Asia-Pacific consensus statement on medication-related osteonecrosis of the jaw in patients with osteoporosis.

Introduction

Jawbone necrosis in the oral and maxillofacial regions is primarily attributable to osteomyelitis and radiation-induced osteonecrosis. Osteomyelitis commonly results from odontogenic infections and leads to sequestration of necrotic bone. Radiation-induced osteonecrosis, a well-recognized complication of high-dose radiation therapy for malignant tumors, is characterized by low cellularity, poor vascularity, and hypoxia [ 1 ]. Radiation impairs osteoblast and osteoclast functions, disrupts bone metabolism, and damages endothelial cells, leading to local circulatory disturbances and reduced blood supply. Another form of jawbone necrosis, oral ulceration with bone sequestration, typically presents with bone exposure and sequestrum formation on the posterior lingual side of the mandible, followed by spontaneous healing [ 2 ]. However, the etiology remains unclear.

In 2003, Marx first described avascular osteonecrosis associated with high-dose intravenous bisphosphonate (BP) therapy, which was used to treat hypercalcemia in patients with multiple myeloma and bone metastases from breast cancer [ 3 ]. The following year, Ruggiero et al. reported that low-dose oral BP therapy could induce refractory osteomyelitis [ 4 ]. Their study introduced the term osteonecrosis of the jaw (ONJ), which quickly gained global recognition. Initially, ONJ was believed to result from the long-term accumulation of BP in the bone and its antiangiogenic effects. However, the emergence of ONJ in patients treated with denosumab, an anti-RANKL antibody with a distinct mechanism, has challenged this hypothesis [ 5 ]. More recently, ONJ was reported in patients receiving anti-sclerostin antibodies, which promote bone formation while inhibiting resorption [ 6 ].

Since the publication of the position papers on bisphosphonate-related osteonecrosis of the jaw (BRONJ) by the American Society for Bone and Mineral Research (ASBMR) and the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2007 [ 7 , 8 ], several position and consensus papers on BRONJ and antiresorptive agent-related ONJ (ARONJ) have been published. With the emergence of drugs with mechanisms distinct from those of antiresorptive agents, such as angiogenesis inhibitors and immunosuppressants, position and consensus papers have redefined the condition as a medication-related jaw disease involving various bone-modifying agents and adopted the term medication-related ONJ (MRONJ).

MRONJ is a rare but clinically significant adverse event associated with the treatment of osteoporosis. Position and consensus papers on BRONJ, ARONJ, and MRONJ have been published not only in Western countries but also in various Asian nations. However, a unified consensus among Asian countries and regions remains to be established. This consensus paper was developed to promote standardized recommendations among member countries of the Asian Federation of Osteoporosis Societies (AFOS). In this study, the term “Asia-Pacific” refers specifically to the Asian member countries and regions of AFOS.

Methods

We conducted a structured survey on MRONJ to evaluate the current level of consensus among countries and regions affiliated with AFOS, aiming to summarize regional perspectives and establish standardized expert opinions on MRONJ in patients with osteoporosis across the Asia-Pacific region. The survey consisted of the following nine questions: 1. Which positions or consensus papers on MRONJ are currently used in your country and region? 2. How is MRONJ defined in your country and region? 3. What clinical symptoms, staging systems, imaging modalities, and histopathological characteristics are used to diagnose MRONJ in your country? 4. What are considered the principal risk factors and underlying pathophysiological mechanisms of MRONJ? 5. What is your opinion on the necessity of temporarily discontinuing antiresorptive agents (eg, for 2–3 months) prior to or following oral surgical procedures such as tooth extraction or dental implant placement? 6. What are the reported prevalence and incidence rates of MRONJ in your country? 7. What standard treatment principles and strategies have been adopted for MRONJ management in your country and region? 8. What are your opinions on the clinical effectiveness of discontinuing antiresorptive agents during MRONJ treatment? 9. How is interdisciplinary collaboration among medical, dental, and pharmaceutical professionals organized in your country and region in relation to MRONJ?

The survey participants included experts from the following countries and regions: Thailand, South Korea, Malaysia, Taiwan, the Philippines, Singapore, Japan, Hong Kong, China, and Macau.

Based on a comprehensive analysis of responses from AFOS member countries and regions, a manual literature review conducted by the lead investigator, and a consensus vote, we synthesized the findings to develop a consensus statement on the diagnosis and management of MRONJ in patients with osteoporosis in Asia. This consensus is primarily based on epidemiological and clinical data from Asia. Evidence from other regions, including Europe and North America, was also reviewed and incorporated as supplementary reference material where relevant.

Results

Survey responses were obtained from eight of the 10 AFOS member countries and regions. Five of these countries—Japan, Thailand, South Korea, Hong Kong, and China—have published national or local position statements, guidelines, and consensus papers on MRONJ. English versions are not available for the most recent publications from Japan (2023) [ 9 ] and Thailand (2022) [ 10 ]. The MRONJ clinical practice guidelines (CPG) in Thailand are part of the Thai Osteoporosis Foundation (TOPF) CPG for the diagnosis and management of osteoporosis (2021). Singapore issued national guidelines on the prevention and management of MRONJ in patients with osteoporosis [ 11 ].

Their frameworks are primarily based on internationally recognized positions or consensus papers, including the 2022 AAOMS Position Paper on MRONJ [12] , 2015 International Task Force on Osteonecrosis of the Jaw [13] , 2024 Italian Position Paper [ 14 ], and the 2022 critical review organized by the European Calcified Tissue Society (ECTS) [ 15 ].

Countries or regions without national positions or consensus statements generally refer to international documents. The current AFOS consensus paper specifically focuses on MRONJ in patients receiving low-dose antiresorptive therapy for osteoporosis, excluding those treated with high-dose agents.

Definition and clinical staging

Definition

The basic diagnostic criteria for MRONJ typically include the following: (1) a history of treatment with antiresorptive agents (BPs or denosumab); (2) exposed bone in the maxillofacial region that persists for more than 8 weeks without healing despite appropriate treatment; and (3) no history of radiation therapy to the jaws. The first formal definition was proposed in the 2007 position papers issued by the ASBMR and the AAOMS [ 7 , 8 ]. Recently, immunomodulators and antiangiogenic agents have been added to the list of medications associated with MRONJ. However, monotherapy with these agents has not been definitively shown to cause MRONJ.

According to recent consensus statements and position papers from South Korea, Hong Kong, Thailand, China, and other AFOS-affiliated regions, which adopt the 2022 AAOMS definition, MRONJ is diagnosed based on the following three criteria: 1. Current or previous treatment with antiresorptive therapy alone or in combination with immunomodulators or antiangiogenic medications. 2. Exposed bone, or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region, persisting for more than 8 weeks. 3. No history of radiation therapy or evidence of metastatic disease to the jaws.

The 2023 Japanese Position Paper introduced a clarification to criterion (3), stating, “As a general rule, there is no history of radiation therapy to the jaws, and the lesion is neither a primary cancer nor a metastasis to the jaws” [ 9 ].

In real-world clinical settings, some patients may develop osteoporosis following prior exposure to radiation therapy for cancer [ 16 ]. Metastatic and primary malignancies of the jaws occasionally occur in patients receiving antiresorptive treatment for osteoporosis. A more specific definition of MRONJ may be warranted for this population because patients with osteoporosis are less likely to be treated with immunomodulatory or antiangiogenic agents.

Peng et al. found positive signals for ONJ associated with romosozumab in the FDA Adverse Event Reporting System (FAERS) [ 17 ]. However, this drug exhibited the lowest risk signal among osteoporosis medications with antiresorptive effects. Nevertheless, the onset time of MRONJ induced by romosozumab was shorter than that associated with other osteoporosis treatments. Therefore, in clinical practice, careful attention should be paid to its potential to cause an earlier onset of MRONJ. Key Points & Recommendations ● Both primary and metastatic jaw cancers may occur in patients with osteoporosis receiving antiresorptive therapy. ● Immunomodulatory or antiangiogenic agents are rarely used in osteoporosis patients. ● MRONJ is defined by all of the following: 1. Current or prior antiresorptive therapy 2. Exposed bone (or bone visible through a fistula) in the maxillofacial region for more than 8 weeks 3. No history of jaw radiation and no evidence of jaw malignancy ● MRONJ risk should also be considered with anti-sclerostin antibody.

Clinical staging

The updated 2025 Korean MRONJ Position Paper adopted the following staging system for MRONJ [ 18 ]: At Risk : Patients with no clinical symptoms and no evidence of exposed or necrotic bone, but with a current or previous history of treatment with antiresorptive or antiangiogenic agents. Stage 0: Patients without exposed bone presenting with nonspecific clinical findings such as pain, altered neurosensory function, tooth mobility, or mucosal swelling. Stage 1: Patients with exposed and necrotic bone or a fistula that probes the bone who are asymptomatic and show no clinical signs of infection or inflammation. Stage 2: Patients with exposed and necrotic bone or a fistula that probes the bone, accompanied by signs and symptoms of infection. The affected area may be painful and erythematous and may present with purulent discharge, soft tissue swelling, or cellulitis. Stage 3: Patients with exposed and necrotic bone or a fistula that probes the bone in conjunction with infection and at least one of the following features: necrosis extending beyond the alveolar bone (eg, to the inferior border or ramus of the mandible, maxillary sinus, nasal cavity, or zygomatic bone), pathological fracture, extraoral fistula, oronasal or oroantral communication, or osteolysis extending to the inferior border of the mandible or floor of the maxillary sinus.

The 2021 Chinese expert consensus on MRONJ introduced a novel staging system with corresponding therapeutic strategies, dividing the disease into eight stages: 0, I, IA, IB, II, IIA, IIB, and III [ 19 ]. This new clinical staging system, known as He's classification, was initially proposed by Yue et al., in 2020. The 2023 Japanese Position Paper states that although the non-exposed bone variant (Stage 0) will remain a classification, it will no longer be included in the diagnosis or statistical reporting of MRONJ, as it does not meet the diagnostic criteria of bone exposure and/or fistula formation [ 9 ]. Key Points & Recommendations General Concept . ● MRONJ is often classified into five stages (At Risk, Stage 0–3) based on clinical findings. 2023 Japanese Position Paper . ● Inclusion of “At Risk” and “Stage 0” is controversial: – Do not meet diagnostic criteria (bone exposure/fistula) – May reflect early or progressing cases ● For epidemiological studies: – Report separately – Exclude from core prevalence/incidence unless progression occurs

Diagnosis

X-ray imaging in dental practice

The early identification of imaging features suggestive of MRONJ is essential for both dentists and physicians. As most cases of MRONJ originate from odontogenic infections, the detection and removal of sources such as chronic periodontitis, apical periodontitis, and pericoronitis are critical. These conditions can be evaluated in general dental practice using intraoral radiography, panoramic radiography, or cone-beam computed tomography (CBCT).

