ΔBSIJ: A quantitative marker for early detection of medication-related osteonecrosis of the jaw in patients with prostate cancer receiving bone-modifying agents

ΔBSIJ: A quantitative marker for early detection of medication-related osteonecrosis of the jaw in patients with prostate cancer receiving bone-modifying agents | 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 ΔBSIJ: A quantitative marker for early detection of medication-related osteonecrosis of the jaw in patients with prostate cancer receiving bone-modifying agents Hidetoshi Kokubun, Toshiki Kijima, Yuumi Tokura, Toshitaka Uematsu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5795022/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jul, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Objective: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bone-modifying agent (BMA) therapy in patients with prostate cancer and bone metastasis. This study aimed to assess the effectiveness of the temporal changes in jaw-specific bone scan index (ΔBSIJ) as quantitative markers for early prediction of MRONJ in patients with prostate cancer receiving BMA therapy. Methods: This retrospective study included 33 patients with prostate cancer with bone metastases who underwent bone scintigraphy before and after BMA initiation. BSIJ was measured using BONENAVI software, and the difference between pre- and post-BMA BSIJ values was considered ΔBSIJ. Statistical analyses, including paired t-test, receiver operating characteristic (ROC) curve analysis, and Kaplan–Meier survival estimate, were employed to assess the predictive value of ΔBSIJ for MRONJ. Results: Of the 33 patients, 10 developed MRONJ during a median follow-up period of 29 months. ΔBSIJ was significantly higher in the MRONJ group than in the non-MRONJ group (0.05 vs. –0.04, p = 0.002). ROC analysis revealed the highest area under the curve (AUC = 0.823) for ΔBSIJ compared with the pre- and post-BMA BSIJ values. A ΔBSIJ cutoff of 0.039 predicted MRONJ with 60% sensitivity and 91% specificity. Patients with ΔBSIJ ≥ 0.039 exhibited significantly shorter MRONJ-free survival than those with ΔBSIJ < 0.039 (median: 18.4 months vs. not reached, p < 0.001). Conclusion: ΔBSIJ is a novel and clinically useful quantitative marker for the early detection of MRONJ in patients with prostate cancer receiving BMA therapy. This study highlights the potential of leveraging functional imaging and temporal changes in BSIJ to improve MRONJ management. ΔBSIJ Medication-related osteonecrosis of the jaw Bone scintigraphy Prostate cancer Bone-modifying agents Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Prostate cancer is a common malignancy in men, and a significant proportion of patients develop bone metastases during the course of the disease. Bone-modifying agents (BMAs), including bisphosphonates and denosumab, are frequently used to reduce skeletal-related events in patients with bone metastasis. However, medication-related osteonecrosis of the jaw (MRONJ), a severe condition that profoundly impacts quality of life (QOL) of the patient and interferes with ongoing cancer treatment, is a well-recognized adverse event of BMA therapy [ 1 , 2 ]. ​ Early detection of MRONJ is crucial to mitigate its progression and associated complications. Once clinically apparent, invasive management strategies, including surgical intervention, are often necessary for MRONJ, which is associated with substantial morbidity [ 3 ]. Conventionally, MRONJ diagnosis relies on imaging modalities such as radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) [ 4 ]. However, these structural imaging techniques primarily detect anatomical changes but not early metabolic alterations in the bone [ 5 ]. Bone scintigraphy, a functional imaging modality widely used in oncology, offers the unique advantage of detecting early metabolic and pathophysiological changes in the bone. Furthermore, bone scintigraphy detects subtle abnormalities in bone turnover before the appearance of structural changes, unlike conventional imaging, rendering it a promising tool for early MRONJ detection [ 5 – 8 ]. Additionally, bone scintigraphy is routinely performed in patients with prostate cancer to detect bone metastasis and for follow-up, making it feasible to repurpose this modality for MRONJ screening without additional imaging. ​ Although several studies have investigated the role of bone scintigraphy in MRONJ prediction, most lack a robust quantitative framework for evaluating disease progression. The bone scan index (BSI), a semi-automated quantitative metric derived from bone scintigraphy, has proven useful in assessing skeletal metastases and prognostication in prostate cancer. However, its application in MRONJ prediction remains underexplored. Furthermore, although quantitative imaging biomarkers have been incorporated in limited studies [ 5 , 8 ], evaluations of the temporal changes using these indices remain sparse. Consequently, in this study, we utilized BSI to develop a quantitative framework for MRONJ prediction. We hypothesized that changes in the jaw-specific BSI (BSIJ) before and after BMA initiation, quantified as ΔBSIJ, could serve as an early indicator of MRONJ risk. Leveraging a novel and semi-automated approach, this study represents a significant step toward improving the early detection and management of MRONJ in patients with prostate cancer receiving BMA therapy. Materials and methods Patients This single-institution retrospective study involved patients with prostate cancer and bone metastases with a history of receiving BMAs and had evaluable bone scintigraphy images taken before and after BMA administration. Patients for enrollment in this study were screen as follows: First, 1,281 patients with prostate cancer who underwent bone scintigraphy at our hospital between 2008 and 2023 were identified. Of these, 209 patients had positive findings for bone metastases, and among them, 94 patients had received BMAs. Of these, 33 patients who underwent bone scintigraphy both before and after the initiation of BMA treatment were included in the study. MRONJ was diagnosed by an oral and maxillofacial surgeon based on clinical examination, radiographic findings from X-ray and CT imaging, and patient history. Patients diagnosed with MRONJ at any point during follow-up were classified into the MRONJ group, while those without MRONJ were placed in the non-MRONJ group. The study protocol was approved by the Institutional Review Board of Dokkyo Medical University (approval number: R-71-6J). The research plan was communicated through in-hospital announcements and the hospital's website, with an opt-out option for patients who did not wish to participate. Individual informed consent was deemed unnecessary owing to the retrospective nature of the study. BSIJ measurement BSIJ was measured using anterior and posterior whole-body bone scintigraphy images. For patients who underwent multiple bone scintigraphy sessions, the scan obtained immediately before BMA administration was selected as pre-BMA bone scintigraphy, and the scan obtained just before the onset of MRONJ and after BMA administration was selected as post-BMA bone scintigraphy. The cranial region with the upper border at the bottom of the nasal cavity and the lower border at the lower end of the mandible was considered the region of interest (ROI) for BSIJ measurement (Figure 1). The BSI was measured using the BONENAVI ® (version 2; PDRadiopharma Inc., Tokyo, Japan). This software utilizes an artificial neural network (ANN) based on a multicenter database of Japanese patients to automatically detect abnormal accumulation areas, calculate the regional BSI (rBSI) as the ratio of the abnormal accumulation area to the total skeletal area, and assign an ANN score ranging from 0 to 1 for each region. The details of this platform have been described previously [9, 10]. Although the total-body BSI only includes regions with an ANN score of ≥0.5, this study included all regions within the ROI for BSIJ, regardless of their ANN scores. The BSIJ was calculated as the sum of all the rBSI values within the ROI for the BSIJ. A urologist (T. Kokubun) blinded for the clinical information manually set the ROI for BSIJ in the BONENAVI ® software and calculated BSIJ for all cases. As described above, the ROI for BSIJ measurement was manually set based on anatomically well-defined landmarks. As the rBSI calculation was fully automated using the BONENAVI software, the measurement process was entirely objective and did not involve any subjective judgment. Therefore, the involvement of a radiologist or nuclear medicine physician was not essential for this study. Statistical analysis Clinical parameters were expressed as N (%) or median (interquartile range). The differences between MRONJ and non-MRONJ groups were determined using the Fisher's exact test and Mann–Whitney U tests. The BSIJ obtained from pre-BMA and post-BMA bone scintigraphy was defined as the pre-BMA BSIJ and post-BMA BSIJ, respectively. The difference between pre- and post-BMA BSIJ was defined as ΔBSIJ (Figure 2). Paired t-tests were used to compare the pre- and post-BMA BSIJ scores within individual cases. The predictive ability of pre-BMA BSIJ, post-BMA BSIJ, and ΔBSIJ for MRONJ onset was assessed using receiver operating characteristic (ROC) analysis. The area under the curve (AUC) was calculated, and the cut-off value for maximizing the predictability of MRONJ was determined. The predictive performance was evaluated and compared based on the AUC, sensitivity, specificity, positive predictive value, and