American Association of Oral and Maxillofacial Surgeons

Position Paper

Medication-Related Osteonecrosis of the Jaw – 2022 Update
Salvatore L. Ruggiero, DMD, MD, Clinical
Professor, Division of Oral and Maxillofacial
Surgery, Stony Brook School of Dental
Medicine, Hofstra North Shore-LIJ Schoolof 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 ofStaff 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 Oraland Facial Surgery and Minnesota Head andNeck 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 forthin the American Association of Oral and Maxillofacial
Surgeons (AAOMS) position papers in 2007, 2009
and 2014. The position papers were developed by acommittee appointed by the AAOMS Board of Trustees
and comprising clinicians with extensive experience incaring for these patients, as well as clinical and basic
science researchers. The knowledge base and experiencein addressing MRONJ continues to evolve and expand,necessitating modifications and refinements to the previous
position papers. Three members of the AAOMS
Committee on Oral, Head, and Neck Oncologic andReconstructive Surgery (COHNORS) and three authorsof the 2014 position paper were appointed to serve as aworking group to analyze the current literature and revise
the guidance as indicated to reflect current knowledge inthis field. This update contains revisions to diagnosis andmanagement strategies and highlights the current researchstatus. AAOMS maintains that it is vitally important forthis information to be disseminated to other relevant
healthcare professionals and organizations.

Introduction
Medications prescribed for dental and medical conditions
have potential side effects that warrant a risk-benefit
discussion. Where therapeutic margins are wide andcomplications are readily corrected, decisions are
implemented in a straightforward fashion. Where
therapeutic margins are wide but complications are
significant, 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 patientsshould not impact decision-making for all other patientswith osteonecrosis of the jaw. The medications associatedwith MRONJ have proven to be safe and effective inclinical trials and postmarketing analyses for mostpatients and should continue as a mainstay therapy whenindicated. Communicating the risks of MRONJ to patientsand providers is critical to ensure appropriate medical
management for the primary disease.
Undoubtedly, risk profiles may change as new medications
come to market. In addition, our understanding of disease
pathophysiology, risk modifiers and treatment strategies
will continue to evolve. It is of the utmost importancethat clinicians base their patient treatment decisions on
currently available scientific evidence.
Strategies for management of patients at risk for or withMRONJ were set forth in AAOMS Position Papers in
2007,1 20092 and 2014.3 These position papers weredeveloped by a committee appointed by the AAOMS
Board of Trustees and comprised of clinicians withextensive experience in caring for these patients as well as
clinical and basic science researchers. The knowledge baseand experience in addressing MRONJ continues to evolveand expand, necessitating modifications and refinements tothe 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 reflect
the current knowledge in this field. 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 bedisseminated to other relevant healthcare professionals andorganizations.

PurposeThe purpose of this position paper is to provide updates
regarding:
1. Risk estimates of developing MRONJ.
2.		Comparisons of the risks and benefits 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 theestablishment of algorithms.
3. Guidance to clinicians regarding:a. the differential diagnosis of MRONJ in patientswith 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

Position Paper
Medications
Bisphosphonates (BPs) are antiresorptive medications
that are effective in managing cancer-related conditions,
including hypercalcemia of malignancy, spinal cord
compression and pathologic fractures (skeletal-related
events [SREs]) associated with bone metastases in thecontext of solid tumors (such as breast, prostate and lungcancers) and multiple myeloma.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 While
the potential for BPs to improve cancer-specific survival
remains controversial, these medications have had asignificant positive effect on the quality of life for patientswith 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) inpatients 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 ina significant reduction in vertebral and nonvertebral
fractures for patients with osteoporosis.17, 18, 19, 20
Bisphosphonate therapy also is indicated for othermetabolic bone diseases such as Paget’s disease of boneand osteogenesis imperfecta.21, 22, 23 However, clinical trials
have not demonstrated the efficacy of bisphosphonate
therapy in the management of fibrous dysplasia.24
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 administeredsubcutaneously every six months, there is a significant
reduction in the risk of vertebral, nonvertebral and hip
fractures in osteoporotic patients.25, 26, 27, 28 Denosumab(Xgeva) also is effective in reducing SREs related
to metastatic bone disease from solid tumors whenadministered monthly.29, 30, 31
RANK ligand inhibitors also have proven efficacy inthe treatment of giant cell tumors of bone and fibrous
dysplasia.32, 33, 34, 35, 36 In contrast to BPs, RANK-L

Position Paper

inhibitors do not bind to bone, and their effects on bone
remodeling are mostly diminished within six months oftreatment 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.37

MRONJ Case Definition
MRONJ should be distinguished from other forms ofosteonecrosis (ONJ) conditions and identified by history
and clinical exam. The clinical criteria required to establish
a diagnosis of MRONJ have remained unchanged from theprevious position paper.3
The case definition 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 fistula(e) in the maxillofacial
region that has persisted for more than eight weeks.
3. No history of radiation therapy to the jaws ormetastatic disease to the jaws.