Lamina dura thickening, delayed healing of extraction sockets, and marginal osteosclerosis may represent early signs of MRONJ [ 12 ]; however, supporting evidence remains limited. Thickening of the lamina dura is regarded as a pharmacological effect of BPs and is not considered a reliable predictive marker [ 20 , 21 ]. Prolonged socket retention due to impaired bone remodeling may lead to secondary infections and MRONJ. Therefore, even after pretreatment tooth extraction and adequate mucosal healing, careful postoperative monitoring is essential [ 9 ].

Periodontal ligament (PDL) widening is commonly observed in patients with periodontitis. However, sudden localized widening, particularly following the initiation of antiresorptive therapy, may indicate early pathological changes and warrants close monitoring. In our randomized controlled trial comparing teriparatide with alendronate, tooth mobility decreased in the teriparatide group but increased significantly in the alendronate group among patients with periodontitis [ 22 ]. Tooth mobility, accompanied by clinical periodontal symptoms and potentially associated with PDL space widening, may serve as both clinical and radiographic markers of stage 0 MRONJ during antiresorptive treatment.

Ueda et al. reported that extracting teeth with marked periapical sclerotic changes before initiating antiresorptive agents may reduce the risk of MRONJ ( Fig. 1 ) [ 23 ]. In contrast, Kanno et al. observed a higher risk of MRONJ in patients with malignancies when teeth with preexisting osteosclerosis were extracted [ 24 ]. Careful postoperative monitoring is essential in such cases. Although not pathognomonic, findings such as sudden widening of the PDL space, ill-defined periapical radiolucencies, and pronounced osteosclerosis require careful radiographic evaluation [ 25 ]. Key Points & Recommendations ● Use panoramic, intraoral, and CBCT imaging to detect dental infections and early bone changes. ● Carefully assess the following radiographic signs: – Ill-defined periapical radiolucencies – Marked osteosclerosis – Widening of the periodontal ligament (PDL) space Fig. 1 Marked osteosclerosis was observed around the root associated with a periodontal abscess (white arrow). Osteonecrosis of the jaw was noted on the buccal aspect of the corresponding mandibular region. Fig. 1

Advanced imaging modalities

MRI is particularly useful for detecting early marrow changes when osteomyelitis is suspected but is not apparent on X-ray images. T1-weighted images typically show low signal intensities in both osteomyelitis and MRONJ. Inflammatory changes appear as high signal intensities on T2-weighted and STIR images, whereas MRONJ may show heterogeneous signals due to sequestration and sclerosis [ 26 ]. T1-weighted imaging may better delineate the extent of the disease, and MRI is valuable for assessing soft tissue involvement.

Computed tomography (CT) and CBCT can reveal bone resorption, osteosclerosis, and characteristic periosteal reactions. MRONJ may present with lamellar, mass-like, or mixed periosteal patterns, sometimes forming a “bone-within-bone” structure [ 27 ]. A gap between the periosteal reaction and the cortical bone may suggest persistent infection and necessitate surgical removal [ 28 ]. In some cases, periosteal reactions appear without cortical bone changes and require careful interpretation.

Advanced-stage MRONJ may involve sequestration, mandibular canal thickening, maxillary sinusitis, or pathological mandibular fractures [ 27 ]. Severe maxillary cases may even exhibit separation of the zygomatic bone. Bone SPECT/CT or PET/CT may incidentally detect early MRONJ, particularly in patients with cancer. Kitagawa et al. reported that standardized uptake values (SUVs) on PET/CT were higher in MRONJ than in other jaw pathologies [ 29 ].

Accurate imaging is essential for the surgical planning of MRONJ. Stockmann et al. reported that CT significantly correlated with the actual extent of surgery, although it tended to underestimate mesiodistal involvement [ 30 ]. In their study, the MRI findings were inconsistent. Hayashi et al. suggested that defining the SPECT-cold region using bone SPECT-SUV may enable estimation of the resection extent in early-to-intermediate-stage MRONJ [ 31 ]. Similarly, Wei et al. noted that the use of 3D SPECT/CT improved the accuracy of determining the osteotomy range in MRONJ surgeries [ 32 ]. Park et al. concluded that SUVs from bone SPECT/CT may serve as valuable prognostic tools for assessing the severity of MRONJ and predicting surgical outcomes [ 33 ]. Key Points & Recommendations ● MRI is useful for evaluating soft tissues and bone marrow. ● CT and CBCT are effective for assessing bone structures. ● SPECT/CT and PET/CT are valuable for determining the extent of MRONJ. ● Standardized uptake values (SUVs) from SPECT/CT correlate with the progression and prognosis of MRONJ.

Differential diagnosis

Conditions that should be differentiated from MRONJ include alveolar osteitis, sinusitis, gingivitis/periodontitis, periapical lesions, and cemento-osseous dysplasia that mimics bone sequestrum. Other important differential diagnoses include suppurative osteomyelitis of odontogenic origin; diffuse sclerosing osteomyelitis associated with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome [ 34 ]; and radiation-induced osteonecrosis. Metastatic jaw involvement should be excluded in patients with a history of malignancy.

Osteomyelitis and radiation-induced osteonecrosis share several clinical and radiographic features with MRONJ. Although radiation-induced osteonecrosis is typically easier to identify due to a clear history of radiotherapy, distinguishing MRONJ from suppurative osteomyelitis remains challenging. Both conditions involve secondary bacterial infection and bone destruction; however, MRONJ is primarily caused by drug-induced alterations in bone remodeling and angiogenesis rather than infection. Currently, a history of exposure to antiresorptive agents is the most important diagnostic criterion.

Recent studies employing nuclear medicine imaging, CBCT, and combined clinical and panoramic analyses have explored approaches to distinguish suppurative osteomyelitis from MRONJ [ 26 ]. However, most of these studies were limited by small sample sizes and single-center designs, highlighting the need for further multicenter studies. Key points ● Differentiate MRONJ from osteomyelitis, radiation-induced osteonecrosis, malignancies, and fibro-osseous lesions. ● A history of antiresorptive therapy is essential for diagnosis.

Biomarkers

C-terminal telopeptide (CTX), a marker of osteoclastic activity, has been proposed as a biomarker of MRONJ. However, a recent systematic review and meta-analysis concluded that CTX was not suitable for predicting the risk of MRONJ in patients receiving antiresorptive therapy who required oral surgical procedures [ 35 ]. Currently, no biomarker has been established as a reliable tool for clinical decision-making regarding MRONJ. Although local changes in bone metabolism may contribute to disease onset and progression, the clinical utility of systemic bone turnover markers remains unclear. Future studies should focus not on validating these markers but on identifying novel and effective predictors of MRONJ risk. Key Points ● No reliable biomarkers exist; future studies should explore novel and effective markers.

Pathogenesis and risk factors

Pathogenesis

The pathogenesis of MRONJ, as described in the updated 2025 Korean Position Paper, is summarized in Table 1 [ 18 ]. The 2023 position paper by the Japanese Committee on MRONJ [ 9 ], the 2024 OSHK guidelines for the clinical management of postmenopausal osteoporosis in Hong Kong [ 36 ], a Thai review article on dental management in patients at risk of MRONJ [ 10 ], and the Chinese expert consensus on the diagnosis and clinical management of MRONJ [ 19 ] all present a similar multifactorial pathogenesis of the condition. Key Points ● Pathogenesis is multifactorial and involves suppressed bone remodeling, impaired angiogenesis, soft tissue toxicity, immune dysfunction, bacterial colonization, mechanical trauma (eg, from dentures), and systemic conditions (eg, diabetes, malnutrition, steroid use). Table 1 Proposed pathogenesis of MRONJ according to the updated 2025 Korean position papers. Table 1 Pathogenic Factor Description Bone Remodeling Suppression Antiresorptive agents inhibit osteoclast activity, leading to accumulation of microdamaged bone. Angiogenesis Inhibition VEGF inhibitors and bisphosphonates reduce local blood supply, impairing bone healing. Immune & Soft Tissue Effects BPs/denosumab impair mucosal immunity via immune cell imbalance. Bacterial Invasion Oral bacteria invade exposed bone, sustaining chronic inflammation. Mechanical Stress Occlusal forces, ill-fitting dentures, or bony tori cause repeated microtrauma. Systemic Factors Conditions such as diabetes, corticosteroid use, and malnutrition delay healing and promote hypoxia. MRONJ, medication-related osteonecrosis of the jaw; BPs, bisphosphonates.

Risk factors

There are diverse perspectives on the risk factors for MRONJ among the member countries and regions of AFOS. Generally, these risk factors can be categorized into five groups: drug-related, local, systemic, lifestyle, and genetic. A summary of major national reports from Japan, South Korea, Hong Kong, Thailand, and China identifying the risk factors for MRONJ in patients with osteoporosis without malignancy is shown in Table 2 . Table 2 Common risk factors for MRONJ: a condensed summary of five key areas (Japan, South Korea, Hong Kong, Thailand, and China). Table 2 Category Key Risk Factors Drug-Related Long-term use of BPs or denosumab High BP potency (eg, zoledronate > risedronate/ibandronate > alendronate) Romosozumab (anti-sclerostin antibody) Glucocorticoids, immunosuppressants (eg, methotrexate) Local Jaw infections (eg, periodontitis, peri-implantitis) Invasive dental procedures (eg, extractions, implants) Poor oral hygiene, ill-fitting dentures, occlusal stress Bony prominences (eg, tori, exostoses) Systemic Age ≥ 65 years, diabetes, autoimmune diseases Renal dialysis, vitamin D deficiency, anemia Bone diseases (eg, Paget's disease, osteomalacia) Lifestyle Smoking, alcohol use Low/high BMI Poor nutrition or socioeconomic status Genetic SNPs in VEGF, RBMS3, SIRT1 , etc. MRONJ, medication-related osteonecrosis of the jaw; BPs, bisphosphonates; BMI, body mass index.

Epidemiology

Estimates of MRONJ incidence vary widely across studies. In particular, data regarding low-dose administration in patients with osteoporosis are limited. According to the International Task Force on ONJ [ 13 ], the incidence of BRONJ in osteoporosis patients is estimated to range from 0.001% to 0.01%, which is only slightly higher than the incidence of ONJ observed in the general population (less than 0.001%). The AAOMS 2022 position paper reported that the risk of BRONJ in patients with osteoporosis is estimated to be between 0.02% and 0.05%, which is comparable to the ONJ risk observed in placebo groups (0–0.02%) [ 12 ].

However, the International Task Force on ONJ has highlighted the difficulty of accurately estimating the incidence of MRONJ [ 13 ]. Clinical trials typically report lower incidence rates than those observed in real-world settings because participants often receive regular dental care and oral hygiene supervision, and MRONJ is diagnosed according to strict criteria.

