Medication-Related Osteonecrosis of the Jaw: An Evidence-Based 2025 Position Statement from a Korean Multidisciplinary Task Force.

INTRODUCTION

South Korea is experiencing one of the world’s most rapid demographic shifts towards a super-aged society, a trend that has profound implications for public health. This aging population has led to a high prevalence of osteoporosis; according to the Korea National Health and Nutrition Examination Survey (2008 to 2011), 22.4% of the population aged 50 and over has osteoporosis, affecting approximately one in five adults in this age group [ 1 ]. The clinical sequelae of this disease are significant, with the incidence of osteoporosis-related fractures nearly doubling from 226,000 in 2008 to 434,000 in 2022 [ 2 ]. Hip fractures, in particular, are associated with a 1-year mortality rate of approximately 17%, underscoring the critical need for effective fracture prevention [ 2 ]. Consequently, the prescription of antiresorptive agents, primarily bisphosphonates (BPs) and denosumab, has risen substantially [ 3 ]. While BP prescriptions peaked in 2019, denosumab use has surged since its introduction in 2016, and the overall use of injectable formulations surpassed oral agents after 2020 [ 4 ].

Since osteonecrosis of the jaw (ONJ) associated with BP therapy was first reported in 2003, the diagnosis and management of what is now known as medication-related osteonecrosis of the jaw (MRONJ) have been subjects of considerable debate and clinical evolution. The American Association of Oral and Maxillofacial Surgeons (AAOMS) has been instrumental in defining the condition, first as BP-related osteonecrosis of the jaw (BRONJ) in 2007 and later expanding the terminology to MRONJ in 2014 to include other agents like denosumab and antiangiogenics [ 5 , 6 ]. However, international guidelines have continued to evolve, with the 2022 AAOMS position paper notably removing specific recommendations for prophylactic drug holidays, instead favoring a more generalized, individualized risk assessment [ 7 ]. While this approach has its merits, it has also created clinical uncertainty. Previous Korean position statements were published in 2015 and 2021 to address local needs [ 3 , 8 ]. The unique epidemiological trends, healthcare system, and clinical practice patterns in Korea—where clinicians often prefer more prescriptive guidance to navigate complex decisions—necessitate a dedicated national consensus that reflects both global evidence and local clinical realities.

The primary objective of this position statement is to develop a practical, evidence-based clinical guideline for MRONJ that is directly applicable in the healthcare setting. This document is the culmination of a Korean multi-society collaboration involving 20 experts from five key academic societies: the Korean Association of Oral and Maxillofacial Surgeons, the Korean Society of Maxillofacial Plastic and Reconstructive Surgeons, the Korean Osteoporosis Society, the Korean Society for Bone and Mineral Research, and the Korean Endocrine Society. This task force established a consensus through a rigorous process of in-depth literature reviews and three rounds of formal surveys, ensuring that the recommendations are grounded in the latest scientific evidence while also reflecting the collective expertise of Korean clinicians. This paper aims to provide a clear, integrated framework for the definition, diagnosis, prevention, and treatment of MRONJ, with the goal of standardizing care and serving as an essential guide for clinicians managing patients on antiresorptive therapies.

DEFINITION, DIAGNOSIS, AND STAGING

Diagnostic criteria for MRONJ

The term MRONJ was adopted by the AAOMS in 2014 to encompass osteonecrosis associated not only with BPs but also with other antiresorptive (e.g., denosumab) and antiangiogenic agents [ 6 ]. While other terms such as ‘denosumab-related osteonecrosis of the jaw (DRONJ)’ or ‘antiresorptive agent-related osteonecrosis of the jaw (ARONJ)’ are used in some contexts, this committee has adopted MRONJ as the standard terminology unless a specific agent needs to be distinguished [ 9 ].

Based on a comprehensive review of recent literature and international guidelines, this committee defines MRONJ by the following three criteria [ 7 , 10 , 11 ]:

(1) Current or previous treatment with an antiresorptive agent alone, or in combination with an immune modulator or antiangiogenic medication.

(2) Exposed bone, or bone that can be probed through an intraoral or extraoral fistula, in the maxillofacial region that has persisted for more than 8 weeks. However, if necrotic bone is confirmed clinically or radiographically, the condition can be diagnosed as MRONJ even if the 8-week criterion has not been met.

(3) No history of radiation therapy to the jaws or evidence of primary or metastatic malignant diseases to the jaws.

The addendum to the second criterion is crucial clarification. It acknowledges that definitive clinical or radiographic evidence of bone necrosis should not be disregarded simply because the 8-week observation period is incomplete, allowing for earlier diagnosis and intervention.

Imaging and other diagnostic aids

While the diagnosis of MRONJ is primarily based on clinical history and examination, various diagnostic aids are essential for assessing the extent of the disease, guiding treatment, and performing differential diagnosis.

• Imaging: Radiographic evaluation is a cornerstone of MRONJ assessment.

• Panoramic radiography: May reveal features such as osteolytic lesions, sequestrum formation, thickening of the lamina dura, or widening of the periodontal ligament space. However, these findings are often present only in mid-later stages and are not specific to MRONJ [ 12 ].

• Computed tomography (CT/cone-beam computed tomography): Provides superior three-dimensional detail, allowing for visualization of bone sclerosis, osteolysis, and periosteal reactions. These findings, while characteristic, are not pathognomonic and may be absent in early-stage disease [ 13 ]. Some reports suggest that BP-related lesions exhibit more pronounced sclerosis on cone-beam computed tomography compared to those associated with denosumab [ 14 ].

• Magnetic resonance imaging: Is particularly useful for evaluating soft tissue involvement and bone marrow changes. In MRONJ, magnetic resonance imaging may show decreased T1 and increased T2 signal intensity, indicative of marrow inflammation and edema [ 15 , 16 ].

•Nuclear medicine: Bone scintigraphy and single-photon emission computed tomography (SPECT/CT) provide functional information on bone metabolism and can help delineate the extent of the necrotic lesion with high sensitivity, often more clearly than anatomical imaging alone [ 17 - 20 ].

• Biomarkers: The use of serum bone turnover markers, particularly C-terminal telopeptide (CTX), was once proposed as a tool for assessing MRONJ risk [ 21 ]. However, subsequent large-scale clinical studies and meta-analyses have demonstrated that CTX levels are not a reliable predictor of MRONJ development [ 22 - 24 ]. Therefore, in alignment with international consensus, this committee does not recommend the use of CTX testing for MRONJ risk assessment. Other potential markers related to angiogenesis (e.g., vascular endothelial growth factor [VEGF]) or bone metabolism (e.g., tartrate-resistant acid phosphatase 5b [TRACP 5b], receptor activator of nuclear factor-κB/osteoprotegerin [RANKL/OPG]) have been investigated but are not yet clinically validated [ 25 - 27 ].

• Biopsy: A bone biopsy provides a definitive histopathological diagnosis but is generally not recommended for MRONJ confirmation. The surgical trauma from the biopsy procedure itself can exacerbate the necrotic process or create a new non-healing lesion [ 28 ]. Its primary role is reserved for cases where there is a clinical suspicion of metastatic disease or primary malignancy that must be ruled out.

• Differential diagnosis: MRONJ must be differentiated from other conditions that present with similar clinical or radiographic features [ 29 ]. These include alveolar osteitis (‘dry socket’), sinusitis, advanced periodontitis, periapical lesions, and fibro-osseous lesions. Other forms of jawbone necrosis, such as osteoradionecrosis (distinguished by a history of radiation therapy) and osteomyelitis of odontogenic origin, must also be considered [ 30 ]. In patients with a history of cancer, metastatic disease to the jaw is a critical differential diagnosis [ 9 ].

Clinical staging system and the rationale for retaining stage 0

Accurate staging is essential for guiding treatment and predicting prognosis. This committee has adopted the widely used AAOMS staging system, which is based on clinical signs and symptoms [ 6 ]. MRONJ staging system and treatment recommendations are detailed in Table 1 .

A significant point of debate in the international community has been the validity and utility of stage 0 [ 31 ]. This stage is characterized by non-specific symptoms (such as unexplained jaw pain, altered sensation, or tooth mobility) and radiographic changes, but without clinical evidence of exposed bone [ 6 ]. The argument against its inclusion is that these symptoms are nonspecific and can overlap with common dental conditions like periodontitis or temporomandibular disorders, potentially leading to over-diagnosis of MRONJ [ 31 ]. Such a diagnosis could cause undue patient anxiety and lead to the inappropriate discontinuation of essential antiresorptive therapy, thereby increasing fracture risk [ 32 ].

Despite these valid concerns, this committee, after extensive discussion and formal surveys, has decided to retain stage 0 in its staging system. This decision is rooted in a clinical philosophy that prioritizes early detection and proactive prevention. Stage 0 serves as a crucial clinical alert, prompting heightened surveillance for high-risk patients who present with suggestive symptoms. By identifying patients at this preclinical stage, clinicians can implement preventive measures, provide patient education, and perform closer monitoring to potentially avert the progression to frank bone exposure [ 33 ]. Retaining stage 0 empowers clinicians to intervene at the earliest possible moment, which is fundamental to minimizing the morbidity associated with advanced MRONJ.

EPIDEMIOLOGY

Osteoporosis

Bisphosphonates

According to a systematic literature review conducted for this position meeting, the prevalence of MRONJ in osteoporosis patients treated with BPs is reported to be 0.01% to 0.10% [ 34 , 35 ]. The incidence is reported to be between 10 and 45.06 per 100,000 person-years [ 34 , 35 ]. A 2008 multi-center study in Korea involving approximately 600,000 patients prescribed BPs identified 254 cases of MRONJ, estimating an incidence of 0.04% [ 36 ]. A 2012 cohort study using data from the National Health Insurance Service, which followed about 330,000 individuals for 4 years, reported a cumulative incidence of 20.9 per 100,000 person-years [ 37 ]. An analysis of 74,491 individuals from the National Health Insurance Service between 2004 and 2015 reported an MRONJ incidence of 45.06 per 100,000 person- years, with a gradual increase corresponding to the cumulative duration of use [ 38 , 39 ].

For osteoporosis patients on oral BPs, the prevalence of MRONJ is reported as 0.10%, and the incidence as 36.6 per 100,000 person-years [ 40 , 41 ]. While large-scale, population-based studies on intravenous (IV) BPs alone are limited compared to oral agents, the prevalence of MRONJ in patients receiving IV BPs for osteoporosis is reported to range from 0.06% to 0.13%, with an incidence of 0–9.6 per 100,000 person-years [ 42 , 43 ]. A pooled analysis of the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and four other randomized controlled trials reported an MRONJ incidence of less than 8 per 100,000 person-years (<1 per 14,200) in osteoporosis patients receiving 5 mg of zoledronate annually [ 34 ]. However, a recent 2025 systematic review and meta-analysis of literature from 2015 to 2020 reported a mean incidence of 0.58% in osteoporosis patients (from an analysis of 498,443 individuals) [ 44 ]. This may indicate a continuing upward trend in MRONJ incidence but also suggests heterogeneity among studies, highlighting the need for future research with sufficient patient numbers and standardized reporting systems ( Supplemental Table S1 ).

Denosumab

In patients treated with denosumab, the prevalence of MRONJ varies widely compared to BP-treated patients, ranging from 0% to 0.18% [ 45 ]. The incidence of MRONJ in denosumab users also varies, from 0 to 283 per 100,000 patient-years [ 46 , 47 ]. In the 10-year Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)-extension trial, 13 cases of osteonecrosis (0.3%) were reported among 4,550 patients, corresponding to an incidence of 5.2 per 10,000 patient-years [ 48 ]. Of these, six cases occurred in the crossover group (placebo for the first 3 years, then denosumab for 7 years) and seven in the long-term group (denosumab for 10 years), showing no clear relationship between the duration of denosumab exposure and MRONJ risk [ 48 ]. The 2022 AAOMS position paper stated that the cumulative incidence of MRONJ related to denosumab in osteoporosis patients is 0.3%, approximately 10 times higher than that of BPs [ 7 ]. Furthermore, the risk of MRONJ is reported to be significantly higher in patients who switch from BPs to denosumab compared to those on monotherapy [ 46 ].