negative predictive value. Kaplan–Meier method was employed to estimate the MRONJ-free survival, defined as the time from the initiation of BMA therapy to the onset of MRONJ. The log-rank test was used to determine the significance. All statistical analyses were performed using JMP PRO, (version 17; SAS Institute, Cary, NC, USA). Statistical significance was set at p < 0.05. Results Patient characteristics The median follow-up period after BMA initiation in 33 patients was 29 (interquartile range: 21–49) months. Of these, MRONJ occurred only in 10 patients during follow-up. Table 1 presents patient characteristics. The median age was 69 years (64–75 years) and the median prostate-specific antigen (PSA) level at diagnosis was 257.5 ng/mL (20–1015 ng/mL), with 29 patients (88%) classified into a Gleason grade group of ≥4. Androgen deprivation therapy involved gonadotropin-releasing hormone agonists and antagonists in 18 (55%) and 15 (45%) patients, respectively. Fourteen (42%) patients had undergone tooth extraction owing to dental conditions. No new diagnoses of tooth decay or periodontitis were made during the follow-up period, and no cases exhibited worsening of these conditions requiring additional treatment. None of the patients in this study had received radiotherapy to the jaw. BMAs denosumab and zoledronic acid were used in 28 (85%) and 5 (15%) patients, respectively. Patients in the MRONJ group were older than those in the non-MRONJ group; however, no differences in other clinical factors were observed between the two groups. The interval from pre-BMA bone scintigraphy to BMA administration was 1.6 (0.8–4.3) months, and the interval from BMA administration to post-BMA bone scintigraphy was 13.0 (7.6–23.2) months. These intervals did not differ significantly between the MRONJ and non-MRONJ groups. Furthermore, the interval from BMA administration to MRONJ onset was 17.9 (15.9–21.5) months in the MRONJ group, whereas the interval from post-BMA bone scintigraphy to MRONJ onset was 7.6 (0.9–9.2) months. BSIJ before and after BMA administration Figure 3 shows BSIJ progression in a representative case wherein the patient developed MRONJ. In this case, the pre-BMA BSIJ score 1 month before BMA administration was 0.00; however, it increased to 0.031 and 0.068 at 6 and 11 months, respectively. The patient developed MRONJ in the 12th month. Therefore, an increase in the BSIJ score after BMA administration may indicate a higher risk of MRONJ onset. Consequently, we examined changes in BSIJ score before and after BMA administration in both groups. In the MRONJ group, the post-BMA BSIJ score was significantly higher than the pre-BMA BSIJ score (p = 0.026). Conversely, in the non-MRONJ group, the pre-BMA BSIJ score was significantly higher than the post-BMA BSIJ score (p = 0.006; Figure 4). To assess the influence of jawbone metastases on ΔBSIJ, we conducted a subgroup analysis comparing MRONJ-positive and MRONJ-negative patients with and without jawbone metastases. The results demonstrated that in MRONJ-negative patients without jawbone metastases, the median (IQR) ΔBSIJ was –0.012 (–0.015 to 0.023), whereas in MRONJ-negative patients with jawbone metastases, the median (IQR) ΔBSIJ was –0.045 (–0.09 to –0.02). In contrast, MRONJ-positive patients without jawbone metastases exhibited a median (IQR) ΔBSIJ of 0.05 (–0.02 to 0.09), and MRONJ-positive patients with jawbone metastases had a median (IQR) ΔBSIJ of 0.09 (0 to 0.17). Despite the small sample size, these findings suggest that ΔBSIJ tends to be negative in non-MRONJ cases and positive in MRONJ cases, regardless of the presence of jawbone metastases. This indicates that the influence of MRONJ on ΔBSIJ is more pronounced than that of jawbone metastases, supporting its utility as a predictive marker for MRONJ development. MRONJ onset prediction using ΔBSIJ The association among pre-BMA BSIJ, post-BMA BSIJ, ΔBSIJ, and MRONJ onset is presented in Table 2. Notably, no significant difference was observed in the pre-BMA BSIJ score between the MRONJ and non-MRONJ groups. Although the post-BMA BSIJ score tended to be higher in the MRONJ group, the difference was not statistically significant. However, ΔBSIJ was significantly higher in the MRONJ group (0.05, interquartile range: –0.01 to 0.11) than in the non-MRONJ group (–0.04, interquartile range: –0.11 to 0.00) (p = 0.002). Next, we performed ROC analysis to evaluate the predictive performance of pre-BMA BSIJ, post-BMA BSIJ, and ΔBSIJ for MRONJ onset (Figure 5). The AUC was the highest for ΔBSIJ at 0.823, followed by post-BMA BSIJ at 0.713 and pre-BMA BSIJ at 0.596. The cutoff value of 0.039, corresponding to the point with the highest sensitivity ˗ (1 – specificity), was determined based on the ROC curve for ΔBSIJ. Of the 8 patients with ΔBSIJ ≥ 0.039, 6 developed MRONJ, whereas of the 25 patients with ΔBSIJ < 0.039, only 4 developed MRONJ (p = 0.004; Table 3). Similarly, the cutoff values for the pre- and post-BMA BSIJ were determined to be 0.031 and 0.068, respectively, from the ROC curve, and their predictive performances were compared (Table 4). ΔBSIJ demonstrated superior specificity (91%), positive predictive value (75%), and negative predictive value (84%) than the pre- and post-BMA BSIJ, whereas sensitivity (60%) was comparable among the metrics. Furthermore, patients with ΔBSIJ ≥ 0.039 exhibited significantly shorter MRONJ-free survival, with a median survival time of 18.4 months compared with those with ΔBSIJ < 0.039, which did not reach the median survival time during the observation period (p < 0.001; Figure 6). Discussion This study highlights ΔBSIJ as a novel and clinically valuable marker for the early prediction of MRONJ in patients with prostate cancer receiving BMA therapy. Our results demonstrate that ΔBSIJ, defined as the difference between pre- and post-BMA BSIJ values, provides superior predictive accuracy compared to static measures such as pre-BMA and post-BMA BSIJ. The MRONJ group exhibited significantly higher ΔBSIJ values than the non-MRONJ group (0.05 vs. − 0.04, p = 0.002), and ROC analysis confirmed its diagnostic utility with an AUC of 0.823. Using a ΔBSIJ cutoff of 0.039, MRONJ could be predicted with 60% sensitivity and 91% specificity, indicating a strong ability to distinguish high-risk patients. Furthermore, Kaplan–Meier analysis revealed that patients with ΔBSIJ ≥ 0.039 had significantly shorter MRONJ-free survival compared to those with ΔBSIJ < 0.039. These findings underscore the clinical importance of ΔBSIJ as a dynamic biomarker that captures temporal changes in bone metabolism, facilitating early MRONJ risk assessment before structural changes become apparent. Additionally, as bone scintigraphy is routinely performed for metastatic prostate cancer management, ΔBSIJ represents a cost-effective and practical tool that can be seamlessly integrated into clinical workflows for MRONJ monitoring without the need for additional imaging procedures. While the sensitivity of ΔBSIJ was 60%, the specificity was remarkably high at 91%. In clinical practice, especially in patients with metastatic prostate cancer receiving BMAs, high specificity is desirable to minimize unnecessary referrals and optimize targeted early interventions. This characteristic makes ΔBSIJ a useful tool for identifying high-risk patients who require closer monitoring or early consultation with an oral and maxillofacial surgeon. MRONJ diagnosis has traditionally relied on structural imaging modalities, including radiography, CT, MRI, and cone-beam CT (CBCT) [ 4 ]. However, these techniques have certain limitations, particularly for early-stage detection. Radiography and panoramic imaging are widely accessible and offer valuable initial assessments; however, their sensitivity for detecting early bone changes is limited. CT and CBCT provide high-resolution imaging of bone structures, allowing detailed assessment of cortical erosion and trabecular density changes. These modalities are particularly effective for assessing advanced stages of MRONJ but exhibit limited utility in detecting early metabolic or vascular changes [ 11 ]. Although MRI is highly sensitive to soft tissue and marrow involvement, it is not always feasible for routine monitoring, particularly in patients with dental implants or extensive prosthodontics [ 11 ]. In contrast, bone scintigraphy detects subtle metabolic changes that often precede structural damage, making it an attractive option for the early diagnosis of MRONJ. Watanabe et al. demonstrated the utility of BSI for detecting abnormal tracer uptake in the jaw before the appearance of clinical symptoms [ 8 ]. However, previous studies are limited to static BSI measures that do not capture temporal changes in bone metabolism. The present study addresses this gap by introducing ΔBSIJ, offering a dynamic assessment that enhances the diagnostic power of bone scintigraphy. This study innovatively utilized ΔBSIJ, which reflects dynamic changes in bone metabolism over time and is particularly valuable for distinguishing between patients with stable or improving bone conditions and those at risk of developing MRONJ. Static measures, such as pre-BMA BSIJ or post-BMA BSIJ, provide a snapshot of bone activity but cannot capture metabolic trends indicative of early disease progression. The ability of ΔBSIJ to capture these changes is valuable in cases where jawbone metastases coexist with the risk of MRONJ. Metastatic lesions often exhibit increased tracer uptake on bone scintigraphy, which can confound the static BSIJ measurements. However, ΔBSIJ effectively