou E, et al.

Osteonecrosis of the jaw related to non-antiresorptive medications:

A systematic review. Support Care Cancer. 27:383, 2019.

148. King R, Tanna N, Patel V. Medication-related osteonecrosis of the

jaw unrelated to bisphosphonates and denosumab-a review. Oral

Surg Oral Med Oral Pathol Oral Radiol. 127:289, 2019.

149. Sacco R, Shah S, Leeson R, et al. Osteonecrosis and osteomyelitis

of the jaw associated with tumour necrosis factor-alpha (TNF-

alpha) inhibitors: A systematic review. Br J Oral Maxillofac Surg.

58:25, 2020

150. Grbic JT, Black DM, Lyles KW, et al. The incidence of

osteonecrosis of the jaw in patients receiving 5 milligrams of

zoledronic acid: Data from the health outcomes and reduced

incidence with zoledronic acid once yearly clinical trials program.

J Am Dent Assoc. 141:1365, 2010..

151. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab

treatment in postmenopausal women with osteoporosis. N Engl J

Med. 375:1532, 2016.

152. Administration USFaD. Background Document for Meeting of

Advisory Committee for Reproductive Health Drugs and Drug

Safety and Risk Management Advisory Committee. Adelphi, MD,

FDA, HHS, 2011.

153. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab

treatment in postmenopausal women with osteoporosis: Results

from the phase 3 randomised FREEDOM trial and open-label

extension. Lancet Diabetes Endocrinol. 5:513, 2017.

154. FDA. Brieng Information for the September 9, 2011 Joint

Meeting of the Reproductive Health Drugs Advisory Committee

and the Drug Safety and Risk Management Advisory Committee.

Adelphi, MD, FDA, HHS, 2011.

155. Rutkowski P, Gaston L, Borkowska A, et al. Denosumab

treatment of inoperable or locally advanced giant cell tumor of

bone multicenter analysis outside clinical trial. Eur J Surg Oncol.

44:1384, 2018.

156. Chawla S, Blay JY, Rutkowski P, et al. Denosumab in patients with

giant-cell tumour of bone: A multicentre, open-label, phase 2 study.

Lancet Oncol. 20:1719, 2019.

PAGE 30 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

157. Hennedige AA, Jayasinghe J, Khajeh J, Macfarlane TV. Systematic

review on the incidence of bisphosphonate related osteonecrosis of

the jaw in children diagnosed with osteogenesis imperfecta. J Oral

Maxillofac Res. 4:e1, 2013.

158. Duarte NT, Rech BO, Martins IG, et al. Can children be aected

by bisphosphonate-related osteonecrosis of the jaw? A systematic

review. Int J Oral Maxillofac Surg. 49:183, 2020.

159. Lo JC, O'Ryan FS, Gordon NP et al. Prevalence of osteonecrosis

of the jaw in patients with oral bisphosphonate exposure. J Oral

Maxillofac Surg. 68: 243, 2010.

160. Aljohani S, Fliefel R, Ihbe J, et al. What is the eect of anti-

resorptive drugs (ARDs) on the development of medication-related

osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A

systematic review. J Craniomaxillofac Surg. 45:1493, 2017.

161. Shudo A, Kishimoto H, Takaoka K, Noguchi K. Long-term oral

bisphosphonates delay healing after tooth extraction: A single

institutional prospective study. Osteoporos Int. 29:2315, 2018.

162. Gaudin E, Seidel L, Bacevic M, et al. Occurrence and risk

indicators of medication-related osteonecrosis of the jaw after

dental extraction: A systematic review and meta-analysis. J Clin

Periodontol. 42:922, 2015.

163. Watts NB, Grbic JT, Binkley N, et al. Invasive oral procedures and

events in postmenopausal women with osteoporosis treated with

denosumab for up to 10 Years. J Clin Endocrinol Metab. 104:2443,

2019.

164. Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on

zoledronic acid therapy. Oral Oncol. 48:817, 2012.

165. Yamazaki T, Yamori M, Ishizaki T, et al. Increased incidence of

osteonecrosis of the jaw after tooth extraction in patients treated

with bisphosphonates: A cohort study. Int J Oral Maxillofac Surg.