Current data on MRONJ related to osteoporosis in AFOS countries and regions are summarized in Table 3 and Fig. 2 . Incidence data have been reported from six AFOS member countries and regions, namely Japan, Thailand, Malaysia, South Korea, Hong Kong, and Taiwan [ [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] ]. Among studies that included patients with both cancer and osteoporosis, only those with osteoporosis were included in our analysis. Studies with small sample sizes (eg, fewer than 1000 participants) were cited for reference purposes but were excluded from the main analysis. For studies that did not report data based on the person-years method and for which the point and period prevalence could not be determined, the annual incidence was calculated. Key Points & Recommendations ● MRONJ incidence varies; interpret data cautiously. ● Low-dose therapy for osteoporosis:0.025–0.136% annual incidence (cumulative) or 21–283 cases per 100,000 person-years (incidence rate). ● Analyze BPs and denosumab separately. ● Higher rates in Asians: evidence remains inconclusive. ● More data from AFOS countries are needed. Table 3 Incidence rate or annual incidence of MRONJ in patients with osteoporosis in AFOS member countries and regions. Table 3 Country or region Drug Type Population No. of Events Incidence Rate (per 100,000 py) or Annual Incidence (%) Reference Japan BPs 11,838 38 0.104% [ 37 ] Japan Denosumab 3756 5 0.133% [ 37 ] Japan BPs 1406 5 0.120% [ 38 ] Japan Mixed 2,664,104 1603 22.9/100,000 py [ 39 ] Japan Denosumab 321,940 311 39.2/100,000 py [ 39 ] Japan BPs 77,752–80,947 45 0.136% [ 40 ] Japan Denosumab 77,752–80,947 16 0.125% [ 40 ] Thailand Mixed 5305 58 0.109% [ 41 ] Thailand BPs 1188 2 0.028% [ 42 ] Malaysia BPs 75 5 1.67% [ 43 ] Korea BPs 164,926 35 21/100,000 py [ 44 ] Korea BPs 74,491 190 45.1/100,000 py [ 45 ] Korea BPs 58,082 145 0.025% [ 46 ] Hong Kong BPs 1284 103 73.5/100,000 py [ 47 ] Taiwan Alendronate 7332 39 283/100,000 py [ 48 ] Taiwan Alendronate 7625 26 262/100,000 py [ 49 ] Taiwan Denosumab 8962 18 147/100,000 py [ 50 ] Taiwan BPs 8962 33 249/100,000 py [ 50 ] AFOS, Asian Federation of Osteoporosis Societies; MRONJ, medication-related osteonecrosis of the jaw; BPs, bisphosphonates; py, person-years. Fig. 2 Annual incidence of medication-related osteonecrosis of the jaw (MRONJ) per 100,000 persons or person-years in patients with osteoporosis across AFOS countries and regions, stratified by medication and reference number. Fig. 2

Management and prevention of MRONJ

Management of MRONJ

While clinical practices may vary depending on individual clinicians’ expertise, experience, and preferences rather than on national consensus in some AFOS countries and regions, the fundamental approach to MRONJ management in osteoporotic patients appears broadly consistent across the region.

The primary goals of MRONJ treatment are to promote soft tissue and bone healing, alleviate pain and other local symptoms, control infection, prevent disease progression or recurrence, and resume antiresorptive therapy for osteoporosis as early as possible, particularly when treatment is interrupted because of advanced MRONJ. These efforts ultimately aim to improve patients’ quality of life. Effective management requires multidisciplinary collaboration between physicians and dentists. Patients should be thoroughly informed about their condition, treatment options, expected duration, potential outcomes, and likelihood of success.

When MRONJ is suspected, a timely referral to a dental specialist is essential for evaluation and treatment planning. Clinical and radiographic assessments should be performed to determine the extent of the lesion and to identify areas requiring intervention. Early treatment is crucial because MRONJ may progress even in the absence of symptoms. Conservative management may be sufficient for small lesions without additional risk factors. Surgical treatment is recommended in cases involving extensive lesions [ 9 , 10 , 18 , 19 , 36 ]. Primary wound closure is recommended, and the excised tissue and bone should be sent for histopathological analysis to confirm the diagnosis and exclude malignancy.

For patients with MRONJ, the recent Asia-Pacific consensus recommends teriparatide, alternatively romosozumab, or selective estrogen receptor modulators (SERMs), to reduce fragility fracture risk [ 57 ]. Dentists should consult physicians regarding osteoporosis management after the onset of MRONJ. Key Points & Recommendations ● Goals: Promote healing, control pain/infection, restart osteoporosis treatment early. ● Educate: Ensure patient understanding and active involvement. ● Refer: Early referral to dental specialists improves outcomes. ● Treat: Use conservative care for early stage; surgery for advanced. ● Consult: Discuss osteoporosis treatment adjustments with the physician following MRONJ onset. ● Collaborate: Multidisciplinary care is essential.

Prevention strategy

To reduce the risk of MRONJ, patients should be informed about its potential occurrence during anti-resorptive therapy and advised to maintain good oral hygiene to prevent infections or inflammation that may necessitate tooth extraction or other jaw surgeries associated with the onset of MRONJ.

Ideally, patients should complete all necessary dental treatments before initiating osteoporosis therapy. Fig. 3 illustrates a flowchart outlining a preventive strategy for patients at high risk of fracture (eg, those with a T-score below −2.5 but no history of fracture) who are about to start antiresorptive therapy. Patients should be educated about osteoporosis and its treatment, and clinicians should assess whether osteoporotic medications can be safely administered prior to dental procedures. Pretreatment dental evaluation is essential, particularly before initiating BPs, and any infectious foci should be eliminated. If feasible, nonurgent dental conditions may be managed as chronic issues, with antiresorptive therapy initiated accordingly. Osteoporosis treatment and dental care may proceed concurrently in patients already receiving antiresorptive agents. Fig. 3 Flowchart outlining a potential strategy for preventing medication-related osteonecrosis of the jaw (MRONJ) in patients at high risk of fracture, such as those with a T-score below −2.5 but no history of fracture. Fig. 3

Certain dental procedures may require one month or longer to complete. In such cases, for how long are physicians willing to wait? Among the nine AFOS countries and regions that responded to the vote, six (66.7%) recommended waiting for 3–6 months, while two (22.2%) suggested a delay of 1–3 months before starting therapy. The remaining respondents indicated that treatment should not be delayed, regardless of the dental needs. Nonsurgical procedures, such as dental cleaning, filling, or prosthesis fitting, do not require the postponement of osteoporosis therapy.

A preventive strategy for MRONJ in patients at very high risk of fracture is shown in Fig. 4 . Patients should be thoroughly educated about their condition and treatment with timely referral to dental specialists. Therapy for osteoporosis should be initiated without delay while concurrently managing dental issues. If the risk of MRONJ is a concern, anabolic agents are preferred for complete dental treatment, including invasive procedures, although romosozumab may still carry some risks. For patients receiving denosumab, invasive procedures (eg, tooth extractions) should ideally be performed 3–4 months after the last injection, when the inhibitory effect of denosumab on bone metabolism begins to wane. For those taking intravenous BPs, the potential risk of MRONJ should be explained, informed consent should be obtained, and treatment should be continued without a drug holiday. Fig. 4 Flowchart outlining a potential strategy for preventing medication-related osteonecrosis of the jaw (MRONJ) in patients at very high risk of fracture or imminent fracture. Fig. 4

Following the completion of dental infection management, patients should maintain good oral hygiene, attend dental checkups every 3–6 months, be referred for dental care when appropriate, and be regularly monitored for early signs of MRONJ. While regular dental follow-up is recommended for patients receiving antiresorptive therapy, the suggested interval of every 3–6 months should be regarded as an ideal approach rather than a mandatory requirement. Given the substantial variations in healthcare systems, reimbursement policies, and access to dental care across AFOS member countries and regions, follow-up intervals should be individualized and adapted according to local resources and the patient's overall risk profile for MRONJ. Among the AFOS respondents, for patients at a very high risk of fracture, seven (77.8%) indicated that osteoporosis treatment should not be delayed, even in the presence of dental needs. The remaining two respondents (22.2%) recommended a 1- to 3-month delay before initiating therapy.

Ideally, it is often difficult for physicians to refer all patients with OP to a dentist. The 2023 position paper by the Japanese Committee on MRONJ recommends referral for patients who (1) have not seen a dentist for more than a year, (2) do not have a regular dentist, (3) have difficulties with mastication, or (4) report oral symptoms. Edentulous patients should also be referred to as potential sources of infection due to ill-fitting dentures, impacted teeth, or residual roots, which may still be present [ 9 ]. A panoramic radiograph should be obtained to assess the jaw condition. Written communication between physicians and dentists is essential in patients taking glucocorticoids or those with comorbidities such as diabetes mellitus, both of which are associated with an increased risk of severe MRONJ. Key Points & Recommendations For Patients at High Risk of Fracture . ● Complete dental treatment before initiating antiresorptive therapy. ● Perform a dental evaluation and eliminate any sources of infection. ● Delay osteoporosis therapy if needed for dental procedures. For Patients at Very High Risk of Fracture . ● Start osteoporosis therapy without delay, even if dental needs exist. ● Manage dental care concurrently with antiresorptive therapy. ● If MRONJ risk is a concern, consider anabolic agents; note that romosozumab also carries some risk. ● Denosumab: Perform extractions ideally 3–4 months after the last injection. ● IV BPs: No drug holiday; explain MRONJ risk and obtain informed consent. General Recommendations . ● Shared decision-making is essential when determining treatment timing. ● Emphasize oral hygiene and schedule regular dental follow-ups, with the interval individualized according to local resources and patient risk (eg, ideally every 3–6 months). ● Nonsurgical procedures (eg, cleaning, filling) do not require treatment delay. ● Refer patients to dentists if they lack a regular provider or present with oral symptoms. ● Ensure medical-dental coordination, especially in patients with diabetes or glucocorticoid use.

