Introducing Equivalent and Threshold Doses in the Assessment of Medication-Related Osteonecrosis of the Jaw Risk: Insights from a Descriptive Study in Iran

Introducing Equivalent and Threshold Doses in the Assessment of Medication-Related Osteonecrosis of the Jaw Risk: Insights from a Descriptive Study in Iran | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Introducing Equivalent and Threshold Doses in the Assessment of Medication-Related Osteonecrosis of the Jaw Risk: Insights from a Descriptive Study in Iran Pegah Mosannen Mozafari, Leila Farhad Molashahi, Maliheh Dadgarmoghaddam, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5922241/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jul, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: To investigate the clinical characteristics and risk factors associated with medication-related osteonecrosis of the jaw (MRONJ) and to introduce two metrics—equivalent dose and threshold dose—as predictive risk assessment tools. Methods: This retrospective study reviewed 193 patient records from Shahab Clinic and the Oral Medicine Department of Mashhad Dental School (2017–2023). Patients were categorized into MRONJ stages (0–3) and an "at-risk" group. Data on demographics, comorbidities, clinical presentations, and detailed medication profiles were analyzed. Equivalent dose was standardized to four years of oral alendronate use, and threshold dose provided a cumulative risk cut-off. Statistical analyses( T-tests, ANOVA, Chi-square tests,.) were applied . Results: MRONJ was identified in 40.4% of cases, while 59.6% were classified as at-risk. Advanced stages were significantly associated with higher equivalent doses, prolonged medication use, and key risk factors, including oncologic diseases, medication type and route of administration, comorbidities, age, and surgical interventions such as extractions and ill-fitting dentures (p < 0.001). The novel metrics demonstrated strong predictive value, with higher equivalent doses correlating closely with MRONJ severity (R = 0.46, p < 0.001) Conclusion: This study offers critical insights into MRONJ risk stratification, highlighting the cumulative impact of medication dose alongside clinical risk factors. The introduction of equivalent and threshold doses represents a transformative advancement in MRONJ risk prediction, enabling precise prevention strategies and guiding clinical management toward standardized care protocols. Introduction Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious condition characterized by jawbone necrosis. Initially recognized in 2003 as an adverse effect of bisphosphonates—drugs used to regulate bone metabolism—MRONJ has since been associated with a broader range of medications. These include anti-angiogenesis agents, cytotoxic drugs, and newer therapies such as CDK4/6 inhibitors, adalimumab, and pembrolizumab. Emerging evidence also suggests that medications like ocrelizumab, recently introduced for the treatment of multiple sclerosis, may contribute to MRONJ development. [ 1 – 7 ] Understanding MRONJ requires a detailed analysis of its clinical features and risk factors across diverse patient populations. Despite the growing body of research, descriptive studies focusing on the frequency and characteristics of MRONJ within large cohorts in Iran remain scarce. This study aims to address this gap by exploring the prevalence, clinical presentations, and associated risk factors of MRONJ at various stages in a substantial cohort. Additionally, this research compares the findings with a cohort of "at-risk" patients currently receiving MRONJ-related medications (MRMs) but who have not yet developed clinical symptoms. To enhance the predictive accuracy of MRONJ risk, this study introduces two novel indices—equivalent dose and threshold dose—that consolidate previously recognized medication-related risk factors into unified metrics. Methods This retrospective study utilized archived patient files from two primary oral medicine clinics in Mashhad, the capital of Khorasan Razavi province, which serve as referral centers for northeastern Iran. The study period spanned from September 2017 to March 2023. The clinics involved were Shahab Clinic, a private oral medicine and special care dentistry center, and the Oral Medicine Department of Mashhad Dental School at Mashhad University of Medical Sciences (MUMS), a public referral institution. Data were collected using a self-designed checklist from patient files, encompassing various stages of MRONJ. Extracted information included demographic data, medical history, laboratory parameters, dental history, clinical features, oral health index scores, and MRONJ staging. Data on patients identified as "at risk" but not yet exhibiting MRONJ symptoms were also gathered. To estimate the risk of MRONJ, an index was employed based on prior studies correlating MRONJ with the duration and cumulative dose of MRONJ-Related Medications(MRMs) [ 8 , 9 ]. An equivalent dose was defined as the cumulative dose of four continuous years of weekly oral alendronate 70 mg, totaling 14,560 mg. Other medications were converted into equivalent doses relative to this threshold, as outlined in Table 1 . In cases of polytherapy, the dosages of multiple medications were summed to calculate a total equivalent dose. Patients exceeding this threshold were considered at increased risk for MRONJ, consistent with findings from previous studies [ 10 – 13 ]. The provided durations represented the time required to reach the equivalent of a 4-year cumulative dose for osteoporosis treatment in a cancer context, based on specified dosing regimens. The study included patients who had not yet surpassed the defined threshold dose. The research protocol was registered with the ethics committee of MUMS under grant number 4010615 and research code R.MUMS.DENTISTRY.REC.1401.065. and was conducted in compliance with the principles outlined in the Declaration of Helsinki. All data were handled confidentially. Inclusion Criteria: Patients at all MRONJ stages, based on the most recent American Association of Oral and Maxillofacial Surgeons (AAOMS) guidelines, were included. These stages were: at risk, stage 0, stage 1, stage 2, or stage 3 [ 1 ]. Eligibility criteria included:Current or previous treatment with antiresorptive therapy, either alone or combined with immunomodulators or antiangiogenic medications. The presence of exposed bone or bone that could be probed through an intraoral or extraoral fistula persisting for more than 8 weeks.No history of radiation therapy or metastatic disease to the jaws. Patients categorized as "at risk" were those undergoing antiresorptive or other MRMs but without clinical signs, symptoms, fistulae, or necrosis. Files lacking sufficient data were excluded. Sample Size and Statistical Analysis: The sample size was determined based on available patient files in the two archives, with data inclusion ending in March 2023. Data were imported into Microsoft Excel 2019 and analyzed using SPSS version 20 (IBM Inc). Descriptive statistics, including measures of central tendency, dispersion indices, and frequency distribution, characterized the data. Statistical tests such as T-test, Fisher exact test, Chi-square test, Mann–Whitney U test, Kruskal-Wallis test, ANOVA, and Welch test were applied, with the significance level set at P < 0.05 Results In this study, 193 cases were enrolled, with 78 cases (40.41%) at various stages of MRONJ and 115 cases (59.58%) at the at-risk stage. The MRONJ group included 12 cases (15.38%) at Stage 0, 14 cases (17.94%) at Stage 1, 30 cases (38.46%) at Stage 2, and 22 cases (28.20%) at Stage 3. The demographic and baseline characteristics of the study population are presented in Table 2. A total of 20 MRONJ patients and 19 at-risk patients presented with comorbid (excluding the primary disease requiring MRM administration) such as diabetes, anemia, cardiovascular disease, thyroid disorders, rheumatologic conditions, gastrointestinal issues, neurologic and dermatologic disorders, renal dysfunction, and respiratory diseases. The remaining cases in both groups had no additional comorbidities. The mean age was significantly higher in the MRONJ group (59.64 ± 13.67 years) compared to the at-risk group (53.24 ± 11.32 years) (P=0.001). Oncologic diseases were more prevalent in the MRONJ group (P=0.01), with prostate and breast cancer showing a particularly strong association with higher MRONJ incidence. No significant differences in variables such as age, sex, BMI, oral health indices, habits, primary disease, and comorbidities were observed across MRONJ stages (P>0.05). Table 3 outlines the events leading to MRONJ across different stages. Tooth extractions and ill-fitting dentures were more commonly associated with higher MRONJ stages; however, the difference was not statistically significant. Cases involving multiple events were linked to more advanced stages. For example, tooth extractions followed by denture placement were reported in eight cases (two in stage 2 and six in stage 3). Implant placement followed by overdenture placement was noted in three cases (two in stage 3 and one in stage 2). One stage 3 patient underwent multiple osteotomy surgeries due to a misdiagnosis of osteomyelitis. When combining the “multiple events” and “extraction” groups, these interventions were significantly associated with higher MRONJ stages (P=0.006). Conversely, patients with spontaneous disease onset, without prior interventions, were more