41:1397, 2012.

166. Scoletta M, Arata V, Arduino PG, et al. Tooth extractions in

intravenous bisphosphonate-treated patients: A rened protocol.

J Oral Maxillofac Surg. 71:994, 2013.

167. Bodem JP, Kargus S, Eckstein S, et al. Incidence of

bisphosphonate-related osteonecrosis of the jaw in high-risk

patients undergoing surgical tooth extraction. J Craniomaxillofac

Surg. 43:510, 2015.

168. McGowan K, McGowan T, Ivanovski S. Risk factors for

medication-related osteonecrosis of the jaws: A systematic review.

Oral Dis. 24:527, 2018.

169. Kyrgidis A, Vahtsevanos K, Koloutsos G, et al. Bisphosphonate-

related osteonecrosis of the jaws: A case-control study of risk

factors in breast cancer patients. J Clin Oncol. 26:4634, 2008.

170. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort

study of risk factors in cancer patients of bisphosphonate-related

osteonecrosis of the jaw. J Clin Oncol. 27:5356, 2009.

171. Tsao C, Darby I, Ebeling PR, et al. Oral health risk factors for

bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac

Surg. 71:1360, 2013.

172. Qi WX, Tang LN, He AN, et al. Risk of osteonecrosis of the jaw

in cancer patients receiving denosumab: A meta-analysis of seven

randomized controlled trials. Int J Clin Oncol. 19:403, 2014.

173. Ripamonti CI, Maniezzo M, Campa T, et al. Decreased occurrence

of osteonecrosis of the jaw after implementation of dental

preventive measures in solid tumour patients with bone metastases

treated with bisphosphonates. The experience of the National

Cancer Institute of Milan. Ann Oncol. 20:137, 2009.

174. Montefusco V, Gay F, Spina F, et al. Antibiotic prophylaxis before

dental procedures may reduce the incidence of osteonecrosis

of the jaw in patients with multiple myeloma treated with

bisphosphonates. Leuk Lymphoma. 49:2156, 2008.

175. Bantis A, Zissimopoulos A, Sountoulides P, et al. Bisphosphonate-

induced osteonecrosis of the jaw in patients with bone metastatic,

hormone-sensitive prostate cancer. Risk factors and prevention

strategies. Tumori. 97:479, 2011.

176. Kunchur R, Goss AN. The oral health status of patients on oral

bisphosphonates for osteoporosis. Aust Dent J. 53:354, 2008.

177. Lodi G, Sardella A, Salis A, et al. Tooth extraction in patients

taking intravenous bisphosphonates: A preventive protocol and

case series. J Oral Maxillofac Surg. 68:107, 2010.

178. Mozzati M, Gallesio G, Arata V, et al. Platelet-rich therapies in the

treatment of intravenous bisphosphonate-related osteonecrosis of

the jaw: A report of 32 cases. Oral Oncol. 48:469, 2012.

179. Ferlito S, Puzzo S, Liardo C. Preventive protocol for tooth

extractions in patients treated with zoledronate: A case series.

J Oral Maxillofac Surg. 69:e1, 2011.

180. Schubert M, Klatte I, Linek W, et al. The saxon bisphosphonate

osteonecrosis of the jaws. Oral Oncol. 48:349, 2012.

181. Bonacina R, Mariani U, Villa F, Villa A. Preventive strategies and

clinical implications for bisphosphonate-related osteonecrosis of

the jaw: A review of 282 patients. J Can Dent Assoc. 77:b147,

2011.

182. Khan AA, Morrison A, Hanley DA, et al. International Task

Force on Osteonecrosis of the Jaw. Diagnosis and management

of osteonecrosis of the jaw: a systematic review and international

consensus. J Bone Miner Res. 30:3, 2015.

PAGE 31 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

183. Japanese Allied Committee on Osteonecrosis of the Jaw, Yoneda

T, Hagino H, Sugimoto T, et al. Antiresorptive agent-related

osteonecrosis of the jaw: Position paper 2017 of the Japanese

Allied Committee on osteonecrosis of the jaw. J Bone Miner

Metab. 35: 6, 2017.