Staging
A staging system for MRONJ was introduced in the2009 AAOMS position paper and then modified in the2014 position paper to characterize more accurately all
aspects of the clinical presentation of MRONJ. Since
these modifications, the AAOMS staging system has
continued to be a straightforward and relevant system toproperly stratify these patients. It has been adopted byseveral 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 different classification systems
are being used by other organizations,38 the Associationconsiders the AAOMS system to be a useful and widely
implemented assessment tool guiding clinicians involvedin 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
PAGE 3 Medication-Related Osteonecrosis of the Jaw – 2022 Updatein the numerator (e.g., cases with radiographic findings
suggestive of MRONJ), but these patients do not fit thecriteria 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 thefemoral head when there is a suspicion of AVN in a patient
at risk, but the diagnostic information is not conclusive.39
AAOMS believes the Stage 0 category for MRONJ is
analogous in principle and does account for the wideranging radiographic presentation of MRONJ that exists
prior to overt bone exposure. Therefore, AAOMS has
decided to maintain the current classification system withno modifications.
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 nonspecific symptoms or clinical andradiographic findings, 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 inflammationand 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 newbone 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).40
These nonspecific findings, which characterize this variantof MRONJ without bone exposure, may occur in patientswith a prior history of Stage 1, 2 or 3 disease who havebeen healed and have no clinical evidence of exposedbone. Progression to Stage 1 disease has been reported
in up to 50 percent of patients with Stage 0 disease41 and,
therefore, AAOMS deems it prudent to consider Stage 0
disease as a potential precursor to MRONJ.
Stage 1
Exposed and necrotic bone or fistula that probes to thebone in patients who are asymptomatic and have noevidence of infection/inflammation. These patients also
may present with radiographic findings mentioned forStage 0 that are localized to the alveolar bone region.
Stage 2
Exposed and necrotic bone, or fistula that probes to thebone, with evidence of infection/inflammation. Thesepatients are symptomatic. These patients also may present
with radiographic findings mentioned for Stage 0 localized
to the alveolar bone region.
Stage 3
Exposed and necrotic bone or fistulae that probes to thebone, with evidence of infection, and one or more of thefollowing:• Exposed necrotic bone extending beyond the regionof alveolar bone (i.e., inferior border and ramus in themandible, maxillary sinus and zygoma in the maxilla).
• Pathologic fracture.
• Extraoral fistula.
• Oral antral/oral-nasal communication.
• Osteolysis extending to the inferior border of themandible or sinus floor.
Causality
It is important to understand that patients at risk for or withestablished MRONJ also can present with other common
clinical conditions not to be confused with MRONJ.
Commonly misdiagnosed conditions may include but

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

Position Paper
are not limited to alveolar osteitis, sinusitis, gingivitis/
periodontitis, caries, periapical pathology, odontalgia,
atypical neuralgias, fibro-osseous lesions, sarcoma,
chronic sclerosing osteomyelitis, and temporomandibular
joint (TMJ) disorders. It also is important to rememberthat delayed healing, exposed bone or sequestra (i.e.,
osteonecrosis [ONJ]), can occur in patients not exposed
to antiresorptive agents.42
Proving causality of any medication-related complicationis 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 thosewith osteogenesis imperfecta – have been treated with
antiresorptive agents without reports of MRONJ.58 Manypatients receiving medications associated with MRONJ
have other comorbidities, which are likely exacerbating orcontributing factors. In combination, these confounding
variables make incidence and prevalence difficult toestimate.
Clinical trials, while being the gold standard for efficacy
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 yearsof patient data did not reveal any jaw bone necrosis as acomplication.17, 59 More recently, the HORIZON Pivotal
Fracture trial tested 3,889 randomized patients given
annual zoledronic acid versus placebo for three years; onepatient developed MRONJ in the intervention group andone in the placebo group.18 Extension of this trial for up to
six years resulted in one additional MRONJ patient in thetreatment group.60 Extension to nice years resulted in no
additional confirmed cases of MRONJ.61
Definitive causality, taken as a whole, remains a difficult
task to prove in general, let alone in individual patients

presenting with clinical symptoms. Clinicians should
be aware of these facts in decisions regarding treatment
recommendations.
Pathophysiology
Since the AAOMS position paper in 2014, significant
knowledge has been gained regarding MRONJ
pathophysiology from both clinical and particularly
preclinical animal studies. It should be noted that animalstudies 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 inunderstanding disease mechanisms and can serve as
one reference point to evidence-based clinical decisionmaking.
Much debate persists among clinicians and researchers,
contributing to the various treatment protocols utilized
for patients today.62, 63, 64, 65 Disease specificity uniqueto the jaws has focused leading hypotheses to include
bone remodeling inhibition, inflammation or infection,
angiogenesis inhibition, innate or acquired immune
dysfunction, as well as genetic predisposition.3,65 Bothanimal and human studies suggest that an antiresorptive
medication, coupled with inflammation or infection, isnecessary and sufficient 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 overallpathophysiology of this disease.3,65