Current research does not provide a definitive conclusion on whether denosumab or BPs carry a higher risk of MRONJ. A large retrospective cohort study in Taiwan comparing 3,823 denosumab users with 5,139 BP users among 84,102 osteoporosis patients reported a lower incidence of MRONJ in the denosumab group (147 vs. 249 per 100,000 patient-years) [ 46 ]. However, this study’s longer observation period for denosumab compared to BPs should be considered. Conversely, a large cohort study in Switzerland reported a significantly higher incidence of MRONJ in denosumab users compared to BP users (283 vs. 45 per 100,000 patient-years) [ 47 ]. It is important to note that nine of the 12 patients who developed MRONJ had previously used BPs before switching to denosumab, with only three on denosumab monotherapy. Additionally, the BP group included patients on less expensive oral agents, making a direct comparison of risk difficult [ 47 ]. While several animal studies have reported that denosumab induces MRONJ at a rate similar to or higher than zoledronate, clinical studies suggesting a relatively higher risk for denosumab are mainly from single-center studies with limited patient numbers [ 49 ]. Thus, there has been not enough evidence to conclude that denosumab carries a higher risk than BPs.

Romosozumab

Case reports have described osteonecrosis associated with romosozumab, but most of these patients had a prior history of BP use, making it difficult to determine the role of romosozumab alone [ 50 , 51 ]. In the Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) randomized controlled trial, two cases of MRONJ were reported among 3,591 patients in the romosozumab group, an incidence of 0.03% to 0.05%, which is similar to the risk associated with alendronate [ 52 , 53 ]. An analysis of the FDA Adverse Event Reporting System (FAERS) also reported an association between romosozumab use and an increased risk of MRONJ [ 54 ]. Further investigation is needed to clarify this association.

Selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs), which are antiresorptive agents, are known to have a relatively lower-risk of MRONJ compared to BPs or denosumab due to their less potent inhibition of bone resorption. Cases of MRONJ in osteoporosis patients using SERMs have mostly been reported as case studies, often involving patients with a prior history of BP use or other risk factors. However, some case reports have described MRONJ in osteoporosis patients using only raloxifene without any prior use of other osteoporosis medications [ 55 ]. A study analyzing the Korean National Health Insurance Service sample cohort from 2002 to 2019 reported 14 cases of MRONJ among 3,101 patients who used only SERMs [ 56 ]. This study, however, did not account for other MRONJ risk factors in its analysis, limiting the interpretation of its findings [ 56 ]. Due to the lack of studies analyzing precise prevalence, a definitive conclusion on the association between SERMs and MRONJ cannot be drawn at this time.

Malignant tumors with bone metastases or multiple myeloma

In patients with bone metastases from malignant tumors, the incidence of MRONJ with zoledronate use is reported to be 0.7%–4.0%, which is much higher than in osteoporosis patients [ 57 , 58 ]. The incidence is slightly higher in multiple myeloma patients, at 2.4%–4% [ 59 , 60 ]. This increased incidence is thought to be due to higher cumulative doses from frequent administration (12–15 times higher), with a relatively high incidence of 0.3%–0.7% reported even with oral BPs [ 61 , 62 ]. This is also related to concomitant medications (anticancer drugs, steroids, antiangiogenic agents), poor general health, and oral hygiene [ 63 ]. Christodoulou et al. [ 64 ] analyzed 116 patients with ONJ receiving IV BPs and found that while the incidence of MRONJ was 1.1% in patients receiving IV BPs alone, it increased to 16% in patients also receiving antiangiogenic agents such as bevacizumab and sunitinib.

The duration of BP therapy, especially at high doses, can influence the development of MRONJ, with incidence varying by duration [ 65 ]. A recent systematic review reported that in cancer patients treated with zoledronate, the incidence of MRONJ was 1.6%–4% within the first 2 years of treatment, increasing to 3.8%-18% with more than 2 years of treatment [ 65 ]. Similarly, for denosumab, the incidence was 1.9% within 2 years and rose to 6.9% after 2 years [ 65 ]. The incidence of MRONJ can also vary by cancer type, and interpretation of incidence in these patient populations requires caution due to their relatively shorter followup periods related to life expectancy [ 65 ]. In some studies with follow-up periods of about 8 years, the incidence of MRONJ in patients with metastatic cancer was reported to be as high as 30% [ 66 , 67 ].

In cancer patients, particularly those being treated for bone metastases, denosumab is administered at a dose of 120 mg every 4 weeks, which is about 12 times more potent than the osteoporosis treatment dose. In large-scale trials, the prevalence of MRONJ in denosumab users was reported to be between 0.8% and 2%, and a recent domestic study of 1,278 patients reported an incidence of 2.66% [ 68 , 69 ]. However, in real-world clinical practice, the risk of MRONJ is reported to be even higher, ranging from 5% to 12.6% in patients receiving combination therapy with biologic agents [ 70 , 71 ]. An even higher incidence was observed in patients who switched from zoledronate to denosumab [ 72 ]. It is not yet clear whether the increased incidence of MRONJ in the denosumab group is due to denosumab itself or the total duration of therapy ( Supplemental Table S2 ) [ 73 ].

Cancer treatment-induced bone loss

In breast cancer patients receiving adjuvant zoledronate to prevent or reduce treatment-induced bone loss, the incidence of MRONJ is reported to be 0%–1.34% compared to 0%–0.24% in control groups, with rates up to 2.1% reported after more than 6 years of follow-up [ 74 - 76 ]. When oral BPs are used as adjuvant therapy in breast cancer patients, the incidence of MRONJ is reported to be 0%–0.27% compared to 0%–0.24% in controls [ 73 , 75 ]. For ibandronate, an incidence of up to 1.94% has been reported when used in conjunction with endocrine therapy ( Supplemental Table S3 ) [ 77 ].

Nonmalignant bone disease

In patients with giant cell tumor of bone receiving denosumab, the incidence of MRONJ is reported to vary widely, from 1% to 13.8% [ 78 - 81 ]. According to a systematic review, no cases of MRONJ were reported in 486 pediatric patients with osteogenesis imperfecta treated with BPs for 4.5 to 6.8 years [ 82 ]. Another systematic review also reported no cases of MRONJ in patients under 24 years of age who used BPs for various diseases [ 83 , 84 ]. With the expansion of indications for antiresorptive agents, interest in the incidence of MRONJ in cancer treatment-induced bone loss and nonmalignant bone diseases is growing, but data are still limited, and further research is needed to clarify the risk in these conditions ( Supplemental Table S4 ).

Other medications associated with MRONJ

In addition to osteoporosis treatments, MRONJ can also be caused by steroids, immunomodulators, and anticancer drugs; lenalidomide, pomalidomide, sunitinib, imatinib, cabozantinib, sorafenib, bevacizumab, everolimus, temsirolimus, palbociclib, nivolumab, docetaxel, paclitaxel, methotrexate, letrozole, radium 223, prednisolone, and dexamethasone [ 8 , 85 ].

PATHOGENESIS AND RISK FACTORS

Pathogenesis

The pathogenesis of MRONJ is a complex, multifactorial process precipitated by the intersection of systemic pharmacological effects and the unique local vulnerabilities of the jawbone [ 51 , 86 ]. The foundational mechanism is the profound suppression of bone remodeling induced by antiresorptive agents, which severely compromises the physiological capacity for skeletal repair and maintenance [ 51 , 86 ]. This state of impaired bone turnover creates a systemic susceptibility, where local insults such as microbial infection, inflammation, or iatrogenic trauma can initiate a pathological cascade culminating in progressive, non-healing bone necrosis [ 7 ]. This process is amplified by a self-perpetuating cycle wherein suppressed repair, chronic infection, and a dysfunctional inflammatory response reinforce one another, leading to the refractory clinical presentation characteristic of MRONJ.

The jawbone is the principal, and often exclusive, site of MRONJ due to a confluence of distinct anatomical, metabolic, and environmental characteristics that render it uniquely vulnerable [ 9 ]. The alveolar bone of the mandible and maxilla possesses a metabolic turnover rate that is up to 10 times higher than that of long bones. This heightened metabolic activity results in a disproportionately greater local accumulation of antiresorptive agents, particularly bone-seeking BPs, which leads to a more profound and localized suppression of remodeling where it is most needed to repair microdamage from masticatory forces [ 8 , 87 ]. This pharmacologically compromised bone is covered by a thin, often friable, mucosal-periosteal barrier that is easily breached by dentoalveolar surgery, trauma from prosthetics, or chronic inflammatory conditions like periodontitis. Such breaches provide a direct portal of entry for the complex oral microbiome, facilitating the establishment of persistent, low-grade infections by various organisms [ 88 ].

The primary pathogenic mechanisms are exacerbated by several synergistic factors. Drug-induced inhibition of angiogenesis, while mechanistically debated for certain drug classes, can further compromise the limited vascular supply to necrotic bone, impairing both nutrient delivery and immune cell trafficking [ 88 , 89 ]. Concurrently, antiresorptive agents can induce immune dysregulation by altering macrophage polarization and T-cell function, which fosters a chronic, non-resolving inflammatory state rather than effective pathogen clearance [ 7 ]. Direct soft tissue toxicity from certain agents on oral keratinocytes and fibroblasts can delay mucosal healing, thereby perpetuating bone exposure [ 90 ]. While several genetic polymorphisms have been investigated as potential predisposing factors, their role appears to be contributory rather than causative [ 91 , 92 ]. Collectively, these factors converge on the uniquely susceptible jawbone to create the pathological cascade of MRONJ.

Risk factors

The risk of developing MRONJ is determined by a complex interplay of drug-related, local, and systemic factors [ 11 ]. Key systemic and local co-factors that modify MRONJ risk are summarized in Table 2 . A comprehensive risk assessment requires a thorough evaluation across all three domains to accurately stratify patients and guide preventive clinical strategies [ 3 ].

While drug exposure and local trauma are primary determinants, a range of systemic and other local factors act as significant co-factors that compound a patient’s overall risk profile [ 29 ]. Tooth extraction remains the single most frequent trigger, precipitating up to 61% of all MRONJ cases [ 93 ]. The risk is magnified when the procedure involves substantial bone trauma, such as ostectomy, or is performed in a site of pre-existing infection [ 94 ]. A patient’s systemic health status and concomitant medications also play a pivotal role [ 95 ].

Drug-related risk

The pharmacological profile of the antiresorptive therapy is the most critical determinant of MRONJ risk [ 7 ]. This risk is not a binary state but exists on a continuum modulated by the cumulative dose, duration of exposure, drug potency, and route of administration [ 96 ]. Recent evidence indicates that risk increases progressively with the duration of therapy, particularly beyond 12 months of use, challenging earlier risk models based on fixed 3- or 4-year thresholds [ 38 ].