Appropriateness of prophylactic drug holiday

Before dental surgery in patients with osteoporosis ( Table 4 )

A multicenter retrospective study by the Japanese Study Group of Cooperative Dentistry with Medicine found no evidence that a short-term drug holiday from oral BPs reduced the risk of MRONJ prior to tooth extraction [ 51 ]. Another multicenter study involving 5639 patients aged ≥ 60 years identified prolonged waiting time before extraction as a potential risk factor for delayed wound healing (> 8 weeks) [ 52 ]. Omori et al. reported that a drug holiday of approximately three months neither reversed osteoclast suppression nor improved treatment outcomes [ 58 ]. Furthermore, both the 2015 and 2022 surveys conducted by the Japan Osteoporosis Society (JOS) demonstrated that prolonged drug holidays were associated with an increased incidence of MRONJ [ 59 , 60 ]. Aboalela et al. concluded in their systematic review and meta-analysis that drug holidays from antiresorptive therapy do not reduce the risk of MRONJ, and therefore cannot be recommended [ 53 ]. Similarly, in Thailand, Ruksakiet et al. reported in their systematic review and network meta-analysis, that a drug holiday may not be necessary before dental procedures in patients receiving oral BPs. Temporary discontinuation of intravenous BPs or denosumab is also unlikely to reduce the risk of MRONJ compared with continued treatment [ 54 ]. Table 4 Summary of studies on drug holidays before dental surgery and the risk of MRONJ/BRONJ (including one study on delayed wound healing). Table 4 Country Study Design [Reference] Outcome No. of Patients Key Findings Japan Multicenter retrospective study [ 51 ] BRONJ 1175 No significant difference in BRONJ between 2- or 3-month drug holidays. Japan Multicenter study using a structured questionnaire [ 52 ] Delayed wound healing (> 8 weeks) 5639 Waiting > 2 months before extraction increased risk (OR = 7.23, P = 0.001). Saudi Arabia Systematic review and meta-analysis [ 53 ] MRONJ 6808 OR = 0.73 (95% CI: 0.51–1.06), drug holiday vs no holiday. Thailand Systematic review and network meta-analysis [ 54 ] MRONJ 717 No significant difference between continuation and discontinuation (RR = 0.81; 95% CI: 0.07–9.42). Taiwan Retrospective study [ 55 ] MRONJ 937 Drug holiday ≥ 3 months lowered MRONJ risk (AOR = 0.11; 95% CI: 0.07–0.17). Korea Nationwide retrospective cohort (IV BPs) [ 56 ] BRONJ 152,299 TSL > 90 days significantly reduced risk: HR = 0.57 to 0.43 across increasing durations. MRONJ, medication-related osteonecrosis of the jaw; BRONJ, bisphosphonate-related osteonecrosis of the jaw; BPs, bisphosphonates; TSL, time since last dose; OR, odds ratio; AOR, adjusted odds ratio; HR, hazard ratio; CI, confidence interval.

The 2023 position paper by the Japanese Committee on MRONJ expressed concerns that delaying tooth extraction during drug holidays may exacerbate odontogenic or jawbone infections. Moreover, prolonged discontinuation of antiresorptive agents may increase the risk of osteoporotic fractures [ 59 , 60 ]. Based on these findings, which do not support the benefits of prophylactic drug holidays, the Japanese Committee recommends that antiresorptive therapy should not be routinely discontinued before tooth extraction [ 9 ].

Conversely, Wei et al. reported that a three-month interruption of antiresorptive therapy before tooth extraction was associated with a reduced risk of MRONJ, particularly among patients undergoing long-term treatment and those receiving extractions in the posterior mandible [ 55 ]. However, these findings require validation through prospective randomized controlled trials. Similarly, using the Korean National Health Insurance Service database, Park et al. found that the risk of MRONJ after tooth extraction was significantly lower when intravenous BP therapy was paused for > 90 days, with the lowest risk observed after a pause exceeding one year [ 56 ]. In contrast, longer intervals since the last dose of intravenous ibandronate or zoledronate were associated with a progressively increased risk of fracture. The adjusted odds ratios ranged from 1.96 to 5.32, with the highest risk observed for hip fractures. A treatment gap of more than one year was associated with an adjusted OR of 8.47 (95% CI: 6.56–10.95).

Representatives from Thailand, Malaysia, and the Philippines indicated in their responses to our MRONJ survey that discontinuation of BPs before dental procedures is not routinely recommended in patients receiving treatment for osteoporosis. Among the nine AFOS countries and regions that responded to the vote, seven (77.8%) did not recommend a drug holiday before dental procedures for patients with osteoporosis, whereas two (22.2%) did.

One representative AFOS member suggested that, for patients receiving denosumab, dental procedures such as extractions should ideally be performed 3–6 months after the last injection, with the subsequent dose administered on schedule or delayed by no more than one month in order to minimize the risk of rebound bone loss and vertebral fractures. Chan et al. emphasized the importance of considering the patient's fracture risk, stating that a drug holiday may be contraindicated in individuals at a high risk of fracture [ 11 ].

Recently, the International ONJ Task Force suggested that antiresorptive therapy should not be discontinued before dental implant placement, although this was a weak recommendation based on very low-quality evidence [ 61 ]. Key Points & Recommendations ● There is no consensus on prophylactic drug holidays. Risks and benefits must be carefully weighed for each patient. International ONJ Task Force Consensus: ● Dental implants: Discontinuation of antiresorptives is not required prior to implant placement (weak recommendation; very low-quality evidence). Korean recommendations: ● Confirm whether the osteoporosis agents can be safely paused for several months before the dental procedure. ● Bisphosphonates: 2-month holiday acceptable; 6–12 months for zoledronate. Restart 6–8 weeks after dental surgery. ● Denosumab: Perform dental surgery at 3–4 months after the last injection → Delay the next dose by 6–8 weeks to maintain the standard 6-month dosing interval. ● In patients at high risk of fracture, explain the potential MRONJ risk, document informed consent, and proceed without a drug holiday.

Impact of drug holidays on treatment outcomes in patients with MRONJ

Wei et al. systematically reviewed prognostic factors in patients undergoing treatment for MRONJ and analyzed 33 studies that met the inclusion criteria out of 1388 screened citations. They concluded that the discontinuation of antiresorptive therapy was significantly associated with better treatment outcomes in patients with MRONJ [ 62 ]. However, only eight studies were included in the meta-analysis that examined the effect of discontinuing antiresorptive therapy. Among these, a significant association between discontinuation and improved treatment outcomes was observed in only three studies. Approximately half of the patients included had malignancies. Furthermore, one of the three studies that showed a significant association was based on a univariate analysis, and no significant association was found in the corresponding multivariate analysis.

Fujimori et al. conducted a prospective cohort study across 25 centers, including 291 patients with MRONJ, and reported that discontinuation of antiresorptive therapy was associated with improved healing rates in patients with both malignancy and osteoporosis [ 63 ]. However, in their multivariate Cox proportional hazards analysis, discontinuation of antiresorptive therapy was not significantly associated with healing rates in patients with osteoporosis-related MRONJ (HR = 1.18, 95% CI: 0.80–1.73, P = 0.40). They suggested that discontinuation of antiresorptive therapy may influence treatment outcomes in patients with malignancies but not in those with osteoporosis.

Hayashida et al. conducted a multicenter retrospective study of 427 patients with MRONJ treated at nine hospitals between 2009 and 2017. They reported that discontinuation of antiresorptive agents significantly improved the cure rate in patients with osteoporosis who underwent nonsurgical treatment [ 64 ]. In patients with malignant tumors who received nonsurgical therapy, discontinuation was associated with better outcomes, although the difference was not statistically significant. In contrast, drug holidays had no impact on treatment outcomes in patients with osteoporosis or malignancy who underwent surgical intervention. Key Points ● In malignancy-related MRONJ, drug discontinuation appears beneficial, while evidence is inconsistent for osteoporosis-related cases. ● Drug holidays do not improve outcomes in patients undergoing surgical treatment, regardless of underlying disease.

Interprofessional collaboration in the prevention of MRONJ

Shared responsibilities among physicians, dentists, and pharmacists include providing explanations and obtaining informed consent from patients regarding osteoporosis, MRONJ, and related medications as well as sharing and exchanging patient information. Sustained interprofessional collaboration, particularly between physicians and dental professionals, is essential to prevent fragility fractures and MRONJ in patients undergoing antiresorptive therapy.

In Japan, notable progress has been made in medical-dental collaborations for MRONJ management. According to the JOS, the proportion of physicians referring patients for dental care prior to initiating antiresorptive therapy will increase from 32.9% in 2015 to 72.7% in 2022 [ 59 , 60 ]. Collaboration increased from 24.8% to 42.4% in the same period. However, these rates vary widely among the 47 prefectures, ranging from 10.0% to 83.3% in the 2022 survey [ 60 ]. For instance, Yamori et al. reported that in Shiga Prefecture, only 30% of physicians referred patients for dental care before initiating BPs or denosumab, and only 23% collaborated with dentists during treatment [ 65 ].

In Korea, self-administered questionnaires have revealed that fewer than 30% of physicians refer patients for dental evaluation [ 66 ]. Another survey found that 29.3% of dentists encountered MRONJ cases. While 65.0% of dentists routinely recorded the type and duration of bone-modifying agent use, only 59.1% consistently requested referral letters from physicians before performing dental surgery [ 67 ]. In Thailand, 44% of physicians advised patients to receive oral health care; the most common reason for not advising was that respondents did not consider themselves adequately knowledgeable about detecting oral health problems [ 68 ]. This highlights the need to emphasize clinical practice guidelines and collaboration between physicians and dentists. Both the 2024 OSHK Hong Kong Osteoporosis Guidelines and the upcoming 2025 Korean Position Paper emphasize the importance of comprehensive pretreatment dental evaluations and regular oral checkups for patients receiving antiresorptive therapy [ 18 , 36 ].

Effective collaboration depends on bidirectional communication and a mutual understanding of clinical domains. Many physicians are unfamiliar with oral conditions and the presentation of MRONJ, whereas dentists may lack sufficient knowledge regarding osteoporosis management [ 60 ]. Although the number of referrals from physicians to dentists is increasing, the opposite is uncommon.

Dental panoramic radiography, which is widely used in general dental practice, may serve as a tool for screening for opportunistic osteoporosis. Mandibular cortical indices detected on dental panoramic radiographs are significantly associated with the bone mineral density (BMD) of the lumbar spine and femoral neck, biochemical markers of bone turnover, and fracture risk [ 69 ]. These findings have been validated by international studies and a recent meta-analysis, supporting the use of panoramic radiographs for osteoporosis screening [ 70 ]. A bidirectional referral system should be implemented to strengthen collaboration. Physicians should refer patients for dental evaluation before starting antiresorptive therapy. Dentists should report oral findings and refer patients with suspected osteoporosis based on radiographic signs. This system could enhance dentists’ understanding of osteoporosis and integrate oral health into broader fracture prevention strategies.

Pharmacists can act as key facilitators in inter-professional education and care coordination. However, evidence indicates that the awareness of MRONJ among pharmacists remains suboptimal [ 71 ]. Regardless, providing accurate information and obtaining informed consent regarding osteoporosis, MRONJ, and pharmacotherapy remains a shared responsibility among healthcare providers.

Osteoporosis Liaison Service (OLS) coordinators may also play an important role in facilitating multidisciplinary care, similar to the Fracture Liaison Service (FLS) models implemented globally [ 72 ]. Although data on their specific roles in MRONJ prevention are limited, several OLS models in Japan have successfully integrated dental hygienists as coordinators [ 73 ]. In these models, dental hygienists act as key liaisons between physicians, dentists, and patients, particularly in oral health management [ 74 , 75 ]. While hospital-based dental hygienists often possess adequate knowledge about MRONJ, those working in private clinics may require additional education [ 74 ].