184. Aparecida Cariolatto F, Carelli J, de Campos Moreira T, et al.

Recommendations for the prevention of bisphosphonate-related

osteonecrosis of the jaw: A systematic review. J Evid Based Dent

Pract. 18:142, 2018.

185. Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O. Interventions

for managing medication-related osteonecrosis of the jaw.

Cochrane Database Syst Rev. 10:CD012432, 2017.

186. Mucke T, Deppe H, Hein J, et al. Prevention of bisphosphonate-

related osteonecrosis of the jaws in patients with prostate cancer

treated with zoledronic acid - a prospective study over 6 years.

J Craniomaxillofac Surg. 44:1689, 2016.

187. Smidt-Hansen T, Folkmar TB, Fode K, et al. Combination of

zoledronic Acid and targeted therapy is active but may induce

osteonecrosis of the jaw in patients with metastatic renal cell

carcinoma. J Oral Maxillofac Surg. 71:1532, 2013.

188. Sivolella S, Lumachi F, Stellini E, Favero L. Denosumab and anti-

angiogenetic drug-related osteonecrosis of the jaw: An uncommon

but potentially severe disease. Anticancer Res. 33:1793, 2013.

189. Patel V, McLeod NM, Rogers SN, Brennan PA. Bisphosphonate

osteonecrosis of the jaw–a literature review of UK policies

versus international policies on bisphosphonates, risk factors and

prevention. Br J Oral Maxillofac Surg. 49:251, 2011.

190. Hellstein JW, Adler RA, Edwards B, et al. Ristic H, American

Dental Association Council on scientic Aairs Expert Panel on

antiresorptive Agents: Managing the care of patients receiving

antiresorptive therapy for prevention and treatment of osteoporosis:

Executive summary of recommendations from the American

Dental Association Council on scientic Aairs. J Am Dent Assoc.

142:1243, 2011.

191. Atalay B, Yalcin S, Emes Y, et al. Bisphosphonate-related

osteonecrosis: Laser-assisted surgical treatment or conventional

surgery? Lasers Med Sci. 26:815, 2011.

192. Guarneri V, Miles D, Robert N, et al. Bevacizumab and

osteonecrosis of the jaw: Incidence and association with

bisphosphonate therapy in three large prospective trials in

advanced breast cancer. Breast Cancer Res Treat. 122:181, 2010.

193. Edwards BJ, Hellstein JW, Jacobsen PL, et al. American Dental

Association Council on scientic Aairs Expert Panel on

bisphosphonate-associated osteonecrosis of the Jaw: Updated

recommendations for managing the care of patients receiving oral

bisphosphonate therapy: An advisory statement from the American

Dental Association Council on scientic Aairs. J Am Dent Assoc.

139:1674, 2008.

194. de-Freitas NR, Lima LB, de-Moura MB, et al. Bisphosphonate

treatment and dental implants: A systematic review. Med Oral

Patol Oral Cir Bucal. 21:e644, 2016.

195. de Molon RS, Cheong S, Bezouglaia O, et al. Spontaneous

osteonecrosis of the jaws in the maxilla of mice on antiresorptive

treatment: A novel ONJ mouse model. Bone. 68:11, 2014.

196. Messer JG, Jiron JM, Mendieta Calle JL, et al. Zoledronate

treatment duration is linked to bisphosphonate-related

osteonecrosis of the jaw prevalence in rice rats with generalized

periodontitis. Oral Dis. 25:1116, 2019.

197. Hinchy NV, Jayaprakash V, Rossitto. RA, et al. Osteonecrosis

of the jaw - prevention and treatment strategies for oral health

professionals. Oral Oncol. 49:878, 2013.

198. Khan AA, Morrison A, Kendler DL, et al. International task

Force on osteonecrosis of the Jaw: Case-based review of

osteonecrosis of the jaw (ONJ) and application of the international

recommendations for management from the international task

Force on ONJ. J Clin Densitom. 20:8, 2017.

199. Ottesen C, Schiodt M, Gotfredsen K. Ecacy of a high-dose

antiresorptive drug holiday to reduce the risk of medication-related

osteonecrosis of the jaw (MRONJ): A systematic review. Heliyon.

6:e03795, 2020.

200. Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical features

of 24 patients with rebound-associated vertebral fractures after

denosumab discontinuation: Systematic review and additional

cases. J Bone Miner Res. 32:1291, 2017.

201. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures

after discontinuation of denosumab: A post Hoc analysis of the

randomized placebo-controlled FREEDOM trial and its extension.

J Bone Miner Res. 33:190, 2018.

202. Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation

of denosumab therapy for osteoporosis: A systematic review and

position statement by ECTS. Bone. 105:11, 2017.

203. Lorenzo-Pouso AI, Perez-Sayans M, Gonzalez-Palanca S, et

al. Biomarkers to predict the onset of biphosphonate-related

osteonecrosis of the jaw: A systematic review. Med Oral Patol Oral

Cir Bucal. 24:e26, 2019.

204. Musolino C, Oteri G, Allegra A, et al. Altered microRNA

expression prole in the peripheral lymphoid compartment

of multiple myeloma patients with bisphosphonate-induced

osteonecrosis of the jaw. Ann Hematol. 97:1259, 2018.

205. Yang R, Tao Y, Wang C, et al. Circulating microRNA Panel as a

novel biomarker to Diagnose bisphosphonate-related osteonecrosis

of the jaw. Int J Med Sci. 15:1694, 2018.

PAGE 32 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

206. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and

bisphosphonates. N Engl J Med. 353:99, 2005.

207. Ho AO, Toth BB, Altundag K, et al. Frequency and risk factors

associated with osteonecrosis of the jaw in cancer patients treated

with intravenous bisphosphonates. J Bone Miner Res. 23:826,

2008.

208. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of

osteonecrosis of the jaw (ONJ) after implementation of preventive

measures in patients with multiple myeloma treated with

zoledronic acid. Ann Oncol. 20:117, 2009.

209. Yarom N, Shapiro CL, Peterson DE, et al. Medication-related

osteonecrosis of the jaw: MASCC/ISOO/ASCO clinical practice

guideline. J Clin Oncol. 37:2270, 2019.

210. Lewiecki EM, Wright NC, Curtis JR, et al. Hip fracture trends in

the United States, 2002 to 2015. Osteoporos Int. 29:717, 2018.

211. Guzon-Illescas O, Perez Fernandez E, Crespi Villarias N, et al.

Mortality after osteoporotic hip fracture: Incidence, trends, and

associated factors. J Orthop Surg Res. 14:203, 2019.

212. McCauley LK. Clinical recommendations for prevention of

secondary fractures in patients with osteoporosis: Implications for

dental care. J Am Dent Assoc. 151:311, 2020.

213. Moinzadeh AT, Shemesh H, Neirynck NA, et al. Bisphosphonates

and their clinical implications in endodontic therapy. Int Endod J.

46:391, 2013.

214. Gelazius R, Poskevicius L, Sakavicius D, et al. Dental implant

placement in patients on bisphosphonate therapy: A systematic

review. J Oral Maxillofac Res. 9:e2, 2018.

215. Holzinger D, Seemann R, Matoni N, et al. Eect of dental implants

on bisphosphonate-related osteonecrosis of the jaws. J Oral

Maxillofac Surg. 72:1937.e1, 2014.

216. Granate-Marques A, Polis-Yanes C, Seminario-Amez M, et al.

Medication-related osteonecrosis of the jaw associated with

implant and regenerative treatments: Systematic review. Med Oral

Patol Oral Cir Bucal. 24:e195, 2019.

217. Stavropoulos A, Bertl K, Pietschmann P, Pandis N, Schiødt M,

Klinge. The eect of antiresorptive drugs on implant therapy:

Systematic review and meta-analysis. B Clin Oral Implants Res.

2018 Oct;29 Suppl 18:54-92.

218. Ryu JI, Kim HY, Kwon YD. Is implant surgery a risk factor for

osteonecrosis of the jaw in older adult patients with osteoporosis?

A national cohort propensity score-matched study. Clin Oral

Implants Res. 32:437, 2021.

219. Giovannacci I, Meleti M, Manfredi M, et al. Medication-related

osteonecrosis of the jaw around dental implants: Implant surgery-

triggered or implant presence-triggered osteonecrosis? J Craniofac

Surg. 27:697, 2016.