commonly found in lower MRONJ stages. The MRONJ group demonstrated significantly higher creatinine levels and lower hemoglobin levels compared to the at-risk group (P=0.009 and P=0.013, respectively). No differences were observed in other laboratory parameters, including FBS, HbA1C, BUN, WBC, RBC, and PLT. Table 4 presents data on MRMs, including type, frequency, and administration route. Table 5 details the dosage, equivalent dose, and threshold dose for both groups. Zoledronic acid users were significantly more prevalent in the MRONJ group (P=0.01), while fewer MRONJ cases involved alendronate. Monthly dosing regimens were more common in the MRONJ group (P=0.003). The median dosage of zoledronic acid was higher in MRONJ patients (P<0.001). The median equivalent dose of MRMs was also significantly higher in the MRONJ group by 1.42 units (P=0.001). A significantly greater proportion of MRONJ patients exceeded the threshold dose compared to the at-risk group (P<0.001). The median duration of MRM use was 13.5 months longer in the MRONJ group, a statistically significant difference (P=0.002). Table 6 explores the dosage, drug regimens, drug combinations, administration routes, equivalent doses, threshold doses, and duration of use for different MRONJ stages. Zoledronic acid use was more frequent in stages 2 and 3 (P=0.005), while denosumab use was more common in stages 0 and 1 (P=0.005). Patients receiving parenteral or combined oral and parenteral medication had the highest prevalence in stages 2 and 3 (P=0.03). Median zoledronic acid doses were highest in stage 3 and lowest in stage 1 (P=0.026). Advanced stages correlated with higher equivalent doses (P<0.001, R=0.46). Prolonged use of MRMs was linked to more advanced stages (P=0.003, R=0.362). While clinical findings such as fistulae, ulcers, tooth mobility, pain, halitosis, and bleeding were not directly correlated with MRONJ stages, multiple concurrent symptoms were more frequent in advanced stages (P<0.001). Patients in stages 2 and 3 exhibited more numerous and diverse clinical signs compared to earlier stages. Although pain was significantly more prevalent in stage 0,compared to other symptoms.(P<0.01) Table 7 shows jaw involvement across MRONJ cases. The mandible was significantly more affected than the maxilla, with 48 cases involving the mandible, 11 cases involving the maxilla, and 9 cases involving both jaws (P0.05). Although no significant difference in oncotherapy protocols was observed between the MRONJ and at-risk groups (P=0.05), higher disease stages were significantly associated with histories of concurrent chemotherapy and radiotherapy or radiotherapy alone (P=0.02). Discussion This study represents the first descriptive analysis of MRONJ in Iran, utilizing data from two leading oral medicine centers in Mashhad. It examines clinical characteristics and risk factors associated with MRONJ across various stages and compares these findings with at-risk individuals who have not yet developed the condition but require focused preventive strategies. A notable contribution of this study is the introduction of the equivalent dose and threshold dose metrics, inspired by Schifter's proposal, which provide novel dimensions to risk assessment by consolidating dosage, duration, and regimen. These findings offer insights into patient demographics, MRMs, symptoms, and disease stages, aligning with previous research that emphasizes cumulative drug exposure as a critical risk factor for MRONJ, particularly in patients requiring aggressive antiresorptive therapy. The results revealed that MRONJ patients tend to be older than those in the at-risk group, likely due to prolonged drug treatment and age-related changes in bone metabolism. Although advanced stages (stages 2 and 3) were more common in older individuals, the age difference across stages was not statistically significant. The observed increase in MRONJ incidence with age is consistent with prior studies. [ 14 , 15 ]. Contrary to some reports, this study found no significant association between MRONJ stages and factors such as sex, tobacco use, BMI, or oral hygiene. [ 16 – 19 ]. Oncologic diseases were significantly more prevalent in the MRONJ group compared to the at-risk group (P = 0.01), with these patients frequently presenting in advanced stages, particularly when undergoing concurrent chemotherapy and radiotherapy. This aligns with studies linking chemotherapy to exacerbated clinical manifestations of MRONJ, likely due to dose-dependent toxicity on bone marrow, soft tissues, and bone metabolism. [ 20 – 25 ]. Our findings also highlight a higher prevalence of MRONJ among patients with multiple myeloma and breast or prostate cancer, consistent with Marcianò's research on cancer metastasis patterns. [ 26 ] However, the study’s limited access to a broader range of cancer patients underscores the need for a national database to track medication and disease histories comprehensively. This restriction introduces a selection bias that impacts the breadth and applicability of our findings. The link between MRMs and an increased risk of MRONJ has been well-documented. Our study found differences in the MRM regimens between the MRONJ group and the at-risk group and across various MRONJ stages. While some studies suggest a higher incidence of MRONJ with zoledronic acid both clinically and on a cellular level [ 27 , 28 ], others indicate a greater risk for cancer patients treated with denosumab [ 29 – 31 ]. In our findings, 48.5% of zoledronic acid users and 44.4% of denosumab users developed MRONJ, compared to only 7.22% of those on alendronate, highlighting a higher risk associated with the first two medications. This high incidence can be due to selection bias and the fact that not all the patients receiving MRMs were recruited. Although guidelines emphasize that individuals should visit a dentist for clearance before starting MRMs, unfortunately, this issue is not taken seriously by either the physicians or the patients. In many cases, patients only visit the dentist after a problem has already developed. Therefore, a large portion of those who receive MRMs and do not experience any issues in the oral and jaw area never seek dental consultation, making our study sample not representative of the entire population at risk. Additionally, the incidence of MRONJ was 50% in individuals using multiple medications, supporting research that combination therapy leads to a higher MRONJ prevalence—13% in users of both bisphosphonates and denosumab, versus 5% and 4% for single-drug users respectively [ 32 ]. Surgical manipulations, particularly tooth extractions and ill-fitting dentures, were significant risk factors for MRONJ, especially in advanced stages. Grouping these factors under "multiple events" highlighted their association with higher MRONJ stages. This finding aligns with cohort studies indicating that tooth extractions increase MRONJ risk 18 times, with a similar increase for users of ill-fitting dentures [ 33 ]. However, our non-cohort study design did not allow for such risk quantification. The analysis of laboratory markers identified higher creatinine and lower hemoglobin levels in MRONJ patients, likely reflecting comorbidities and older age. Elevated creatinine suggests impaired renal function, while lower hemoglobin points to systemic conditions that may exacerbate MRONJ. [ 1 , 34 ] Route of administration was identified as a potential risk factor for MRONJ, with parenteral administration, alone or combined with oral, showing a significantly higher occurrence in stages 2 and 3 of the disease (P = 0.03). Evidence supports that parenteral administration of MRMs is linked to MRONJ [ 35 , 36 ], and sometimes it is independent of dosage [ 37 ]. However, the introduction of the equivalent dose and threshold dose concepts in this study challenges this correlation, suggesting that the medicine itself, rather than its administration route, poses a risk, as parenteral routes achieve threshold doses more rapidly. In our study, the highest doses of zoledronic acid and denosumab were associated with stage 3 of the disease, and there was a correlation between the dose of zoledronic acid and the disease stages. Studies have shown that the cumulative dose of zoledronic acid and denosumab in patients with MRONJ is higher [ 36 , 38 ]. However, to date, no study has examined the cumulative dose of medications concerning the disease stage, and therefore it is not possible to compare the results of our study directly. We introduced the equivalent dose instead of the cumulative dose. Our study confirmed that a longer duration of MRMs’ use correlates with a higher incidence of MRONJ, consistent with prior research. Aljohani highlighted prolonged bisphosphonate use as a risk factor for MRONJ [ 39 ]. Ng and colleagues' systematic review showed that MRONJ risk among cancer patients using zoledronic acid increased from 1.6–4% after two years and 3.8–18% after more than two years; whereas, for denosumab users, the risk was 1.9% for less than 24 months and rose to 6.9% for longer than 24 months [ 40 ]. However, contrasting findings from Mirkhani and Saad suggest that the duration of denosumab use does not consistently affect MRONJ occurrence, indicating that other factors may also influence MRONJ risk [ 16 , 41 ]. In our study, the equivalent dose—a cumulative measure incorporating dose, type, duration, and regimen of medication—was higher in MRONJ patients than in those at risk, particularly in stage 3. This suggests