Bone Remodeling Inhibition
The definition of MRONJ includes oral or parenteraladministration of antiresorptive medications, such thatbone remodeling suppression is a central hypothesis
in its pathophysiology. Antiresorptive medications,
including BPs and denosumab (DMB), have direct effects
on osteoclast formation, differentiation or function. In
osteoporosis, BPs are a first-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 bonemetastases 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
significantly 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 Thisis supported in the jaws as animal studies demonstrate
PAGE 5 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper
absent osteoclasts around the alveolar bone of DMBtreated mice.76 Human bone specimens also show anincreased number of nonfunctional osteoclasts surrounding
necrotic bone in BP-treated patients,77 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 remodelingin MRONJ prevention and resolution. Rodents withestablished ONJ failed to resolve when antiresorptives
were withdrawn. However, discontinuing DMB, but notBPs, prior to tooth extraction successfully prevented
MRONJ development in rats.78,79 Moreover, parathyroid
hormone, which acts directly on osteoblasts to inducebone formation and indirectly increases osteoclastic bone
resorption and overall remodeling, has been shown toprevent MRONJ and improve extraction socket healing
in rodents and preliminarily in patients.80, 81, 82 Thisobservation provides further support for the central roleof osteoclast inhibition in MRONJ pathogenesis.

Inflammation or Infection
Although most studies report tooth extraction as the
major inciting event for MRONJ development, it is clearthat most extracted teeth had pre-existing periodontal or
periapical disease.3, 64, 83, 84 From this patient information,
animal models of inflammation or infection weredeveloped to replicate clinical, radiographic and histologic
features of MRONJ.85, 86, 87, 88 Presence of inflammatory
cytokines, specifically at the site of MRONJ, also
support the strong role of inflammation.89 As evidence ofincreased systemic inflammation 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 inflammatory infiltrateand larger areas of histologic necrosis.90 Further support
for the inflammatory etiology showed that removal of
the inflammatory nidus in ligature-induced periodontitis
ameliorated MRONJ development in mice, demonstratingreduced inflammation and prevention of diseaseprogression.91 Moreover, transplantation of peripheral
blood mononuclear cells with anti-inflammatory properties
reduced MRONJ prevalence by improving soft-tissue
healing, decreasing inflammatory polymorphonuclear
cells and inflammatory marker expression, as well as
enhancing vascularity.92 These preclinical findings confirm
the irrefutable role of inflammation or infection in MRONJ
disease prevalence, severity and resolution.
The presence of bacteria on the exposed necrotic bonealso contributes to disease severity, where pain and signsof infection define Stage 2 MRONJ.3, 93, 94 This is not
surprising since poor oral hygiene and biofilm presence areassociated with MRONJ development,95, 96 and oral healthmaintenance and dental prophylaxis before initiating
antiresorptive therapy can decrease MRONJ prevalence.97,
98
Importantly, clinical treatment protocols to reduce thebiofilm and eradicate infection have emerged as importantalternatives to debridement and resection in patients who
may not be ideal surgical candidates.63

Angiogenesis Inhibition
Osteonecrosis is traditionally defined as avascular necrosis
or aseptic necrosis, most commonly characterized as
osteocyte death after decreased blood flow to the femoral
head.99 However, MRONJ is defined as necrotic bonein the maxillofacial region after exposure to either
antiresorptive or antiangiogenic medications.3 BPs such as
zoledronic acid directly inhibit angiogenesis in vitro and invivo100, 101, 102, 103 and animal models demonstrate decreased
vascularity in sites of MRONJ and decreased microvessel
numbers during early stages of bone healing.104 In
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 beassociated 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 thanthose taking antiresorptive medications.
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Position Paper
Innate or Acquired Immune Dysfunction
Although animal studies confirm that an antiresorptive
medication—coupled with inflammation or infection—is necessary and sufficient to produce MRONJ, not all
patients with dental infections develop the disease. It is
well-known that patients with medical comorbidities suchas diabetes or rheumatoid arthritis or immunocompromised
states are at significantly higher risk for MRONJ withor 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 confirmed 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 withmesenchymal 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 ofT-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 preventionof MRONJ lesions after systemic infusion with adipose orbone marrow-derived MSCs.123, 124, 125

Genetic Factors
In the 2014 paper, the authors identified several reports
describing single-nucleotide polymorphisms (SNPs) thatwere associated with the development of MRONJ. Mostof these SNPs were located within regions of the geneassociated with either bone turnover, collagen formationor certain metabolic bone diseases. Indeed, increasing
evidence is available to support the role of SNPs withMRONJ.126, 127 Specific 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 inflammation andinduction of angiogenesis, suggesting a role in several

of the leading MRONJ hypotheses.128 Other genes also
have been reported to increase MRONJ risk throughtheir role in angiogenesis, bone remodeling and immune
responses, including PPAR gamma, CYP2C8 and manyothers.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 To
determine predisposition, studies with larger sample sizes
should be performed, with genetic risks confirmed in both
BPs and DMB-treated patients who have breast or prostatecancer metastases, multiple myeloma or osteoporosis.