differentiates between changes associated with effective treatment of metastases (leading to decreased uptake) and those indicative of early necrosis (leading to increased uptake), ensuring accurate diagnosis and appropriate management of high-risk populations​. Furthermore, patients with prostate cancer frequently develop jawbone metastases, which are more common than in patients with other malignancies. ΔBSIJ addresses these unique challenges by emphasizing temporal changes over static values. For instance, ΔBSIJ is typically negative in cases of jawbone metastases without MRONJ development owing to decreased tracer uptake following effective treatment. Conversely, in cases with MRONJ, ΔBSIJ is positive regardless of the metastases, presenting it as a robust tool for risk stratification across diverse clinical scenarios. Moreover, ΔBSIJ overcomes the limitation of region-specific thresholds for the maxilla and mandible [ 8 ], which has been highlighted as a notable challenge in previous studies using static BSIJ measures. This simplification enhances its clinical applicability, facilitating its easier implementation in routine practice without additional training or resources. The integration of ΔBSIJ into clinical practice has significant implications for the management of patients with metastatic prostate cancer receiving BMAs. Current guidelines emphasize the importance of imaging for monitoring disease progression and treatment response, particularly in the era of advanced androgen receptor-targeting therapies [ 12 – 14 ]. These therapies often lower PSA levels to undetectable ranges, reducing the reliability of traditional biomarkers for disease monitoring. In such cases, imaging modalities, such as bone scintigraphy, are vital for detecting disease progression that may not be evident through PSA monitoring alone [ 14 ]. Early MRONJ detection can be achieved by incorporating ΔBSIJ into regular imaging protocols, prompting timely interventions to prevent disease progression and associated complications, thereby aligning with the principles of precision medicine, which prioritize personalized risk assessment and early detection to improve patient outcomes. Although bone scintigraphy offers significant advantages for MRONJ detection, other functional imaging modalities such as fluorodeoxyglucose-positron emission tomography (FDG-PET) have also been explored [ 15 , 16 ]. FDG-PET is highly sensitive in detecting metabolic activity, with promising results in identifying MRONJ lesions. However, it is impractical for routine use in most clinical settings owing to its high cost and limited availability. In contrast, bone scintigraphy is widely accessible, cost-effective, and has been integrated into the care of patients with metastatic prostate cancer. Additionally, ΔBSIJ further enhances its utility by offering a robust and affordable method for dynamic monitoring. The BONENAVI® software [ 9 , 10 ] improves the clinical utility of bone scintigraphy by automating BSI calculations, ensuring consistent and objective measurements. This also eliminates observer variability, a common limitation of qualitative imaging assessments, supporting the widespread adoption of the ΔBSIJ in clinical practice. Moreover, integration of artificial intelligence and extensive multicenter data in BONENAVI® further strengthens its reliability and reproducibility​. This study also has some limitations. It is subject to potential selection bias dowingue to its retrospective design. The timing of bone scintigraphy was determined by each attending physician rather than following a standardized protocol. Consequently, only 33 out of the 94 patients who received BMA therapy had both pre- and post-BMA imaging results available. This selection was not intentional but was based solely on imaging availability. While this reflects real-world clinical practice, it may limit the generalizability of our findings. Future prospective studies with standardized imaging protocols are needed to validate our results. Larger prospective studies are warranted to validate ΔBSIJ effectiveness across diverse populations and clinical settings. Additionally, although ΔBSIJ demonstrated significant predictive value, its accuracy can be enhanced further by integrating other clinical risk factors, such as age, diabetes or prolonged BMA use. The association between age and the development of MRONJ is supported by some studies but not consistently. While some studies have identified age as a significant predictor[ 17 , 18 ], others have not found a statistically significant relationship. This discrepancy highlights the multifactorial nature of MRONJ and the necessity of considering multiple risk factors beyond age alone. Although prolonged BMA administration is a known risk factor for MRONJ [ 17 , 19 ], in our study, the duration of BMA therapy did not significantly differ between the MRONJ and non-MRONJ groups. This suggests that ΔBSIJ serves as an independent predictor of MRONJ risk beyond the duration of BMA therapy. Exploring additional quantitative metrics, such as combining ΔBSIJ with other imaging biomarkers, may provide new insights into the pathophysiology and progression of MRONJ. Future research should also investigate the cost-effectiveness of implementing ΔBSIJ in routine practice and its impact on clinical outcomes. Correspondingly, ΔBSIJ can be further refined and optimized for widespread adoption in MRONJ management. Conclusion This study highlights ΔBSIJ as a novel and effective marker for the early prediction of MRONJ in patients with prostate cancer receiving BMAs. By capturing dynamic changes in jaw-specific bone metabolism, ΔBSIJ demonstrated superior predictive accuracy over static BSIJ measures, representing a robust clinically applicable tool. ΔBSIJ incorporation into routine bone scintigraphy offers a cost-effective and objective approach to enhance MRONJ risk assessment. Future research should focus on validating these findings in larger prospective cohorts and on exploring ΔBSIJ application across broader clinical contexts to optimize MRONJ management and improve patient outcomes. Declarations Acknowledgement The authors thank Hideki Nobira, Tomokazu Oshiki, and Masamichi Kajita from PDRadiopharma Inc., Tokyo, Japan for their invaluable support and collaboration in the planning of this study and interpretation of the results. Conflict of interest No potential conflicts of interest were disclosed. Author contributions All the authors contributed to the conception and design of this study. Hidetoshi Kokubun performed all radiographical assessments using BONENAVI ® software. Toshiki Kijima accumulated patient clinical information, including MRONJ development, and analyzed the predictive ability of BSI-related variables for MRONJ. Hidetoshi Kokubun and Toshiki Kijima wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All the authors have read and approved the final version of this manuscript. Data availability The datasets generated and/or analyzed in this study are available from the corresponding author upon reasonable request. Study registration N/A Funding None. References Murphy J, Mannion CJ. Medication-related osteonecrosis of the jaws and quality of life: review and structured analysis . Br J Oral Maxillofac Surg 2020;58:619–24. Wei LY, et al. Prognosis of medication-related osteonecrosis of the jaws in metastatic prostate cancer patients . Oral Dis 2022;28:182–92. Ristow O, et al. 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Patient characteristics Variables Total (n=33) MRONJ (n=10) No MRONJ (n=23) p-value Age (years) 69 (64–75) 73 (69–79) 65 (63–74) <0.01 BMI (kg/m 2 ) 22.4 (19.7–25.4) 21.6 (18.3–25.7) 22.4 (20.0–25.5) 0.57 Diabetes mellitus 11 (33%) 4 (40%) 7 (30%) 0.70 PSA at diagnosis (ng/ml) 257.5 (20–1015) 127 (21.4–723) 298 (16.9–1527) 0.71 Gleason grade group 0.18 <4 3 (9%) 1 (10%) 2 (9%) ≥4 29 (88%) 9 (90%) 20 (87%) Unknown 1 (3%) 1 (4%) Prior tooth extraction owing to dental conditions 14 (42%) 5 (50%) 9 (39%) 0.71 Jawbone metastases 14 (42%) 2 (20%) 12 (52%) 0.13 Types of Androgen Deprivation Therapy GnRH agonist 18 (55%) 4 (40%) 14 (61%) 0.448 GnRH antagonist 15 (45%) 6 (60%) 9 (39%) Typres of bone modifying agents 1.00 Denosumab 28 (85%) 9 (90%) 19 (83%) Zoledronic acid 5 (15%) 1 (10%) 4 (17%) Interval between pre-BMA bone scan and BMA administration (months) 1.6 (0.8–4.3) 1.5 (0.8–5.1) 2.0 (0.9–3.8) 1.00 Interval between BMA administration and post-BMA bone scan (months) 13.0 (7.6–23.2) 10.3 (8.8–17.9) 14.6 (7.1–24.3) 0.57 Interval between BMA administration and MRONJ onset (months) 17.9 (15.9–21.5) Interval between post-BMA bone scan and onset of MRONJ (months) 7.6 (0.9–9.2) Values are presented as N (%) or median (interquartile range). Table 2. Relationship between the development of MRONJ and BSIJ-related values MRONJ (n=10) No MRONJ (n=23) p-value Pre-BMA BSIJ 0.10 (0.02 to 0.12) 0.08 (0.05 to 0.18) 0.265 Post-BMA BSIJ 0.12 (0.06 to 0.22) 0.05 (0.02 to 0.10) 0.084 ΔBSIJ 0.05 (–0.01 to 0.11) –0.04 (–0.11 to 0.00) 0.002 Values are presented as median (interquartile range). Table 3. MRONJ (n=10) No MRONJ (n=23) p-value ΔBSIJ ≥ 0.039 (n=8) 6 (60%) 2 (9%) 0.004 ΔBSIJ < 0.039 (n=25) 4 (40%) 21 (91%) Values are presented as N (%). Table 4. Screening accuracy of BSIJ-related values for predicting MRONJ Cut-off Sensitivity Specificity PPV NPV Pre-BMA BSIJ 0.031 70% 13% 26% 50% Post-BMA BSIJ 0.068 80% 70% 53% 88% ΔBSIJ 0.039 60% 91% 75% 84% Cite Share Download PDF Status: Published Journal Publication published 03 Jul, 2025 Read the published version in Annals of Nuclear Medicine → Version 1 posted Reviewers agreed at journal 21 Apr, 2025 Reviewers invited by journal 20 Apr, 2025 Editor assigned by journal 24 Mar, 2025 First submitted to journal 22 Mar, 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. 