that the equivalent dose, by accounting for these factors individually, can help explain their separate impacts on both the occurrence and severity of MRONJ. Also, we could present a threshold dose as the cut-off point for the risk estimate of MRONJ. In agreement with other studies, the majority of MRONJ lesions occurred in the lower jaw [ 23 , 42 , 43 ]. One study explained this by noting that the lower jaw is exposed to greater chewing forces than the upper jaw, which may increase the risk of trauma and infection [ 44 ]. Bleeding, ulcers, and trismus were more commonly observed in stage 3 of the disease. In the study by Wang and colleagues, bone exposure and pain were among the most common clinical findings in affected individuals [ 45 ]. Based on our findings, individuals who are at stage 0 of the disease may only experience pain, which could serve as an early warning sign for the onset of MRONJ. The main limitation of this retrospective study is the reliance on medical records from dental centers not specifically designed for this research, which may restrict the data quality and complicate identifying potential confounding factors. This limitation is compounded by the fact that the data comes from dental services where many patients were seeking MRONJ treatment or dental check-up, thus hindering the ability to calculate the true incidence and limiting the generalizability of the results. Additionally, while the study highlights the role of cumulative dosage in MRONJ development, it does not fully explore the interaction between medication regimens and other contributing factors such as genetics, underlying health conditions, and concurrent treatments like chemotherapy or radiotherapy. The most novel aspect of this study is the introduction of the equivalent and threshold doses, which consolidate variables like dosage, duration, and regimen. This approach enables the calculation of risk for patients who have used multiple MRMs. Although the calculation of these two new variables is based on Schifter’s proposal, more studies with larger sample sizes are needed for a more precise calculation and to identify a finer risk index. [ 8 ] In conclusion, this study highlights the need for dentists and medical professionals to be aware of the MRONJ risk, particularly for patients using MRMs and those with symptoms, especially pain, as potential early signs of MRONJ. Preventive measures, such as regular examinations of at-risk patients and dental interventions following established protocols, are recommended to mitigate the risk of MRONJ. Future research should evaluate the relationship between the equivalent dose of MRMs, the type of chemotherapy regimen, and the occurrence and severity of MRONJ to provide a more holistic understanding. Declarations Competing Interests PMM serves as the Scientific Mentor at Shahab Clinic. SS and Parham Aghasizadeh Sharbaf are research assistant at Shahab Clinic. Other authors have no competing interests. Human Ethics Declaration: This study was conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Mashhad University of Medical Sciences on August 31, 2022, under grant number 4010615 and code 1401.065 IR.MUMS.DENTISTRY.REC. Fundings: This work was supported by the Vice-Chancellor for Research at Mashhad University of Medical Sciences [grant number 4010615]. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Pooria AS, ANF, MD, SSA and SVK. The first draft of the manuscript was written by PMM and LFM. Project administration was done by PMM. RF and ERF supervised the submission and Writing - Review & Editing process. All authors commented on previous versions of the manuscript. All authors read and approved of the final manuscript. Acknowledgement This article is based on an undergraduate thesis (ANF undergraduate thesis for general dentistry doctorate - number: 3485) presented to Mashhad Dental School. The authors are grateful to the Vice-Chancellor for Research at MUMS, who funded this study. The authors are thankful to Shahab Oral Medicine and Special Care Dentistry Clinic for providing access to patient records while maintaining confidentiality and supporting the researchers throughout the various stages of the study. References Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D(2022) American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg. https://doi.org/10.1016/j.joms.2022.02.008 Patel V, Carey B (2023) Pembrolizumab-related osteonecrosis of the jaw. Br J Oral Maxillofac Surg . https://doi.org/10.1016/j.bjoms.2023.08.241 Sisalli L, Giordano F, Chiacchio A, Acerra A, Caggiano M (2023) Medication-Related Osteonecrosis of the Jaw: A Case Report of an Unusual Side Effect of Adalimumab. Case Rep Dent. https://doi.org/10.1155/2023/5544285 Mozafari PM, Farrokhie ZS, Nahayati MA, Anbiaee N (2023) Medication-Related Osteonecrosis of the Jaw (MRONJ) as a Consequence of Multiple Sclerosis Treatment. Clin Oral Sci Dent 6:1. Nicolatou-Galitis O, Kouri M, Papadopoulou E, Vardas E, Galiti D, Epstein JB, et al (2019) Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer https://doi.org/10.1007/s00520-018-4501-x Senín LD, Pancorbo DM, Garcés MYR, Santos-Rubio MD, Calero JB (2024) Relationship between Medication-Related Osteonecrosis of the Jaw and CDK4/6 Inhibitors in Breast Cancer. Curr Oncol . https://doi.org/10.3390/curroncol31010016 Ahdi H, Wichelmann TA, Pandravada S, Ehrenpreis E (2024) Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab: A Case Series from the FDA Adverse Event Reporting System (FAERS) Database. https://doi.org/10.21203/rs.3.rs-4088785/v1 Schifter M, McLean M, Sukumar S (2021) Disorders of the Endocrine System and of Metabolism. In: Burket's Oral Medicine. Wiley, New York, pp 817–902. https://doi.org/10.1002/9781119597797.ch22 Lo JC, O'Ryan F, Gordon NP, Yang J, Hui RL, Martin DC, et al (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2009.03.050 Drudge-Coates L, Van den Wyngaert T, Schiødt M, Van Muilekom H, Demonty G, Otto S (2020) Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals. Support Care Cancer . https://doi.org/10.1007/s00520-020-05440-x Ottesen C, Schiødt M, Gotfredsen K (2020) Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): A systematic review. Heliyon https://doi.org/10.1016/j.heliyon.2020.e03795 Nicolatou-Galitis O, Schiødt M, Mendes RA, Ripamonti C, Hope S, Drudge-Coates L, et al (2019) Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2018.09.008 Kajizono M, Sada H, Sugiura Y, Soga Y, Kitamura Y, Matsuoka J, Sendo T (2015) Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull . https://doi.org/10.1248/bpb.b15-00385 Feng Z, An J, Zhang Y (2021) Factors influencing severity of medication-related osteonecrosis of the jaw: A retrospective study. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2020.12.045 Kang MH, Lee DK, Kim CW, Song IS, Jun SH (2018) Clinical characteristics and recurrence-related factors of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg . https://doi.org/10.1016/j.heliyon.2020.e03795 Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck A, et al (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. https://doi.org/10.1093/annonc/mdr435 Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al (2008) Bisphosphonate-related osteonecrosis of the jaws: A case-control study of risk factors in breast cancer patients. J Clin Oncol . https://doi.org/10.1200/JCO.2008.16.2768 Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, et al (2012) Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg . https://doi.org/10.1016/j.ijom.2012.06.020 Tsao C, Darby I, Ebeling PR, Walsh K, O'Brien-Simpson N, Reynolds E, Borromeo G (2014) Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2013.02.016 Fusco V, Cabras M, Erovigni F, Dell’Acqua A, Arduino PG, Pentenero M, et al (2021) A multicenter observational study on medication-related osteonecrosis of the jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy. Med Oral Patol Oral Cir Bucal . https://doi.org/10.4317/medoral.24318 Banfi A, Podestà M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, et al (2001) High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer . https://doi.org/10.1002/1097-0142(20011101)92:93.0.CO;2-K Oteri G, Campisi G, Panzarella V, Morreale I, Nucera R, Di Fede O, et al (2018) Could the combined administration of bone antiresorptive drug, taxanes, and corticosteroids worsen medication-related osteonecrosis of the jaws in cancer patients? Biomed Res Int. https://doi.org/10.1155/2018/4021952 Zhou Y, Yu Y, Shi Y, Li M, Yang C, Wang S (2020) Combined administration of bisphosphonates, chemotherapeutic agents, and/or targeted drugs increases the risk for stage 3 medication-related osteonecrosis of the jaw: A 4-year retrospective study. Biomed Res Int. https://doi.org/10.1155/2020/5847429 Shim K, MacKenzie MJ, Winquist E (2008) Chemotherapy-associated osteonecrosis in cancer patients with solid tumours: a systematic review. Drug Saf. https://doi.org/0114-5916/08/0005-0359/$48.00/0 Bi Y, Gao Y, Ehirchiou D, Cao C, Kikuiri T, Le A, et al (2010) Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol . https://doi.org/10.2353/ajpath.2010.090592 Marcianò A, Ingrasciotta Y, Isgrò V, L'Abbate L, Foti SS, Picone A, et al (2021) Cancer patients at risk for medication-related osteonecrosis of the jaw: A case and control study analyzing predictors of MRONJ onset. J Clin Med . https://doi.org/10.3390/jcm10204762 Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2014.04.031 Roato I, Pavone L, Pedraza R, Bosso I, Baima G, Erovigni F, Mussano F (2023) Denosumab and zoledronic acid differently affect circulating immune subsets: a possible role in the onset of MRONJ. Cells . https://doi.org/10.3390/cells12202430 Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm A, Bornstein MM, Molinero-Mourelle P (2020) Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab vs zoledronic acid: A systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal . https://doi.org/10.4317/medoral.23324 Hallmer F, Bjarnadottir O, Götrick B, Malmström P, Andersson G (2020) Incidence of and risk factors for medication-related osteonecrosis of the jaw in women with breast cancer with bone metastasis: a population-based study. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2020.04.808 Ikesue H, Mouri M, Tomita H, Hirabatake M, Ikemura M, Muroi N, et al (2021) Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases. Support Care Cancer . https://doi.org/10.1007/s00520-021-06018-x Srivastava A, Nogueras Gonzalez GM, Geng Y, Won AM, Cabanillas ME, Naing A, et al (2021) Prevalence of medication-related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis. Support Care Cancer . https://doi.org/10.1007/s00520-020-05882-3 Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis C, et al (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol . https://doi.org/10.1200/JCO.2009.21.9584 Kim YH, Park HK, Choi NR, Kim SW, Kim GC, Hwang DS, et al (2017) Relationship between disease stage and renal function in bisphosphonate-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg . https://doi.org/10.5125/jkaoms.2017.43.1.16 Graves LL, Bukata SV, Aghazadehsanai N, Chang TI, Garrett NR, Friedlander AH (2016) Patients receiving parenteral bisphosphonates for malignant disease and having developed an atypical femoral fracture are at risk of concomitant osteonecrosis of the jaw: an evidence-based review. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2016.06.003 Yao S, Ding X, Rong G, Zhou J, Zhang B (2023) Association between malignant diseases and medication-related osteonecrosis of the jaw (MRONJ): A systematic review and meta-analysis. J Craniofac Surg . https://doi.org/10.1097/SCS.0000000000009033 Kim HW, Lee MW, Lee JH, Kim MY (2021) Comparison of the effect of oral versus intravenous bisphosphonate administration on osteoclastogenesis in advanced-stage medication-related osteonecrosis of the jaw patients. J Clin Med . Feng Z, An J, He Y, Zhang Y (2022) A comparative study of the clinical characteristics of patients with medication-related osteonecrosis of the jaw and osteoporosis or malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2022.04.049 Aljohani S, Fliefel R, Ihbe J, Kühnisch J, Ehrenfeld M, Otto S (2017) What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review. J Cranio-Maxillofac Surg . https://doi.org/10.1016/j.jcms.2017.05.028 Ng TL, Tu MM, Ibrahim MFK, Basulaiman B, McGee SF, Srikanthan A, et al (2021) Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review. Support Care Cancer . https://doi.org/10.1007/s00520-020-05556-0 Zakhary I, Khanafer A, Mirkhani M (2017) Idiopathic incidence of MRONJ in patients on denosumab. Clin Surg 2:1410. de Oliveira CC, de Sousa FB (2016) Osteonecrosis of the jaw induced by receptor activator of nuclear factor-kappa B ligand (denosumab)-Review. Med Oral Patol Oral Cir Bucal .https://doi.org/10.4317/medoral.21044 Zirk M, Kreppel M, Buller J, Pristup J, Peters F, Dreiseidler T, Zinser M, Zöller JE (2017) The impact of surgical intervention and antibiotics on MRONJ stage II and III: a retrospective study. J Cranio-Maxillofac Surg . https://doi.org/10.1016/j.jcms.2017.05.027 Inchingolo AM, Malcangi G, Ferrara I, Patano A, Viapiano F, Netti A, et al (2023) MRONJ treatment strategies: A systematic review and two case reports. Appl Sci . https://doi.org/10.3390/app13074370 Wang Q, Liu J, Qi S, Liao X, Liu D, Pan J (2018) Clinical analysis of medication-related osteonecrosis of the jaws: A growing severe complication in China. J Dent Sci . https://doi.org/10.1016/j.jds.2017.12.003 Tables Tables 1 to 7 are available in the Supplementary Files section. Additional Declarations Competing interest reported. PMM serves as the Scientific Mentor at Shahab Clinic. SS and Parham Aghasizadeh Sharbaf are research assistant at Shahab Clinic. Other authors have no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Published Journal Publication published 06 Jul, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 16 Apr, 2025 Reviews received at journal 12 Apr, 2025 Reviewers agreed at journal 02 Apr, 2025 Reviewers invited by journal 02 Apr, 2025 Editor assigned by journal 07 Mar, 2025 Submission checks completed at journal 04 Feb, 2025 First submitted to journal 29 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5922241","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":411080779,"identity":"47c59560-ecf4-498e-8e9d-bf98f7c81e47","order_by":0,"name":"Pegah Mosannen Mozafari","email":"","orcid":"","institution":"Shahab Dental Clinic (Oral Medicine and Special Care Dentistry)","correspondingAuthor":false,"prefix":"","firstName":"Pegah","middleName":"Mosannen","lastName":"Mozafari","suffix":""},{"id":411080780,"identity":"41117ec0-0ff8-499f-91f6-0f50559edb31","order_by":1,"name":"Leila Farhad Molashahi","email":"data:image/png;base64,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","orcid":"","institution":"Oral \u0026 Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Leila","middleName":"Farhad","lastName":"Molashahi","suffix":""},{"id":411080781,"identity":"47937e1c-1349-469a-a12f-1b3db6df6c51","order_by":2,"name":"Maliheh Dadgarmoghaddam","email":"","orcid":"","institution":"Community and Family Medicine Department, , Faculty of Medicine, Mashhad University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Maliheh","middleName":"","lastName":"Dadgarmoghaddam","suffix":""},{"id":411080782,"identity":"55067bdf-378a-47e0-b0dc-29c10d93555c","order_by":3,"name":"Seyedeh Vajiheh Kazemian","email":"","orcid":"","institution":"Community and Family Medicine Department, , Faculty of Medicine, Mashhad University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Seyedeh","middleName":"Vajiheh","lastName":"Kazemian","suffix":""},{"id":411080783,"identity":"088a220f-5838-4c5e-a051-0b4475161bf3","order_by":4,"name":"Amirreza Nabavi Fard","email":"","orcid":"","institution":"Vice Chancellor for Health, Sabzevar University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Amirreza","middleName":"Nabavi","lastName":"Fard","suffix":""},{"id":411080784,"identity":"7ea092a1-534a-4edc-9908-4366aa0d42e5","order_by":5,"name":"Pooria Aghasizadeh Sharbaf","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Pooria","middleName":"Aghasizadeh","lastName":"Sharbaf","suffix":""},{"id":411080785,"identity":"22588242-b99c-4d7b-8864-97bfdff7cd80","order_by":6,"name":"Sajedeh Sheikhi Azghandi","email":"","orcid":"","institution":"Shahab Dental Clinic (Oral Medicine and Special Care Dentistry)","correspondingAuthor":false,"prefix":"","firstName":"Sajedeh","middleName":"Sheikhi","lastName":"Azghandi","suffix":""},{"id":411080786,"identity":"f6410357-c958-41da-9db3-2534be7b65aa","order_by":7,"name":"Parham Aghasizadeh Sharbaf","email":"","orcid":"","institution":"Kavian Institute of Higher Education","correspondingAuthor":false,"prefix":"","firstName":"Parham","middleName":"Aghasizadeh","lastName":"Sharbaf","suffix":""},{"id":411080787,"identity":"0777ec8a-8e24-4651-a8ed-440c4c265e1c","order_by":8,"name":"Reid Friesen","email":"","orcid":"","institution":"Mike Petryk School of Dentistry Petry School of Dentistry, Faculty of Medicine and Dentistry, University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Reid","middleName":"","lastName":"Friesen","suffix":""},{"id":411080788,"identity":"2cefb880-43c2-4349-8add-f0eba28f691f","order_by":9,"name":"Eduardo Rodrigues Fregnani1","email":"","orcid":"","institution":"Centro de Oncologia Molecular, Instituto de Ensino e Pesquisa, Hospital Sírio-Libanês","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"Rodrigues","lastName":"Fregnani1","suffix":""}],"badges":[],"createdAt":"2025-01-29 06:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5922241/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5922241/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00520-025-09649-6","type":"published","date":"2025-07-06T15:57:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86179240,"identity":"d3e744a6-c8cc-4599-adfe-82ca9d1c9a47","added_by":"auto","created_at":"2025-07-07 16:17:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":495907,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5922241/v1/e5115724-7a44-4e0a-8fc3-8801df7597d6.pdf"},{"id":75649228,"identity":"df87d397-3241-4295-95d6-187e1476362d","added_by":"auto","created_at":"2025-02-06 17:31:57","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":39689,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5922241/v1/5ba78ee08b3ea5839bfc680c.docx"}],"financialInterests":"Competing interest reported. PMM serves as the Scientific Mentor at Shahab Clinic. SS and Parham Aghasizadeh Sharbaf are research assistant at Shahab Clinic. Other authors have no competing interests.","formattedTitle":"Introducing Equivalent and Threshold Doses in the Assessment of Medication-Related Osteonecrosis of the Jaw Risk: Insights from a Descriptive Study in Iran","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMedication-related osteonecrosis of the jaw (MRONJ) is a rare but serious condition characterized by jawbone necrosis. Initially recognized in 2003 as an adverse effect of bisphosphonates\u0026mdash;drugs used to regulate bone metabolism\u0026mdash;MRONJ has since been associated with a broader range of medications. These include anti-angiogenesis agents, cytotoxic drugs, and newer therapies such as CDK4/6 inhibitors, adalimumab, and pembrolizumab. Emerging evidence also suggests that medications like ocrelizumab, recently introduced for the treatment of multiple sclerosis, may contribute to MRONJ development. [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eUnderstanding MRONJ requires a detailed analysis of its clinical features and risk factors across diverse patient populations. Despite the growing body of research, descriptive studies focusing on the frequency and characteristics of MRONJ within large cohorts in Iran remain scarce. This study aims to address this gap by exploring the prevalence, clinical presentations, and associated risk factors of MRONJ at various stages in a substantial cohort.