Risk factors for MRONJ
Medication-related Risk Factors
To estimate the risk for medications associated withMRONJ, the primary parameter to be considered is thetherapeutic indication for treatment (e.g., malignancy
or osteoporosis/osteopenia). The data suggest that
antiresorptive medications (i.e., BPs and DMB) areassociated with an increased risk for developing MRONJ.
The risk of MRONJ is considerably higher in themalignancy group (<5%) than in the osteoporosis group(<0.05%). Current data are insufficient to identify othermedications 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 placebogroups 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, therisk of MRONJ ranges from 0 percent to 6.9
percent, with most studies reporting rates <5percent.113,134,135,138,141,142,144,145 The risk for MRONJPAGE 7 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paperamong cancer patients exposed to DMB iscomparable to the risk of MRONJ in cancer patients
exposed to zoledronate.135,141,142,144,145
Since the 2014 update, investigators have implicatednumerous 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 (aflibercept),
mTOR inhibitors (everolimus), radiopharmaceuticals(radium 223), selective estrogen receptor modulators(raloxifene) and immunosuppressants (methotrexate andcorticosteroids).
When compared to antiresorptive medications, thelevel of evidence supporting other medication families
as risk factors for MRONJ is level 5 (e.g., isolatedcase reports or mini-case series [<5 cases]).146, 147, 148,
149
Given that the poly-pharmaceutical management ofcancer patients combined with the fact that cancer andimmunosuppression 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-caseseries. 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 evaluatepatients 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 riskof 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).

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 toromosozumab (0.03 percent to 0.05 percent) is
comparable to alendronate (0.05 percent).37,151 In theplacebo 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 patientstreated with BPs ranges from 0.02 percent to0.05 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 alarger range—from 0.04 percent to 0.3 percent.
As such, additional research will be needed tobetter 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 refine its association andrisk 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, exposedto these drugs.154

MRONJ Risk Among Patientswith Nonmalignant Bone Diseasea. AAOMS identified two studies where DMB wasused to manage aggressive giant cell tumors ofbone.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 therisks of developing MRONJ in subjects treatedwith DMB for malignancies (range = 0 percent
to 6.9 percent). Additional studies will be needed
to confirm the risk estimate for MRONJ among
patients with nonmalignant bone disease treatedwith antiresorptives.
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Position Paper
b. There are very limited data describing theoccurrence of MRONJ in the pediatric populationfor osteogenesis imperfecta and other conditions. Ina systematic review estimating the risk of MRONJ
among children with osteogenesis imperfecta, there
were no cases of MRONJ identified in a sampleof 486 subjects treated for 4.5 to 6.8 years.157 In adifferent systematic review that estimated the risk
for MRONJ among those under the age of 24 forseveral conditions treated using BPs, no cases of
MRONJ were reported.158 The overall quality ofthe studies included in both systematic reviews waslimited by small sample sizes or lack of MRONJrelated 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.5 In a more recent
systematic review by Ng et al., the risk of MRONJ amongcancer 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 >24months 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 overtime 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
significant increase in MRONJ in patients treated for up
to nine years.18,60,61 In addition, there are no postmarketingdata or general clinical experience to support an MRONJ
prevalence of 0.21 percent in any osteoporosis-treatedgroup. Therefore, while duration may be a risk factor, theoverall risk remains low.

Position Paper

Local Factors

Dentoalveolar Operations
Dentoalveolar operations are the most common identifiablepredisposing 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 isimportant, it is not what most patients or clinicians want toknow. Most providers and patients want an answer to thefollowing clinical question: “Among patients exposed toantiresorptive 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-riskpatients undergoing tooth extraction vary, they cluster
between 1 percent and 5 percent, similar to estimates ofosteoradionecrosis following tooth extraction in irradiatedpatients.
The risk of developing MRONJ among patients who
have been exposed to antiresorptive medications forother 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 tobe 0.5 percent.163 Absent better data, AAOMS cautions
the use of these procedures in cancer patients exposed toantiresorptive therapies and recommends osteoporosis
patients be informed of potential risks, albeit low,
including development of MRONJ, early and late implantfailure all of which have been described in case reports andclinical trials.

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

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 amongcancer patients exposed to zoledronate (OR = 4.9; 95
percent CI = 1.2 to 20.1).169 In a study by Vahtsevanos etal., using a sample of 1,621 cancer patients treated withintravenous zoledronate, ibandronate or pamidronate, there
was a twofold increased risk for MRONJ among denture
wearers.170

Concomitant Oral Disease
Preexisting inflammatory dental disease such as
periodontal disease or periapical pathology is cited as arisk factor.75,168 Among cancer patients with MRONJ, thepreexisting inflammatory dental disease was a risk factor
among 50 percent of the cases.5,165
Given that a common treatment of inflammatory dental
disease is tooth extraction, pre-existing dental disease may
confound the relationship between tooth extraction andrisk for MRONJ. Tooth extraction may expose MRONJ
as opposed to being the precipitating event. It would bevaluable to see an estimate of the association between
tooth extraction and MRONJ adjusted for pre-existing
inflammatory dental disease.
After tooth extraction and periodontal disease, the next
most common risk factor is reported as “spontaneous”
MRONJ with no identifiable 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 reflectionof the underlying disease for which the agents are beingprescribed (e.g., osteoporosis, breast cancer).
As noted previously, those under the age of 24 treatedwith antiresorptives for benign bone diseases have notdemonstrated any risk for MRONJ even after an extended

Position Paper

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 pediatricpopulation 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 approachedstatistical significance as a risk factor for MRONJ incancer 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 anassociation 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 reaffirms that the riskof MRONJ is significantly 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 ofdeveloping 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 benefit from the therapeutic
effect of antiresorptive therapy by controlling bone
pain and reducing the incidence of other SREs.