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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-5795022","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":445478002,"identity":"82dec926-589b-43ef-bf64-57653f2f1ed2","order_by":0,"name":"Hidetoshi Kokubun","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hidetoshi","middleName":"","lastName":"Kokubun","suffix":""},{"id":445478003,"identity":"f1d088ea-93e5-4a1d-ac20-c24a30f7890d","order_by":1,"name":"Toshiki Kijima","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYDACHsYGgwQGBjmGA2zMEJEDYGE8OqBajEnRAqETG1C14AH2PIcbCh7m2KX3HW9LNuap2CbHd4D54QcGmTu4beFtbDBI3JacO/PMscPJPGduG0seYDOWYOB5hlsLPyNIC3PuhhvpzYd5224nbjjAYAYUP0xIS326AVRL/YYD7N/wa4E47HCCwY20w8lALQkGB3gI2HLmIEjLcUOgX5IN55y5bTjzME+xRAIev7D3pD8z/LmtWp7veJuxxJuK20BG+8YPH3twhxgQsBnAWEzgSAJFT2LPAXxamB/AWIw/4II/8GoZBaNgFIyCkQUA3YNcgeKGbsYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4380-9294","institution":"Dokkyo Medical University","correspondingAuthor":true,"prefix":"","firstName":"Toshiki","middleName":"","lastName":"Kijima","suffix":""},{"id":445478004,"identity":"32f03d24-981f-4f23-94f7-83272103d030","order_by":2,"name":"Yuumi Tokura","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuumi","middleName":"","lastName":"Tokura","suffix":""},{"id":445478005,"identity":"31580c9d-41ee-4db6-aef9-3666baf84f7f","order_by":3,"name":"Toshitaka Uematsu","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Toshitaka","middleName":"","lastName":"Uematsu","suffix":""},{"id":445478006,"identity":"8ef3fe20-319d-4818-993e-87900be9d5ed","order_by":4,"name":"Kohei Takei","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Takei","suffix":""},{"id":445478007,"identity":"45140e6b-91b2-44c4-b544-5341b191801e","order_by":5,"name":"Hironori Betsunoh","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hironori","middleName":"","lastName":"Betsunoh","suffix":""},{"id":445478008,"identity":"a94c1803-71c6-49c3-86c5-800a4e12af64","order_by":6,"name":"Masahiro Yashi","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Yashi","suffix":""},{"id":445478009,"identity":"a666403e-e1a9-454e-a619-f5e4fe7fcfa9","order_by":7,"name":"Yoshihiro Nakagami","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiro","middleName":"","lastName":"Nakagami","suffix":""},{"id":445478010,"identity":"f38b97ec-a2f9-412a-9c08-008605835454","order_by":8,"name":"Shigeyoshi Soga","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shigeyoshi","middleName":"","lastName":"Soga","suffix":""},{"id":445478011,"identity":"5976a3f2-e62c-478c-bd40-e9c5e72c1471","order_by":9,"name":"Takao Kamai","email":"","orcid":"","institution":"Dokkyo Medical University","correspondingAuthor":false,"prefix":"","firstName":"Takao","middleName":"","lastName":"Kamai","suffix":""}],"badges":[],"createdAt":"2025-01-09 09:22:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5795022/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5795022/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12149-025-02078-9","type":"published","date":"2025-07-03T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82048683,"identity":"bdcdf23c-e031-4ac6-9715-b942ae201463","added_by":"auto","created_at":"2025-05-06 09:47:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":534476,"visible":true,"origin":"","legend":"\u003cp\u003eRegion of interest (ROI) for BSIJ measurement. The cranial region with the upper border at the bottom of the nasal cavity and the lower border at the lower end of the mandible was considered ROI.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/59dc4d66ad96778a21b74532.png"},{"id":82048597,"identity":"50e90b47-f67e-461e-a848-74277ea882e9","added_by":"auto","created_at":"2025-05-06 09:47:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1300843,"visible":true,"origin":"","legend":"\u003cp\u003eDefinition of ΔBSIJ. BSIJ was measured at both pre- and post-BMA time points. ΔBSIJ was calculated as the difference between post- and pre-BMA BSIJ.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/29779c55e3b9090902bd6a7e.png"},{"id":82046570,"identity":"391c29dc-cdf8-4bd7-9d99-76886add3828","added_by":"auto","created_at":"2025-05-06 09:39:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":775381,"visible":true,"origin":"","legend":"\u003cp\u003eTemporal changes in BSIJ in a patient who developed MRONJ after BMA initiation. The pre-BMA BSIJ score was 0.000 with no tracer uptake within the ROI for BSIJ. Tracer uptake outside the ROI (black arrowhead) was identified as cervical spine metastases, which resolved with treatment. At 6 months post-BMA initiation, tracer uptake emerged within the ROI for BSIJ and intensified at 11 months, increasing post-BMA BSIJ to 0.068. MRONJ was diagnosed at 12 months post-BMA initiation.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/5b962bb8857acac28c6e3d26.png"},{"id":82046559,"identity":"36f6781e-1854-43e7-8940-44fb9fcf7419","added_by":"auto","created_at":"2025-05-06 09:39:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":299133,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of pre- and post-BMA BSIJ between patients with and without MRONJ. Significant differences were observed in BSIJ changes for both groups.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/40c54bfeee1e4f7b2e3e034b.png"},{"id":82046571,"identity":"f5699720-5a65-44ad-9b8f-182dcda0ceab","added_by":"auto","created_at":"2025-05-06 09:39:08","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":158279,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curves evaluating the predictive performance of BSIJ-related factors for MRONJ onset.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/0168863ca65e4b25f10f2248.png"},{"id":82046579,"identity":"e2adcc48-fc9d-42f9-9a71-60a077a132c3","added_by":"auto","created_at":"2025-05-06 09:39:08","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":127636,"visible":true,"origin":"","legend":"\u003cp\u003eMRONJ-free survival curves based on ΔBSIJ. Patients were divided into two groups using a cutoff value of ΔBSIJ = 0.039.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/e16efeb0b35d6fc5bdcb35b4.png"},{"id":86180108,"identity":"7b9f68c6-bdb6-4692-b9f4-ff4c74cd6af8","added_by":"auto","created_at":"2025-07-07 16:21:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4757043,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5795022/v1/276a76ee-c81d-4833-a07e-76dd6105bc63.pdf"}],"financialInterests":"","formattedTitle":"ΔBSIJ: A quantitative marker for early detection of medication-related osteonecrosis of the jaw in patients with prostate cancer receiving bone-modifying agents","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer is a common malignancy in men, and a significant proportion of patients develop bone metastases during the course of the disease. Bone-modifying agents (BMAs), including bisphosphonates and denosumab, are frequently used to reduce skeletal-related events in patients with bone metastasis. However, medication-related osteonecrosis of the jaw (MRONJ), a severe condition that profoundly impacts quality of life (QOL) of the patient and interferes with ongoing cancer treatment, is a well-recognized adverse event of BMA therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e​ Early detection of MRONJ is crucial to mitigate its progression and associated complications. Once clinically apparent, invasive management strategies, including surgical intervention, are often necessary for MRONJ, which is associated with substantial morbidity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Conventionally, MRONJ diagnosis relies on imaging modalities such as radiographs, computed tomography (CT), and magnetic resonance imaging (MRI) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, these structural imaging techniques primarily detect anatomical changes but not early metabolic alterations in the bone [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBone scintigraphy, a functional imaging modality widely used in oncology, offers the unique advantage of detecting early metabolic and pathophysiological changes in the bone. Furthermore, bone scintigraphy detects subtle abnormalities in bone turnover before the appearance of structural changes, unlike conventional imaging, rendering it a promising tool for early MRONJ detection [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, bone scintigraphy is routinely performed in patients with prostate cancer to detect bone metastasis and for follow-up, making it feasible to repurpose this modality for MRONJ screening without additional imaging.\u003c/p\u003e \u003cp\u003e​ Although several studies have investigated the role of bone scintigraphy in MRONJ prediction, most lack a robust quantitative framework for evaluating disease progression. The bone scan index (BSI), a semi-automated quantitative metric derived from bone scintigraphy, has proven useful in assessing skeletal metastases and prognostication in prostate cancer. However, its application in MRONJ prediction remains underexplored. Furthermore, although quantitative imaging biomarkers have been incorporated in limited studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], evaluations of the temporal changes using these indices remain sparse.