Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer

Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer | 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 Article Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer Alexander Cole, Zhiyu Qian, Mansoo Cho, Stephan Korn, Hanna Zurl, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8658712/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Androgen receptor pathway inhibitors (ARPIs) improve the survival of men with various states of advanced prostate cancer, but complications, including bone fractures, have been associated with treatment. Although rates of SREs are reported in ARPI registration trials, real-world data describing SRE rates during treatment with ARPIs is lacking. Methods We conducted a global pharmacovigilance study using VigiBase, the World Health Organization’s international database of adverse drug reaction reports. All reports involving abiraterone, enzalutamide, apalutamide, or darolutamide in adult men from 2011 to September 2024 were included. Fractures were defined using standardized MedDRA terms, and disproportionality analyses quantified reporting odds ratios (RORs) with 95% confidence intervals and Bayesian shrinkage estimates (EB05). Two prespecified sensitivity analyses were performed, redefining the reference group as men on androgen deprivation therapy (ADT) alone and stratifying results by age groups. Results Among 282,143 VigiBase reports involving ARPIs, 1,140 (0.4%) included fractures. In primary analysis, ARPI therapy demonstrated a pharmacovigilance signal for increased SRE reporting (ROR 1.87, 95% CI 1.77–1.98; EB05 1.77). Signals were consistent for abiraterone, enzalutamide, and apalutamide, but not for darolutamide. Using ADT as reference, ARPIs remained associated with higher reporting of fractures (ROR 1.43, 95% CI 1.29–1.58; EB05 1.08). Age-stratified analyses demonstrated signals across all categories, with numerically larger disproportionality estimates among older men. Conclusions In this global pharmacovigilance analysis, ARPIs were consistently associated with increased reporting of fractures, including when compared with ADT alone. This highlights the potentially additive skeletal toxicity of treatment intensification, and underscore the importance of bone health monitoring and preventive strategies, particularly among older patients. Health sciences/Diseases/Urogenital diseases/Urological cancer/Prostate cancer Health sciences/Medical research/Outcomes research Prostate Cancer Androgen Receptor Pathway Inhibitor Skeletal Related Event VigiBase Disproportionality Analysis Pharmacovigilance INTRODUCTION Prostate cancer is the most common non-skin malignancy among men in the United States, with approximately 313,780 new diagnoses and 35,770 deaths projected in 2025. 1 , 2 Nearly one in four men present with metastatic disease at diagnosis. For metastatic hormone-sensitive prostate cancer, contemporary standards rely on intensified ADT which includes an androgen receptor pathway inhibitor (ARPI), such as enzalutamide, apalutamide, darolutamide, or abiraterone with or without taxane agents. 2 Clinical trials and real-world studies consistently show substantial survival benefits with ARPI-based regimens, establishing them as the current guideline-endorsed first-line therapy across all stages of advanced prostate cancer. 3 Although effective, ARPI-based regimens are accompanied by a spectrum of adverse effects, including hot flashes, fatigue, hypertension, hypokalemia, cardiovascular complications, central nervous system effects, rashes, and drug-specific toxicities. 4 , 5 Among these, bone fractures and skeletal related events are especially concerning, as they contribute to declines in quality of life, increased morbidity, mortality, and higher healthcare utilization. 4 , 6 Current guidelines recommend preventive measures such as baseline and serial bone density assessment, calcium and vitamin D supplementation, and use of bone-modifying agents when appropriate. 7 Despite these efforts, residual risk remains, reflecting the complex mechanisms underlying skeletal fragility in this setting. ADT induces hypogonadism, lowering testosterone and estrogen levels, which accelerates bone turnover and reduces bone mineral density. The addition of ARPIs—particularly when combined with glucocorticoids, as with abiraterone plus prednisone—may further compromise bone integrity compared to ADT along. 8 In men with preexisting bone metastases, these effects are compounded by disrupted bone remodeling, leaving patients especially vulnerable to fractures and other skeletal-related events. 9 Little is known about the real-world effects of ARPIs on bone health. Randomized trials have generally reported higher rates of fractures and other skeletal complications in men receiving ARPIs compared with ADT alone, raising concerns about additive toxicity. 