220. Kwon TG, Lee CO, Park JW, et al. Osteonecrosis associated with

dental implants in patients undergoing bisphosphonate treatment.

Clin Oral Implants Res. 25:632, 2014.

221. Pogrel MA, Ruggiero SL. Previously successful dental implants

can fail when patients commence anti-resorptive therapy-a case

series. Int J Oral Maxillofac Surg. 47:220, 2018.

222. Walton K, Grogan TR, Eshaghzadeh E, et al. Medication related

osteonecrosis of the jaw in osteoporotic vs oncologic patients -

quantifying radiographic appearance and relationship to clinical

ndings. Dentomaxillofac Radiol. 48:20180128, 2019.

223. Coropciuc RG, Grisar K, Aerden T, et al. Medication-related

osteonecrosis of the jaw in oncological patients with skeletal

metastases: Conservative treatment is eective up to stage 2.

Br J Oral Maxillofac Surg. 55:787, 2017.

224. Akrivoula Soundia, Danny Hadaya, Sanjay M Mallya, Tara L

Aghaloo, Sotirios Tetradis. Radiographic predictors of bone

exposure in patients with stage 0 medication-related osteonecrosis

of the jaws. Surg Oral Med Oral Pathol Oral Radiol. 126(6), 2018.

225. Varoni EM, Lombardi N, Villa G, et al. Conservative management

of medication-related osteonecrosis of the jaws (MRONJ): A

retrospective cohort study. Antibiotics (Basel). 10, 2021.

226. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Ecacy

and safety of medical ozone (O(3)) delivered in oil suspension

applications for the treatment of osteonecrosis of the jaw in

patients with bone metastases treated with bisphosphonates:

Preliminary results of a phase I-II study. Oral Oncol. 47:185, 2011.

227. Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is the

role of hyperbaric oxygen in the management of bisphosphonate-

related osteonecrosis of the jaw: A randomized controlled trial of

hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral

Maxillofac Surg. 70:1573, 2012.

228. Epstein MS, Wicknick FW, Epstein JB, et al. Management of

bisphosphonate-associated osteonecrosis: Pentoxifylline and

tocopherol in addition to antimicrobial therapy. An initial case

series. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.

110:593, 2010.

229. Morishita K, Yamada SI, Kawakita A, et al. Treatment outcomes of

adjunctive teriparatide therapy for medication-related osteonecrosis

of the jaw (MRONJ): A multicenter retrospective analysis in Japan.

J Orthop Sci. 25:1079, 2020.

230. Sim IW, Borromeo GL, Tsao C, et al. Teriparatide promotes bone

healing in medication-related osteonecrosis of the jaw: A placebo-

controlled, randomized trial. J Clin Oncol. 38:2971, 2020.

231. Carlson ER, Basile JD. The role of surgical resection in the

management of bisphosphonate-related osteonecrosis of the jaws.

J Oral Maxillofac Surg. 67:85, 2009.

PAGE 33 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

232. Abu-Id MH, Warnke PH, Gottschalk J, et al. "Bisphossy jaws" -

high and low risk factors for bisphosphonate-induced osteonecrosis

of the jaw. J Craniomaxillofac Surg. 36:95, 2008.

233. Wutzl A, Biedermann E, Wanschitz F, et al. Treatment results of

bisphosphonate-related osteonecrosis of the jaws. Head Neck.

30:1224, 2008.

234. Stanton DC, Balasanian E. Outcome of surgical management of

bisphosphonate-related osteonecrosis of the jaws: Review of 33

surgical cases. J Oral Maxillofac Surg. 67:943, 2009.

235. Wilde F, Heufelder M, Winter K, et al. The role of surgical therapy

in the management of intravenous bisphosphonates-related

osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral

Radiol Endod. 111:153, 2011.

236. Adornato MC, Morcos I, Rozanski J. The treatment of

bisphosphonate-associated osteonecrosis of the jaws with bone

resection and autologous platelet-derived growth factors. J Am

Dent Assoc. 138:971, 2007.

237. Williamson R. Surgical management of bisphosphonate induced

osteonecrosis of the jaws. Int J Oral Maxillofac Surg. 39.:251,

2010.

