Review Article ISSN 2639-9490

Oral Health & Dental Science

Medication-Related Osteonecrosis of the Jaw – 2024 Update

David D. Seo and James L. Borke*

*
Correspondence:
JAMES L. BORKE, PHD, Professor and Associate Dean for
Western University of Health Sciences, College of Dental Biomedical Sciences and Research, College of Dental Medicine,
Medicine, Pomona, California. Western University of Health Sciences, 309 E. Second Street,
Pomona, California, Office: 909-469-8442 Fax: 909-706-3800.

Received: 26 Dec 2023; Accepted: 29 Jan 2024; Published: 06 Feb 2024

Citation: David D. Seo, James L. Borke. Medication-Related Osteonecrosis of the Jaw – 2024 Update. Oral Health Dental Sci. 2024;
8(1); 1-6.

ABSTRACT
As the global number of patients with osteoporosis and malignant diseases such as breast cancer, multiple
myeloma, and prostate cancer increases every year, there is an associated rise in the use of antiangiogenic
medications and antiresorptive medications. With increasing frequencies in the use of antiangiogenic and
antiresorptive medications, there is an associated increase in the number of medication-related osteonecrosis
of the jaw (MRONJ) cases reported from patients. MRONJ has emerged as a significant comorbidity in cancer
patients treated with antiangiogenics or high doses of potent antiresorptive agents, such as bisphosphonates (BPs)
or denosumab. MRONJ first emerged from BP-treated cancer patients who presented with a spectrum of dental
problems, including delayed wound healing following a dental extraction or oral surgery, exposed bone, soft
tissue infection and inflammation, anesthesia, paresthesia, odontalgia, sinus pain, and aching bone pain in the
mandible, which continues to be a significant source of problems for dentists, physicians, and patients today. A
significant number of MRONJ cases secondary to osteoporosis have also been reported in osteoporotic patients
receiving antiresorptive medications. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has
established diagnostic standards for MRONJ based on pharmacological history, clinical signs, and radiographic
findings. However, as the expertise and knowledge base for MRONJ continues to evolve, revisions and refinements
for MRONJ pathogenesis and treatment strategies are necessary to reflect the current research status of the disease
correctly. This review highlights current scientific information associated with MRONJ to identify and summarize
preventative measures, and treatment interventions for reading the impact of this debiliating disorders.

Keywords of potent antiresorptive agents, such as bisphosphonates (BPs)

Malignant diseases, Osteonecrosis, BP. or denosumab [1-3]. The first case of MRONJ was in BP-treated
cancer patients in 2003 [4] who presented with a spectrum of
Background dental problems, including delayed wound healing following
As the global number of patients with osteoporosis and malignant dental extraction or oral surgery, exposed bone, soft tissue
diseases such as breast cancer, multiple myeloma, and prostate infection and inflammation, anesthesia, paresthesia, odontalgia,
cancer increases every year, there is an associated rise in the use sinus pain, and aching bone pain in the mandible; which continues
of antiangiogenic medications and antiresorptive medications. to be a significant source of problems for dentists, physicians, and
With increasing frequencies in the use of antiangiogenic and patients today [3,4]. A notable number of MRONJ cases secondary
antiresorptive medications, there is an associated increase in the to osteoporosis have also been reported in osteoporotic patients
number of medication-related osteonecrosis of the jaw (MRONJ) receiving antiresorptive medications (e.g., BPs and denosumab).
cases reported from patients [1]. MRONJ has emerged as a
significant comorbidity in cancer patients treated with high doses MRONJ significantly deteriorates the overall oral health-related