The clinical indication for therapy functions as a powerful risk multiplier [ 97 ]. High-potency IV BPs, such as zoledronate, and high-dose denosumab regimens (120 mg monthly for oncologic indications) confer a substantially greater risk than lower-potency oral agents or low-dose osteoporosis regimens (e.g., denosumab 60 mg every 6 months) [ 98 ]. Patients with malignancy not only receive drug dosages that are an order of magnitude higher and administered far more frequently, but they are also often exposed to synergistic risk factors, including concomitant corticosteroids, antiangiogenic agents, and chemotherapy [ 11 ]. This convergence of factors results in an exponential, rather than merely additive, increase in overall risk, explaining why MRONJ incidence can be up to 100-fold higher in oncology populations (1%–15%) compared to osteoporosis populations (0.01%–0.10%) [ 99 ]. Furthermore, switching from a BP to denosumab may also elevate risk due to the combined and cumulative suppressive effects on bone turnover [ 46 ].

Local risk factor

Dentoalveolar surgery is the most common precipitating event for MRONJ, and especially, tooth extraction and dental implant procedures represent a unique and significant category of iatrogenic risk [ 9 ]. The surgical trauma associated with implant placement, including osteotomy and flap elevation, can directly trigger necrosis [ 100 ]. This risk is particularly acute in high-risk oncology patients, for whom elective implant therapy is generally considered contraindicated [ 101 ]. In low-risk osteoporosis patients, while evidence suggests that early implant failure rates are not significantly elevated, the potential for MRONJ induction remains a critical consideration that necessitates thorough informed consent prior to the procedure [ 102 ].

Furthermore, MRONJ can manifest years after successful implant osseointegration, a phenomenon termed ‘late implant-associated MRONJ [ 103 ].’ This condition is pathologically distinct from conventional peri-implantitis, although it is often precipitated by it [ 104 ]. Chronic inflammation at the implant-bone interface can breach the mucosal seal, introducing the oral microbiome to the pharmacologically compromised peri-implant bone [ 105 ]. Consequently, the presence of an osseointegrated implant, particularly one with suboptimal oral hygiene, constitutes a long-term local risk factor that requires meticulous professional maintenance and patient surveillance [ 106 ].

PREVENTION OF MRONJ

The critical role of pre-treatment dental evaluation and management

The most effective strategy for mitigating the risk of MRONJ is prevention [ 28 , 107 ]. A cornerstone of this strategy is a comprehensive dental evaluation and the completion of any necessary dental treatment before a patient initiates high-risk antiresorptive therapy [ 6 ]. Numerous studies have demonstrated that implementing a preventive dental care protocol can significantly reduce the incidence of MRONJ [ 108 , 109 ]. One meta-analysis reported that pre-treatment dental evaluation and preventive care reduced MRONJ incidence by 77.3% in cancer patients receiving high-dose BPs [ 110 ].

The preventive protocol should include a thorough clinical and radiographic examination to identify and eliminate potential sources of infection and inflammation. Key management steps include [ 3 ]:

• Extraction of non-restorable teeth or teeth with a poor prognosis [ 28 ].

• Treatment of active periodontal and periapical disease [ 107 ].

• Adjustment or replacement of ill-fitting prostheses to prevent mucosal trauma [ 9 ].

• Patient education on the importance of maintaining excellent oral hygiene and the signs and symptoms of MRONJ [ 11 ].

For patients scheduled to receive high-dose antiresorptives for oncologic indications, this dental evaluation is considered mandatory and should be completed ideally before therapy begins. For osteoporosis patients starting low-dose therapy, a pretreatment evaluation is not essential but is strongly recommended, either before treatment or within the first 6 months of initiation [ 3 ].

Prophylactic drug holiday

The practice of temporarily discontinuing antiresorptive therapy before invasive dental procedures—a ‘prophylactic drug holiday’—remains one of the most controversial issues in MRONJ management [ 7 ]. In 2022, the AAOMS position paper—citing insufficient clinical evidence—deliberately offered no fixed time-based drug holiday recommendations, a change that has left many clinicians uncertain about how best to proceed [ 7 ]. In contrast, 2024 Italian position paper recommended that any prophylactic holiday for oral BP users be kept very short under 1 week [ 98 ].

Current evidence remains inconclusive on whether prophylactic drug holidays reduce MRONJ risk [ 111 ]. A 2022 systematic review concluded that the available data are not strong enough to either support or refute the routine use of a drug holiday; in pooled analysis, the relative risk of MRONJ in patients who took a holiday was 0.73 (95% confidence interval, 0.51 to 1.06) compared to those who did not—a difference that was not statistically significant [ 111 ]. Likewise, a systematic review in 2023 reported that short-term interruption of antiresorptive therapy prior to tooth extraction did not lower the incidence of MRONJ [ 112 ]. However, a more recent study suggested that among patients with over 2 years of antiresorptive exposure, those who had a holiday of over 3 months experienced a significantly lower MRONJ risk than those with a holiday under 3 months [ 113 ].

Interpreting these findings is complicated since many earlier studies pooled oral and IV BPs despite major pharmacokinetic differences between these agents [ 114 ]. For example, zoledronic acid has a much higher antiresorptive potency and a far longer skeletal half-life than other BPs, a profile that could plausibly necessitate a more prolonged drug holiday [ 115 ]. Supporting this agent-specific perspective, a Korean nationwide cohort study of IV BP users found that MRONJ risk after a dental procedure began to decline around 90 days following the last ibandronate dose, whereas after zoledronate the risk did not begin to decrease until 6 months and only became significant after ≥1 year since the last dose [ 116 ]. Collectively, these data imply that if a drug holiday is considered, its optimal duration is likely to be drug-specific, reflecting differences in pharmacologic persistence and potency [ 111 ]. Definitive guidance, however, will require prospective studies that balance any benefit in MRONJ risk reduction against the potential increase in fracture risk from interrupting therapy.

The Korean Multi-Society Task Force, recognizing this clinical need through its formal survey process, has developed a pragmatic, drug-specific guideline based on pharmacokinetic principles and expert consensus. This approach provides a structured framework that balances the theoretical benefit of reducing MRONJ risk with the distinct pharmacological profiles and systemic risks associated with each drug class. The committee’s recommendations are summarized in Table 3 .

Recommendations for bisphosphonates

BPs have an extremely long skeletal retention, binding to bone and remaining present for months to years; this enduring presence complicates the concept of a meaningful drug holiday [ 117 ]. Nevertheless, the rationale for a temporary pause is that reducing or halting therapy may limit the amount of drug available at sites of active bone healing during the post-procedure remodeling phase [ 116 ]. For low-risk patients with short exposure on BP and no additional risk factors, in general, no alteration of the antiresorptive regimen is necessary prior to dental treatment. Invasive procedures can proceed without a drug holiday, though the patient should be informed (through an appropriate consent process) of the small long-term risk of implant failure or MRONJ.

• Alendronate, risedronate, ibandronate: For patients with prolonged BP therapy or significant risk factors, a drug holiday of 2 months before an invasive dental procedure may be considered.

• IV zoledronic acid: Owing to this drug’s high potency and prolonged effect, a substantially longer holiday of approximately 6–12 months is recommended before any elective invasive dental procedure. A recent Korean cohort study showed that MRONJ risk after zoledronate does not appreciably decline until at least 6 months (and is significantly reduced only after ≥12 months) since the last infusion [ 116 ].

• Post-intervention period: Following a dental extraction or other jaw surgery, resumption of BP therapy should be delayed for about 6–8 weeks to allow soft tissue and bone to heal without drug-related inhibition.

Any prophylactic drug holiday should be individualized based on the patient’s MRONJ risk and fracture risk, and planned with close communication between the dentist and the prescribing physician ( Fig. 1 ).

Recommendations for denosumab

Denosumab, unlike BPs, does not bind to bone. Its suppression of bone remodeling is reversible and dissipates within about 6 months after each injection [ 45 ]. This pharmacokinetic characteristic makes the timing of invasive dental procedures in relation to denosumab dosing both more feasible and more critical ( Fig. 2 ) [ 118 ].

• Timing of intervention: Schedule invasive dental procedures ideally 3–4 months after the last denosumab dose. At 3–4 months post-injection, the drug’s effect on bone turnover has begun to decrease, while this timing still precedes the period of elevated risk for rebound vertebral fractures which typically starts around 6–9 months after an injection [ 119 , 120 ].

• Post-intervention period: Do not resume denosumab for approximately 6–8 weeks after intervention to allow proper mucosal and bony healing. By ensuring that the procedure and initial healing occur within a single 6-month dosing interval, this strategy minimizes the risk of rapid bone loss or fractures due to denosumab’s rebound effect upon delayed dosing. If an extended drug holiday is necessary in a high–fracture-risk patient, consider interim therapy with a SERM (e.g., raloxifene) to partially mitigate the rebound effect, although this approach may not fully prevent it [ 97 , 121 , 122 ].

MANAGEMENT OF ESTABLISHED MRONJ AND RECURRENCE

The treatment of established MRONJ is guided by the stage of the disease, with the primary goals being to eliminate pain, control infection, and prevent the progression of bone necrosis [ 7 ]. The committee’s stage-based treatment recommendations are outlined in Table 1 . Conservative, non-operative management is the foundation of treatment for all stages and may be the definitive therapy for early-stage disease [ 7 ]. This includes the use of antimicrobial mouth rinses (e.g., 0.12% chlorhexidine), systemic antibiotic therapy for stages with active infection (stage 2 and 3), pain management, and debridement of loose bony sequestra [ 6 , 7 ].

While past guidelines often reserved surgical intervention for advanced, refractory disease (stage 3), a paradigm shift has occurred based on accumulating evidence [ 123 ]. Recent studies consistently demonstrate that surgical treatment yields significantly higher rates of complete and long-term resolution compared to conservative management alone [ 124 - 127 ]. Success rates for surgical resection are reported to be in the range of 60%–90%, whereas conservative therapy often results in disease stabilization at best, with complete healing rates reported from 0% to 54% [ 124 , 125 , 128 ]. One study found that among 92 stage 1 lesions managed conservatively, 91.3% still had exposed bone, and many progressed to a higher stage requiring eventual surgery [ 128 ].

Therefore, this committee recommends that surgical intervention should be considered for all stages of MRONJ, including stage 1, particularly if the lesion persists or if the patient’s quality of life is affected [ 128 ]. The surgical principle is the complete resection of all necrotic bone back to healthy, bleeding bone margins, followed by a tension-free primary soft tissue closure [ 129 ]. Early surgical management can prevent the progression to more extensive lesions, reduce long-term morbidity, and improve patient quality of life [ 128 ].

Adjunctive therapies: the role of teriparatide and other modalities

• Teriparatide: Among various adjunctive therapies, teriparatide, a recombinant human parathyroid hormone analog (rhPTH[ 1 - 34 ]), has the most robust evidence supporting its use in MRONJ management [ 130 - 136 ]. As a bone anabolic agent, it stimulates bone formation and increases bone remodeling, directly counteracting the suppressed bone turnover state induced by antiresorptive drugs [ 137 , 138 ]. A placebo-controlled, randomized trial demonstrated that a 6-month course of daily teriparatide (20 μg) significantly promoted the resolution of MRONJ lesions when combined with surgical treatment [ 130 ]. Both daily and weekly formulations have shown efficacy [ 139 , 140 ]. It is important to note; however, that transitioning from denosumab to teriparatide is generally not recommended for osteoporosis management due to a risk of transient bone density loss; therefore, its use in denosumab-related MRONJ requires careful multidisciplinary assessment of fracture risk (Supplemental Table S5) [ 118 ].

• Other adjunctive therapies: Several other modalities have been explored to enhance healing in MRONJ, though the evidence for their efficacy is less compelling.

• Recombinant human bone morphogenetic protein-2 (rh- BMP-2): Can induce bone formation and may be beneficial when applied to surgical defects, particularly in combination with other carriers like platelet concentrates [ 141 - 143 ].

• Hyperbaric oxygen therapy: May promote angiogenesis and stimulate bone turnover, but clinical trials have shown mixed results, with no significant benefit over standard care in some studies [ 144 ].