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

Prioritization and support of continued bone health andthe prevention of fragility fractures:○ Patients with osteoporosis, osteopenia and othermetabolic bone diseases benefit from antiresorptive
therapy by significantly 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 developmentof new areas of necrosis.

Prevention of MRONJ
Numerous studies demonstrate potentially modifiablefactors 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 anddiabetes optimization. Although no individual strategy norcollection of strategies eliminates all MRONJ risks, thesepreventive procedures are recommended.
The prevention of MRONJ begins with the realizationthat patients receiving antiresorptive therapies may havealtered 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 coordinateddental care and pretreatment management in minimizing
the risk of MRONJ. This requires a continuous effort
to educate patients, dentists and medical professionals
about the real risks associated with these therapies andclinical prevention paradigms that can mitigate MRONJ
development.
AAOMS re-emphasizes the importance of amultidisciplinary approach to the treatment of patients
who are receiving antiresorptive therapies. This may also

apply to other immune modulators or targeted therapies
taken alone or in combination with antiresorptives. Thisapproach includes consultation with an appropriate dental
professional when it is determined a patient would benefit
from these therapies.

Position Paper

Optimization of Oral Health
The 2014 AAOMS position paper identified valid
prophylactic treatment strategies that reduce theincidence of MRONJ. The efficacies of these strategies
remain validated by subsequent studies that demonstrate
the importance of pretreatment dental screening andregimented 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 benefits that all patients
enjoy with optimum oral health.186, 187, 188, 189, 190, 191, 192, 193
In a prospective study of prostate cancer patients withbone 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 aremany animal studies that demonstrate that periodontal
or periapical inflammation plays a key role in creating
a local environment that supports the development ofbone 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 theoral cavity and a radiographic assessment when indicated.
It is important to identify both acute infection and sites ofpotential 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,fluoride application, chlorhexidine rinses, tooth mobility,
periodontal disease, presence of root fragments, caries,
periapical pathology, edentulism and denture stability.197
An additional benefit of early dental consultation, when theuse of antiresorptive therapy is being considered, is thatthe patient is informed of the risk associated with thesedrug therapies and the risk incurred by not undergoingrecommended dental preventive measures before
consenting to treatment.
PAGE 11 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Cessation of At-Risk Medication Therapy (DrugHoliday) Prior to Tooth Extraction or Other
Procedures that Involve Osseous Injury (e.g.,
Dental Implant Placement, Periodontal or ApicalEndodontic Treatment)
The clinical practice of antiresorptive drug holidays tomitigate MRONJ risk in patients undergoing dentoalveolar
surgery was controversial at the time of the previous
AAOMS position paper in 2014 and remained the casein 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 orrefute such positions remains inconclusive. The difficultyin establishing or refuting the efficacy of drug holidays isdue to the rarity of MRONJ in these patient populations.
Therefore, since few events are reported, randomizedcontrolled trials provide insufficient data to create soundtreatment protocols. In a 2020 systematic review thatstudied the efficacy of antiresorptive drug holiday inpreventing MRONJ, a variety of papers were identified
with differing conclusions suggesting that a high level ofevidence for supporting or refuting the use of a holiday is
missing.199
The historical use of a drug holiday was intended todecrease the prevalence of MRONJ subsequent to theperformance of high-risk surgical procedures. The
concern regarding this practice is the loss of efficacy of
antiresorptive therapy with the development of SREs andfragility 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/
inflammation and extent of surgery to be performed.
Of note, the working group was unable to reach aconsensus regarding a recommendation on drug
holidays and was evenly split between offering drug
holidays to patients on a case-by-case basis using priorrecommendations and those who never recommend drug
holidays, believing that the risks of potential deleterious
effects of suspending antiresorptive therapy may outweigha benefit.

A special concern should be considered for suspendingRANKL 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 If
DMB is to be suspended, the timing and duration of theholiday should be optimized in order to minimize thisrisk. The planned dentoalveolar surgery can be completed
3-4 months following the last dose of DMB when thelevel 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 ashift away from bone turnover markers. No biomarkers
are validated for clinical decision-making, and continued
research and prospective studies are required before thesemarkers can be considered efficacious 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 decisionmaking.
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 affected patients
experience this complication following dentoalveolar
surgery.5,112,165,206,207 Therefore, if systemic conditions
permit, initiation of antiresorptive therapy should bedelayed until dental health is optimized.173,208 This decisionmust 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 efficacious andof paramount importance.38,185,186,209 Medical oncologists
should educate their patients about the importance ofdental health and the efficacy of prophylactic dental
treatment in the prevention of MRONJ. Similar to patients
PAGE 12 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper
who are to receive radiation therapy, optimizing thedental health in patients receiving antiresorptives or othertherapies that can compromise bone healing is essential.
The pretreatment evaluation of dental health must extend
beyond a review of systems and include a physical andradiographic exam. Therefore, a comprehensive dental
examination performed by a dental health professional
would be a prudent approach for all patients prior toreceiving antiresorptive therapy for malignant disease. Thislevel of dental health assessment is most appropriately
performed by a dental health professional.
The importance of minimizing the burden of dental
infection and inflammation prior to dentoalveolar surgery
in this cohort of patients with an elevated MRONJ risk
cannot be over-emphasized. Nonrestorable teeth and thosewith 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 thesurgical 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 functionallysound teeth. This level of care must be continued on afrequent and indefinite basis.185
The posterior lingual plate region is a common site fortrauma 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 flange region. It also is critical that patientsbe educated as to the importance of dental hygiene andregular dental evaluations, and specifically instructed toreport 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 asignificantly 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