\u003c/p\u003e \u003cp\u003eConsequently, in this study, we utilized BSI to develop a quantitative framework for MRONJ prediction. We hypothesized that changes in the jaw-specific BSI (BSIJ) before and after BMA initiation, quantified as ΔBSIJ, could serve as an early indicator of MRONJ risk. Leveraging a novel and semi-automated approach, this study represents a significant step toward improving the early detection and management of MRONJ in patients with prostate cancer receiving BMA therapy.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-institution retrospective study involved patients with prostate cancer and bone metastases with a history of receiving BMAs and had evaluable bone scintigraphy images taken before and after BMA administration. Patients for enrollment in this study were screen as follows: First, 1,281 patients with prostate cancer who underwent bone scintigraphy at our hospital between 2008 and 2023 were identified. Of these, 209 patients had positive findings for bone metastases, and among them, 94 patients had received BMAs. Of these, 33 patients who underwent bone scintigraphy both before and after the initiation of BMA treatment were included in the study.\u003c/p\u003e\n\u003cp\u003eMRONJ was diagnosed by an oral and maxillofacial surgeon based on clinical examination, radiographic findings from X-ray and CT imaging, and patient history. Patients diagnosed with MRONJ at any point during follow-up were classified into the MRONJ group, while those without MRONJ were placed in the non-MRONJ group.\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Board of Dokkyo Medical University (approval number: R-71-6J). The research plan was communicated through in-hospital announcements and the hospital\u0026apos;s website, with an opt-out option for patients who did not wish to participate. Individual informed consent was deemed unnecessary owing to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBSIJ measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBSIJ was measured using anterior and posterior whole-body bone scintigraphy images. For patients who underwent multiple bone scintigraphy sessions, the scan obtained immediately before BMA administration was selected as pre-BMA bone scintigraphy, and the scan obtained just before the onset of MRONJ and after BMA administration was selected as post-BMA bone scintigraphy.\u003c/p\u003e\n\u003cp\u003eThe cranial region with the upper border at the bottom of the nasal cavity and the lower border at the lower end of the mandible was considered the region of interest (ROI) for BSIJ measurement (Figure 1). The BSI was measured using the BONENAVI\u003csub\u003e\u0026reg;\u003c/sub\u003e (version 2; PDRadiopharma Inc., Tokyo, Japan). This software utilizes an artificial neural network (ANN) based on a multicenter database of Japanese patients to automatically detect abnormal accumulation areas, calculate the regional BSI (rBSI) as the ratio of the abnormal accumulation area to the total skeletal area, and assign an ANN score ranging from 0 to 1 for each region. The details of this platform have been described previously [9, 10]. Although the total-body BSI only includes regions with an ANN score of \u0026ge;0.5, this study included all regions within the ROI for BSIJ, regardless of their ANN scores. The BSIJ was calculated as the sum of all the rBSI values within the ROI for the BSIJ. A urologist (T. Kokubun) blinded for the clinical information manually set the ROI for BSIJ in the BONENAVI\u003csub\u003e\u0026reg;\u003c/sub\u003e software and calculated BSIJ for all cases.\u003c/p\u003e\n\u003cp\u003eAs described above, the ROI for BSIJ measurement was manually set based on anatomically well-defined landmarks. As the rBSI calculation was fully automated using the BONENAVI software, the measurement process was entirely objective and did not involve any subjective judgment. Therefore, the involvement of a radiologist or nuclear medicine physician was not essential for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical parameters were expressed as N (%) or median (interquartile range). The differences between MRONJ and non-MRONJ groups were determined using the Fisher\u0026apos;s exact test and Mann\u0026ndash;Whitney U tests. The BSIJ obtained from pre-BMA and post-BMA bone scintigraphy was defined as the pre-BMA BSIJ and post-BMA BSIJ, respectively. The difference between pre- and post-BMA BSIJ was defined as \u0026Delta;BSIJ (Figure 2). Paired t-tests were used to compare the pre- and post-BMA BSIJ scores within individual cases. The predictive ability of pre-BMA BSIJ, post-BMA BSIJ, and \u0026Delta;BSIJ for MRONJ onset was assessed using receiver operating characteristic (ROC) analysis. The area under the curve (AUC) was calculated, and the cut-off value for maximizing the predictability of MRONJ was determined. The predictive performance was evaluated and compared based on the AUC, sensitivity, specificity, positive predictive value, and negative predictive value. Kaplan\u0026ndash;Meier method was employed to estimate the MRONJ-free survival, defined as the time from the initiation of BMA therapy to the onset of MRONJ. The log-rank test was used to determine the significance. All statistical analyses were performed using JMP PRO, (version 17; SAS Institute, Cary, NC, USA). Statistical significance was set at p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up period after BMA initiation in 33 patients was 29 (interquartile range: 21\u0026ndash;49) months. Of these, MRONJ occurred only in 10 patients during follow-up. Table 1 presents patient characteristics. The median age was 69 years (64\u0026ndash;75 years) and the median prostate-specific antigen (PSA) level at diagnosis was 257.5 ng/mL (20\u0026ndash;1015 ng/mL), with 29 patients (88%) classified into a Gleason grade group of \u0026ge;4. Androgen deprivation therapy involved gonadotropin-releasing hormone agonists and antagonists in 18 (55%) and 15 (45%) patients, respectively. Fourteen (42%) patients had undergone tooth extraction owing to dental conditions. No new diagnoses of tooth decay or periodontitis were made during the follow-up period, and no cases exhibited worsening of these conditions requiring additional treatment. None of the patients in this study had received radiotherapy to the jaw. BMAs denosumab and zoledronic acid were used in 28 (85%) and 5 (15%) patients, respectively. Patients in the MRONJ group were older than those in the non-MRONJ group; however, no differences in other clinical factors were observed between the two groups.\u003c/p\u003e\n\u003cp\u003eThe interval from pre-BMA bone scintigraphy to BMA administration was 1.6 (0.8\u0026ndash;4.3) months, and the interval from BMA administration to post-BMA bone scintigraphy was 13.0 (7.6\u0026ndash;23.2) months. These intervals did not differ significantly between the MRONJ and non-MRONJ groups. Furthermore, the interval from BMA administration to MRONJ onset was 17.9 (15.9\u0026ndash;21.5) months in the MRONJ group, whereas the interval from post-BMA bone scintigraphy to MRONJ onset was 7.6 (0.9\u0026ndash;9.2) months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBSIJ before and after BMA administration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 3 shows BSIJ progression in a representative case wherein the patient developed MRONJ. In this case, the pre-BMA BSIJ score 1 month before BMA administration was 0.00; however, it increased to 0.031 and 0.068 at 6 and 11 months, respectively. The patient developed MRONJ in the 12th month. Therefore, an increase in the BSIJ score after BMA administration may indicate a higher risk of MRONJ onset. Consequently, we examined changes in BSIJ score before and after BMA administration in both groups. In the MRONJ group, the post-BMA BSIJ score was significantly higher than the pre-BMA BSIJ score (p = 0.026). Conversely, in the non-MRONJ group, the pre-BMA BSIJ score was significantly higher than the post-BMA BSIJ score (p = 0.006; Figure 4).\u003c/p\u003e\n\u003cp\u003eTo assess the influence of jawbone metastases on \u0026Delta;BSIJ, we conducted a subgroup analysis comparing MRONJ-positive and MRONJ-negative patients with and without jawbone metastases. The results demonstrated that in MRONJ-negative patients without jawbone metastases, the median (IQR) \u0026Delta;BSIJ was \u0026ndash;0.012 (\u0026ndash;0.015 to 0.023), whereas in MRONJ-negative patients with jawbone metastases, the median (IQR) \u0026Delta;BSIJ was \u0026ndash;0.045 (\u0026ndash;0.09 to \u0026ndash;0.02). In contrast, MRONJ-positive patients without jawbone metastases exhibited a median (IQR) \u0026Delta;BSIJ of 0.05 (\u0026ndash;0.02 to 0.09), and MRONJ-positive patients with jawbone metastases had a median (IQR) \u0026Delta;BSIJ of 0.09 (0 to 0.17). Despite the small sample size, these findings suggest that \u0026Delta;BSIJ tends to be negative in non-MRONJ cases and positive in MRONJ cases, regardless of the presence of jawbone metastases. This indicates that the influence of MRONJ on \u0026Delta;BSIJ is more pronounced than that of jawbone metastases, supporting its utility as a predictive marker for MRONJ development.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRONJ onset prediction using \u0026Delta;BSIJ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe association among pre-BMA BSIJ, post-BMA BSIJ, \u0026Delta;BSIJ, and MRONJ onset is presented in Table 2. Notably, no significant difference was observed in the pre-BMA BSIJ score between the MRONJ and non-MRONJ groups. Although the post-BMA BSIJ score tended to be higher in the MRONJ group, the difference was not statistically significant. However, \u0026Delta;BSIJ was significantly higher in the MRONJ group (0.05, interquartile range: \u0026ndash;0.01 to 0.11) than in the non-MRONJ group (\u0026ndash;0.04, interquartile range: \u0026ndash;0.11 to 0.00) (p = 0.002).