\u003c/p\u003e \u003cp\u003eAdditionally, this research compares the findings with a cohort of \"at-risk\" patients currently receiving MRONJ-related medications (MRMs) but who have not yet developed clinical symptoms. To enhance the predictive accuracy of MRONJ risk, this study introduces two novel indices\u0026mdash;equivalent dose and threshold dose\u0026mdash;that consolidate previously recognized medication-related risk factors into unified metrics.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective study utilized archived patient files from two primary oral medicine clinics in Mashhad, the capital of Khorasan Razavi province, which serve as referral centers for northeastern Iran. The study period spanned from September 2017 to March 2023. The clinics involved were Shahab Clinic, a private oral medicine and special care dentistry center, and the Oral Medicine Department of Mashhad Dental School at Mashhad University of Medical Sciences (MUMS), a public referral institution.\u003c/p\u003e\n\u003cp\u003eData were collected using a self-designed checklist from patient files, encompassing various stages of MRONJ. Extracted information included demographic data, medical history, laboratory parameters, dental history, clinical features, oral health index scores, and MRONJ staging. Data on patients identified as \u0026quot;at risk\u0026quot; but not yet exhibiting MRONJ symptoms were also gathered.\u003c/p\u003e\n\u003cp\u003eTo estimate the risk of MRONJ, an index was employed based on prior studies correlating MRONJ with the duration and cumulative dose of MRONJ-Related Medications(MRMs) [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. An equivalent dose was defined as the cumulative dose of four continuous years of weekly oral alendronate 70 mg, totaling 14,560 mg. Other medications were converted into equivalent doses relative to this threshold, as outlined in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. In cases of polytherapy, the dosages of multiple medications were summed to calculate a total equivalent dose. Patients exceeding this threshold were considered at increased risk for MRONJ, consistent with findings from previous studies [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe provided durations represented the time required to reach the equivalent of a 4-year cumulative dose for osteoporosis treatment in a cancer context, based on specified dosing regimens. The study included patients who had not yet surpassed the defined threshold dose.\u003c/p\u003e\n\u003cp\u003eThe research protocol was registered with the ethics committee of MUMS under grant number 4010615 and research code R.MUMS.DENTISTRY.REC.1401.065. and was conducted in compliance with the principles outlined in the Declaration of Helsinki. All data were handled confidentially.\u003c/p\u003e\n\u003cp\u003eInclusion Criteria: Patients at all MRONJ stages, based on the most recent American Association of Oral and Maxillofacial Surgeons (AAOMS) guidelines, were included. These stages were: at risk, stage 0, stage 1, stage 2, or stage 3 [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Eligibility criteria included:Current or previous treatment with antiresorptive therapy, either alone or combined with immunomodulators or antiangiogenic medications. The presence of exposed bone or bone that could be probed through an intraoral or extraoral fistula persisting for more than 8 weeks.No history of radiation therapy or metastatic disease to the jaws.\u003c/p\u003e\n\u003cp\u003ePatients categorized as \u0026quot;at risk\u0026quot; were those undergoing antiresorptive or other MRMs but without clinical signs, symptoms, fistulae, or necrosis. Files lacking sufficient data were excluded.\u003c/p\u003e\n\u003cp\u003eSample Size and Statistical Analysis: The sample size was determined based on available patient files in the two archives, with data inclusion ending in March 2023. Data were imported into Microsoft Excel 2019 and analyzed using SPSS version 20 (IBM Inc). Descriptive statistics, including measures of central tendency, dispersion indices, and frequency distribution, characterized the data. Statistical tests such as T-test, Fisher exact test, Chi-square test, Mann\u0026ndash;Whitney U test, Kruskal-Wallis test, ANOVA, and Welch test were applied, with the significance level set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, 193 cases were enrolled, with 78 cases (40.41%) at various stages of MRONJ and 115 cases (59.58%) at the at-risk stage. The MRONJ group included 12 cases (15.38%) at Stage 0, 14 cases (17.94%) at Stage 1, 30 cases (38.46%) at Stage 2, and 22 cases (28.20%) at Stage 3. The demographic and baseline characteristics of the study population are presented in Table 2.\u003c/p\u003e\n\u003cp\u003eA total of 20 MRONJ patients and 19 at-risk patients presented with comorbid (excluding the primary disease requiring MRM administration) such as diabetes, anemia, cardiovascular disease, thyroid disorders, rheumatologic conditions, gastrointestinal issues, neurologic and dermatologic disorders, renal dysfunction, and respiratory diseases. The remaining cases in both groups had no additional comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean age was significantly higher in the MRONJ group (59.64 ± 13.67 years) compared to the at-risk group (53.24 ± 11.32 years) (P=0.001). Oncologic diseases were more prevalent in the MRONJ group (P=0.01), with prostate and breast cancer showing a particularly strong association with higher MRONJ incidence.\u003c/p\u003e\n\u003cp\u003eNo significant differences in variables such as age, sex, BMI, oral health indices, habits, primary disease, and comorbidities were observed across MRONJ stages (P\u0026gt;0.05). Table 3 outlines the events leading to MRONJ across different stages. Tooth extractions and ill-fitting dentures were more commonly associated with higher MRONJ stages; however, the difference was not statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCases involving multiple events were linked to more advanced stages. For example, tooth extractions followed by denture placement were reported in eight cases (two in stage 2 and six in stage 3). Implant placement followed by overdenture placement was noted in three cases (two in stage 3 and one in stage 2). One stage 3 patient underwent multiple osteotomy surgeries due to a misdiagnosis of osteomyelitis. When combining the “multiple events” and “extraction” groups, these interventions were significantly associated with higher MRONJ stages (P=0.006). Conversely, patients with spontaneous disease onset, without prior interventions, were more commonly found in lower MRONJ stages.\u003c/p\u003e\n\u003cp\u003eThe MRONJ group demonstrated significantly higher creatinine levels and lower hemoglobin levels compared to the at-risk group (P=0.009 and P=0.013, respectively). No differences were observed in other laboratory parameters, including FBS, HbA1C, BUN, WBC, RBC, and PLT.\u003c/p\u003e\n\u003cp\u003eTable 4 presents data on MRMs, including type, frequency, and administration route. Table 5 details the dosage, equivalent dose, and threshold dose for both groups. Zoledronic acid users were significantly more prevalent in the MRONJ group (P=0.01), while fewer MRONJ cases involved alendronate. Monthly dosing regimens were more common in the MRONJ group (P=0.003). The median dosage of zoledronic acid was higher in MRONJ patients (P\u0026lt;0.001). The median equivalent dose of MRMs was also significantly higher in the MRONJ group by 1.42 units (P=0.001).\u003c/p\u003e\n\u003cp\u003eA significantly greater proportion of MRONJ patients exceeded the threshold dose compared to the at-risk group (P\u0026lt;0.001). The median duration of MRM use was 13.5 months longer in the MRONJ group, a statistically significant difference (P=0.002).\u003c/p\u003e\n\u003cp\u003eTable 6 explores the dosage, drug regimens, drug combinations, administration routes, equivalent doses, threshold doses, and duration of use for different MRONJ stages. Zoledronic acid use was more frequent in stages 2 and 3 (P=0.005), while denosumab use was more common in stages 0 and 1 (P=0.005). Patients receiving parenteral or combined oral and parenteral medication had the highest prevalence in stages 2 and 3 (P=0.03). Median zoledronic acid doses were highest in stage 3 and lowest in stage 1 (P=0.026). Advanced stages correlated with higher equivalent doses (P\u0026lt;0.001, R=0.46). Prolonged use of MRMs was linked to more advanced stages (P=0.003, R=0.362).