238. Carlson ER. Management of antiresorptive osteonecrosis of the

jaws with primary surgical resection. J Oral Maxillofac Surg. 72:

655, 2014.

239. Watters AL, Hansen HJ, Williams T, et al. Intravenous

bisphosphonate-related osteonecrosis of the jaw: Long-term

follow-up of 109 patients. Oral Surg Oral Med Oral Pathol Oral

Radiol. 115:192, 2013.

240. Ristow O, Ruckschloss T, Muller M, et al. Is the conservative non-

surgical management of medication-related osteonecrosis of the

jaw an appropriate treatment option for early stages? A long-term

single-center cohort study. J Craniomaxillofac Surg. 47:491, 2019.

241. Carlson ER, Schlott BJ: Anti-resorptive osteonecrosis of the

jaws. Facts forgotten, questions answered, lessons learned. Oral

Maxillofac Surg Clin North Am. 26:171, 2014.

242. Klingelhoer C, Zeman F, Meier J, et al. Evaluation of surgical

outcome and inuencing risk factors in patients with medication-

related osteonecrosis of the jaws. J Craniomaxillofac Surg.

44:1694, 2016.

243. Nisi M, La Ferla F, Karapetsa D, et al. Conservative surgical

management of patients with bisphosphonate-related osteonecrosis

of the jaws: A series of 120 patients. Br J Oral Maxillofac Surg.

54:930, 2016

244. Park H, Copeland C, Henry S, Barbul A: Complex wounds and

their management. Surg Clin North Am. 90:1181, 2010.

245. Giudice A, Barone S, Diodati F, et al: Can surgical management

improve resolution of medication-related osteonecrosis of the jaw

at early stages? A prospective cohort study. J Oral Maxillofac Surg.

78:1986, 2020.

246. Rachner TD, Coleman R, Hadji P, Hofbauer LC: Individualized

bone-protective management in long-term cancer survivors with

bone metastases. J Bone Miner Res. 36:1906, 2021.

247. Gnant M, Mlineritsch B, Stoeger H, et al. Colorectal cancer study

group VA: Zoledronic acid combined with adjuvant endocrine

therapy of tamoxifen versus anastrozol plus ovarian function

suppression in premenopausal early breast cancer: Final analysis of

the Austrian breast and Colorectal cancer study group trial 12. Ann

Oncol 26:313, 2015.

248. Yang YL, Xiang ZJ, Yang JH, et al. The incidence and relative risk

of adverse events in patients treated with bisphosphonate therapy

for breast cancer: A systematic review and meta-analysis. Ther Adv

Med Oncol. June 9;11, 2019.

PAGE 34 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper

DISCLAIMER

The American Association of Oral and Maxillofacial Surgeons

(AAOMS) is providing this position paper on Medication Related

Osteonecrosis of the Jaw (MRONJ) to inform practitioners,

patients and other interested parties. The position paper is based

on a review of the existing literature and the clinical observations

of a Special Committee composed of oral and maxillofacial

surgeons, oral pathologists, and oncologists experienced in the

diagnosis, surgical and adjunctive treatment of diseases, injuries

and defects involving both the functional and esthetic aspects

of the hard and soft tissues of the oral and maxillofacial regions,

epidemiologists, and basic researchers.

The position paper is informational in nature and is not intended

to set any standards of care. AAOMS cautions all readers that

the strategies described in the position paper are NOT practice

parameters or guidelines and may NOT be suitable for every, or

any, purpose or application. This position paper cannot substitute

for the individual judgment brought to each clinical situation by

the patient's oral and maxillofacial surgeon. As with all clinical

materials, the position paper reects the science related to

MRONJ at the time of the paper’s development, and it should

be used with the clear understanding that continued research

and practice may result in new knowledge or recommendations.

AAOMS makes no express or implied warranty regarding the

accuracy, content, completeness, reliability, operability, or legality

of information contained within the position paper, including,

without limitation, the warranties of merchantability, tness for a

particular purpose, and non-infringement of proprietary rights. In

no event shall the AAOMS be liable to the user of the position

paper or anyone else for any decision made or action taken by

him or her in reliance on such information.