\u003c/p\u003e\n\u003cp\u003eNext, we performed ROC analysis to evaluate the predictive performance of pre-BMA BSIJ, post-BMA BSIJ, and \u0026Delta;BSIJ for MRONJ onset (Figure 5). The AUC was the highest for \u0026Delta;BSIJ at 0.823, followed by post-BMA BSIJ at 0.713 and pre-BMA BSIJ at 0.596. The cutoff value of 0.039, corresponding to the point with the highest sensitivity ˗ (1 \u0026ndash; specificity), was determined based on the ROC curve for \u0026Delta;BSIJ. Of the 8 patients with \u0026Delta;BSIJ \u0026ge; 0.039, 6 developed MRONJ, whereas of the 25 patients with \u0026Delta;BSIJ \u0026lt; 0.039, only 4 developed MRONJ (p = 0.004; Table 3). Similarly, the cutoff values for the pre- and post-BMA BSIJ were determined to be 0.031 and 0.068, respectively, from the ROC curve, and their predictive performances were compared (Table 4). \u0026Delta;BSIJ demonstrated superior specificity (91%), positive predictive value (75%), and negative predictive value (84%) than the pre- and post-BMA BSIJ, whereas sensitivity (60%) was comparable among the metrics. Furthermore, patients with \u0026Delta;BSIJ \u0026ge; 0.039 exhibited significantly shorter MRONJ-free survival, with a median survival time of 18.4 months compared with those with \u0026Delta;BSIJ \u0026lt; 0.039, which did not reach the median survival time during the observation period (p \u0026lt; 0.001; Figure 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study highlights ΔBSIJ as a novel and clinically valuable marker for the early prediction of MRONJ in patients with prostate cancer receiving BMA therapy. Our results demonstrate that ΔBSIJ, defined as the difference between pre- and post-BMA BSIJ values, provides superior predictive accuracy compared to static measures such as pre-BMA and post-BMA BSIJ. The MRONJ group exhibited significantly higher ΔBSIJ values than the non-MRONJ group (0.05 vs. \u0026minus;\u0026thinsp;0.04, p\u0026thinsp;=\u0026thinsp;0.002), and ROC analysis confirmed its diagnostic utility with an AUC of 0.823. Using a ΔBSIJ cutoff of 0.039, MRONJ could be predicted with 60% sensitivity and 91% specificity, indicating a strong ability to distinguish high-risk patients. Furthermore, Kaplan\u0026ndash;Meier analysis revealed that patients with ΔBSIJ\u0026thinsp;\u0026ge;\u0026thinsp;0.039 had significantly shorter MRONJ-free survival compared to those with ΔBSIJ\u0026thinsp;\u0026lt;\u0026thinsp;0.039. These findings underscore the clinical importance of ΔBSIJ as a dynamic biomarker that captures temporal changes in bone metabolism, facilitating early MRONJ risk assessment before structural changes become apparent. Additionally, as bone scintigraphy is routinely performed for metastatic prostate cancer management, ΔBSIJ represents a cost-effective and practical tool that can be seamlessly integrated into clinical workflows for MRONJ monitoring without the need for additional imaging procedures.\u003c/p\u003e \u003cp\u003eWhile the sensitivity of ΔBSIJ was 60%, the specificity was remarkably high at 91%. In clinical practice, especially in patients with metastatic prostate cancer receiving BMAs, high specificity is desirable to minimize unnecessary referrals and optimize targeted early interventions. This characteristic makes ΔBSIJ a useful tool for identifying high-risk patients who require closer monitoring or early consultation with an oral and maxillofacial surgeon.\u003c/p\u003e \u003cp\u003eMRONJ diagnosis has traditionally relied on structural imaging modalities, including radiography, CT, MRI, and cone-beam CT (CBCT) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, these techniques have certain limitations, particularly for early-stage detection. Radiography and panoramic imaging are widely accessible and offer valuable initial assessments; however, their sensitivity for detecting early bone changes is limited. CT and CBCT provide high-resolution imaging of bone structures, allowing detailed assessment of cortical erosion and trabecular density changes. These modalities are particularly effective for assessing advanced stages of MRONJ but exhibit limited utility in detecting early metabolic or vascular changes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although MRI is highly sensitive to soft tissue and marrow involvement, it is not always feasible for routine monitoring, particularly in patients with dental implants or extensive prosthodontics [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In contrast, bone scintigraphy detects subtle metabolic changes that often precede structural damage, making it an attractive option for the early diagnosis of MRONJ. Watanabe et al. demonstrated the utility of BSI for detecting abnormal tracer uptake in the jaw before the appearance of clinical symptoms [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, previous studies are limited to static BSI measures that do not capture temporal changes in bone metabolism. The present study addresses this gap by introducing ΔBSIJ, offering a dynamic assessment that enhances the diagnostic power of bone scintigraphy.\u003c/p\u003e \u003cp\u003eThis study innovatively utilized ΔBSIJ, which reflects dynamic changes in bone metabolism over time and is particularly valuable for distinguishing between patients with stable or improving bone conditions and those at risk of developing MRONJ. Static measures, such as pre-BMA BSIJ or post-BMA BSIJ, provide a snapshot of bone activity but cannot capture metabolic trends indicative of early disease progression. The ability of ΔBSIJ to capture these changes is valuable in cases where jawbone metastases coexist with the risk of MRONJ. Metastatic lesions often exhibit increased tracer uptake on bone scintigraphy, which can confound the static BSIJ measurements. However, ΔBSIJ effectively differentiates between changes associated with effective treatment of metastases (leading to decreased uptake) and those indicative of early necrosis (leading to increased uptake), ensuring accurate diagnosis and appropriate management of high-risk populations​. Furthermore, patients with prostate cancer frequently develop jawbone metastases, which are more common than in patients with other malignancies. ΔBSIJ addresses these unique challenges by emphasizing temporal changes over static values. For instance, ΔBSIJ is typically negative in cases of jawbone metastases without MRONJ development owing to decreased tracer uptake following effective treatment. Conversely, in cases with MRONJ, ΔBSIJ is positive regardless of the metastases, presenting it as a robust tool for risk stratification across diverse clinical scenarios. Moreover, ΔBSIJ overcomes the limitation of region-specific thresholds for the maxilla and mandible [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which has been highlighted as a notable challenge in previous studies using static BSIJ measures. This simplification enhances its clinical applicability, facilitating its easier implementation in routine practice without additional training or resources.\u003c/p\u003e \u003cp\u003eThe integration of ΔBSIJ into clinical practice has significant implications for the management of patients with metastatic prostate cancer receiving BMAs. Current guidelines emphasize the importance of imaging for monitoring disease progression and treatment response, particularly in the era of advanced androgen receptor-targeting therapies [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These therapies often lower PSA levels to undetectable ranges, reducing the reliability of traditional biomarkers for disease monitoring. In such cases, imaging modalities, such as bone scintigraphy, are vital for detecting disease progression that may not be evident through PSA monitoring alone [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Early MRONJ detection can be achieved by incorporating ΔBSIJ into regular imaging protocols, prompting timely interventions to prevent disease progression and associated complications, thereby aligning with the principles of precision medicine, which prioritize personalized risk assessment and early detection to improve patient outcomes.\u003c/p\u003e \u003cp\u003eAlthough bone scintigraphy offers significant advantages for MRONJ detection, other functional imaging modalities such as fluorodeoxyglucose-positron emission tomography (FDG-PET) have also been explored [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. FDG-PET is highly sensitive in detecting metabolic activity, with promising results in identifying MRONJ lesions. However, it is impractical for routine use in most clinical settings owing to its high cost and limited availability. In contrast, bone scintigraphy is widely accessible, cost-effective, and has been integrated into the care of patients with metastatic prostate cancer. Additionally, ΔBSIJ further enhances its utility by offering a robust and affordable method for dynamic monitoring.\u003c/p\u003e \u003cp\u003eThe BONENAVI\u0026reg; software [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] improves the clinical utility of bone scintigraphy by automating BSI calculations, ensuring consistent and objective measurements. This also eliminates observer variability, a common limitation of qualitative imaging assessments, supporting the widespread adoption of the ΔBSIJ in clinical practice. Moreover, integration of artificial intelligence and extensive multicenter data in BONENAVI\u0026reg; further strengthens its reliability and reproducibility​.