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quality of life, hinders the attainment of ideal dental treatment, symptoms.
and diminishes the ability to perform everyday activities. This • Stage 1: Asymptomatic patients with exposed and necrotic
is primarily attributed to impaired chewing functionality and bone or fistulas that probe to the bone but with no evidence
jawbone defects resulting from surgical intervention(s) and/or of infection.
the progressive advancement of MRONJ [2,3,5]. Unfortunately, • Stage 2: Infection is present, as indicated by pain and redness
there is limited scientific knowledge about the underlying causes in the area of exposed bone, along with exposed and necrotic
and definitive treatment options for MRONJ. While various bone or fistulas probing the bone. Purulent drainage may or
therapies have been attempted, the current methods need more may not be present.
scientific evidence to establish their effectiveness [3]. The • Stage 3: Patients experience pain infection and have one or
American Association of Oral and Maxillofacial Surgeons more of the following: exposed and necrotic bone extending
(AAOMS) has established diagnostic standards for MRONJ beyond the alveolar bone area (such as the inferior border and
based on pharmacological history, clinical signs, and radiographic ramus in the mandible, the maxillary sinus, and the zygoma in
findings. However, as the expertise and knowledge base for the maxilla) causing pathologic fracture, extraoral fistula, oral
MRONJ continues to evolve, it is crucial to understand the exact antral or oral nasal communication, or osteolysis extending to
mechanisms and develop effective treatment strategies for MRONJ the inferior border of the mandible or the sinus floor [3].
to reflect the current research status of the disease correctly [2,5].
This manuscript aims to comprehensively review current scientific Imaging
information associated with MRONJ to determine all causative To assess patients with MRONJ or suspected cases,
agents and summarize the latest preventative measures, diagnostic orthopantomography is crucial and should be the initial investigative
standards, and treatment interventions for MRONJ. method. A general overview of the whole mandible and maxilla
can be visualized and observed through orthopantomographic,
Summaries and Updates panoramic examination. Radiographic characteristics such as
Each subheading below begins with a short paragraph discussing sclerotic bone, or a combination of radiopaque and radiolucent
the state of knowledge for that area as published in the literature lesions, along with the presence of a nonhealing extraction
through 2020. This is followed by published updates to this socket, are commonly present in the early stages of MRONJ. The
information from 2021 through the time of publication of this orthopantomogram (Figure 1) shows osteosclerosis in the body of
review. the left mandible with diffuse radiolucency, indicating a change
in bone mineralization [6]. The radiographic presentation in
Diagnostic Criteria and Stages of MRONJ advanced stages of MRONJ may including sequestrum formation,
According to the American Academy of Oral and Maxillofacial lamina dura thickening, and pathological fractures [7,8]. For a
Surgeons (AAOMS), a patient must meet all the following more thorough examination, digital imaging techniques such
elements of the case definition of MRONJ to establish a correct as computed tomography (CT) and cone-beam CT (CBCT) can
MRONJ diagnosis [3]: produce high-quality tomographic images that reveal the presence
1) Previous or current use of antiangiogenic or antiresorptive of MRONJ lesions [7,9]. Signs such as diffuse osteosclerosis, bone
medications alone or in combination with antiangiogenic resorption, degeneration of cortical bone, periosteal reaction, and
medications or immune modulators; bone fistulas can indicate the spread and extent of the lesion [7].
2) More than eight weeks of persistent oral bone exposure that
can be probed through a maxillofacial extraoral or intraoral
fistula; and
3) No history of jaw radiation therapy or metastatic disease to
the jaw.

Ruggiero et al. [3] developed the MRONJ staging system in 2006,

which was introduced and adopted by the AAOMS in their 2009
MRONJ position paper, which was then updated in the AAOMS’
2014 MRONJ position paper [4]. The 2014 AAOMS staging
system has proven to be a straightforward and valid system that
successfully stratifies the different stages of MRONJ. As a result, Figure 1: The Radiographic Presentation of MRONJ.
the AAOMS has chosen to keep the current classification system
in place with no changes [3,4]. The classification of MRONJ (2014 Panoramic radiograph of MRONJ. Focal osteosclerosis is
AAOMS staging system) is as follows: observable in the posterior body of the left mandible with diffuse
• Patients at risk: Those treated with oral or intravenous radiolucency. Reprinted from “Medication-Related Osteonecrosis
bisphosphonates but do not show any apparent necrotic bone. of the Jaw: Update and Future Possibilities,” by J. L. Borke, 2018,
• Stage 0: No clinical signs of necrotic bone, but there may Journal of the California Dental Association, Vol. 46 (Issue 5),
be nonspecific clinical findings, radiographic changes, and pages 301-305. Copyright 2018 by the Journal of the California