All healthcare professionals, including physicians, dentists, pharmacists, OLS/FLS coordinators, and patients must be well-informed and actively involved in ensuring safe and effective osteoporosis management. Continuous education through workshops, inter-professional seminars, professional society meetings, and public outreach is vital for fostering collaborative care and improving patient outcomes.

An overall summary of the key points and recommendations across multiple categories and topics is presented in Table 5 . Key Points & Recommendations Shared Responsibilities . Physicians, dentists, and pharmacists should: – Provide explanations and obtain informed consent (regarding osteoporosis, MRONJ, and medications). – Share and exchange patient information. Role-Specific Actions . – Physicians: Refer patients for oral hygiene management. – Dentists: Report oral conditions and screen for osteoporosis. System Support . – FLS/OLS coordinators facilitate communication among healthcare providers. – Interdisciplinary education is essential for MRONJ prevention and osteoporosis care. – Team-based care improves outcomes and ensures continuous follow-up. Table 5 Summary of key points and recommendations. Table 5 Definition ● Both primary and metastatic jaw cancers may occur in patients with osteoporosis receiving antiresorptive therapy. ● Immunomodulatory or antiangiogenic agents are rarely used in osteoporosis patients. ● MRONJ is defined by all of the following: 1 Current or prior antiresorptive therapy 2 Exposed bone (or bone visible through a fistula) in the maxillofacial region for more than 8 weeks 3 No history of jaw radiation and no evidence of jaw malignancy ● MRONJ risk should also be considered with anti-sclerostin antibody. Clinical staging General Concept ● MRONJ is often classified into five stages (At Risk, Stage 0–3) based on clinical findings. 2023 Japanese Position Paper ● Inclusion of “At Risk” and “Stage 0” is controversial: – Do not meet diagnostic criteria (bone exposure/fistula) – May reflect early or progressing cases ● For epidemiological studies: – Report separately – Exclude from core prevalence/incidence unless progression occurs X-ray imaging in dental practice ● Use panoramic, intraoral, and CBCT imaging to detect dental infections and early bone changes. ● Carefully assess the following radiographic signs: – Ill-defined periapical radiolucencies – Marked osteosclerosis – Widening of the periodontal ligament (PDL) space Advanced imaging modalities ● MRI is useful for evaluating soft tissues and bone marrow. ● CT and CBCT are effective for assessing bone structures. ● SPECT/CT and PET/CT are valuable for determining the extent of MRONJ. ● Standardized uptake values (SUVs) from SPECT/CT correlate with the progression and prognosis of MRONJ. Differential diagnosis ● Differentiate MRONJ from osteomyelitis, radiation-induced osteonecrosis, malignancies, and fibro-osseous lesions. ● A history of antiresorptive therapy is essential for diagnosis. Biomarkers ● No reliable biomarkers exist; future studies should explore novel and effective markers. Pathogenesis ● Pathogenesis is multifactorial and involves suppressed bone remodeling, impaired angiogenesis, soft tissue toxicity, immune dysfunction, bacterial colonization, mechanical trauma (eg, from dentures), and systemic conditions (eg, diabetes, malnutrition, steroid use). Epidemiology ● MRONJ incidence varies; interpret data cautiously. ● Low-dose therapy for osteoporosis: 0.025–0.136% annual incidence (cumulative) or 21–283 cases per 100,000 person-years (incidence rate). ● Analyze BPs and denosumab separately. ● Higher rates in Asians: evidence remains inconclusive. ● More data from AFOS countries are needed. Management of MRONJ ● Goals: Promote healing, control pain/infection, restart osteoporosis treatment early. ● Educate: Ensure patient understanding and active involvement. ● Refer: Early referral to dental specialists improves outcomes. ● Treat: Use conservative care for the early stage; surgery for the advanced stage. ● Consult: Discuss osteoporosis treatment adjustments with the physician following MRONJ onset. ● Collaborate: Multidisciplinary care is essential. Prevention strategy For Patients at High Risk of Fracture ● Complete dental treatment before initiating antiresorptive therapy. ● Perform a dental evaluation and eliminate any sources of infection. ● Delay osteoporosis therapy if needed for dental procedures. For Patients at Very High Risk of Fracture ● Start osteoporosis therapy without delay, even if dental needs exist. ● Manage dental care concurrently with antiresorptive therapy. ● If MRONJ risk is a concern, consider anabolic agents; note that romosozumab also carries some risk. ● Denosumab: Perform extractions ideally 3–4 months after the last injection. ● IV BPs: No drug holiday; explain MRONJ risk and obtain informed consent. General Recommendations ● Shared decision-making is essential when determining treatment timing. ● Emphasize oral hygiene and schedule regular dental follow-ups, with the interval individualized according to local resources and patient risk (eg, ideally every 3–6 months). ● Nonsurgical procedures (eg, cleaning, filling) do not require treatment delay. ● Refer patients to dentists if they lack a regular provider or present with oral symptoms. ● Ensure medical-dental coordination, especially in patients with diabetes or glucocorticoid use. Prophylactic drug holiday before dental surgery in patients with osteoporosis ● There is no consensus on prophylactic drug holidays. Risks and benefits must be carefully weighed for each patient. International ONJ Task Force Consensus ● Dental implants: Discontinuation of antiresorptives is not required prior to implant placement (weak recommendation; very low-quality evidence). Korean recommendations: ● Confirm whether the osteoporosis agents can be safely paused for several months before the dental procedure. ● Bisphosphonates: 2-month holiday acceptable; 6–12 months for zoledronate. Restart 6–8 weeks after dental surgery. ● Perform dental surgery at 3–4 months after the last injection of denosumab → Delay the next dose by 6–8 weeks to maintain the standard 6-month dosing interval. ● In patients at high risk of fracture, explain the potential MRONJ risk, document informed consent, and proceed without a drug holiday. Impact of drug holidays on treatment outcomes in patients with MRONJ ● In malignancy-related MRONJ, drug discontinuation appears beneficial, while evidence is inconsistent for osteoporosis-related cases. ● Drug holidays do not improve outcomes in patients undergoing surgical treatment, regardless of underlying disease. Interprofessional collaboration in the prevention of MRONJ Shared Responsibilities Physicians, dentists, and pharmacists should: – Provide explanations and obtain informed consent (regarding osteoporosis, MRONJ, and medications) – Share and exchange patient information Role-Specific Actions – Physicians: Refer patients for oral hygiene management – Dentists: Report oral conditions and screen for osteoporosis System Support – FLS/OLS coordinators facilitate communication among healthcare providers – Interdisciplinary education is essential for MRONJ prevention and osteoporosis care – Team-based care improves outcomes and ensures continuous follow-up

Discussion

The definition of MRONJ is particularly important when comparing its incidence across countries with that of AFOS. Recent consensus statements from AFOS member countries and regions have largely adopted the three diagnostic criteria outlined in the 2022 AAOMS definition [ 12 ]. This definition aligns closely with those used in other regions such as Europe [ 14 , 15 ]. However, concerns remain regarding their application. One issue involves the criterion of “current or previous treatment with antiresorptive therapy.” A key clinical question is how far back the use of antiresorptive agents should be considered when assessing the risk of MRONJ. The influence of patient adherence to antiresorptive therapy on MRONJ risk should also be taken into account [ 76 ]. Moreover, whether combining anabolic agents with antiresorptive therapy affects the incidence of MRONJ in real-world clinical practice remains unclear. However, randomized controlled trial data have demonstrated that teriparatide improved the rate of resolution of MRONJ lesions [ 77 ] and represented an efficacious and safe treatment.

Another concern involves MRONJ cases that manifest within eight weeks. Waiting for eight weeks to confirm the diagnosis may allow disease progression. A 2023 Japanese position paper noted that MRONJ can be diagnosed within eight weeks if the clinical course and imaging findings clearly indicate bone necrosis without signs of healing [ 9 ]. Determining the primary etiology can be challenging in patients receiving both radiation therapy and antiresorptive agents. A comprehensive evaluation that considers radiation dose, cumulative drug exposure, and imaging findings is essential. In patients with osteoporosis receiving antiresorptive therapy, dentists may initially suspect MRONJ in cases of jawbone destruction, potentially overlooking primary or metastatic malignancies.

The 2023 Japanese position paper [ 9 ] described the clinical manifestations of the non-exposed bone variant (stage 0) as patients without clinical evidence of osteonecrosis but presenting with nonspecific symptoms or clinical findings. It is important to note that periodontal disease or periapical lesions may, in some cases, progress to MRONJ. Symptoms include tooth pain indistinguishable from periodontal disease or apical periodontitis, dull bone pain radiating to the TMJ, sinus pain, inflammation of the maxillary sinus wall, mucosal thickening, and neurosensory changes. Clinical findings include tooth mobility and intraoral or extraoral swelling. The AAOMS position paper emphasizes that stage 0 MRONJ is not odontogenic [ 12 ]. However, in Japan, the term “not odontogenic” has been removed from descriptions of non-exposed lesions owing to the high prevalence of MRONJ cases originating from odontogenic infections.

Tooth extraction has been reported as a potential trigger for MRONJ. However, Shudo et al. found no cases of BRONJ among 132 patients with osteoporosis receiving oral BPs who underwent 274 tooth extractions [ 78 ]. Notably, oral BP therapy exceeding five years significantly delayed healing compared with therapy under five years. In their study, the duration of BP use was distributed as follows: < 2 years (N = 51), 2–5 years (N = 41), 5–10 years (N = 28), and > 10 years (N = 12). Similarly, in a retrospective cohort study, Otto et al. concluded that tooth extraction in patients receiving BPs can be performed safely and predictably, even in high-risk patients, when conducted in accordance with established guidelines [ 79 ]. These findings suggest that it is not the tooth extraction itself but a preexisting infection that may represent a key risk factor for MRONJ development.

Although BPs are cleared from the circulation within days, their high affinity for hydroxyapatite results in a skeletal half-life of several years. Therefore, even a short perioperative interruption cannot eliminate active drugs from the bone [ 80 ]. This pharmacokinetic complexity, along with the reliance on observational or registry-based data, may explain why the 2022 AAOMS panel did not endorse routine drug holidays and why the 2024 SIPMO-SICMF guidelines recommended only a nominal one-week interruption [ 14 , 12 ]. In this context, a nationwide Korean cohort study is noteworthy, and the 90-day discontinuation of intravenous BP therapy prior to tooth extraction was associated with a significantly reduced risk of post-extraction MRONJ. However, interruptions exceeding one year were linked to an eightfold increase in hip fracture incidence [ 56 ]. Systematic reviews of sequential antiresorptive therapy suggest that brief, well-timed interruptions may reduce the risk of MRONJ without substantially compromising skeletal protection [ 81 ]. These findings support individualized drug discontinuation strategies based on the risk of MRONJ, cumulative BP exposure, and fracture vulnerability.