\u003c/p\u003e \u003cp\u003eThis study also has some limitations. It is subject to potential selection bias dowingue to its retrospective design. The timing of bone scintigraphy was determined by each attending physician rather than following a standardized protocol. Consequently, only 33 out of the 94 patients who received BMA therapy had both pre- and post-BMA imaging results available. This selection was not intentional but was based solely on imaging availability. While this reflects real-world clinical practice, it may limit the generalizability of our findings. Future prospective studies with standardized imaging protocols are needed to validate our results. Larger prospective studies are warranted to validate ΔBSIJ effectiveness across diverse populations and clinical settings. Additionally, although ΔBSIJ demonstrated significant predictive value, its accuracy can be enhanced further by integrating other clinical risk factors, such as age, diabetes or prolonged BMA use. The association between age and the development of MRONJ is supported by some studies but not consistently. While some studies have identified age as a significant predictor[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], others have not found a statistically significant relationship. This discrepancy highlights the multifactorial nature of MRONJ and the necessity of considering multiple risk factors beyond age alone. Although prolonged BMA administration is a known risk factor for MRONJ [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], in our study, the duration of BMA therapy did not significantly differ between the MRONJ and non-MRONJ groups. This suggests that ΔBSIJ serves as an independent predictor of MRONJ risk beyond the duration of BMA therapy. Exploring additional quantitative metrics, such as combining ΔBSIJ with other imaging biomarkers, may provide new insights into the pathophysiology and progression of MRONJ. Future research should also investigate the cost-effectiveness of implementing ΔBSIJ in routine practice and its impact on clinical outcomes. Correspondingly, ΔBSIJ can be further refined and optimized for widespread adoption in MRONJ management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study highlights ΔBSIJ as a novel and effective marker for the early prediction of MRONJ in patients with prostate cancer receiving BMAs. By capturing dynamic changes in jaw-specific bone metabolism, ΔBSIJ demonstrated superior predictive accuracy over static BSIJ measures, representing a robust clinically applicable tool. ΔBSIJ incorporation into routine bone scintigraphy offers a cost-effective and objective approach to enhance MRONJ risk assessment. Future research should focus on validating these findings in larger prospective cohorts and on exploring ΔBSIJ application across broader clinical contexts to optimize MRONJ management and improve patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Hideki Nobira, Tomokazu Oshiki, and Masamichi Kajita from PDRadiopharma Inc., Tokyo, Japan for their invaluable support and collaboration in the planning of this study and interpretation of the results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo potential conflicts of interest were disclosed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors contributed to the conception and design of this study. Hidetoshi Kokubun performed all radiographical assessments using BONENAVI\u003csub\u003e\u0026reg;\u003c/sub\u003e software. Toshiki Kijima accumulated patient clinical information, including MRONJ development, and analyzed the predictive ability of BSI-related variables for MRONJ. Hidetoshi Kokubun and Toshiki Kijima wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All the authors have read and approved the final version of this manuscript.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed in this study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMurphy J, Mannion CJ. Medication-related osteonecrosis of the jaws and quality of life: review and structured analysis\u003cem\u003e.\u003c/em\u003e Br J Oral Maxillofac Surg 2020;58:619\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eWei LY, et al. Prognosis of medication-related osteonecrosis of the jaws in metastatic prostate cancer patients\u003cem\u003e.\u003c/em\u003e Oral Dis 2022;28:182\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eRistow O, et al. Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ)\u003cem\u003e.\u003c/em\u003e J Craniomaxillofac Surg 2015;43:290\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eStockmann P, et al. Panoramic radiograph, computed tomography or magnetic resonance imaging\u003cem\u003e. \u003c/em\u003eWhich imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study. Clin Oral Investig 2010;14:311\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eYamamoto Y, et al. Quantitative bone scan imaging using BSI and BUV: an approach to evaluate ARONJ early\u003cem\u003e.\u003c/em\u003e Ann Nucl Med 2020;34:74\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Ryan FS, et al. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator\u003cem\u003e.\u003c/em\u003e J Oral Maxillofac Surg 2009;67:1363\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eThomas C, et al. Bone scintigraphy predicts bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in patients with metastatic castration-resistant prostate cancer (mCRPC)\u003cem\u003e.\u003c/em\u003e Clin Oral Investig 2016;20:753\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eWatanabe S, et al. Bone scan index of the jaw: a new approach for evaluating early-stage anti-resorptive agents-related osteonecrosis\u003cem\u003e.\u003c/em\u003e Ann Nucl Med 2017;31:201\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eUlmert D, et al. A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the Bone Scan Index\u003cem\u003e.\u003c/em\u003e Eur Urol 2012;62:78\u0026ndash;84.\u003c/li\u003e\n\u003cli\u003eNakajima K, et al. Enhanced diagnostic accuracy for quantitative bone scan using an artificial neural network system: a Japanese multi-center database project\u003cem\u003e.\u003c/em\u003e EJNMMI Res 2013;3:83. \u003c/li\u003e\n\u003cli\u003eWongratwanich P, et al. Do various imaging modalities provide potential early detection and diagnosis of medication-related osteonecrosis of the jaw? A review\u003cem\u003e.\u003c/em\u003e Dento Maxillo Fac Radiol 2021;50:20200417. \u003c/li\u003e\n\u003cli\u003eBryce AH, et al. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL\u003cem\u003e.\u003c/em\u003e Prostate Cancer Prostatic Dis 2017;20:221\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBryce AH, et al. Patterns of cancer progression of metastatic hormone-sensitive prostate cancer in the ECOG3805 CHAARTED trial\u003cem\u003e.\u003c/em\u003e Eur Urol Oncol 2020;3:717\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eHara T, et al. Real-world analysis of metastatic prostate cancer demonstrates increased frequency of PSA-imaging discordance with visceral metastases and upfront ARAT/docetaxel therapy\u003cem\u003e.\u003c/em\u003e Prostate 2023;83:1270\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003e\u0026Ouml;zt\u0026uuml;rk AE, et al. A comparison of 18 F-FDG PET/CT and 68 ga-PSMA PET/CT in detecting osteonecrosis of the jaw in a patient with prostate cancer\u003cem\u003e.\u003c/em\u003e Clin Nucl Med 2024;49:e68\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eWatanabe S, Nakajima K, Kinuya S. \u003cem\u003e(\u003c/em\u003e\u003cem\u003e☆\u003c/em\u003e\u003cem\u003e)Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (5), \u003c/em\u003eutility of bone scintigraphy and (18)F-FDG PET/CT in early detection and risk assessment of medication-related osteonecrosis of the jaw (secondary publication)\u003cem\u003e.\u003c/em\u003e Jpn Dent Sci Rev 2019;55:76\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eCiobanu GA, et al. Risk Factors for Medication-Related Osteonecrosis of the Jaw-A Binomial Analysis of Data of Cancer Patients from Craiova and Constanta Treated with Zoledronic Acid. J Clin Med. 2023; 12: 3747.\u003c/li\u003e\n\u003cli\u003eKwack DW, Park SM. Prediction of medication-related osteonecrosis of the jaw (MRONJ) using automated machine learning in patients with osteoporosis associated with dental extraction and implantation: a retrospective study. J Korean Assoc Oral Maxillofac Surg. 2023; 49: 135-41.\u003c/li\u003e\n\u003cli\u003eKwon YD, et al. A clinical retrospective study of implant as a risk factor for medication-related osteonecrosis of the jaw: surgery vs loading? Maxillofac Plast Reconstr Surg. 2023; 45: 31.