Oral Health Dental Sci, 2024 Volume 8 | Issue 1 | 2 of 6

Dental Association. Reprinted with permission [6]. the absorbed drug selectively retained by the skeleton and the
remainder excreted out of the body as urine [1,17,18]. This is
CT imaging has become the standard method for detecting the because BPs are polar with a negative charge, which prevents
most common characteristics of MRONJ, which include osteolysis them from paracellular transportation between the cells of the
and osteosclerosis [10,11]. Due to its ability to visualize a larger intestinal epithelia. In addition, BPs are lipophilic, so they cannot
area than what can be seen clinically, CT can accurately determine perform transcellular transport through the intestinal epithelial cell
the extent of the lesion(s) [10]. Unlike panoramic radiographs, membranes [1,17,18]. This inhibition of both methods of intestinal
CT is also effective in detecting MRONJ signs such as changes in diffusion based on the properties of BPs may explain the drug’s
trabecular bone density and bone sequestrum/sequestra [10,11]. In poor absorption rate and limited bioavailability when taken orally.
a clinical trial involving 28 MRONJ patients [12], CT showed a In contrast, approximately 50% of intravenously administered BPs
higher sensitivity in detecting MRONJ at 96%, compared to 54% are readily bioavailable to bind to their bone target cells compared
for panoramic radiographs and 92% for MRI [10]. For staging to the minuscule <1% bioavailability seen in orally administered
purposes, CT imaging is highly recommended [10,11]. BPs. This is in line with the clinical finding that MRONJ occurs
most in individuals who receive intravenously administered BPs.
As such, a secondary-level examination is sometimes
necessary for suspected cases of MRONJ to provide further BPs can only bind to bone hydroxyapatite crystal binding sites
comprehensive diagnostic imaging to confirm suspected MRONJ in a neutral pH environment [19-21] and are rendered inactive
diagnoses. CT imaging achieves this by visualizing images with until activation through acidic milieus. These aforementioned
radiological findings that are generally more comprehensive than pharmacological mechanisms take place physiologically where
orthopantomography and serves as a conclusive component of BPs locally accumulate, which is in Howship’s lacunae of bone;
the overall radiological assessment [4]. Advanced investigations during osteoclastic bone resorption, an increase in pH value has
(e.g. MRI and PET) are typically reserved for unclear cases or been reported to cause the release and activation of BPs that allows
to differentiate MRONJ from other conditions, such as distant for the exertion of the drug’s effects [19-21]. This mechanism
solid malignant bone metastases [4]. However, MRI's diagnostic between BPs and their method of activation through acidic milieus
effectiveness in detecting MRONJ has yet to be fully established [7]. has not been associated with MRONJ until recently [19]. It may
play a substantial role in the multifactorial etiology of MRONJ
New insights into the pathogenesis of MRONJ manifestation and its localization to the jawbone. Sato and
The exact pathogenesis of MRONJ remains unclear [1,3]. colleagues [20,22] justified these BP activation claims through
However, there are several proposed hypotheses for MRONJ acidic milieus in their rat model experiments. These activating,
pathogenesis from researchers, which are associated with the over- acidic conditions occur most often in the jawbone due to the oral
suppression of bone resorption, soft tissue BP toxicity, constant cavity's high susceptibility to apical infections, marginal infections,
microtrauma, inhibition of angiogenesis, suppression of innate and dento-alveolar surgeries (post-op infections); especially
or acquired immunity, vitamin D deficiency, alterations in bone regarding dental extractions [19]. These different types of infections,
remodeling, and infection or inflammation [1,3,13]. Thus, it is whether individually present or all present, all result in the same
critical to develop a more scientifically sound understanding of effect: the local acidification of jaw bone areas that leads to the
the pathogenesis of MRONJ to assist in the development of future release and activation of BPs to possibly even toxic levels that lead
MRONJ treatment interventions [14]. to MRONJ [20]. With a dental extraction-induced, acidic-infectious
environment of the jaw with localized soft tissue toxicity (from
Antiresorptive Drugs and MRONJ locally concentrated BPs), antiangiogenic BP effects, BP-induced
Bisphosphonates osteoclastic inhibition, and even further local accumulation of BPs
An essential component of the pharmacology of BPs is that targeting and binding to more and more alveolar bone with high
they have a high affinity for bone, especially for bone with high rates of bone remodeling in the jaw, there is a resulting multifactorial
rates of bone remodeling, such as alveolar bone in the mandible cascade of processes that each may cumulatively contribute to
[15,16]. BPs have a high affinity to bone tissue rather than other explain why the jawbone is exclusively targeted by MRONJ.
types of tissue because they are site-specific and naturally bind
to hydroxyapatite crystal binding sites that are predominantly Denosumab
abundant in skeletal sites with active bone remodeling, such as the Denosumab is a commonly used alternative antiresorptive agent
alveolar regions of the mandible [15,16]. The significant factors that is a fully humanized antibody against RANKL and inhibits
required for high BP-bone retention are high rates of bone turnover osteoclast function and its associated bone resorption process
and the amount of bone surface available. [3,23,24]. RANKL is secreted by bone marrow stromal cells
and osteoblasts, and under normal conditions, RANKL binds
The bioavailability of BPs is a significant feature that governs to the RANK receptor on osteoclasts and promotes osteoclast
its pharmacology [1,17,18]. BPs can be given as intravenous differentiation and activity [25]. However, denosumab blocks the
infusions, or they can be taken orally. However, oral BPs have binding of RANKL to RANK on osteoclasts by having RANKL
an intestinal absorption rate of only <1-3%, with only 50% of bind to denosumab directly rather than RANKL binding to RANK