\u003c/p\u003e\n\u003cp\u003eWhile clinical findings such as fistulae, ulcers, tooth mobility, pain, halitosis, and bleeding were not directly correlated with MRONJ stages, multiple concurrent symptoms were more frequent in advanced stages (P\u0026lt;0.001). Patients in stages 2 and 3 exhibited more numerous and diverse clinical signs compared to earlier stages. Although pain was significantly more prevalent in stage 0,compared to other symptoms.(P\u0026lt;0.01)\u003c/p\u003e\n\u003cp\u003eTable 7 shows jaw involvement across MRONJ cases. The mandible was significantly more affected than the maxilla, with 48 cases involving the mandible, 11 cases involving the maxilla, and 9 cases involving both jaws (P\u0026lt;0.001). No significant differences were noted between posterior and anterior jaw portions or across MRONJ stages (P\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eAlthough no significant difference in oncotherapy protocols was observed between the MRONJ and at-risk groups (P=0.05), higher disease stages were significantly associated with histories of concurrent chemotherapy and radiotherapy or radiotherapy alone (P=0.02).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e This study represents the first descriptive analysis of MRONJ in Iran, utilizing data from two leading oral medicine centers in Mashhad. It examines clinical characteristics and risk factors associated with MRONJ across various stages and compares these findings with at-risk individuals who have not yet developed the condition but require focused preventive strategies. A notable contribution of this study is the introduction of the equivalent dose and threshold dose metrics, inspired by Schifter's proposal, which provide novel dimensions to risk assessment by consolidating dosage, duration, and regimen. These findings offer insights into patient demographics, MRMs, symptoms, and disease stages, aligning with previous research that emphasizes cumulative drug exposure as a critical risk factor for MRONJ, particularly in patients requiring aggressive antiresorptive therapy.\u003c/p\u003e \u003cp\u003eThe results revealed that MRONJ patients tend to be older than those in the at-risk group, likely due to prolonged drug treatment and age-related changes in bone metabolism. Although advanced stages (stages 2 and 3) were more common in older individuals, the age difference across stages was not statistically significant. The observed increase in MRONJ incidence with age is consistent with prior studies. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Contrary to some reports, this study found no significant association between MRONJ stages and factors such as sex, tobacco use, BMI, or oral hygiene. [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOncologic diseases were significantly more prevalent in the MRONJ group compared to the at-risk group (P\u0026thinsp;=\u0026thinsp;0.01), with these patients frequently presenting in advanced stages, particularly when undergoing concurrent chemotherapy and radiotherapy. This aligns with studies linking chemotherapy to exacerbated clinical manifestations of MRONJ, likely due to dose-dependent toxicity on bone marrow, soft tissues, and bone metabolism. [\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our findings also highlight a higher prevalence of MRONJ among patients with multiple myeloma and breast or prostate cancer, consistent with Marcian\u0026ograve;'s research on cancer metastasis patterns. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] However, the study\u0026rsquo;s limited access to a broader range of cancer patients underscores the need for a national database to track medication and disease histories comprehensively. This restriction introduces a selection bias that impacts the breadth and applicability of our findings.\u003c/p\u003e \u003cp\u003eThe link between MRMs and an increased risk of MRONJ has been well-documented. Our study found differences in the MRM regimens between the MRONJ group and the at-risk group and across various MRONJ stages. While some studies suggest a higher incidence of MRONJ with zoledronic acid both clinically and on a cellular level [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], others indicate a greater risk for cancer patients treated with denosumab [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In our findings, 48.5% of zoledronic acid users and 44.4% of denosumab users developed MRONJ, compared to only 7.22% of those on alendronate, highlighting a higher risk associated with the first two medications. This high incidence can be due to selection bias and the fact that not all the patients receiving MRMs were recruited. Although guidelines emphasize that individuals should visit a dentist for clearance before starting MRMs, unfortunately, this issue is not taken seriously by either the physicians or the patients. In many cases, patients only visit the dentist after a problem has already developed. Therefore, a large portion of those who receive MRMs and do not experience any issues in the oral and jaw area never seek dental consultation, making our study sample not representative of the entire population at risk. Additionally, the incidence of MRONJ was 50% in individuals using multiple medications, supporting research that combination therapy leads to a higher MRONJ prevalence\u0026mdash;13% in users of both bisphosphonates and denosumab, versus 5% and 4% for single-drug users respectively [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSurgical manipulations, particularly tooth extractions and ill-fitting dentures, were significant risk factors for MRONJ, especially in advanced stages. Grouping these factors under \"multiple events\" highlighted their association with higher MRONJ stages. This finding aligns with cohort studies indicating that tooth extractions increase MRONJ risk 18 times, with a similar increase for users of ill-fitting dentures [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, our non-cohort study design did not allow for such risk quantification.\u003c/p\u003e \u003cp\u003eThe analysis of laboratory markers identified higher creatinine and lower hemoglobin levels in MRONJ patients, likely reflecting comorbidities and older age. Elevated creatinine suggests impaired renal function, while lower hemoglobin points to systemic conditions that may exacerbate MRONJ. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eRoute of administration was identified as a potential risk factor for MRONJ, with parenteral administration, alone or combined with oral, showing a significantly higher occurrence in stages 2 and 3 of the disease (P\u0026thinsp;=\u0026thinsp;0.03). Evidence supports that parenteral administration of MRMs is linked to MRONJ [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], and sometimes it is independent of dosage [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, the introduction of the equivalent dose and threshold dose concepts in this study challenges this correlation, suggesting that the medicine itself, rather than its administration route, poses a risk, as parenteral routes achieve threshold doses more rapidly.\u003c/p\u003e \u003cp\u003eIn our study, the highest doses of zoledronic acid and denosumab were associated with stage 3 of the disease, and there was a correlation between the dose of zoledronic acid and the disease stages. Studies have shown that the cumulative dose of zoledronic acid and denosumab in patients with MRONJ is higher [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. However, to date, no study has examined the cumulative dose of medications concerning the disease stage, and therefore it is not possible to compare the results of our study directly. We introduced the equivalent dose instead of the cumulative dose.\u003c/p\u003e \u003cp\u003eOur study confirmed that a longer duration of MRMs\u0026rsquo; use correlates with a higher incidence of MRONJ, consistent with prior research. Aljohani highlighted prolonged bisphosphonate use as a risk factor for MRONJ [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Ng and colleagues' systematic review showed that MRONJ risk among cancer patients using zoledronic acid increased from 1.6\u0026ndash;4% after two years and 3.8\u0026ndash;18% after more than two years; whereas, for denosumab users, the risk was 1.9% for less than 24 months and rose to 6.9% for longer than 24 months [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, contrasting findings from Mirkhani and Saad suggest that the duration of denosumab use does not consistently affect MRONJ occurrence, indicating that other factors may also influence MRONJ risk [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, the equivalent dose\u0026mdash;a cumulative measure incorporating dose, type, duration, and regimen of medication\u0026mdash;was higher in MRONJ patients than in those at risk, particularly in stage 3. This suggests that the equivalent dose, by accounting for these factors individually, can help explain their separate impacts on both the occurrence and severity of MRONJ. Also, we could present a threshold dose as the cut-off point for the risk estimate of MRONJ.