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Patient characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eTotal (n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eMRONJ (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNo MRONJ (n=23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e69 (64\u0026ndash;75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e73 (69\u0026ndash;79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e65 (63\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e22.4 (19.7\u0026ndash;25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e21.6 (18.3\u0026ndash;25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e22.4 (20.0\u0026ndash;25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e11 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e4 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e7 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePSA at diagnosis (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e257.5 (20\u0026ndash;1015)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e127 (21.4\u0026ndash;723)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e298 (16.9\u0026ndash;1527)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eGleason grade group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026lt;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026ge;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e29 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e9 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e20 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003ePrior tooth extraction owing to dental conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e14 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eJawbone metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e14 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12 (52%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eTypes of Androgen Deprivation Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;GnRH agonist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e18 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e4 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e14 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;GnRH antagonist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e15 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e6 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eTypres of bone modifying agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;Denosumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e28 (85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e9 (90%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e19 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;Zoledronic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eInterval between pre-BMA bone scan and BMA administration (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.6 (0.8\u0026ndash;4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.5 (0.8\u0026ndash;5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.0 (0.9\u0026ndash;3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eInterval between BMA administration and post-BMA bone scan (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e13.0 (7.6\u0026ndash;23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e10.3 (8.8\u0026ndash;17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e14.6 (7.1\u0026ndash;24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eInterval between BMA administration and MRONJ onset (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e17.9 (15.9\u0026ndash;21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003eInterval between post-BMA bone scan and onset of MRONJ (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e7.6 (0.9\u0026ndash;9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are presented as N (%) or median (interquartile range). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Relationship between the development of MRONJ and BSIJ-related values\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMRONJ (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eNo MRONJ (n=23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ep-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePre-BMA BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0.10 (0.02 to 0.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.08 (0.05 to 0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e0.265\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePost-BMA BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0.12 (0.06 to 0.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0.05 (0.02 to 0.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026Delta;BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0.05 (\u0026ndash;0.01 to 0.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026ndash;0.04 (\u0026ndash;0.11 to 0.00)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are presented as median (interquartile range).\u003c/p\u003e\n\u003cp\u003eTable 3.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMRONJ (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eNo MRONJ (n=23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003ep-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026Delta;BSIJ \u0026ge; 0.039 (n=8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e6 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e2 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026Delta;BSIJ \u0026lt; 0.039 (n=25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e4 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e21 (91%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are presented as N (%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Screening accuracy of BSIJ-related values for predicting MRONJ\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"644\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eCut-off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eSensitivity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eSpecificity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePPV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eNPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePre-BMA BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e26%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePost-BMA BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e53%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026Delta;BSIJ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e91%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e75%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e84%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ΔBSIJ, Medication-related osteonecrosis of the jaw, Bone scintigraphy, Prostate cancer, Bone-modifying agents","lastPublishedDoi":"10.21203/rs.3.rs-5795022/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5795022/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eMedication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bone-modifying agent (BMA) therapy in patients with prostate cancer and bone metastasis. This study aimed to assess the effectiveness of the temporal changes in jaw-specific bone scan index (ΔBSIJ) as quantitative markers for early prediction of MRONJ in patients with prostate cancer receiving BMA therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective study included 33 patients with prostate cancer with bone metastases who underwent bone scintigraphy before and after BMA initiation. BSIJ was measured using BONENAVI software, and the difference between pre- and post-BMA BSIJ values was considered ΔBSIJ. Statistical analyses, including paired t-test, receiver operating characteristic (ROC) curve analysis, and Kaplan–Meier survival estimate, were employed to assess the predictive value of ΔBSIJ for MRONJ.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOf the 33 patients, 10 developed MRONJ during a median follow-up period of 29 months. ΔBSIJ was significantly higher in the MRONJ group than in the non-MRONJ group (0.05 vs. –0.04, p = 0.002). ROC analysis revealed the highest area under the curve (AUC = 0.823) for ΔBSIJ compared with the pre- and post-BMA BSIJ values. A ΔBSIJ cutoff of 0.039 predicted MRONJ with 60% sensitivity and 91% specificity. Patients with ΔBSIJ ≥ 0.039 exhibited significantly shorter MRONJ-free survival than those with ΔBSIJ \u0026lt; 0.039 (median: 18.4 months vs. not reached, p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eΔBSIJ is a novel and clinically useful quantitative marker for the early detection of MRONJ in patients with prostate cancer receiving BMA therapy. This study highlights the potential of leveraging functional imaging and temporal changes in BSIJ to improve MRONJ management.\u003c/p\u003e","manuscriptTitle":"ΔBSIJ: A quantitative marker for early detection of medication-related osteonecrosis of the jaw in patients with prostate cancer receiving bone-modifying agents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 09:38:41","doi":"10.21203/rs.3.rs-5795022/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-21T11:40:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-21T02:01:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-24T09:17:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Nuclear Medicine","date":"2025-03-22T17:15:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-nuclear-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anme","sideBox":"Learn more about [Annals of Nuclear Medicine](http://link.springer.com/journal/12149)","snPcode":"12149","submissionUrl":"https://www.editorialmanager.com/anme/default2.aspx","title":"Annals of Nuclear Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cddad8a9-fa8e-46c1-a113-ef28925f2bd5","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:14:34+00:00","versionOfRecord":{"articleIdentity":"rs-5795022","link":"https://doi.org/10.1007/s12149-025-02078-9","journal":{"identity":"annals-of-nuclear-medicine","isVorOnly":false,"title":"Annals of Nuclear Medicine"},"publishedOn":"2025-07-03 15:57:06","publishedOnDateReadable":"July 3rd, 2025"},"versionCreatedAt":"2025-05-06 09:38:41","video":"","vorDoi":"10.1007/s12149-025-02078-9","vorDoiUrl":"https://doi.org/10.1007/s12149-025-02078-9","workflowStages":[]},"version":"v1","identity":"rs-5795022","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5795022","identity":"rs-5795022","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}