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receptors, which inhibits and slows osteoclast resorption [3]. dental and medical professionals who prescribe the related
Denosumab is administered subcutaneously every six months to medications to prevent ONJ effectively. It is crucial to prioritize
reduce the risk of hip, vertebral, and non-vertebral fractures for overall health optimization, specifically focusing on dental
individuals diagnosed with osteopenia or osteoporosis [3,26]. In health. Educating patients about the potential risks of medication
contrast to BPs, RANK ligand inhibitors do not bind directly to therapy and the impact of compromised oral health is essential at
bone, and their bone remodeling effects diminish within six months all stages of care. Prior to initiating antiresorptive treatment, it is
of treatment cessation [3,26,27]. In addition, Limones et al. [1] recommended to address any existing periapical or periodontal
reported that the incidence of MRONJ is significantly greater with inflammation to reduce the likelihood of future extractions or other
denosumab than with ZA. bone trauma [3,38].

Antiangiogenics and MRONJ Different preventative approaches have been used in cases where
Angiogenesis is the formation of new of new blood vessels [28]. dentoalveolar surgery is necessary after starting antiresorptive
Angiogenesis inhibitors (antiangiogenic medications) such as therapy, such as minimal access surgery, perioperative antibiotics,
human monoclonal antibodies, vascular endothelial growth factor antimicrobial rinses, and closing extraction sites. The level of
(VEGF) inhibitors, thalidomide, mTOR inhibitors, and tyrosine evidence supporting the "drug holiday" concept is limited, and
kinase inhibitors interfere with the formation of new blood therefore, the AAOMS panel has not reached a consensus on
vessels by binding to various signaling molecules that disrupts its recommendation [3,38]. There is currently no validation for
the angiogenesis-signaling cascade [28]. These novel medications using bone turnover markers to determine the optimal timing
have demonstrated efficacy in treating gastrointestinal tumors, for dentoalveolar surgery in patients using antiresorptive agents.
renal cell carcinomas, and neuroendocrine tumors. However, Recently, biomarkers associated with angiogenesis, VEGF activity,
exposure to antiangiogenic medications is associated with an endocrine function, and PTH have been identified. However, these
increased risk of the manifestation of exposed maxillofacial bone biomarkers are still in the exploratory phase and have not yet been
that leads to MRONJ [3,28]. validated for clinical use [3].