\u003c/p\u003e \u003cp\u003eIn agreement with other studies, the majority of MRONJ lesions occurred in the lower jaw [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. One study explained this by noting that the lower jaw is exposed to greater chewing forces than the upper jaw, which may increase the risk of trauma and infection [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Bleeding, ulcers, and trismus were more commonly observed in stage 3 of the disease. In the study by Wang and colleagues, bone exposure and pain were among the most common clinical findings in affected individuals [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Based on our findings, individuals who are at stage 0 of the disease may only experience pain, which could serve as an early warning sign for the onset of MRONJ.\u003c/p\u003e \u003cp\u003eThe main limitation of this retrospective study is the reliance on medical records from dental centers not specifically designed for this research, which may restrict the data quality and complicate identifying potential confounding factors. This limitation is compounded by the fact that the data comes from dental services where many patients were seeking MRONJ treatment or dental check-up, thus hindering the ability to calculate the true incidence and limiting the generalizability of the results. Additionally, while the study highlights the role of cumulative dosage in MRONJ development, it does not fully explore the interaction between medication regimens and other contributing factors such as genetics, underlying health conditions, and concurrent treatments like chemotherapy or radiotherapy.\u003c/p\u003e \u003cp\u003eThe most novel aspect of this study is the introduction of the equivalent and threshold doses, which consolidate variables like dosage, duration, and regimen. This approach enables the calculation of risk for patients who have used multiple MRMs. Although the calculation of these two new variables is based on Schifter\u0026rsquo;s proposal, more studies with larger sample sizes are needed for a more precise calculation and to identify a finer risk index. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn conclusion, this study highlights the need for dentists and medical professionals to be aware of the MRONJ risk, particularly for patients using MRMs and those with symptoms, especially pain, as potential early signs of MRONJ. Preventive measures, such as regular examinations of at-risk patients and dental interventions following established protocols, are recommended to mitigate the risk of MRONJ. Future research should evaluate the relationship between the equivalent dose of MRMs, the type of chemotherapy regimen, and the occurrence and severity of MRONJ to provide a more holistic understanding.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003ePMM serves as the Scientific Mentor at Shahab Clinic. SS and Parham Aghasizadeh Sharbaf are research assistant at Shahab Clinic. Other authors have no competing interests.\u003c/p\u003e \u003ch2\u003eHuman Ethics Declaration:\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Mashhad University of Medical Sciences on August 31, 2022, under grant number 4010615 and code 1401.065 IR.MUMS.DENTISTRY.REC.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFundings:\u003c/h2\u003e \u003cp\u003eThis work was supported by the Vice-Chancellor for Research at Mashhad University of Medical Sciences [grant number 4010615].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Pooria AS, ANF, MD, SSA and SVK. The first draft of the manuscript was written by PMM and LFM. Project administration was done by PMM. RF and ERF supervised the submission and Writing - Review \u0026amp; Editing process. All authors commented on previous versions of the manuscript. All authors read and approved of the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis article is based on an undergraduate thesis (ANF undergraduate thesis for general dentistry doctorate - number: 3485) presented to Mashhad Dental School. The authors are grateful to the Vice-Chancellor for Research at MUMS, who funded this study. The authors are thankful to Shahab Oral Medicine and Special Care Dentistry Clinic for providing access to patient records while maintaining confidentiality and supporting the researchers throughout the various stages of the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRuggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D(2022) American Association of Oral and Maxillofacial Surgeons\u0026apos; Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg. https://doi.org/10.1016/j.joms.2022.02.008\u003c/li\u003e\n\u003cli\u003ePatel V, Carey B (2023) Pembrolizumab-related osteonecrosis of the jaw. Br J Oral Maxillofac Surg . https://doi.org/10.1016/j.bjoms.2023.08.241\u003c/li\u003e\n\u003cli\u003eSisalli L, Giordano F, Chiacchio A, Acerra A, Caggiano M (2023) Medication-Related Osteonecrosis of the Jaw: A Case Report of an Unusual Side Effect of Adalimumab. Case Rep Dent. https://doi.org/10.1155/2023/5544285\u003c/li\u003e\n\u003cli\u003eMozafari PM, Farrokhie ZS, Nahayati MA, Anbiaee N (2023) Medication-Related Osteonecrosis of the Jaw (MRONJ) as a Consequence of Multiple Sclerosis Treatment. Clin Oral Sci Dent 6:1.\u003c/li\u003e\n\u003cli\u003eNicolatou-Galitis O, Kouri M, Papadopoulou E, Vardas E, Galiti D, Epstein JB, et al (2019) Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer https://doi.org/10.1007/s00520-018-4501-x\u003c/li\u003e\n\u003cli\u003eSen\u0026iacute;n LD, Pancorbo DM, Garc\u0026eacute;s MYR, Santos-Rubio MD, Calero JB (2024) Relationship between Medication-Related Osteonecrosis of the Jaw and CDK4/6 Inhibitors in Breast Cancer. Curr Oncol . https://doi.org/10.3390/curroncol31010016\u003c/li\u003e\n\u003cli\u003eAhdi H, Wichelmann TA, Pandravada S, Ehrenpreis E (2024) Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab: A Case Series from the FDA Adverse Event Reporting System (FAERS) Database. https://doi.org/10.21203/rs.3.rs-4088785/v1 \u003c/li\u003e\n\u003cli\u003eSchifter M, McLean M, Sukumar S (2021) Disorders of the Endocrine System and of Metabolism. In: Burket\u0026apos;s Oral Medicine. Wiley, New York, pp 817\u0026ndash;902. https://doi.org/10.1002/9781119597797.ch22\u003c/li\u003e\n\u003cli\u003eLo JC, O\u0026apos;Ryan F, Gordon NP, Yang J, Hui RL, Martin DC, et al (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2009.03.050\u003c/li\u003e\n\u003cli\u003eDrudge-Coates L, Van den Wyngaert T, Schi\u0026oslash;dt M, Van Muilekom H, Demonty G, Otto S (2020) Preventing, identifying, and managing medication-related osteonecrosis of the jaw: a practical guide for nurses and other allied healthcare professionals. Support Care Cancer . https://doi.org/10.1007/s00520-020-05440-x\u003c/li\u003e\n\u003cli\u003eOttesen C, Schi\u0026oslash;dt M, Gotfredsen K (2020) Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): A systematic review. Heliyon https://doi.org/10.1016/j.heliyon.2020.e03795 \u003c/li\u003e\n\u003cli\u003eNicolatou-Galitis O, Schi\u0026oslash;dt M, Mendes RA, Ripamonti C, Hope S, Drudge-Coates L, et al (2019) Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2018.09.008 \u003c/li\u003e\n\u003cli\u003eKajizono M, Sada H, Sugiura Y, Soga Y, Kitamura Y, Matsuoka J, Sendo T (2015) Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull . https://doi.org/10.1248/bpb.b15-00385 \u003c/li\u003e\n\u003cli\u003eFeng Z, An J, Zhang Y (2021) Factors influencing severity of medication-related osteonecrosis of the jaw: A retrospective study. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2020.12.045 \u003c/li\u003e\n\u003cli\u003eKang MH, Lee DK, Kim CW, Song IS, Jun SH (2018) Clinical characteristics and recurrence-related factors of medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg . https://doi.org/10.1016/j.heliyon.2020.e03795 \u003c/li\u003e\n\u003cli\u003eSaad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck A, et al (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. https://doi.org/10.1093/annonc/mdr435 \u003c/li\u003e\n\u003cli\u003eKyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, et al (2008) Bisphosphonate-related osteonecrosis of the jaws: A case-control study of risk factors in breast cancer patients. J Clin Oncol . https://doi.org/10.1200/JCO.2008.16.2768 \u003c/li\u003e\n\u003cli\u003eYamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, et al (2012) Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg . https://doi.org/10.1016/j.ijom.2012.06.020 \u003c/li\u003e\n\u003cli\u003eTsao C, Darby I, Ebeling PR, Walsh K, O\u0026apos;Brien-Simpson N, Reynolds E, Borromeo G (2014) Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2013.02.016 \u003c/li\u003e\n\u003cli\u003eFusco V, Cabras M, Erovigni F, Dell\u0026rsquo;Acqua A, Arduino PG, Pentenero M, et al (2021) A multicenter observational study on medication-related osteonecrosis of the jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy. Med Oral Patol Oral Cir Bucal . https://doi.org/10.4317/medoral.24318 \u003c/li\u003e\n\u003cli\u003eBanfi A, Podest\u0026agrave; M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, et al (2001) High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer . https://doi.org/10.1002/1097-0142(20011101)92:9\u0026lt;2419::AID-CNCR1591\u0026gt;3.0.CO;2-K \u003c/li\u003e\n\u003cli\u003eOteri G, Campisi G, Panzarella V, Morreale I, Nucera R, Di Fede O, et al (2018) Could the combined administration of bone antiresorptive drug, taxanes, and corticosteroids worsen medication-related osteonecrosis of the jaws in cancer patients? Biomed Res Int. https://doi.org/10.1155/2018/4021952 \u003c/li\u003e\n\u003cli\u003eZhou Y, Yu Y, Shi Y, Li M, Yang C, Wang S (2020) Combined administration of bisphosphonates, chemotherapeutic agents, and/or targeted drugs increases