of MRONJ. The importance of optimizing dental healththroughout this treatment period and beyond cannot be
underestimated.

Position Paper

It is not uncommon for patients to seek the consultation ofan 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 benefits
into the proper perspective. More specifically, patientsshould be reminded of the benefits associated with
antiresorptive therapies in preventing fragility fractures
and an acknowledgment of the rare occurrence of MRONJ.

Asymptomatic patients receiving
antiresorptive therapies for cancer

The initial enthusiasm and attention associated with thediscovery of MRONJ have had unintended consequences.
When initially described, a “class effect” 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 andis hypothesized to be associated with various safetyconcerns, such as MRONJ. Patients are becoming
increasingly more reluctant to begin or comply with their
antiresorptive therapy. Current evidence also confirms anincrease in fragility fractures with significant associatedmorbidity. 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 for2013 to 2015, attributable to an “osteoporosis treatmentgap.”210 Hip fracture carries significant 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 arerepresentative of a true health crisis. The documented
risk for developing MRONJ is low; however, the patientperceived risk is not. As such, patients are unwilling tostart or continue antiresorptive medical therapy. Patientsare irrationally denying themselves the tangible therapeutic
benefit of antiresorptive therapy to minimize the risk offragility fractures in order to prevent a minuscule risk ofdeveloping MRONJ.

Asymptomatic patients receiving
antiresorptive therapy for osteoporosis

It is clear the benefit of fracture prevention outweighs
the risk of MRONJ development in osteoporotic
patients.212 This benefit is even more favorable in thecancer population where bone-stabilizing medications
significantly improve quality of life, and it is detrimental
when antiresorptives are withheld due to MRONJ safetyconcerns.

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

Maintaining good oral hygiene and dental care is ofparamount 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 surgicalprocedure is unavoidable (e.g., fractured tooth, advanced
periodontal disease), patients should be informed of theassociated risks. The benefit of a drug holiday remains
unsubstantiated in this setting. Nonrestorable teeth may betreated by removal of the crowns and endodontic treatmentof 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 andsystematic reviews have reported necrosis associated with
antiresorptive therapy and implant placement.194, 214, 215, 216

Since the 2014 position paper, epidemiologic data
regarding the risk of MRONJ in patients receiving
antiresorptive therapy for osteoporosis remain limited dueto the lack of sound prospective studies with sufficient
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 forthe development of MRONJ in these patients includes theabove-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 anarea of research interest. Several systematic reviews haveacknowledged the lack of quality data and randomized
clinical trials. Some studies have recommended caution,

especially with a longer duration of therapy or steroid
use.194,216 For example, in their systematic review, Granate
et al.,216 identified several studies that reported an elevated
MRONJ risk associated with implants placed in theposterior 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 etal., 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 riskincrease for patients who underwent tooth extraction.218
Reports of implant-related (MRONJ) necrosis can bedivided into the early (implant surgery-triggered) or late
(implant presence-triggered) category.215,219,220 In thesereviews, 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 thecommon peri-implantitis failure and considered by someto be pathognomonic of MRONJ. Although there are noprospective studies or systematic reviews pertaining to
implant-related necrosis associated with RANKL inhibitors
or other targeted therapies, AAOMS considers this to havea similar level of risk.
In summary, robust data do not exist, and available data
are conflicting. 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 andlate implant failure. These patients should be placed on aregular 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 withMRONJ. These strategies are based on a current review of
nonoperative and operative therapies and their associatedoutcomes. Emphasis is placed on both nonoperative andoperative management being acceptable for all stages of
disease based on surgical judgment and patient factors in ashared decision-making model.
PAGE 14 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper
Nonoperative therapy
The efficacy of nonoperative therapies in the managementof MRONJ is documented in the literature and provides
a useful adjunct to the spectrum of management
strategies that also include operative treatment (Figure2). Nonoperative strategies can be useful in all stages,
especially where significant comorbidities preclude
operative treatment. They may also result in stabilizationof 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 shouldbe patient-specific and tailored to individual needs. The
risk versus benefit ratio (including quality of life with theircurrent symptomology), ability to perform good woundcare to prevent infection and disease spread, morbidityfrom a major surgical procedure, as well as oral function
or dental rehabilitation after marginal or segmental
resection should be considered. Radiographic imaging isof utmost importance in the evaluation of MRONJ lesions.
Three-dimensional imaging can identify forming or fully
formed sequestra and potentially decrease the invasivenessof a surgical procedure. Maintenance of maxillary or
mandibular integrity is desirable, as the reconstruction ofsurgical 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 thebiofilm from the necrotic bone surface.63 Surgery may not
be indicated in the absence of disease progression, withpatient 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 benefit 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