New Insights into Mechanisms Underlying the Development of New Management and Treatment Options for MRONJ
MRONJ MRONJ treatment options and management strategies include
Local Factors operative and nonoperative therapies. Both operative and
In a retrospective study with 240 MRONJ patients [29], it was nonoperative therapies are viable and accepted management
found that dental extractions preceded the development of MRONJ forms for all MRONJ stages. In the context of reducing MRONJ-
in 40% of the cases. When analyzing the combined data from associated acute inflammatory signs, infection, and pain in the
three phase III trials that resulted in the approval of denosumab early asymptomatic stages of MRONJ, the literature supports the
for preventing skeletal-related events (SREs), it was observed that non-invasive/nonoperative treatment approaches, especially in
a dental extraction had occurred prior to the onset of MRONJ in MRONJ patients with risky comorbidities that prevent the option
61.8% of the cases [29]. It has also been observed that denture of operative therapy [39]. Nonoperative therapies for MRONJ
usage increases the likelihood of developing MRONJ. Patients include patient reassurance, patient education, and the management
with pre-existing oral conditions such as periodontal disease or of pain and secondary infections [3,40]. Other forms of the
periapical pathology are at a heightened risk of developing MRONJ conservative management of MRONJ include hyperbaric oxygen
[29]. Observational data from real-world studies on the use of therapy [41] and ozone therapy [42] to stimulate the proliferation
zoledronic acid in cancer patients has revealed that undergoing an of new cells and soft-tissue healing required to ameliorate MRONJ
invasive dental procedure is linked to a 4.67-fold increased risk pain. Low-level laser therapy (LLLT) is a form of nonoperative/
of developing MRONJ (95% CI, 1.75-12.42; p=0.002) [29,30]. noninvasive therapy that has been reported [43-45] to have positive
Patients with concomitant oral conditions, such as periodontal biostimulatory effects on the reparative process of MRONJ by
disease or periapical pathology, are predisposed to a heightened increasing inorganic bone matrix, increasing osteoblastic mitotic
risk of developing MRONJ [31]. index, and stimulating blood and lymphatic capillary growth [46].
Systemic antibiotics (metronidazole penicillin or clindamycin),
Systemic Factors antimycotic agents (nystatin, fluconazole, or ketoconazole) [47],
Prolonged use of BPs is correlated with a higher risk of MRONJ, and oral rinses (hydrogen peroxide or chlorhexidine gluconate)
especially when taken for over four years [32,33]. The risk of are used to treat patients with MRONJ bone exposure [3,45].
MRONJ is also elevated with the simultaneous use of steroids and MRONJ patients are generally advanced in age and have risky
BPs [34], which may weaken immunity and hinder wound healing comorbidities such as cancer that require chemotherapy [48],
[19,35]. Furthermore, MRONJ has been associated with older age, which compromises the health status of these patients and renders
particularly individuals over 65 years old [34,36], and the presence them unable to bear the side effects associated with a prolonged
of diabetes mellitus [37]. or permanent antibiotic schedule. In many cases with patients
New Recommendations for the Prevention of MRONJ with late-mid stage MRONJ (e.g., Stage II Refractory – Stage
The AAOMS panel suggests a collaborative approach involving III) or reoccurring MRONJ, surgical management of MRONJ

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