• Low-level laser therapy: May aid in pain reduction and promote mucosal healing, but its effect on bone necrosis is limited, especially in advanced stages [ 145 , 146 ].

• Autologous platelet concentrates: Preparations like platelet-rich plasma and platelet-rich fibrin can be applied to surgical sites to deliver a high concentration of growth factors, potentially enhancing soft tissue and bone healing. However, systematic reviews have found the evidence for their efficacy in treating or preventing MRONJ to be inconsistent [ 147 - 149 ].

• Furthermore, preliminary studies on polydeoxyribonucleotide suggest it may be a promising agent for enhancing soft tissue and bone healing in MRONJ, warranting further investigation.

Therapeutic drug holiday and resumption of antiresorptive therapy

Once MRONJ is diagnosed, the decision of whether to continue or temporarily halt antiresorptive therapy—a ‘therapeutic drug holiday’—is complex. This decision places the localized need for jaw healing in direct conflict with the systemic risk of skeletal-related events (SREs) or osteoporotic fractures [ 150 ]. The existing body of literature presents a divided view on the efficacy of a therapeutic drug holiday for established MRONJ [ 11 ]. The conflicting findings are not arbitrary but rather reflect significant heterogeneity across studies in terms of patient populations (oncology vs. osteoporosis), the specific antiresorptive agents used, and the primary treatment modalities employed for MRONJ [ 151 ].

Several retrospective analyses and case series suggest a tangible benefit to discontinuing therapy. An analysis by Hinson et al. [ 152 ] reported that patients who stopped BP treatment at the time of MRONJ diagnosis experienced symptom resolution approximately 6 months sooner than those who continued the medication. Similarly, a Korean retrospective study of 54 MRONJ patients found a statistically significant correlation between a longer drug holiday (median 9 months) and a more favorable prognosis following surgical treatment [ 153 ]. Further supporting this view, a meta-analysis involving 13 clinical studies reported a substantially higher complete cure rate in patients who underwent a drug holiday (85%) compared to those who did not (56.4%) [ 154 ].

Conversely, an equally compelling set of studies has failed to demonstrate a significant correlation between drug discontinuation and improved MRONJ outcomes [ 132 ]. For instance, large retrospective studies from Japan, which analyzed outcomes in both osteoporosis and oncology patients, found that drug holidays of various durations (ranging from 60 to 180 days) did not lead to better surgical results [ 155 ]. Other clinical reports have similarly concluded that discontinuing potent agents like zoledronate or denosumab did not resolve established MRONJ lesions [ 156 ]. These disparate findings highlight that the potential benefit of a drug holiday is likely influenced by a confluence of factors, including the underlying disease, the specific drug’s pharmacology, and the stage of the MRONJ lesion [ 157 ].

The decision to implement a therapeutic holiday must be informed by the distinct pharmacological properties of BPs and denosumab [ 86 ]. BPs are characterized by their extremely long skeletal retention; they bind avidly to hydroxyapatite and can remain embedded in the bone matrix for months to years [ 120 ]. This prolonged biological presence means that even after therapy is discontinued, the drug continues to exert its antiresorptive effects locally [ 11 ]. Consequently, the biological impact of a short-term drug holiday on the healing of an established MRONJ lesion is likely limited. While some position papers suggest a modest benefit, the prevailing view, grounded in pharmacokinetics, is that discontinuation offers a marginal, if any, immediate advantage for healing [ 7 ]. Nonetheless, a short-term perioperative discontinuation as suggested in Italian guidelines [ 98 ], may be considered a pragmatic strategy to limit the accumulation of additional drug at a surgical site during the critical healing phase, even if this approach is not supported by robust evidence.

Unlike BPs, denosumab does not bind to bone, and its potent antiresorptive effect is fully reversible, dissipating within approximately 6 months of the last injection [ 120 ]. While this reversibility theoretically creates an opportunity for a drug holiday to facilitate jaw healing, it is inextricably linked to a risk of rebound fractures [ 119 ]. Cessation of denosumab leads to a rapid surge in bone turnover that overshoots baseline levels, resulting in accelerated bone loss and a high-risk of multiple, spontaneous fractures [ 119 ].

Recommendations for resumption of therapy

Given the clinical equipoise and the need for practical guidance, the decision to halt or continue therapy must be individualized, weighing the severity and symptoms of the MRONJ lesion against the patient’s systemic risk for fractures or SREs.

A foundational principle is the establishment of a minimum post-operative healing period. Following surgical intervention for MRONJ, the committees recommend to delay the resumption of any antiresorptive therapy for a minimum of 6 to 8 weeks. This period allows for initial soft tissue epithelialization and maturation, providing a window for healing without the inhibitory effects of the medication [ 9 ].

For high-risk patients with oncologic disease receiving high-dose therapy or osteoporosis patients with a very high imminent fracture risk, antiresorptive therapy should be resumed promptly after the initial 6- to 8-week healing period is complete and stable soft tissue coverage is confirmed. The primary goal is to minimize the duration of systemic skeletal vulnerability [ 158 ]. For osteoporosis patients with a lower fracture risk, a more extended therapeutic holiday, potentially until the MRONJ lesion has demonstrated complete clinical and radiographic resolution, may be considered [ 120 ].

For patients on denosumab, a highly specific guideline is necessary to mitigate the risk of rebound phenomena. Any planned delay in the next scheduled dose to facilitate MRONJ treatment should not exceed 3 months from the originally scheduled date. This corresponds to a maximum interval of 9 months from the last injection ( Table 4 ) [ 118 ].

Risk factors for recurrence

Despite successful initial treatment, MRONJ has a significant rate of recurrence. The most significant predictors of recurrence are associated with the intensity of the antiresorptive therapy and the patient’s underlying disease state. The cumulative dose and duration of antiresorptive therapy are strongly correlated with recurrence risk. For potent agents like zoledronate, continuous use for over 18 months has been identified as a significant risk factor. Perhaps the most critical and modifiable factor is the early resumption of antiresorptive therapy after the initial MRONJ lesion has been treated. A 13-year cohort study from Hong Kong provides a compelling illustration: the only two cases of recurrence occurred in patients who resumed potent antiresorptive therapy within months of treatment [ 159 ]. This suggests that an aggressive resumption of therapy can directly trigger a recurrence.

The clinical presentation of the initial MRONJ episode is also predictive. Patients who present with an advanced stage of disease (stage 2 or 3) are at a higher risk of recurrence compared to those with stage 1 lesions. Furthermore, lesions located in the maxilla have been consistently associated with a greater likelihood of recurrence. Finally, the underlying diagnosis remains a powerful determinant; patients receiving high-dose IV therapy for metastatic bone disease have a significantly higher recurrence risk than osteoporosis patients on low-dose regimens. This is likely a reflection of the synergistic effect of higher drug potency, longer duration, and the frequent use of concomitant corticosteroids or chemotherapy in the oncology setting.

While pharmacological factors create systemic susceptibility, the primary local driver of recurrence is the incomplete surgical resection of necrotic bone during the initial treatment. This observation suggests that many instances of ‘recurrence’ are not truly new disease events but rather the clinical manifestation of a persistent, inadequately treated primary lesion. The boundary between necrotic, non-remodeling bone and healthy, viable bone is often difficult to discern with the naked eye, leading to the unintentional retention of microscopic foci of compromised bone. These residual areas can act as a nidus for subsequent infection and breakdown, leading to clinical recurrence months or years later. To help address this surgical challenge, emerging technologies such as biofluorescence-guided systems are being investigated as intraoperative adjuncts to aid in the differentiation of viable bone from necrotic margins.

This concept is supported by multiple lines of evidence. Studies have shown significantly higher recurrence rates in patients with post-operative radiographic evidence of residual osteolysis or irregular periosteal reactions [ 1 ]. Furthermore, patients who undergo a conservative debridement or marginal resection have a recurrence rate that is three to four times higher than those who receive a complete resection with wide, healthy margins [ 1 ]. This reframes the problem of recurrence from being an inherent patient characteristic to being, in large part, a consequence of the initial treatment’s thoroughness. It places immense importance on optimizing the primary surgical intervention.

Strategies for recurrence prevention and management

Preventing MRONJ recurrence requires a multi-pronged, proactive strategy that begins with comprehensive initial treatment and extends to careful, personalized long-term pharmacological management. The most effective way to prevent recurrence is to ensure the complete and definitive resolution of the primary MRONJ episode.

Thorough primary treatment reinforces the recommendation for early and aggressive surgical intervention. The goal should be a complete resection of all non-viable bone with sufficiently wide margins to reach healthy, bleeding bone, thereby removing the nidus for potential recurrence. Evidence consistently shows that this approach yields higher rates of complete mucosal healing and lower recurrence rates compared to more conservative methods.

The implementation of a standardized pre- and post-operative antibiotic protocol has been shown to be an effective adjunctive measure. Studies have reported that the use of perioperative antibiotics can reduce MRONJ recurrence rates from approximately 30%–35% to 18%–20% [ 3 , 160 ]. After an MRONJ episode has been treated, regular oral examinations at 6- to 12-month intervals are crucial for detecting any early signs of recurrence, allowing for prompt intervention.

It is crucial to establish an optimal treatment plan by comprehensively considering the patient’s underlying disease, the specific medication used, and the duration of therapy [ 161 , 162 ]. For instance, this may involve shortening the duration of zoledronate administration or implementing continuous monitoring for high-risk patients [ 163 ].

According to recent reports, switching to teriparatide monotherapy is not a panacea for MRONJ that develops during denosumab treatment [ 164 ]. As recommended in the guidelines for atypical femoral fractures [ 165 ], an alternative strategy such as sequential therapy with teriparatide followed by raloxifene may be considered to minimize recurrence after MRONJ treatment. However, upon discontinuing denosumab and transitioning to teriparatide, different patterns of change in spine and hip bone mineral density (BMD) are observed; therefore, DXA follow-up at 6-month intervals is recommended [ 118 ]. A strategy of switching to alendronate or raloxifene after discontinuing denosumab [ 166 ] contributes to the maintenance of systemic BMD but may offer limited hip protection, warranting caution in high-risk patients.

In the previously report from Hong Kong [ 159 ], seven out of eight patients (87.5%) who underwent sequential therapy transitioning from teriparatide to raloxifene (for 18 to 24 months) after an MRONJ episode showed stabilization or improvement in BMD, with no reported recurrences. Conversely, two patients who immediately resumed treatment with an antiresorptive agent of the same class following MRONJ treatment both experienced recurrence. Therefore, for patients with a relatively low fracture risk (T-score >–2.5 or fracture risk assessment tool major osteoporotic fracture risk <20%), a short-term drug holiday or low-dose/intermittent therapy should be considered first. For high-risk patients, an approach that manages fracture risk while avoiding excessive re-administration, such as teriparatide-based sequential therapy, may be considered.

CONCLUSIONS

This 2025 Korean Position Statement on MRONJ was developed to provide clear, evidence-based, and clinically practical guidelines for a growing health concern. The committee, representing five key medical and dental societies, has established a consensus that emphasizes a proactive and comprehensive approach. Key recommendations include:

(1) Definition and staging : Adherence to the standard diagnostic criteria, with the crucial addition of allowing diagnosis based on definitive radiographic or clinical findings prior to 8 weeks, and the retention of stage 0 to facilitate early detection.

(2) Prevention : A strong emphasis on pre-treatment dental evaluation and management as the most effective preventive measure.

(3) Prophylactic drug holidays : Provision of specific, drug-class-dependent recommendations for temporary discontinuation of antiresorptives around invasive dental procedures, offering pragmatic guidance where international consensus is lacking (see ‘Risk factors’ in ‘Pathogenesis and Risk Factors’ for details).