However, denosumab presents a distinct clinical dilemma. Unlike BPs, the antiresorptive effect declines rapidly 3–4 months after administration, and treatment delays can lead to rebound increases in bone turnover and vertebral fractures. Bone turnover markers rise around nine months after the final dose [ 82 ], and FREEDOM extension data show increased vertebral fractures within six months of cessation [ 83 ]. Therefore, a more tailored approach is required. For example, invasive dental procedures can be scheduled 3–4 months after injection, with 6–8 weeks allowed for healing, and denosumab can be resumed within the 6-month interval to prevent rebound effects.

For high-risk fracture patients or those who recently transitioned from BPs to denosumab, a combination associated with increased MRONJ incidence, alternative strategies such as strict infection control and prophylactic antibiotics may be preferable to treatment interruption. These findings underscore the importance of a multidisciplinary risk-stratified approach to perioperative antiresorptive management that balances MRONJ prevention and skeletal integrity.

In AFOS countries and regions, the incidence of MRONJ associated with low-dose antiresorptive therapy (including BPs and denosumab) ranges from 21 to 283 cases per 100,000 person-years, with an annual incidence of 0.025–0.136%. However, the underlying data sources are highly heterogeneous and include regional registries, hospital cohorts, insurance databases, and post-marketing surveillance. While some studies suggest a higher incidence of MRONJ in Asian populations than in European and North American populations, the current evidence is insufficient for definitive conclusions.

In Japan, the incidence of MRONJ derived from the National Health Insurance Database is markedly lower than that reported in other domestic studies [ 39 ]. The authors noted that MRONJ case definitions lacked validation, relying on three Japanese-specific disease codes in addition to the ICD-10. However, it is unclear whether general dentists and oral surgeons can accurately diagnose MRONJ. Furthermore, the database included 363,915 patients with osteoporosis under the age of 50 years (13.7% of the sample), for whom MRONJ was considered unlikely.

As noted by the International Task Force on ONJ [ 13 ], accurately estimating the incidence of MRONJ is difficult when strict diagnostic criteria (eg, bone exposed for > 8 weeks) are used. In practice, patients with MRONJ-like symptoms lasting < 8 weeks may be excluded from the diagnosis, leading to an underestimation. Additionally, the Japanese database lacks information on smoking status, BMI, severity of osteoporosis, oral health, and adherence to antiresorptive therapy [ 39 ]. Drug switching and discontinuation were not assessed. Despite the large sample size of the database, these limitations may have significantly affected the accuracy of incidence estimates.

Interprofessional collaboration between physicians, dentists, pharmacists, nurses, dental hygienists, and other healthcare professionals is essential for MRONJ prevention. In Kure City, Japan, the local government has joined collaborative initiatives to prevent fragility fractures and MRONJ [ 40 ]. However, several challenges remain before such efforts can be effectively implemented.

The first challenge is the lack of information sharing between physicians and dentists. Physicians often lack knowledge of oral health and MRONJ characteristics, and dentists may be unfamiliar with osteoporosis management and antiresorptive pharmacology. The second limitation is the absence of dedicated coordinators to support communication and collaboration. Although medical and dental societies have initiated partnerships, these efforts often fail because of a lack of personnel. The third limitation is inadequate patient education. Many patients do not understand the necessity of dental evaluations before or during osteoporosis treatment. Even when patients are willing to seek care, access to underserved areas may be limited. Addressing these issues is crucial for the successful prevention and management of MRONJ.

Conclusions

Several key aspects of MRONJ, including its definition, clinical staging, and diagnostic procedures, such as imaging, pathogenesis, risk factors, management, and preventive strategies, are generally consistent across AFOS member countries and regions. However, the effectiveness of drug discontinuation before dental procedures in patients with osteoporosis remains unclear and requires further investigation. Large-scale studies across all AFOS members are required to determine the true incidence of MRONJ in patients with osteoporosis. These findings may help to develop more effective prevention strategies for this population.

CRediT author statement

Akira Taguchi: Conceptualization, Methodology, Project administration, Formal analysis and investigation, Writing - original draft preparation, Writing - Review and Editing, Funding acquisition, Supervision. Daisuke Inoue: Conceptualization, Methodology, Project administration, Writing - Review and Editing, Supervision. Jin-Woo Kim: Conceptualization, Methodology, Formal analysis and investigation, Writing - Review and Editing, Supervision. Keskanya Subbalekha: Methodology, Writing - Review and Editing, Supervision. Wai Sin Chan: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Hee Dong Chae: Conceptualization, Methodology, Writing - Review and Editing. Chung-Hwan Chen: Methodology, Writing - Review and Editing. Ching-Lung Cheung: Conceptualization, Methodology, Supervision. Eddie Siu Lun Chow: Methodology, Writing - Review and Editing, Supervision. Yoon-Sok Chung: Conceptualization, Methodology. Linsey Gani: Methodology, Writing - Review and Editing. Muhammad Kamil bin Hassan: Conceptualization, Methodology. Unnop Jaisamrarn: Conceptualization, Methodology, Supervision. Chakorn Vorakulpipat: Conceptualization, Methodology. Nutchada Sriyaranya: Conceptualization, Methodology. Aasis Unnanuntana: Conceptualization, Methodology. Tanawat Amphansap: Conceptualization, Methodology. Seng Bin Ang: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Fen Lee Hew: Conceptualization, Methodology, Supervision. Julie Li-Yu: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Terence Ong Ing Wei: Methodology, Writing - Review and Editing. Jeyakantha Ratnasingam: Methodology, Writing - Review and Editing. Mark Anthony Sandoval: Methodology, Writing - Review and Editing. Thawee Songpatanasilp: Conceptualization, Methodology. Monica Therese Cating-Cabral: Conceptualization, Methodology. Thanut Valleenukul: Conceptualization, Methodology. Lalita Wattanachanya: Conceptualization, Methodology, Project administration. Chih-Hsing Wu: Conceptualization, Methodology, Formal analysis and investigation, Writing - Review and Editing, Supervision. Weibo Xia: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Jawl-Shan Hwang: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Hiroshi Hagino: Conceptualization, Methodology, Writing - Review and Editing, Supervision. Natthinee Charatcharoenwitthaya: Conceptualization, Methodology, Project administration, Writing - Review and Editing, Supervision.

Conflicts of interest

Akira Taguchi received lecture fees from MEDIA Co., Ltd., Asahi Kasei Pharma Corp., Daiichi Sankyo Co., Ltd., Amgen Inc., and Taisho Pharmaceutical Co., Ltd.; Daisuke Inoue received lecture fees from Amgen Inc., Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., and Teijin Pharma, Ltd.; Jin-Woo Kim received lecture fees from Amgen Inc.; Chung-Hwan Chen received lecture fees from Amgen Inc.; and Linsey Gani received lecture fees from Amgen, DKSH, Servier, and Zuellig. The advisory board member of Viatris, Organon. Seng Bin Ang received lectures and advisory fees from Novo Nordisk, Organon, Amgen, GSK, Pfizer, Galderma, Astellas, and Abbott. Research grants from Roche, Amgen, and Otsuka; Julie Li-Yu received honoraria/lecture fees from Zuellig Pharma; Terence Ong Ing Wei received honoraria/lecture fees from Zuellig Pharma, Amgen, and Abbott; Natthinee Charatcharoenwitthaya received honoraria from Amgen Zuellig Pharma, Alvogen, Organon, Sandoz, and Novo Nordisk. All the other authors declare no competing interests.

References

1 Marx R.E. Osteoradionecrosis: a new concept of its pathophysiology J Oral Maxillofac Surg 41 1983 283 288 6572704 10.1016/0278-2391(83)90294-x

2 Lidhar T. Ethunandan A. Ethunandan M. Spontaneous oral ulceration with bone sequestration: its relevance in current clinical practice Br J Oral Maxillofac Surg 58 2020 e75 e79 32651016 10.1016/j.bjoms.2020.06.030

3 Marx R.E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 61 2003 1115 1117 12966493 10.1016/s0278-2391(03)00720-1

4 Ruggiero S.L. Mehrotra B. Rosenberg T.J. Engroff S.L. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases J Oral Maxillofac Surg 62 2004 527 534 15122554 10.1016/j.joms.2004.02.004

5 Aghaloo T.L. Felsenfeld A.L. Tetradis S. Osteonecrosis of the jaw in a patient on denosumab J Oral Maxillofac Surg 68 2010 959 963 20149510 10.1016/j.joms.2009.10.010 PMC2880179

6 Cosman F. Crittenden D.B. Adachi J.D. Binkley N. Czerwinski E. Ferrari S. Romosozumab treatment in postmenopausal women with osteoporosis N Engl J Med 375 2016 1532 1543 27641143 10.1056/NEJMoa1607948

7 Khosla S. Burr D. Cauley J. Dempster D.W. Ebeling P.R. Felsenberg D. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American society for bone and mineral research J Bone Miner Res 22 2007 1479 1491 17663640 10.1359/jbmr.0707onj

8 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 65 2007 369 376 17307580 10.1016/j.joms.2006.11.003

9 Kishimoto H. Hagino H. Kitagawa Y. Nomura T. Arai S. Kurita H. Pathophysiology and management of medication-related osteonecrosis of the jaw: 2023 position paper of the committee on jaw osteonecrosis 2023 Japanese Society of Oral and Maxillofacial Surgeons Tokyo [in Japanese]. Available from: https://www.jsoms.or.jp/medical/work/guideline/

10 Benjar Issaranggun Na Ayuthayal Siripaiboonpong Nisachon Medication-related osteonecrosis of the jaw; MRONJ (MRONJ) J Dent Assoc Thai 72 2022 204 249 [in Thai] https://www.jdat.org/main/archive/9/2022/170

11 Chan B.H. Yee R. Puvanendran R. Ang S.B. Medication-related osteonecrosis of the jaw in osteoporotic patients: prevention and management Singap Med J 59 2018 70 75 10.11622/smedj.2018014 PMC6119741 29568850

12 Ruggiero S.L. Dodson T.B. Aghaloo T. Carlson E.R. Ward B.B. Kademani D. American association of oral and maxillofacial surgeons' position paper on medication-related osteonecrosis of the Jaws-2022 update J Oral Maxillofac Surg 80 2022 920 943 35300956 10.1016/j.joms.2022.02.008

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

14 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 30 2024 3679 3709 38317291 10.1111/odi.14887

15 Anastasilakis A.D. Pepe J. Napoli N. Palermo A. Magopoulos C. Khan A.A. Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by the ECTS J Clin Endocrinol Metab 107 2022 1441 1460 34922381 10.1210/clinem/dgab888 PMC9016445