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 andcontrolled trials have yet to demonstrate the efficacy of
the aforementioned treatments.226, 227, 228, 229 Therefore, these
therapies should not be recommended as a mainstay oftreatment at this time.
The use of vitamin E and pentoxifylline as an adjunct tostandard MRONJ therapies have been reported only in casestudies. A randomized, prospective, placebo-controlled
trial of vitamin E and pentoxifylline is underway andwill 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 identified high success rates associated with resectionof MRONJ lesions.231, 232, 233, 234, 235, 236, 237 Importantly, onemust consider that MRONJ may progress over time, albeit
in an unpredictable manner.238 Furthermore, adopting anonoperative approach to MRONJ does not uniformly
result in sequestration of the exposed necrotic bone withdisease resolution.239 Thus, operative intervention should
be explored and presented as a treatment option in an
attempt to reduce the progression of disease with therecognition that early surgical intervention can predict
beneficial patient outcomes.240
Segmental or marginal resection of the mandible andpartial maxillectomy are effective methods to control
MRONJ.231, 232, 233, 234, 235, 236, 237, 238,241 This approach can beapplied to patients with all stages of MRONJ, includingStage 1 disease.169 These resections require margins
beyond the borders of the necrotic bone to an area ofvital, bleeding bone. Additional reports have identified
success when surgical resection of MRONJ was performedby experienced surgeons.242,243 Consistent with surgicalprinciples, control of comorbid conditions is paramountin managing MRONJ.241 Physiologically compromised
patients, such as those with an increasing burden of
distant metastatic disease, may not respond favorably to
PAGE 15 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Position Paper
resection of their osteonecrotic jaw and may occasionallydevelop refractory disease.241 Finally, surgical resection for
MRONJ in patients with metastatic cancer may identify
metastases in the jaw specimen, albeit in a minority ofpatients.62
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, surgicalresection of MRONJ should be performed without first
instituting prolonged nonoperative measures. MRONJ
represents a complex wound whereby operative therapy
can be performed in a timely fashion.241,244 Althoughcontroversy between operative and nonoperative therapies
exist, operative treatment of patients has demonstrated
maintenance of mucosal coverage, improved quality of lifeand expedient resumption of antiresorptive therapy for all
stages of MRONJ disease.245 The benefit 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 manyquestions remain unanswered. Continued preclinicaland clinical data are required, especially in the form ofprospective studies. Continued research efforts and theoutcomes that result should be considered the foundation
upon which recommendations are developed that will
guide patients and providers. While the data supportingthe conclusion that antiresorptives represent genuine
risk factors are robust, this is not the case for otherclassifications 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 effectbetween 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antiresorptive medication is a risk factor for developing
MRONJ. However, this has been difficult to demonstrate,possibly as a result of not having a good measure of
exposure other than years of treatment. Similar to thecancer risk associated with tobacco use (e.g., pack/years),
the antiresorptive exposure risk MRONJ may be better
defined as a cumulative dose load (e.g., mg equivalentof BP/years of exposure) that would account for risk
associated with different 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 efforts
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 effectiveness of biomarkers
and drug holidays or validate a risk relationship withgenetic markers and MRONJ. Until these relationships
are established or refuted, AAOMS considers it prudent
to recognize that these factors may play a role in thedevelopment and management of MRONJ.

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

Position Paper

Position Paper

Table 1MRONJ Disease Frequency Grouped by Disease Status vs Medication*
Indications fortreatment

Medication
Placebo

Zoledronate

Oral BPs

Denosumab

RomosozumabStudydesignMalignancy
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
reviewO’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, etal. (2016)135

0.1%

1.14%

Coleman (2020)138
Gnant, et al.
(2015)134

1.7%

Systematic
review

0.2% (2,218)

5.4% (2,214)

RCT

0% (1,709)

0% (1,711)

RCT

4.1% (850)

RCT

Raje, et al. (2018)113

2.8% (82)Himelstein(2017)140

1.5% (1,822)

Henry (2014)141

1.1% (786)Yang, et al.
(2019)247

2% (8,525)

Peddi, et al.
(2013)142

1.3% (2,846)

1.8% (2,885)

1.6-4%‡

1.9%‡

3.8-18%§6.9%§

1.4% (1,013)

2% (1,020)

Ng, et al. (2021)145
Wang, et al.
(2014)144

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

RCT
0.8% (792)

RCT
Systematic
review
Systematic
review
Systematic
review
Systematic
review(continued on following page)Position Paper(continued from previous page)

Indications fortreatment

Medications
Placebo

Zoledronate

Oral BPs

Denosumab

RomosozumabStudydesignOsteoporosis
Papapoulos, et al.
(2012)26

0% (3,383)

Grbic, et al.
(2010)150

0.02% (4,945)

Cosman, et al.
(2016)151

0% (3,322)