(4) Treatment : Early surgical intervention can be recommended as the primary treatment modality for all stages of MRONJ, based on superior long-term resolution rates.

(5) Recurrence : Identification of key risk factors and advocacy for personalized post-treatment management, including advanced sequential therapy strategies for high-risk patients.

Identifying knowledge gaps and proposing a research agenda

Despite significant advances, many questions regarding MRONJ remain unanswered. This committee has identified several key areas that require future research to further refine clinical practice:

• Prospective comparative studies : There is a pressing need for large-scale, prospective cohort studies to directly compare the long-term outcomes (resolution, recurrence, quality of life) of different treatment strategies, including conservative vs. surgical management and the efficacy of various adjunctive therapies.

• Biomarker discovery : Research is needed to identify and validate reliable blood or salivary biomarkers that can accurately predict an individual’s risk of developing MRONJ or experiencing a recurrence. Such markers would enable truly personalized risk stratification and management.

• Long-term impact of drug holidays : The long-term effects of both prophylactic and therapeutic drug holidays on systemic outcomes—namely, fracture risk and cancer progression—are not well understood. Multidisciplinary, long-term follow-up studies are essential to clarify the risk-benefit balance.

• Risk of newer agents : While this paper focuses on BPs and denosumab, the MRONJ risk associated with newer osteoporosis medications, such as romosozumab, needs to be evaluated in large, prospective clinical studies.

• Pharmacogenomics : Investigating the genetic basis of MRONJ susceptibility is a critical frontier. Identifying genetic polymorphisms related to bone metabolism, immunity, or angiogenesis could allow for the screening of high-risk individuals and the development of personalized preventive strategies.

It is the hope of this committee that these guidelines will standardize and improve the care of patients with MRONJ, and that the proposed research agenda will stimulate further investigation to address the remaining uncertainties in this complex field.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the support and encouragement of the following presidents for the MRONJ Position Meeting: Ki-Hyun Baek (Korean Society for Bone and Mineral Research), Boo-Kyu Lee (Korean Association of Oral and Maxillofacial Surgeons), Jung-Keun Lee (Korean Association of Maxillofacial Plastic and Reconstructive Surgeons), Yoon-Sok Chung (Korean Endocrine Society), and Hee-Dong Chae (Korean Society of Osteoporosis).

Society endorsement and editorial coordination: This consensus statement was developed under the auspices of the participating five societies and submitted with a request for coordinated co‑publication. We thank both editorial offices for their cooperation in ensuring accurate and simultaneous dissemination to both medical and surgical communities.

This position statement is jointly endorsed by the Korean Society for Bone and Mineral Research, Korean Association of Oral and Maxillofacial Surgeons, Korean Association of Maxillofacial Plastic and Reconstructive Surgeons, Korean Endocrine Society, and Korean Society of Osteoporosis. By agreement of the Editors‑in‑Chief, this article is being published simultaneously in Endocrinology and Metabolism (EnM) and the Journal of the Korean Association of Oral and Maxillofacial Surgeons (JKAOMS). The two versions are identical except for journal‑specific front matter and copyediting. Either version may be cited; please reference the journal you consult.

Supplementary Material

Supplemental Table S1.

MRONJ Frequency according to Regimen of Antiresorptive Agents in Patients with Osteoporosis a

Supplemental Table S2.

MRONJ Frequency according to Regimen of Antiresorptive Agents in Patients with Bone Metastasis or Multiple Myeloma a

Supplemental Table S3.

MRONJ Frequency according to Regimen of Antiresorptive Agents in Patients with CTIBL a

Supplemental Table S4.

MRONJ Frequency according to Regimen of Antiresorptive Agents in Patients with Nonmalignant Bone Disease a

Supplemental Table S5.

Human Studies of Teriparatide Administration for MRONJ Treatment in the Past 10 Years

SUPPLEMENTAL REFERENCES

REFERENCES

1 Korea Disease Control and Prevention Agency Korea National Health and Nutrition Examination Survey 2022 Cheongju KDCA 2022

2 The Korean Society for Bone and Mineral Research. Osteoporosis and osteoporotic fracture: fact sheet 2023. Seoul: The Korean Society for Bone and Mineral Research; 2023 [cited 2025 Nov 18]. Available from: https://www.ksbmr.org/bbs/index.html?code=fact&category=&gubun=&page=1&number=1543&mode=view&keyfield=&key=

3 Kim JW Kwak MK Han JJ Lee ST Kim HY Kim SH Medication related osteonecrosis of the jaw: 2021 position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons J Bone Metab 2021 28 279 96 34905675 10.11005/jbm.2021.28.4.279 PMC8671025

4 National Health Insurance Service Ilsan Hospital. Analysis of trends and factors of medication-related osteonecrosis of the jaw in osteoporosis patients treated with bisphosphonates or denosumab in dental care (Research Report NHIMC-2022-PR-023) [Internet]. Goyang: National Health Insurance Service Ilsan Hospital; 2023 [cited 2025 Nov 18]. Available from: https://repository.nhimc.or.kr/bitstream/2023.oak/263/2/NHIMC-2022-PR-023.pdf

5 Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws American Association of Oral and Maxillofacial Surgeons American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws J Oral Maxillofac Surg 2007 65 369 76 17307580 10.1016/j.joms.2006.11.003

6 Ruggiero SL Dodson TB Fantasia J Goodday R Aghaloo T Mehrotra B American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw: 2014 update J Oral Maxillofac Surg 2014 72 1938 56 25234529 10.1016/j.joms.2014.04.031

7 Ruggiero SL Dodson TB Aghaloo T Carlson ER Ward BB Kademani D American Association of Oral and Maxillofacial Surgeons’ position paper on medication-related osteonecrosis of the jaws: 2022 update J Oral Maxillofac Surg 2022 80 920 43 35300956 10.1016/j.joms.2022.02.008

8 Kim KM Rhee Y Kwon YD Kwon TG Lee JK Kim DY Medication related osteonecrosis of the jaw: 2015 position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons J Bone Metab 2015 22 151 65 26713306 10.11005/jbm.2015.22.4.151 PMC4691589

9 Yoneda T Hagino H Sugimoto T Ohta H Takahashi S Soen S Antiresorptive agent-related osteonecrosis of the jaw: position paper 2017 of the Japanese Allied Committee on osteonecrosis of the jaw J Bone Miner Metab 2017 35 6 19 28035494 10.1007/s00774-016-0810-7

10 Colella G Campisi G Fusco V American Association of Oral and Maxillofacial Surgeons position paper: bisphosphonate-related osteonecrosis of the jaws: 2009 update: the need to refine the BRONJ definition J Oral Maxillofac Surg 2009 67 2698 9 19925998 10.1016/j.joms.2009.07.097

11 Khan AA Morrison A Hanley DA Felsenberg D McCauley LK O’Ryan F Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus J Bone Miner Res 2015 30 3 23 25414052 10.1002/jbmr.2405

12 Klingelhoffer C Klingelhoffer M Muller S Ettl T Wahlmann U Can dental panoramic radiographic findings serve as indicators for the development of medication-related osteonecrosis of the jaw? Dentomaxillofac Radiol 2016 45 20160065 27213837 10.1259/dmfr.20160065 PMC5084706

13 Arce K Assael LA Weissman JL Markiewicz MR Imaging findings in bisphosphonate-related osteonecrosis of jaws J Oral Maxillofac Surg 2009 67(5 Suppl) 75 84 19371818 10.1016/j.joms.2008.12.002

14 Ko YY Yang WF Leung YY The role of cone beam computed tomography (CBCT) in the diagnosis and clinical management of medication-related osteonecrosis of the jaw (MRONJ) Diagnostics (Basel) 2024 14 1700 39202187 10.3390/diagnostics14161700 PMC11353876

15 Guggenberger R Fischer DR Metzler P Andreisek G Nanz D Jacobsen C Bisphosphonate-induced osteonecrosis of the jaw: comparison of disease extent on contrast-enhanced MR imaging, [18F] fluoride PET/CT, and conebeam CT imaging AJNR Am J Neuroradiol 2013 34 1242 7 23221951 10.3174/ajnr.A3355 PMC7964583

16 Y Ariji E Ariji Role of magnetic resonance imaging in diagnosis of bisphosphonate-related osteonecrosis of the jaw Oral Radiol 2013 29 111 20

17 Dore F Filippi L Biasotto M Chiandussi S Cavalli F Di Lenarda R Bone scintigraphy and SPECT/CT of bisphosphonate-induced osteonecrosis of the jaw J Nucl Med 2009 50 30 5 19091894 10.2967/jnumed.107.048785

18 Ogura I Kobayashi E Nakahara K Igarashi K Haga-Tsujimura M Toshima H Quantitative SPECT/CT imaging for medication-related osteonecrosis of the jaw: a preliminary study using volume-based parameters, comparison with chronic osteomyelitis Ann Nucl Med 2019 33 776 82 31342316 10.1007/s12149-019-01390-5

19 Toshima H Ogura I Assessment of inflammatory jaw pathologies using bone SPECT/CT maximum standardized uptake value Dentomaxillofac Radiol 2020 49 20200043 32491931 10.1259/dmfr.20200043 PMC7719856

20 Park JH Yoon DM Yoon HJ Kim JW Utility of quantitative standardized uptake value from pre-operative bone SPECT/CT for predicting post-surgical MRONJ healing response EJNMMI Res 2025 15 29 40164939 10.1186/s13550-025-01220-y PMC11958904

21 Marx RE Cillo JE Ulloa JJ Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment J Oral Maxillofac Surg 2007 65 2397 410 18022461 10.1016/j.joms.2007.08.003

22 Awad ME Sun C Jernigan J Elsalanty M Serum C-terminal cross-linking telopeptide level as a predictive biomarker of osteonecrosis after dentoalveolar surgery in patients receiving bisphosphonate therapy: systematic review and meta-analysis J Am Dent Assoc 2019 150 664 75.e8 31256803 10.1016/j.adaj.2019.03.006 PMC6839407

23 Traboulsi-Garet B Jorba-Garcia A Camps-Font O Alves FA Figueiredo R Valmaseda-Castellon E Is serum C-terminal telopeptide cross-link of type 1 collagen a reliable parameter for predicting the risk of medication-related osteonecrosis of the jaws?: a systematic review and meta-analysis of diagnostic test accuracy Clin Oral Investig 2022 26 2371 82 10.1007/s00784-022-04383-3 35124731

24 Kim JW Kong KA Kim SJ Choi SK Cha IH Kim MR Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates Bone 2013 57 201 5 23954759 10.1016/j.bone.2013.08.005

25 Park JH Cho S Kim SJ Jeong TD Mun YC Kim JW Serum biomarkers for bisphosphonate-related osteonecrosis of the jaw: a prospective clinical study Osteoporos Int 2022 33 367 77 34471956 10.1007/s00198-021-06137-5

26 Kim JW Cha IH Kim SJ Kim MR Biomarkers for bisphosphonate-related osteonecrosis of the jaw Clin Implant Dent Relat Res 2016 18 281 91 25726720 10.1111/cid.12297

27 Lorenzo-Pouso AI Perez-Sayans M Gonzalez-Palanca S Chamorro-Petronacci C Bagan J Garcia-Garcia A Biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw: a systematic review Med Oral Patol Oral Cir Bucal 2019 24 e26 36 30595601 10.4317/medoral.22763 PMC6344011

28 Ruggiero S Gralow J Marx RE Hoff AO Schubert MM Huryn JM Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer J Oncol Pract 2006 2 7 14 20871729 10.1200/jop.2006.2.1.7 PMC2794643