16 Obermeier K.T. Smolka W. Palla B. Kraus M. Steybe D. Hartung J.T. Antiresorptive therapy in combination with radiation results in enhanced risk for necrosis and associated complications Oral Surg Oral Med Oral Pathol Oral Radiol 139 2025 11 19 39472248 10.1016/j.oooo.2024.07.008

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

18 Kim J.W. Kong S.H. Kim J.Y. Kwak M.K. Kim J.Y. Oh J.H. Medication-related osteonecrosis of the jaw: an evidence-based 2025 position statement from a Korean multidisciplinary task force Endocrinol Metab (Seoul) 40 2025 787 810 41391453 10.3803/EnM.2025.2712 PMC12765892

19 Ruan H.J. Chen H. Hou J.S. An J.G. Guo Y.X. Liu B. Chinese expert consensus on the diagnosis and clinical management of medication-related osteonecrosis of the jaw J Bone Oncol 49 2024 100650 10.1016/j.jbo.2024.100650 PMC11621599 39651419

20 Suei Y. Radiographic findings of bisphosphonate-related osteomyelitis of the jaw: investigation of the diagnostic points by comparison with radiation osteomyelitis, suppurative osteomyelitis, and diffuse sclerosing osteomyelitis Oral Radiol 29 2013 121 134

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

22 Taguchi A. Tanaka S. Ozaki T. Arai K. Mori S. Ohta H. Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: japanese osteoporosis intervention Trial-05 (JOINT-05) J Bone Miner Metabol 41 2023 854 864 10.1007/s00774-023-01466-3 37897672

23 Ueda N. Nakashima C. Aoki K. Shimotsuji H. Nakaue K. Yoshioka H. Does inflammatory dental disease affect the development of medication-related osteonecrosis of the jaw in patients using high-dose bone-modifying agents? Clin Oral Invest 25 2021 3087 3093 10.1007/s00784-020-03632-7 33057886

24 Kanno C. Kojima M. Tezuka Y. Yaginuma S. Kanaya Y. Kaneko T. Antiresorptive agent-related osteonecrosis of the jaw risk in cancer patients before bone-modifying agent therapy: a retrospective study of 511 patients Bone 177 2023 116892 10.1016/j.bone.2023.116892 37689127

25 Nakamura N. Otsuru M. Miyoshi T. Suyama K. Omori K. Morishita K. Risk factors for the development of medication-related osteonecrosis of the jaw and effects of tooth extraction with local infection J Dent Sci 19 2024 1770 1782 39035297 10.1016/j.jds.2023.10.006 PMC11259623

26 Kawasaki M. Shimamoto H. Nishimura D.A. Yamao N. Takagawa N. Uchimoto Y. The usefulness of different imaging modalities in mandibular osteonecrosis and osteomyelitis diagnosis Sci Rep 15 2025 12272 10.1038/s41598-025-96910-x PMC11986015 40210732

27 Wongratwanich P. Shimabukuro K. Konishi M. Nagasaki T. Ohtsuka M. Suei Y. Do various imaging modalities provide potential early detection and diagnosis of medication-related osteonecrosis of the jaw? A review Dentomaxillofacial Radiol 50 2021 20200417 10.1259/dmfr.20200417 PMC8404513 33411572

28 Suyama K. Otsuru M. Nakamura N. Morishita K. Miyoshi T. Omori K. Bone resection methods in medication-related osteonecrosis of the jaw in the mandible: an investigation of 206 patients undergoing surgical treatment J Dent Sci 19 2024 1758 1769 39035329 10.1016/j.jds.2023.10.007 PMC11259631

29 Kitagawa Y. Ohga N. Asaka T. Sato J. Hata H. Helman J. Imaging modalities for drug-related osteonecrosis of the jaw (3), positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw Jpn Dent Sci Rev 55 2019 65 70 30949253 10.1016/j.jdsr.2018.12.001 PMC6430078

30 Stockmann P. Hinkmann F.M. Lell M.M. Fenner M. Vairaktaris E. Neukam F.W. Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study Clin Oral Invest 14 2010 311 317 10.1007/s00784-009-0293-1 19513765

31 Hayashi N. Matsutomo N. Tokorodani R. Fukami M. Nishimori M. Nakatani K. Pilot study of a novel resection extent determination method using bone single-photon emission computed tomography-standardized uptake value in medication-related osteonecrosis of the jaw Dentomaxillofac Radiol 54 2025 495 501 40233239 10.1093/dmfr/twaf032 PMC12394943

32 Wei Y. Li D. Wang M. Wang C. Liu X. Zhang Y. Clinical effectiveness of 3D SPECT/CT imaging in determining osteotomy range for surgical treatment of medication-related osteonecrosis of the jaw: a retrospective study J Stomatol Oral Maxillofac Surg 2025 102375 10.1016/j.jormas.2025.102375 40246200

33 Park J.H. Yoon D.M. Yoon H.J. Kim J.W. Utility of quantitative standardized uptake value from pre-operative bone SPECT/CT for predicting post-surgical MRONJ healing response EJNMMI Res 15 2025 29 40164939 10.1186/s13550-025-01220-y PMC11958904

34 Suei Y. Taguchi A. Tanimoto K. Diagnostic points and possible origin of osteomyelitis in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome: a radiographic study of 77 mandibular osteomyelitis cases Rheumatology 42 2003 1398 1403 12867589 10.1093/rheumatology/keg396

35 Traboulsi-Garet B. Jorba-García A. Camps-Font O. Alves F.A. Figueiredo R. Valmaseda-Castellón 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 Invest 26 2022 2371 2382 10.1007/s00784-022-04383-3 35124731

36 OSHK Task Group for the Formulation of the 2024 OSHK Guideline for Clinical Management of Postmenopausal Osteoporosis in Hong Kong Ip T.P. Lee C.A. Lui T.D. Wong R.M.Y. Cheung C.L. Chiu K.C.P. OSHK guideline for clinical management of postmenopausal osteoporosis in Hong Kong Hong Kong Med J 30 Suppl 2 2024 1 44 2024 39113555

37 Fujimori M. Toriyabe Y. Kaku N. Shimazaki K. Suzuki T. Abe T. Multicenter prospective study on the incidence and cure rates of medication-related osteonecrosis of the jaw (complete translation) J Oral Maxillofac Surg Med Pathol 37 2025 765 777

38 Takada J. Sato S. Arai K. Kito Y. Oshita Y. Saito K. Safety and effectiveness of once-yearly zoledronic acid in Japanese osteoporosis patients: three-year post-marketing surveillance J Bone Miner Metabol 41 2023 268 277 10.1007/s00774-023-01410-5 PMC9978276 36862212

39 Ishimaru M. Ono S. Morita K. Matsui H. Hagiwara Y. Yasunaga H. Prevalence, incidence rate, and risk factors of medication-related osteonecrosis of the jaw in patients with osteoporosis and cancer: a nationwide population-based study in Japan J Oral Maxillofac Surg 80 2022 714 727 35033505 10.1016/j.joms.2021.12.007

40 Kunihara T. Tohmori H. Tsukamoto M. Kobayashi M. Okumura T. Teramoto H. Incidence and trend of antiresorptive agent-related osteonecrosis of the jaw from 2016 to 2020 in kure, Japan Osteoporos Int 34 2023 1101 1109 37002373 10.1007/s00198-023-06732-8 PMC10203006

41 Warin K. Lochanachit S. Pavarangkoon P. Techapanurak E. Somyanonthanakul R. Prediction of medication-related osteonecrosis of the jaw in patients receiving antiresorptive therapy using machine learning models J Oral Maxillofac Surg 83 2025 353 365 39701551 10.1016/j.joms.2024.11.013

42 Settavanit C. Kettratad-Pruksapong M. Raksamani N. Patntirapong S. Prevalence of medication-related osteonecrosis of the jaw in osteoporotic patients treated with antiresorptive drugs at Pranangklao Tertiary Care Hospital in Nonthaburi Province, Thailand J Med Assoc Thai 106 2023 341 348

43 Alblazi K. Nabil S. Tumian N.R. Yunus S.S.M. Ramli R. Potential role of comprehensive dental care in preventing medication related osteonecrosis of the jaw (MRONJ): a single centre study BMC Oral Health 24 2024 1291 39455955 10.1186/s12903-024-05081-0 PMC11512473

44 Kim S.H. Lee Y.K. Kim T.Y. Ha Y.C. Jang S. Kim H.Y. Incidence of and risk for osteonecrosis of the jaw in Korean osteoporosis patients treated with bisphosphonates: a nationwide cohort-study Bone 143 2021 115650 10.1016/j.bone.2020.115650 32956854

45 Park J.H. Kwoen M.J. Lee J.R. Kim K.S. Lee H.J. Kim J.W. Gradual, but not sudden, dose-dependent increase of ONJ risk with bisphosphonate exposure: a nationwide cohort study in women with osteoporosis Front Endocrinol 12 2021 774820 10.3389/fendo.2021.774820 PMC8695600 34956086

46 Ko S.Y. Hwang T.Y. 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 41 2024 39 44 38173345 10.12701/jyms.2023.01116 PMC10834263

47 Kwok T. Choy T.K. Kwok W.L. Prevalence of bisphosphonate-related osteonecrosis of the jaw in Hong Kong Hong Kong Med J 22 Suppl 2 2016 S46 S47 26908345

48 Chiu W.Y. Chien J.Y. Yang W.S. Juang J.M. Lee J.J. Tsai K.S. The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene J Clin Endocrinol Metab 99 2014 2729 2735 24758181 10.1210/jc.2013-4119

49 Chiu W.Y. Yang W.S. Chien J.Y. Lee J.J. Tsai K.S. The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects PLoS One 13 2018 e0196419 10.1371/journal.pone.0196419 PMC5918995 29694412

50 Liu F.C. Luk K.C. Chen Y.C. 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 34 2023 1729 1737 37326685 10.1007/s00198-023-06818-3 PMC10511380

51 Hasegawa T. Kawakita A. Ueda N. Funahara R. Tachibana A. Kobayashi M. A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporos Int 28 2017 2465 2473 28451732 10.1007/s00198-017-4063-7

52 Kamimura M. Taguchi A. Komatsu M. Koiwai H. Ashizawa R. Ichinose A. Long waiting time before tooth extraction may increase delayed wound healing in elderly Japanese Osteoporos Int 30 2019 621 628 30460382 10.1007/s00198-018-4775-3

53 Aboalela A.A. Farook F.F. Alqahtani A.S. Almousa M.A. Alanazi R.T. Almohammadi D.S. The effect of antiresorptive drug holidays on medication-related osteonecrosis of the jaw: a systematic review and meta-analysis Cureus 14 2022 e30485 10.7759/cureus.30485 PMC9674041 36415385