0.04% (4,549)

Systematic
review

0.02% (5,864)

Saag, et al. (2017)37

RCT
0.05% (2,047)

RCT
0.3% (2,343)

Bone, et al.
(2017)153
Hallmer, et al.
(2018)75

RCT

10-yr f/u

RCT
Population
study(50,000)

0.043%

Non-malignant
bone disease
Chawla, et al.
(2019)156

5% (532)

Prospective
case series

Rutkowski155

0.7% (138)

Retrospective
case series*Sample size in parentheses†‡Randomized clinical trial‡ <2 years of followup§ >2 years of followup

PAGE 18 Medication-Related Osteonecrosis of the Jaw – 2022 UpdateTable 2

Position Paper

MRONJ Prevention Strategies

Pretherapy (nonmalignant disease)• Educate patient about the potential risks associatedwith long-term ART.*• Optimization of dental health can occur concurrent
with ART.
• Educate patients about the higher risk of MRONJ
and the importance of regimented dental care.

Pretherapy (malignant disease)• Optimization of the dental health prior to the initiationof ART if systemic conditions permit (extraction of
nonrestorable teeth or teeth with a poor prognosis).
• No alteration of operative plan for most patients.

During antiresorptive therapy(nonmalignant disease)• Considerations include drug schedule, duration oftherapy, comorbidities, other medications (especiallychemotherapy, steroids or antiangiogenics), degree ofunderlying infection/inflammation and extent of surgery
to be performed. Drug holidays are controversial.
• BTM† are not a useful tool to assess MRONJ risk.
• Educate patients about the higher MRONJ risk in thesetting of malignant disease.

During antiresorptive therapy/targeted
therapies (malignant disease)• Educate the patient about the importance of regimenteddental 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 19 Medication-Related Osteonecrosis of the Jaw – 2022 Update

Figure 1

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

Position Paper

Figure 2

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

Position Paper

Figure 3

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

Position Paper

Figure 4

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

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171. Tsao C, Darby I, Ebeling PR, et al. Oral health risk factors forbisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac
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160. Aljohani S, Fliefel R, Ihbe J, et al. What is the effect of antiresorptive drugs (ARDs) on the development of medication-related
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163. Watts NB, Grbic JT, Binkley N, et al. Invasive oral procedures andevents in postmenopausal women with osteoporosis treated withdenosumab for up to 10 Years. J Clin Endocrinol Metab. 104:2443,
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173. Ripamonti CI, Maniezzo M, Campa T, et al. Decreased occurrenceof osteonecrosis of the jaw after implementation of dental
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165. Yamazaki T, Yamori M, Ishizaki T, et al. Increased incidence ofosteonecrosis of the jaw after tooth extraction in patients treatedwith bisphosphonates: A cohort study. Int J Oral Maxillofac Surg.
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177. Lodi G, Sardella A, Salis A, et al. Tooth extraction in patientstaking intravenous bisphosphonates: A preventive protocol andcase series. J Oral Maxillofac Surg. 68:107, 2010.

166. Scoletta M, Arata V, Arduino PG, et al. Tooth extractions inintravenous bisphosphonate-treated patients: A refined protocol.
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178. Mozzati M, Gallesio G, Arata V, et al. Platelet-rich therapies in thetreatment of intravenous bisphosphonate-related osteonecrosis of
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179. Ferlito S, Puzzo S, Liardo C. Preventive protocol for tooth
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208. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of
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222. Walton K, Grogan TR, Eshaghzadeh E, et al. Medication related
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210. Lewiecki EM, Wright NC, Curtis JR, et al. Hip fracture trends in
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223. Coropciuc RG, Grisar K, Aerden T, et al. Medication-related
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224. Akrivoula Soundia, Danny Hadaya, Sanjay M Mallya, Tara L
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213. Moinzadeh AT, Shemesh H, Neirynck NA, et al. Bisphosphonates
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225. Varoni EM, Lombardi N, Villa G, et al. Conservative managementof medication-related osteonecrosis of the jaws (MRONJ): A
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214. Gelazius R, Poskevicius L, Sakavicius D, et al. Dental implant
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226. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Efficacy
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215. Holzinger D, Seemann R, Matoni N, et al. Effect of dental implants
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227. Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is therole of hyperbaric oxygen in the management of bisphosphonaterelated osteonecrosis of the jaw: A randomized controlled trial of
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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 basedon a review of the existing literature and the clinical observationsof 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 aspectsof 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 thatthe strategies described in the position paper are NOT practiceparameters or guidelines and may NOT be suitable for every, orany, purpose or application. This position paper cannot substitutefor the individual judgment brought to each clinical situation by
the patient's oral and maxillofacial surgeon. As with all clinicalmaterials, the position paper reflects the science related to
MRONJ at the time of the paper’s development, and it should
be used with the clear understanding that continued researchand practice may result in new knowledge or recommendations.
AAOMS makes no express or implied warranty regarding theaccuracy, content, completeness, reliability, operability, or legalityof information contained within the position paper, including,
without limitation, the warranties of merchantability, fitness for aparticular 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 byhim or her in reliance on such information.

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

Position Paper