29 Kawahara M Kuroshima S Sawase T Clinical considerations for medication-related osteonecrosis of the jaw: a comprehensive literature review Int J Implant Dent 2021 7 47 33987769 10.1186/s40729-021-00323-0 PMC8119587

30 Gaeta-Araujo H Vanderhaeghen O Vasconcelos KF Coucke W Coropciuc R Politis C Osteomyelitis, osteoradionecrosis, or medication-related osteonecrosis of the jaws?: can CBCT enhance radiographic diagnosis? Oral Dis 2021 27 312 9 32623770 10.1111/odi.13534

31 Patel S Choyee S Uyanne J Nguyen AL Lee P Sedghizadeh PP Non-exposed bisphosphonate-related osteonecrosis of the jaw: a critical assessment of current definition, staging, and treatment guidelines Oral Dis 2012 18 625 32 22420684 10.1111/j.1601-0825.2012.01911.x

32 Schiodt M Otto S Fedele S Bedogni A Nicolatou-Galitis O Guggenberger R Workshop of European task force on medication-related osteonecrosis of the jaw: current challenges Oral Dis 2019 25 1815 21 31325201 10.1111/odi.13160

33 Fedele S Bedogni G Scoletta M Favia G Colella G Agrillo A Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed Br J Oral Maxillofac Surg 2015 53 13 7 25282593 10.1016/j.bjoms.2014.09.001

34 Grbic JT Black DM Lyles KW Reid DM Orwoll E Mc-Clung M The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program J Am Dent Assoc 2010 141 1365 70 21037195 10.14219/jada.archive.2010.0082

35 Tennis P Rothman KJ Bohn RL Tan H Zavras A Laskarides C Incidence of osteonecrosis of the jaw among users of bisphosphonates with selected cancers or osteoporosis Pharmacoepidemiol Drug Saf 2012 21 810 7 22711458 10.1002/pds.3292

36 Lee JK Kim KW Choi JY Moon SY Kim SG Kim CH Bisphosphonates-related osteonecrosis of the jaw in Korea: a preliminary report J Korean Assoc Oral Maxillofac Surg 2013 39 9 13 24471011 10.5125/jkaoms.2013.39.1.9 PMC3858159

37 Kim SH Lee YK Kim TY Ha YC Jang S Kim HY Incidence of and risk for osteonecrosis of the jaw in Korean osteoporosis patients treated with bisphosphonates: a nationwide cohort-study Bone 2021 143 115650 32956854 10.1016/j.bone.2020.115650

38 Park JH Kwoen MJ Lee JR Kim KS Lee HJ Kim JW Gradual, but not sudden, dose-dependent increase of ONJ risk with bisphosphonate exposure: a nationwide cohort study in women with osteoporosis Front Endocrinol (Lausanne) 2021 12 774820 34956086 10.3389/fendo.2021.774820 PMC8695600

39 Kim HY Kim JW Kim SJ Lee SH Lee HS Uncertainty of current algorithm for bisphosphonate-related osteonecrosis of the jaw in population-based studies: a systematic review J Bone Miner Res 2017 32 584 91 27736017 10.1002/jbmr.3017

40 Wang Q Yu Q Zeng P Ai W Efficacy and safety of annual infusion of zoledronic acid and weekly oral alendronate in the treatment of primary osteoporosis: a meta-analysis J Clin Pharmacol 2023 63 455 65 36433675 10.1002/jcph.2181

41 Lo JC O’Ryan FS Gordon NP Yang J Hui RL Martin D Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure J Oral Maxillofac Surg 2010 68 243 53 19772941 10.1016/j.joms.2009.03.050 PMC10159647

42 Grbic JT Landesberg R Lin SQ Mesenbrink P Reid IR Leung PC Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial J Am Dent Assoc 2008 139 32 40 18167382 10.14219/jada.archive.2008.0017

43 Sieber P Lardelli P Kraenzlin CA Kraenzlin ME Meier C Intravenous bisphosphonates for postmenopausal osteoporosis: safety profiles of zoledronic acid and ibandronate in clinical practice Clin Drug Investig 2013 33 117 22 10.1007/s40261-012-0041-1 23184667

44 Clark ASE Glenny AM The issue with incidence: a scoping review of reported medication-related osteonecrosis of the jaws (MRONJ) incidence around the globe BMJ Public Health 2025 3 e002009 40196437 10.1136/bmjph-2024-002009 PMC11973752

45 Bone HG Wagman RB Brandi ML Brown JP Chapurlat R Cummings SR 10 Years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension Lancet Diabetes Endocrinol 2017 5 513 23 28546097 10.1016/S2213-8587(17)30138-9

46 Liu FC Luk KC Chen YC Risk comparison of osteonecrosis of the jaw in osteoporotic patients treated with bisphosphonates vs. denosumab: a multi-institutional retrospective cohort study in Taiwan Osteoporos Int 2023 34 1729 37 37326685 10.1007/s00198-023-06818-3 PMC10511380

47 Everts-Graber J Lehmann D Burkard JP Schaller B Gahl B Hauselmann H Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis J Bone Miner Res 2022 37 340 8 34787342 10.1002/jbmr.4472

48 Watts NB Grbic JT Binkley N Papapoulos S Butler PW Yin X Invasive oral procedures and events in postmenopausal women with osteoporosis treated with denosumab for up to 10 years J Clin Endocrinol Metab 2019 104 2443 52 30759221 10.1210/jc.2018-01965

49 Williams DW Lee C Kim T Yagita H Wu H Park S Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jawlike lesions by bisphosphonate and anti-receptor activator of NF-κB ligand antibody in mice Am J Pathol 2014 184 3084 93 25173134 10.1016/j.ajpath.2014.07.010 PMC4215026

50 Szaraz D Perina V Treglerova J Machacek C Zendulka O Borilova Linhartova P Case report: single low-dose of denosumab as a trigger of MRONJ development in a patient with osteoporosis after bisphosphonate therapy Front Oral Health 2024 5 1473049 39697786 10.3389/froh.2024.1473049 PMC11652535

51 Lee K Kim K Kim JY Kim JW Kang YH Kim YH Mechanisms underlying medication-related osteonecrosis of the jaw Oral Dis 2025 31 1073 83 39552606 10.1111/odi.15198 PMC12022389

52 Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S Romosozumab treatment in postmenopausal women with osteoporosis N Engl J Med 2016 375 1532 43 27641143 10.1056/NEJMoa1607948

53 Cosman F Crittenden DB Ferrari S Lewiecki EM Jaller-Raad J Zerbini C Romosozumab FRAME study: a post hoc analysis of the role of regional background fracture risk on nonvertebral fracture outcome J Bone Miner Res 2018 33 1407 16 29750828 10.1002/jbmr.3439

54 Peng J Wang H Liu Z Xu ZL Wang MX Chen QM Real-world study of antiresorptive-related osteonecrosis of jaw based on the US food and drug administration adverse event reporting system database Front Pharmacol 2022 13 1017391 36339548 10.3389/fphar.2022.1017391 PMC9627332

55 Bindakhil M Shanti RM Mupparapu M Raloxifene-induced osteonecrosis of the jaw (MRONJ) with no exposure to bisphosphonates: clinical and radiographic findings Quintessence Int 2021 52 258 63 33491398 10.3290/j.qi.b912675

56 Ko SY Hwang TY Baek K Park C Incidence and severity of medication-related osteonecrosis of the jaw in patients with osteoporosis using data from a Korean nationwide sample cohort in 2002 to 2019: a retrospective study J Yeungnam Med Sci 2024 41 39 44 38173345 10.12701/jyms.2023.01116 PMC10834263

57 Coleman R Woodward E Brown J Cameron D Bell R Dodwell D Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer Breast Cancer Res Treat 2011 127 429 38 21394500 10.1007/s10549-011-1429-y

58 Coleman R Cameron D Dodwell D Bell R Wilson C Rathbone E Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial Lancet Oncol 2014 15 997 1006 25035292 10.1016/S1470-2045(14)70302-X

59 Hoff AO Toth BB Altundag K Johnson MM Warneke CL Hu M Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates J Bone Miner Res 2008 23 826 36 18558816 10.1359/JBMR.080205 PMC2677083

60 Raje N Terpos E Willenbacher W Shimizu K Garcia-Sanz R Durie B Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study Lancet Oncol 2018 19 370 81 29429912 10.1016/S1470-2045(18)30072-X

61 Himelstein AL Foster JC Khatcheressian JL Roberts JD Seisler DK Novotny PJ Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: a randomized clinical trial JAMA 2017 317 48 58 28030702 10.1001/jama.2016.19425 PMC5321662

62 Barrett-Lee P Casbard A Abraham J Hood K Coleman R Simmonds P Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial Lancet Oncol 2014 15 114 22 24332514 10.1016/S1470-2045(13)70539-4

63 Querrer R Ferrare N Melo N Stefani CM Dos Reis PED Mesquita CRM Differences between bisphosphonate-related and denosumab-related osteonecrosis of the jaws: a systematic review Support Care Cancer 2021 29 2811 20 33140246 10.1007/s00520-020-05855-6

64 Christodoulou C Pervena A Klouvas G Galani E Falagas ME Tsakalos G Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone Oncology 2009 76 209 11 19212145 10.1159/000201931

65 Ng TL Tu MM Ibrahim MF Basulaiman B McGee SF Srikanthan A Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review Support Care Cancer 2021 29 925 43 32535678 10.1007/s00520-020-05556-0

66 Amigues C Fresse A Roux CH Gauthier S Vieillard MH Drici MD Zoledronate and osteonecrosis of the jaw in osteoporosis: incidence and risk factors: analysis of the French Pharmacovigilance Database Joint Bone Spine 2023 90 105599 37271278 10.1016/j.jbspin.2023.105599

67 Hata H Imamachi K Ueda M Matsuzaka M Hiraga H Osanai T Prognosis by cancer type and incidence of zoledronic acid-related osteonecrosis of the jaw: a single-center retrospective study Support Care Cancer 2022 30 4505 14 35113225 10.1007/s00520-022-06839-4

68 Henry D Vadhan-Raj S Hirsh V von Moos R Hungria V Costa L Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors Support Care Cancer 2014 22 679 87 24162260 10.1007/s00520-013-2022-1

69 Moon C Kim H Park JH Park W Kim HJ Jung YS High-dose denosumab (Xgeva®) associated Medication-Related Osteonecrosis of the Jaws (MRONJ): incidence and clinical characteristics in a retrospective analysis of 1278 patients Support Care Cancer 2024 32 774 39499349 10.1007/s00520-024-08974-6

70 Ikesue H Mouri M Tomita H Hirabatake M Ikemura M Muroi N Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases Support Care Cancer 2021 29 4763 72 33527228 10.1007/s00520-021-06018-x PMC8236436

71 Ikesue H Doi K Morimoto M Hirabatake M Muroi N Yamamoto S Risk evaluation of denosumab and zoledronic acid for medication-related osteonecrosis of the jaw in patients with bone metastases: a propensity score-matched analysis Support Care Cancer 2022 30 2341 8 34738163 10.1007/s00520-021-06634-7 PMC8794983

72 Loyson T Van Cann T Schoffski P Clement PM Bechter O Spriet I Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab Acta Clin Belg 2018 73 100 9 28693379 10.1080/17843286.2017.1348001

73 Srivastava A Nogueras Gonzalez GM Geng Y Won AM Cabanillas ME Naing A Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis Support Care Cancer 2021 29 2305 17 33190182 10.1007/s00520-020-05882-3 PMC12010772

74 Mauri D Valachis A Polyzos IP Polyzos NP Kamposioras K Pesce LL Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis Breast Cancer Res Treat 2009 116 433 9 19521766 10.1007/s10549-009-0432-z

75 Valachis A Polyzos NP Coleman RE Gnant M Eidtmann H Brufsky AM Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis Oncologist 2013 18 353 61 23404816 10.1634/theoncologist.2012-0261 PMC3639520