54 Ruksakiet K. Jarusriwanna A. Sadaeng W. Laoruengthana A. Sang-Ngoen T. Dhippayom T. Effects of discontinuing different antiresorptive regimens on medication-related osteonecrosis of the jaw in patients undergoing dental procedures: a systematic review and network meta-analysis EFORT Open Rev 10 2025 258 266 40326547 10.1530/EOR-2024-0133 PMC12061011

55 Wei L.Y. Cheng Y.W. Chiu W.Y. Kok S.H. Chang H.H. Cheng S.J. Risk factors influencing medication-related osteonecrosis of the jaws (MRONJ) following dental extraction among osteoporotic patients in Taiwan Head Neck 47 2025 1151 1161 39611589 10.1002/hed.28011

56 Park J.H. Kong S.H. Lee J. Oh J. Lee J.R. Lee H.J. Time since last intravenous bisphosphonate and risk of osteonecrosis of the jaw in osteoporotic patients Nat Commun 16 2025 4367 40350503 10.1038/s41467-025-59718-x PMC12066712

57 Tai T.W. Chen H.Y. Shih C.A. Huang C.F. McCloskey E. Lee J.K. Asia-Pacific consensus on long-term and sequential therapy for osteoporosis Osteoporos Sarcopenia 10 2024 3 10 38690538 10.1016/j.afos.2024.02.001 PMC11056428

58 Omori K. Otsuru M. Morishita K. Hayashida S. Suyama K. Naruse T. Ineffectiveness of antiresorptive agent drug holidays in osteoporosis patients for treatment of medication-related osteonecrosis of the jaw: consideration from immunohistological observation of osteoclast suppression and treatment outcomes Int J Environ Res Publ Health 19 2022 10898 10.3390/ijerph191710898 PMC9517825 36078614

59 Taguchi A. Shiraki M. Sugimoto T. Ohta H. Soen S. Japan Osteoporosis Society Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw Curr Med Res Opin 32 2016 1261 1268 27007294 10.1185/03007995.2016.1170005

60 Taguchi A. Hagino H. Inoue D. Endo N. Society J.O. Cooperation between physicians and dentists for osteonecrosis of the jaw: a 2022 Japanese survey J Bone Miner Metabol 41 2023 829 837 10.1007/s00774-023-01458-3 37516668

61 Ali D.S. Khan A.A. Morrison A. Tetradis S. Mirza R.D. El Rabbany M. Antiresorptive therapy to reduce fracture risk and effects on dental implant outcomes in patients with osteoporosis: a systematic review and osteonecrosis of the jaw taskforce consensus statement Endocr Pract 31 2025 686 698 40335186 10.1016/j.eprac.2025.02.016

62 Wei L.Y. Chiu C.M. Kok S.H. Lin H.Y. Chiu W.Y. Yang C.W. Lee J.J. Prognostic indicators in medication-related osteonecrosis of the jaw: a systematic review and meta-analysis Osteoporos Int 36 2025 969 979 40126604 10.1007/s00198-025-07464-7

63 Fujimori M. Toriyabe Y. Sakakibara N. Nojima M. Makino S. Hokkaido Association of Hospital Dentistry Medication-Related Osteonecrosis of the Jaw Research Group What affects healing rates in patients treated for medication-related osteonecrosis of the Jaw? The role of operative therapy and other clinical factors J Oral Maxillofac Surg 82 2024 1441 1455 39013476 10.1016/j.joms.2024.06.176

64 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 Metabol 38 2020 126 134 10.1007/s00774-019-01035-7 31410544

65 Yamori M. Tamura M. Mikami M. Mori T. Noi M. Machida Y. Differences in the knowledge and experience of physicians and dentists about medication-related osteonecrosis of the jaw in osteoporotic patients Int Dent J 71 2021 336 342 33518370 10.1016/j.identj.2020.12.005 PMC9275204

66 Kim J.W. Jeong S.R. Kim S.J. Kim Y. Perceptions of medical doctors on bisphosphonate-related osteonecrosis of the jaw BMC Oral Health 16 2016 92 27604159 10.1186/s12903-016-0290-0 PMC5015333

67 Han A.L. The awareness and practice of dentists regarding medication-related osteonecrosis of the jaw and its prevention: a cross-sectional survey BMC Oral Health 21 2021 155 33761923 10.1186/s12903-021-01475-6 PMC7992948

68 Supanumpar N. Pisarnturakit P.P. Charatcharoenwitthaya N. Subbalekha K. Physicians' awareness of medication-related osteonecrosis of the jaw in patients with osteoporosis PLoS One 19 2024 e0297500 10.1371/journal.pone.0297500 PMC10817186 38277387

69 Taguchi A. Tanaka R. Kakimoto N. Morimoto Y. Arai Y. Hayashi T. Clinical guidelines for the application of panoramic radiographs in screening for osteoporosis Oral Radiol 37 2021 189 208 33620644 10.1007/s11282-021-00518-6

70 Heuchert J. Kozieł S. Spinek A.E. Radiomorphometric indices of the mandible as indicators of decreased bone mineral density and osteoporosis - meta-analysis and systematic review Osteoporos Int 35 2024 401 412 37870561 10.1007/s00198-023-06949-7 PMC10867062

71 Sturrock A. Preshaw P.M. Hayes C. Wilkes S. Attitudes and perceptions of GPs and community pharmacists towards their role in the prevention of bisphosphonate-related osteonecrosis of the jaw: a qualitative study in the North East of England BMJ Open 7 2017 e016047 10.1136/bmjopen-2017-016047 PMC5640123 28965092

72 Suzuki A. Multidisciplinary approach to management of osteoporosis with osteoporosis liaison service (OLS) Endocr J 70 2023 459 464 37019656 10.1507/endocrj.EJ23-0040

73 Okamura M. Oomura Y. Tanaka K. Kitamura K. Iguchi Y. Takaishi R. Activity of the Tokyo dental college Ichikawa General Hospital Osteoporosis Liaison Service (OLS) team and the research of oral condition in insufficiency fracture patients Shika Gakuho 120 2020 321 329 [Japanese]

74 Mah Y.J. Kang G.Y. Kim S.J. Survey on awareness and perceptions of bisphosphonate-related osteonecrosis of the jaw in dental hygienists in Seoul Int J Dent Hyg 13 2015 222 227 25677614 10.1111/idh.12122

75 Iijima Y. Yamada M. Amano M. Watanabe S. Fujimaru M. Uematsu A. Dental hygienists' awareness of medication-related osteonecrosis of the jaw in private dental clinics in Japan Gerontol Geriatr Med 10 2024 Oct 31 23337214241292794 10.1177/23337214241292794 PMC11528679 39494315

76 Kosaka Y. Sugiyama T. Hara K. Kobayashi Y. Adherence to daily, weekly, and monthly dosing regimens of bisphosphonates for osteoporosis treatment in postmenopausal women in Japan: a retrospective study using claims data Tohoku J Exp Med 255 2021 147 155 34690222 10.1620/tjem.255.147

77 Sim I.W. Borromeo G.L. Tsao C. Hardiman R. Hofman M.S. Papatziamos Hjelle C. Teriparatide promotes bone healing in medication-related osteonecrosis of the jaw: a placebo-controlled, randomized trial J Clin Oncol 38 2020 2971 2980 32614699 10.1200/JCO.19.02192

78 Shudo A. Kishimoto H. Takaoka K. Noguchi K. Long-term oral bisphosphonates delay healing after tooth extraction: a single institutional prospective study Osteoporos Int 29 2018 2315 2321 29967931 10.1007/s00198-018-4621-7

79 Otto S. Tröltzsch M. Jambrovic V. Panya S. Probst F. Ristow O. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg 43 2015 847 854 25958767 10.1016/j.jcms.2015.03.039

80 Reid I.R. Zoledronate: efficacy and safety J Bone Miner Res 21 Suppl 2 2006 83 87 10.1359/jbmr.06s215 17229014

81 Srivastava A. Nogueras Gonzalez G.M. Geng Y. Won A.M. Cabanillas M.E. Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis Support Care Cancer 29 2021 2305 2317 33190182 10.1007/s00520-020-05882-3 PMC12010772

82 Bone H.G. Bolognese M.A. Yuen C.K. Kendler D.L. Miller P.D. Yang Y.C. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass J Clin Endocrinol Metab 96 2011 972 980 21289258 10.1210/jc.2010-1502

83 Cummings S.R. Ferrari S. Eastell R. Gilchrist N. Jensen J.B. 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 33 2018 190 198 29105841 10.1002/jbmr.3337

Acknowledgments

We would like to express our sincere gratitude to all experts who contributed to this survey.

This study was funded, in part, by Grants-in-Aid for Scientific Research from the 10.13039/501100001691 Japan Society for the Promotion of Science (grant numbers 25K13238 and 24K22197 ). ORCID Akira Taguchi: 0000-0003-2620-1487. Daisuke Inoue: 0000-0002-8311-0787. Jin-Woo Kim: 0000-0002-1672-5730. Keskanya Subbalekha: 0000-0002-1570-2289. Wai Sin Chan: 0000-0002-0365-0266. Hee Dong Chae: 0000-0003-0129-9422. Chung-Hwan Chen: 0000-0001-8941-4792. Ching-Lung Cheung: 0000-0002-6233-9144. Eddie Siu Lun Chow: 0000-0002-3191-8987. Yoon-Sok Chung: 0000-0003-0179-4386. Linsey Gani: 0000-0002-3699-2406. Muhammad Kamil bin Hassan: 0000-0002-8605-7651. Unnop Jaisamrarn: 0000-0003-2412-9805. Chakorn Vorakulpipat: 0000-0001-6627-8732. Nutchada Sriyaranya: 0000-0002-8479-368X. Aasis Unnanuntana: 0000-0002-5742-298X. Tanawat Amphansap: 0000-0003-2148-3921. Seng Bin Ang: 0000-0003-0883-634X. Fen Lee Hew: 0000-0001-6135-4257. Julie Li-Yu: 0000-0002-1626-9747. Terence Ong Ing Wei: 0000-0001-7473-446X. Jeyakantha Ratnasingam: 0000-0002-4993-6470. Mark Anthony Sandoval: 0000-0003-0622-8287. Thawee Songpatanasilp: 0000-0002-0612-5299. Monica Therese Cating-Cabral: 0000-0001-7848-7785. Thanut Valleenukul: 0009-0009-9777-5411. Lalita Wattanachanya: 0009-0007-2400-4697. Chih-Hsing Wu: 0000-0002-0504-2053. Weibo Xia: 0000-0001-7768-5536. Jawl-Shan Hwang: 0000-0003-1979-6160. Hiroshi Hagino: 0000-0001-8053-1095. Natthinee Charatcharoenwitthaya: 0000-0002-6472-7511.