the risk for stage 3 medication-related osteonecrosis of the jaw: A 4-year retrospective study. Biomed Res Int. https://doi.org/10.1155/2020/5847429 \u003c/li\u003e\n\u003cli\u003eShim K, MacKenzie MJ, Winquist E (2008) Chemotherapy-associated osteonecrosis in cancer patients with solid tumours: a systematic review. Drug Saf. https://doi.org/0114-5916/08/0005-0359/$48.00/0 \u003c/li\u003e\n\u003cli\u003eBi Y, Gao Y, Ehirchiou D, Cao C, Kikuiri T, Le A, et al (2010) Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol . https://doi.org/10.2353/ajpath.2010.090592 \u003c/li\u003e\n\u003cli\u003eMarcian\u0026ograve; A, Ingrasciotta Y, Isgr\u0026ograve; V, L\u0026apos;Abbate L, Foti SS, Picone A, et al (2021) Cancer patients at risk for medication-related osteonecrosis of the jaw: A case and control study analyzing predictors of MRONJ onset. J Clin Med . https://doi.org/10.3390/jcm10204762 \u003c/li\u003e\n\u003cli\u003eRuggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O\u0026apos;Ryan F (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2014.04.031 \u003c/li\u003e\n\u003cli\u003eRoato I, Pavone L, Pedraza R, Bosso I, Baima G, Erovigni F, Mussano F (2023) Denosumab and zoledronic acid differently affect circulating immune subsets: a possible role in the onset of MRONJ. Cells . https://doi.org/10.3390/cells12202430 \u003c/li\u003e\n\u003cli\u003eLimones A, S\u0026aacute;ez-Alcaide LM, D\u0026iacute;az-Parre\u0026ntilde;o SA, Helm A, Bornstein MM, Molinero-Mourelle P (2020) Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab vs zoledronic acid: A systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal . https://doi.org/10.4317/medoral.23324 \u003c/li\u003e\n\u003cli\u003eHallmer F, Bjarnadottir O, G\u0026ouml;trick B, Malmstr\u0026ouml;m P, Andersson G (2020) Incidence of and risk factors for medication-related osteonecrosis of the jaw in women with breast cancer with bone metastasis: a population-based study. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2020.04.808 \u003c/li\u003e\n\u003cli\u003eIkesue H, Mouri M, Tomita H, Hirabatake M, Ikemura M, Muroi N, et al (2021) Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases. Support Care Cancer . https://doi.org/10.1007/s00520-021-06018-x \u003c/li\u003e\n\u003cli\u003eSrivastava A, Nogueras Gonzalez GM, Geng Y, Won AM, Cabanillas ME, Naing A, et al (2021) Prevalence of medication-related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis. Support Care Cancer . https://doi.org/10.1007/s00520-020-05882-3 \u003c/li\u003e\n\u003cli\u003eVahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis C, et al (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol . https://doi.org/10.1200/JCO.2009.21.9584 \u003c/li\u003e\n\u003cli\u003eKim YH, Park HK, Choi NR, Kim SW, Kim GC, Hwang DS, et al (2017) Relationship between disease stage and renal function in bisphosphonate-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg . https://doi.org/10.5125/jkaoms.2017.43.1.16\u003c/li\u003e\n\u003cli\u003eGraves LL, Bukata SV, Aghazadehsanai N, Chang TI, Garrett NR, Friedlander AH (2016) Patients receiving parenteral bisphosphonates for malignant disease and having developed an atypical femoral fracture are at risk of concomitant osteonecrosis of the jaw: an evidence-based review. J Oral Maxillofac Surg . https://doi.org/10.1016/j.joms.2016.06.003\u003c/li\u003e\n\u003cli\u003eYao S, Ding X, Rong G, Zhou J, Zhang B (2023) Association between malignant diseases and medication-related osteonecrosis of the jaw (MRONJ): A systematic review and meta-analysis. J Craniofac Surg . https://doi.org/10.1097/SCS.0000000000009033\u003c/li\u003e\n\u003cli\u003eKim HW, Lee MW, Lee JH, Kim MY (2021) Comparison of the effect of oral versus intravenous bisphosphonate administration on osteoclastogenesis in advanced-stage medication-related osteonecrosis of the jaw patients. J Clin Med .\u003c/li\u003e\n\u003cli\u003eFeng Z, An J, He Y, Zhang Y (2022) A comparative study of the clinical characteristics of patients with medication-related osteonecrosis of the jaw and osteoporosis or malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol . https://doi.org/10.1016/j.oooo.2022.04.049\u003c/li\u003e\n\u003cli\u003eAljohani S, Fliefel R, Ihbe J, K\u0026uuml;hnisch J, Ehrenfeld M, Otto S (2017) What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review. J Cranio-Maxillofac Surg . https://doi.org/10.1016/j.jcms.2017.05.028\u003c/li\u003e\n\u003cli\u003eNg TL, Tu MM, Ibrahim MFK, Basulaiman B, McGee SF, Srikanthan A, et al (2021) Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review. Support Care Cancer . https://doi.org/10.1007/s00520-020-05556-0\u003c/li\u003e\n\u003cli\u003eZakhary I, Khanafer A, Mirkhani M (2017) Idiopathic incidence of MRONJ in patients on denosumab. Clin Surg 2:1410.\u003c/li\u003e\n\u003cli\u003ede Oliveira CC, de Sousa FB (2016) Osteonecrosis of the jaw induced by receptor activator of nuclear factor-kappa B ligand (denosumab)-Review. Med Oral Patol Oral Cir Bucal .https://doi.org/10.4317/medoral.21044\u003c/li\u003e\n\u003cli\u003eZirk M, Kreppel M, Buller J, Pristup J, Peters F, Dreiseidler T, Zinser M, Z\u0026ouml;ller JE (2017) The impact of surgical intervention and antibiotics on MRONJ stage II and III: a retrospective study. J Cranio-Maxillofac Surg . https://doi.org/10.1016/j.jcms.2017.05.027\u003c/li\u003e\n\u003cli\u003eInchingolo AM, Malcangi G, Ferrara I, Patano A, Viapiano F, Netti A, et al (2023) MRONJ treatment strategies: A systematic review and two case reports. Appl Sci . https://doi.org/10.3390/app13074370\u003c/li\u003e\n\u003cli\u003eWang Q, Liu J, Qi S, Liao X, Liu D, Pan J (2018) Clinical analysis of medication-related osteonecrosis of the jaws: A growing severe complication in China. J Dent Sci . https://doi.org/10.1016/j.jds.2017.12.003\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 7 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5922241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5922241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose:\u003c/h2\u003e \u003cp\u003eTo investigate the clinical characteristics and risk factors associated with medication-related osteonecrosis of the jaw (MRONJ) and to introduce two metrics\u0026mdash;equivalent dose and threshold dose\u0026mdash;as predictive risk assessment tools.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e This retrospective study reviewed 193 patient records from Shahab Clinic and the Oral Medicine Department of Mashhad Dental School (2017\u0026ndash;2023). Patients were categorized into MRONJ stages (0\u0026ndash;3) and an \"at-risk\" group. Data on demographics, comorbidities, clinical presentations, and detailed medication profiles were analyzed. Equivalent dose was standardized to four years of oral alendronate use, and threshold dose provided a cumulative risk cut-off. Statistical analyses( T-tests, ANOVA, Chi-square tests,.) were applied .\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eMRONJ was identified in 40.4% of cases, while 59.6% were classified as at-risk. Advanced stages were significantly associated with higher equivalent doses, prolonged medication use, and key risk factors, including oncologic diseases, medication type and route of administration, comorbidities, age, and surgical interventions such as extractions and ill-fitting dentures (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The novel metrics demonstrated strong predictive value, with higher equivalent doses correlating closely with MRONJ severity (R\u0026thinsp;=\u0026thinsp;0.46, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis study offers critical insights into MRONJ risk stratification, highlighting the cumulative impact of medication dose alongside clinical risk factors. The introduction of equivalent and threshold doses represents a transformative advancement in MRONJ risk prediction, enabling precise prevention strategies and guiding clinical management toward standardized care protocols.\u003c/p\u003e","manuscriptTitle":"Introducing Equivalent and Threshold Doses in the Assessment of Medication-Related Osteonecrosis of the Jaw Risk: Insights from a Descriptive Study in Iran","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-06 17:31:52","doi":"10.21203/rs.3.rs-5922241/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-17T03:54:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-12T13:08:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44376488057362238954118365681267654154","date":"2025-04-02T21:52:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-02T16:28:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-07T21:04:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-04T13:29:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-01-29T06:31:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0cf2fcec-c809-4f98-8c95-d9adb70d63d2","owner":[],"postedDate":"February 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:06:57+00:00","versionOfRecord":{"articleIdentity":"rs-5922241","link":"https://doi.org/10.1007/s00520-025-09649-6","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2025-07-06 15:57:14","publishedOnDateReadable":"July 6th, 2025"},"versionCreatedAt":"2025-02-06 17:31:52","video":"","vorDoi":"10.1007/s00520-025-09649-6","vorDoiUrl":"https://doi.org/10.1007/s00520-025-09649-6","workflowStages":[]},"version":"v1","identity":"rs-5922241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5922241","identity":"rs-5922241","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}