76 Rathbone EJ Brown JE Marshall HC Collinson M Liversedge V Murden GA Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04) J Clin Oncol 2013 31 2685 91 23796998 10.1200/JCO.2012.46.4792

77 Vliek SB Noordhoek I Meershoek-Klein Kranenbarg E van Rossum AGJ Dezentje VO Jager A Daily oral ibandronate with adjuvant endocrine therapy in postmenopausal women with estrogen receptor-positive breast cancer (BOOG 2006-04): randomized phase III team-IIB trial J Clin Oncol 2022 40 2934 45 35442755 10.1200/JCO.21.00311

78 Palmerini E Chawla NS Ferrari S Sudan M Picci P Marchesi E Denosumab in advanced/unresectable giantcell tumour of bone (GCTB): for how long? Eur J Cancer 2017 76 118 24 28324746 10.1016/j.ejca.2017.01.028

79 Raimondi A Simeone N Guzzo M Maniezzo M Collini P Morosi C Rechallenge of denosumab in jaw osteonecrosis of patients with unresectable giant cell tumour of bone: a case series analysis and literature review ESMO Open 2020 5 e000663 32661185 10.1136/esmoopen-2019-000663 PMC7359187

80 Rutkowski P Gaston L Borkowska A Stacchiotti S Gelderblom H Baldi GG Denosumab treatment of inoperable or locally advanced giant cell tumor of bone: multicenter analysis outside clinical trial Eur J Surg Oncol 2018 44 1384 90 29650420 10.1016/j.ejso.2018.03.020

81 Jiang CY Zhao L Schuetze SM Chugh R Giant cell tumor of bone: effect of longer dosing intervals of denosumab on tumor control and bone-related complications Oncologist 2022 27 595 9 35589095 10.1093/oncolo/oyac066 PMC9256029

82 Duarte NT Rech BO Martins IG Franco JB Ortega KL Can children be affected by bisphosphonate-related osteonecrosis of the jaw?: a systematic review Int J Oral Maxillofac Surg 2020 49 183 91 31447218 10.1016/j.ijom.2019.08.004

83 Hennedige AA Jayasinghe J Khajeh J Macfarlane TV Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta J Oral Maxillofac Res 2013 4 e1 10.5037/jomr.2013.4401 PMC3904727 24478911

84 Constantino CS Krzak JJ Fial AV Kruger KM Rammer JR Radmanovic K Effect of bisphosphonates on function and mobility among children with osteogenesis imperfecta: a systematic review JBMR Plus 2019 3 e10216 31687649 10.1002/jbm4.10216 PMC6820458

85 Ahdi HS Wichelmann TA Pandravada S Ehrenpreis ED Medication-induced osteonecrosis of the jaw: a review of cases from the Food and Drug Administration Adverse Event Reporting System (FAERS) BMC Pharmacol Toxicol 2023 24 15 36879299 10.1186/s40360-023-00657-y PMC9987072

86 Baron R Ferrari S Russell RG Denosumab and bisphosphonates: different mechanisms of action and effects Bone 2011 48 677 92 21145999 10.1016/j.bone.2010.11.020

87 Kim JW Landayan ME Lee JY Tatad JC Kim SJ Kim MR Role of microcracks in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw Clin Oral Investig 2016 20 2251 8 10.1007/s00784-016-1718-2 26795624

88 He L Sun X Liu Z Qiu Y Niu Y Pathogenesis and multi-disciplinary management of medication-related osteonecrosis of the jaw Int J Oral Sci 2020 12 30 33087699 10.1038/s41368-020-00093-2 PMC7578793

89 Ristow O Gerngross C Schwaiger M Hohlweg-Majert B Kehl V Jansen H Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg 2014 72 903 10 24485975 10.1016/j.joms.2013.11.005

90 Landesberg R Woo V Cremers S Cozin M Marolt D Vunjak-Novakovic G Potential pathophysiological mechanisms in osteonecrosis of the jaw Ann N Y Acad Sci 2011 1218 62 79 21291478 10.1111/j.1749-6632.2010.05835.x PMC4477826

91 Kim JW Yee J Oh SH Kim SH Kim SJ Chung JE Machine learning approaches for predicting bisphosphonate-related osteonecrosis in women with osteoporosis using VEGFA gene polymorphisms J Pers Med 2021 11 541 34200782 10.3390/jpm11060541 PMC8230421

92 Choi SY Kim JW Oh SH Cheon S Yee J Kim SJ Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information Front Med (Lausanne) 2023 10 1140620 37415765 10.3389/fmed.2023.1140620 PMC10321771

93 Gaudin E Seidel L Bacevic M Rompen E Lambert F Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis J Clin Periodontol 2015 42 922 32 26362756 10.1111/jcpe.12455

94 Soutome S Otsuru M Hayashida S Murata M Yanamoto S Sawada S Relationship between tooth extraction and development of medication-related osteonecrosis of the jaw in cancer patients Sci Rep 2021 11 17226 34446755 10.1038/s41598-021-96480-8 PMC8390686

95 Saad F Brown JE Van Poznak C Ibrahim T Stemmer SM Stopeck AT Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases Ann Oncol 2012 23 1341 7 21986094 10.1093/annonc/mdr435

96 Aljohani S Gaudin R Weiser J Troltzsch M Ehrenfeld M Kaeppler G Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series J Craniomaxillofac Surg 2018 46 1515 25 29983309 10.1016/j.jcms.2018.05.046

97 Yarom N Shapiro CL Peterson DE Van Poznak CH Bohlke K Ruggiero SL Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO clinical practice guideline J Clin Oncol 2019 37 2270 90 31329513 10.1200/JCO.19.01186

98 Bedogni A Mauceri R Fusco V Bertoldo F Bettini G Di Fede O Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ) Oral Dis 2024 30 3679 709 38317291 10.1111/odi.14887

99 Tani M Hatano K Yoshimura A Horibe Y Liu Y Sassi N Cumulative incidence and risk factors for medication-related osteonecrosis of the jaw during long-term prostate cancer management Sci Rep 2024 14 13451 38862617 10.1038/s41598-024-64440-7 PMC11167048

100 Giovannacci I Meleti M Manfredi M Mortellaro C Greco Lucchina A Bonanini M Medication-related osteonecrosis of the jaw around dental implants: implant surgery-triggered or implant presence-triggered osteonecrosis? J Craniofac Surg 2016 27 697 701 27092912 10.1097/SCS.0000000000002564

101 Al-Nawas B Lambert F Andersen SW Bornstein MM Gahlert M Jokstad A Group 3 ITI consensus report: materials and antiresorptive drug-associated outcomes in implant dentistry Clin Oral Implants Res 2023 34 Suppl 26 169 76 37750518 10.1111/clr.14135

102 Jung J Ryu JI Shim GJ Kwon YD Effect of agents affecting bone homeostasis on short- and long-term implant failure Clin Oral Implants Res 2023 34 Suppl 26 143 68 37750523 10.1111/clr.14144

103 Escobedo MF Cobo JL Junquera S Milla J Olay S Junquera LM Medication-related osteonecrosis of the jaw: implant presence-triggered osteonecrosis: case series and literature review J Stomatol Oral Maxillofac Surg 2020 121 40 8 31035023 10.1016/j.jormas.2019.04.012

104 Lazarovici TS Yahalom R Taicher S Schwartz-Arad D Peleg O Yarom N Bisphosphonate-related osteonecrosis of the jaw associated with dental implants J Oral Maxillofac Surg 2010 68 790 6 20307764 10.1016/j.joms.2009.09.017

105 Otto S Aljohani S Fliefel R Ecke S Ristow O Burian E Infection as an important factor in Medication-Related Osteonecrosis of the Jaw (MRONJ) Medicina (Kaunas) 2021 57 463 34065104 10.3390/medicina57050463 PMC8151678

106 Sher J Kirkham-Ali K Luo JD Miller C Sharma D Dental implant placement in patients with a history of medications related to osteonecrosis of the jaws: a systematic review J Oral Implantol 2021 47 249 68 32699903 10.1563/aaid-joi-D-19-00351

107 Campisi G Mauceri R Bertoldo F Bettini G Biasotto M Colella G Medication-related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian consensus update 2020 Int J Environ Res Public Health 2020 17 5998 32824826 10.3390/ijerph17165998 PMC7460511

108 Dimopoulos MA Kastritis E Bamia C Melakopoulos I Gika D Roussou M Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid Ann Oncol 2009 20 117 20 18689864 10.1093/annonc/mdn554

109 Bonacina R Mariani U Villa F Villa A Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients J Can Dent Assoc 2011 77 b147 22129778

110 Karna H Gonzalez J Radia HS Sedghizadeh PP Enciso R Risk-reductive dental strategies for medication related osteonecrosis of the jaw among cancer patients: a systematic review with meta-analyses Oral Oncol 2018 85 15 23 30220314 10.1016/j.oraloncology.2018.08.003

111 Aboalela AA Farook FF Alqahtani AS Almousa MA Alanazi RT Almohammadi DS The effect of antiresorptive drug holidays on medication-related osteonecrosis of the jaw: a systematic review and meta-analysis Cureus 2022 14 e30485 36415385 10.7759/cureus.30485 PMC9674041

112 Takeda D Kurita H Kashima Y Hasegawa T Miyakoshi M Yamada SI Is withdrawal of antiresorptive agents necessary before and after tooth extraction?: a systematic review Clin Oral Investig 2023 28 38 10.1007/s00784-023-05462-9 38150155

113 Wei LY Cheng YW Chiu WY Kok SH Chang HH Cheng SJ Risk factors influencing medication-related osteonecrosis of the jaws (MRONJ) following dental extraction among osteoporotic patients in Taiwan Head Neck 2025 47 1151 61 39611589 10.1002/hed.28011

114 Kim HY Review and update of the risk factors and prevention of antiresorptive-related osteonecrosis of the jaw Endocrinol Metab (Seoul) 2021 36 917 27 34674506 10.3803/EnM.2021.1170 PMC8566140

115 Reid IR Zoledronate: efficacy and safety J Bone Miner Res 2006 21 Suppl 2 P83 7 17229014 10.1359/jbmr.06s215

116 Park JH Kong SH Lee J Oh J Lee JR Lee HJ Time since last intravenous bisphosphonate and risk of osteonecrosis of the jaw in osteoporotic patients Nat Commun 2025 16 4367 40350503 10.1038/s41467-025-59718-x PMC12066712

117 Watts NB Diab DL Long-term use of bisphosphonates in osteoporosis J Clin Endocrinol Metab 2010 95 1555 65 20173017 10.1210/jc.2009-1947

118 Leder BZ Tsai JN Uihlein AV Wallace PM Lee H Neer RM Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial Lancet 2015 386 1147 55 26144908 10.1016/S0140-6736(15)61120-5 PMC4620731

119 Cummings SR Ferrari S Eastell R Gilchrist N Jensen JB McClung M Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension J Bone Miner Res 2018 33 190 8 29105841 10.1002/jbmr.3337

120 Tsourdi E Langdahl B Cohen-Solal M Aubry-Rozier B Eriksen EF Guanabens N Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS Bone 2017 105 11 7 28789921 10.1016/j.bone.2017.08.003

121 Srivastava A Nogueras Gonzalez GM Geng Y Won AM Myers J Li Y Medication-related osteonecrosis of the jaw in patients treated concurrently with antiresorptive and antiangiogenic agents: systematic review and meta-analysis J Immunother Precis Oncol 2021 4 196 207 35665023 10.36401/JIPO-21-14 PMC9138478

122 Diana A Carlino F Giunta EF Franzese E Guerrera LP Di Lauro V Cancer treatment-induced bone loss (CTIBL): state of the art and proper management in breast cancer patients on endocrine therapy Curr Treat Options Oncol 2021 22 45 33864145 10.1007/s11864-021-00835-2 PMC8052225

123 Carlson ER Management of antiresorptive osteonecrosis of the jaws with primary surgical resection J Oral Maxillofac Surg 2014 72 655 7 24480762 10.1016/j.joms.2013.12.007

124 Favia G Tempesta A Limongelli L Crincoli V Maiorano E Medication-related osteonecrosis of the jaw: surgical or non-surgical treatment? Oral Dis 2018 24 238 42 29480596 10.1111/odi.12764

125 Hoefert S Yuan A Munz A Grimm M Elayouti A Reinert S Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ) J Craniomaxillofac Surg 2017 45 570 8 28238559 10.1016/j.jcms.2017.01.013

126 Hamid A Thomas S Bell C Gormley M Case series of medication-related osteonecrosis of the jaw (MRONJ) patients prescribed a drug holiday Br J Oral Maxillofac Surg 2023 61 227 32 36935312 10.1016/j.bjoms.2023.02.003

127 Natu M Meuric V Roginski P Gamby R Lejeune S Medication-related osteonecrosis of the jaw: evaluation of a therapeutic strategy in oral surgery J Stomatol Oral Maxillofac Surg 2024 125(12 Suppl 2) 101877 38641175 10.1016/j.jormas.2024.101877

128 Ristow O Ruckschloss T Muller M Berger M Kargus S Pautke C Is the conservative non-surgical management of medication-related osteonecrosis of the jaw an appropriate treatment option for early stages?: a long-term single-center cohort study J Craniomaxillofac Surg 2019 47 491 9 30642734 10.1016/j.jcms.2018.12.014

129 Kim HY Lee SJ Kim SM Myoung H Hwang SJ Choi JY Extensive surgical procedures result in better treatment outcomes for bisphosphonate-related osteonecrosis of the jaw in patients with osteoporosis J Oral Maxillofac Surg 2017 75 1404 13 28039736 10.1016/j.joms.2016.12.014

130 Sim IW Borromeo GL Tsao C Hardiman R Hofman MS Papatziamos Hjelle C Teriparatide promotes bone healing in medication-related osteonecrosis of the jaw: a placebo-controlled, randomized trial J Clin Oncol 2020 38 2971 80 32614699 10.1200/JCO.19.02192

131 Choi SY Yoon D Kim KM Kim SJ Kim HY Kim JW Adjunctive recombinant human parathyroid hormone agents for the treatment of medication-related osteonecrosis of the jaw: a report of three cases J Korean Assoc Oral Maxillofac Surg 2024 50 103 9 38693133 10.5125/jkaoms.2024.50.2.103 PMC11063736

132 Morishita K Yamada SI Kawakita A Hashidume M Tachibana A Takeuchi N Treatment outcomes of adjunctive teriparatide therapy for medication-related osteonecrosis of the jaw (MRONJ): a multicenter retrospective analysis in Japan J Orthop Sci 2020 25 1079 83 32111549 10.1016/j.jos.2020.01.012

133 Kim JY Park JH Jung HD Jung YS Treatment of medication-related osteonecrosis of the jaw around the dental implant with a once-weekly teriparatide: a case report and literature review J Oral Implantol 2019 45 403 7 31429640 10.1563/aaid-joi-D-19-00040

134 Kim KM Park W Oh SY Kim HJ Nam W Lim SK Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw Osteoporos Int 2014 25 1625 32 24554340 10.1007/s00198-014-2622-8

135 Jung J Yoo HY Kim GT Lee JW Lee YA Kim DY Short-term teriparatide and recombinant human bone morphogenetic protein-2 for regenerative approach to medication-related osteonecrosis of the jaw: a preliminary study J Bone Miner Res 2017 32 2445 52 28815779 10.1002/jbmr.3237

136 Ohbayashi Y Iwasaki A Nakai F Mashiba T Miyake M A comparative effectiveness pilot study of teriparatide for medication-related osteonecrosis of the jaw: daily versus weekly administration Osteoporos Int 2020 31 577 85 31768589 10.1007/s00198-019-05199-w

137 Rubin MR Bilezikian JP The anabolic effects of parathyroid hormone therapy Clin Geriatr Med 2003 19 415 32 12916294 10.1016/s0749-0690(02)00074-5

138 Neer RM Arnaud CD Zanchetta JR Prince R Gaich GA Reginster JY Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis N Engl J Med 2001 344 1434 41 11346808 10.1056/NEJM200105103441904

139 Yoshiga D Yoshioka I Habu M Sasaguri M Tominaga K Effective ancillary role and long-term course of daily or weekly teriparatide treatment on refractory medication-related osteonecrosis of the jaw: a clinical case series Br J Oral Maxillofac Surg 2022 60 604 9 34996629 10.1016/j.bjoms.2021.10.004

140 Kim KM Kim S Hwang H Kim HY Kim D Park JH Effects of daily versus weekly teriparatide for medication-related osteonecrosis of the jaw: a case-control study Oral Dis 2024 30 3286 95 37927178 10.1111/odi.14801

141 Park JH Kim JW Kim SJ Does the addition of bone morphogenetic protein 2 to platelet-rich fibrin improve healing after treatment for medication-related osteonecrosis of the jaw? J Oral Maxillofac Surg 2017 75 1176 84 28042979 10.1016/j.joms.2016.12.005

142 Kim JW Kim SJ Kim MR Simultaneous application of bone morphogenetic protein-2 and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of jaw J Oral Implantol 2016 42 205 8 26103458 10.1563/aaid-joi-D-14-00309

143 Moraes-da-Silva AF Maluf G Rubira-Bullen IR Santos PS Bone morphogenetic protein 2 plus leukocyte and platelet-rich fibrin for the treatment of MRONJ J Craniofac Surg 2023 34 e338 41 36217220 10.1097/SCS.0000000000009059

144 Freiberger JJ Padilla-Burgos R McGraw T Suliman HB Kraft KH Stolp BW What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics J Oral Maxillofac Surg 2012 70 1573 83 22698292 10.1016/j.joms.2012.04.001

145 Li FL Wu CB Sun HJ Zhou Q Effectiveness of laser-assisted treatments for medication-related osteonecrosis of the jaw: a systematic review Br J Oral Maxillofac Surg 2020 58 256 67 31926767 10.1016/j.bjoms.2019.12.001

146 Scoletta M Arduino PG Reggio L Dalmasso P Mozzati M Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study Photomed Laser Surg 2010 28 179 84 19795990 10.1089/pho.2009.2501

147 Fortunato L Bennardo F Buffone C Giudice A Is the application of platelet concentrates effective in the prevention and treatment of medication-related osteonecrosis of the jaw?: a systematic review J Craniomaxillofac Surg 2020 48 268 85 32063481 10.1016/j.jcms.2020.01.014

148 Kim JW Kim SJ Kim MR Leucocyte-rich and platelet-rich fibrin for the treatment of bisphosphonate-related osteonecrosis of the jaw: a prospective feasibility study Br J Oral Maxillofac Surg 2014 52 854 9 25138613 10.1016/j.bjoms.2014.07.256

149 Del Fabbro M Gallesio G Mozzati M Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention: a systematic review of the literature Eur J Cancer 2015 51 62 74 25466505 10.1016/j.ejca.2014.10.015

150 Hellstein JW Adler RA Edwards B Jacobsen PL Kalmar JR Koka S Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs J Am Dent Assoc 2011 142 1243 51 22041409 10.14219/jada.archive.2011.0108

151 Hayashida S Yanamoto S Fujita S Hasegawa T Komori T Kojima Y Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw J Bone Miner Metab 2020 38 126 34 31410544 10.1007/s00774-019-01035-7

152 Hinson AM Siegel ER Stack BC Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis J Oral Maxillofac Surg 2015 73 53 62 25511956 10.1016/j.joms.2014.07.012

153 Kim YH Lee HK Song SI Lee JK Drug holiday as a prognostic factor of medication-related osteonecrosis of the jaw J Korean Assoc Oral Maxillofac Surg 2014 40 206 10 25368832 10.5125/jkaoms.2014.40.5.206 PMC4217272

154 Ramaglia L Guida A Iorio-Siciliano V Cuozzo A Blasi A Sculean A Stage-specific therapeutic strategies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol Clin Oral Investig 2018 22 597 615 10.1007/s00784-017-2325-6 29332231

155 Otsuru M Soutome S Omori K Suyama K Morishita K Hayashida S Relationship between drug holidays of antiresorptive agents and surgical outcomes in cancer patients with medication-related osteonecrosis of the jaw Int J Environ Res Public Health 2022 19 4624 35457491 10.3390/ijerph19084624 PMC9027682

156 Hadaya D Soundia A Gkouveris I Bezouglaia O Dry SM Pirih FQ Antiresorptive-type and discontinuation-timing affect ONJ burden J Dent Res 2021 100 746 53 33478337 10.1177/0022034520986804 PMC8221704

157 Malan J Ettinger K Naumann E Beirne OR The relationship of denosumab pharmacology and osteonecrosis of the jaws Oral Surg Oral Med Oral Pathol Oral Radiol 2012 114 671 6 23159111 10.1016/j.oooo.2012.08.439

158 Coleman R Hadji P Body JJ Santini D Chow E Terpos E Bone health in cancer: ESMO clinical practice guidelines Ann Oncol 2020 31 1650 63 32801018 10.1016/j.annonc.2020.07.019

159 Wong CH Tsoi KH Pu JJ Jiang NS Chan SS Loong CH Osteoporosis management after the occurrence of medication-related osteonecrosis of the jaw: a 13-year experience at a tertiary center Endocrinol Metab (Seoul) 2025 40 974 90 40509705 10.3803/EnM.2024.2262 PMC12765866

160 Zirk M Kreppel M Buller J Pristup J Peters F Dreiseidler T The impact of surgical intervention and antibiotics on MRONJ stage II and III: retrospective study J Craniomaxillofac Surg 2017 45 1183 9 28684074 10.1016/j.jcms.2017.05.027

161 Jung S Kim J Park JH Kim KY Kim HJ Park W A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients Sci Rep 2022 12 8641 35606457 10.1038/s41598-022-11615-9 PMC9126865

162 El-Rabbany M Blanas N Sutherland S Lam DK Shah PS Azarpazhooh A Surgical therapy in patients with medication-related osteonecrosis of the jaw is associated with disease resolution and improved quality of life: a prospective cohort study J Oral Maxillofac Surg 2022 80 1084 93 35183496 10.1016/j.joms.2022.01.012

163 Chen S Ren H He Y An J Zhang Y Recurrence-related factors of medication-related osteonecrosis of the jaw: a five-year experience J Oral Maxillofac Surg 2021 79 2472 81 34481810 10.1016/j.joms.2021.07.029

164 Park KS Jung SM Park YJ Kim KJ Denosumab-related osteonecrosis of the jaw may not be a subject of teriparatide treatment J Bone Miner Res 2022 37 2044 5 35751544 10.1002/jbmr.4625

165 van de Laarschot DM McKenna MJ Abrahamsen B Langdahl B Cohen-Solal M Guanabens N Medical management of patients after atypical femur fractures: a systematic review and recommendations from the European Calcified Tissue Society J Clin Endocrinol Metab 2020 105 1682 99 31867670 10.1210/clinem/dgz295 PMC7121199

166 Ramchand SK Tsai JN Lee H Sassana-Khadka G Jordan M Ryan S The comparison of alendronate and raloxifene after denosumab (CARD) study: a comparative efficacy trial Osteoporos Int 2024 35 255 63 37798320 10.1007/s00198-023-06932-2