10 , 11 Yet beyond these controlled settings, real-world data are limited, making it unclear whether these risks translate consistently into routine practice. Such limitations highlight a critical evidence gap in understanding skeletal safety in everyday care. A global pharmacovigilance study thus offers a valuable opportunity to systematically assess real-world bone fracture signals associated with ARPIs, compare patterns among agents, and evaluate consistency across demographic and clinical subgroups. This study aims to leverage the World Health Organization’s global safety database Vigibase to address this question. We hypothesize that ARPI therapy is associated with increased reporting of fractures compared with ADT alone, and that the strength of this signal may vary across individual ARPI agents. METHODS Data Source We used VigiBase, the World Health Organization (WHO)’s global database of adverse drug reaction reports, maintained by the Uppsala Monitoring Centre. VigiBase is the largest pharmacovigilance database in the world, with more than 30 million reports submitted by over 150 national drug safety centers since 1968. 12 Reports are contributed by healthcare professionals, patients, and pharmaceutical companies, and are standardized using the WHO Drug Dictionary and the Medical Dictionary for Regulatory Activities (MedDRA). Each entry includes information on patient demographics, suspected and concomitant drugs, treatment indication, reported adverse events, seriousness, and event timing. VigiBase has been used extensively in prior pharmacovigilance studies to identify clinically important safety concerns such as mental health, infections, and cardiovascular side effects, many of which were later substantiated through dedicated epidemiologic or clinical investigations. 13 – 15 Study Population We included individual case safety reports for adult men (≥ 18 years) in which an androgen receptor pathway inhibitor (ARPI) was identified as a suspected or interacting drug. ARPIs of interest were abiraterone, enzalutamide, apalutamide, and darolutamide, identified through WHO Drug Dictionary preferred base names and synonyms. To ensure relevance to contemporary clinical practice, we restricted the analytic period to reports submitted between 2011 (the year of the first ARPI approval: abiraterone) and the most recent database at the time of analysis (cutoff date September 2024). Reports were excluded if temporality fields indicated that the adverse event occurred before initiation of the ARPI, or if data quality checks suggested implausible entries. Suspected duplicate reports were handled using the standard VigiMatch algorithm applied by the Uppsala Monitoring Centre, which designates the most complete report as preferred while retaining all others in the database. 16 Outcomes The primary outcome was bone fracture, defined using MedDRA preferred terms encompassing all fracture types. The full list of MedDRA terms is provided in Supplementary File 1. Study Design and Comparators We conducted a disproportionality analysis to assess whether fractures were reported more frequently with ARPIs than would be expected by chance. 13 , 15 , 17 , 18 The primary analysis compared ARPI reports with all other drug–event pairs submitted for adult men. Agent-specific analyses were performed to examine heterogeneity of signals across abiraterone, enzalutamide, apalutamide, and darolutamide. Two prespecified sensitivity analyses were performed. First, we redefined the comparator group as men receiving ADT alone. These included luteinizing hormone–releasing hormone modifiers and androgen receptor antagonists (Supplementary File 2). This sensitivity analysis aimed to address the question of whether ARPI intensification increases the risk of fractures beyond that of ADT alone, consistent with standard doublet or triplet regimens. Second, we stratified analyses by age group (< 65, 65–74, and ≥ 75 years) to assess whether older patients may experience disproportionate risks. This was motivated by prior evidence suggesting that intensified therapy may confer greater toxicity in older men. Statistical Analysis We first summarized the descriptive characteristics using frequencies and proportions for categorical variables and medians with interquartile ranges for continuous variables. We then conducted disproportionality analyses to quantify associations between ARPI exposure and fractures. Two-by-two contingency tables were constructed to compare the reporting of fractures with ARPIs versus comparator groups. Reporting odds ratios (RORs) with 95% confidence intervals were calculated as the primary disproportionality measure. To address statistical instability with rare events, we also applied Bayesian shrinkage estimates (EB05). A statistically significant signal for an association between drug and the adverse event was considered present if the EB05 was greater than 1.0. 17 All analyses were conducted using R version 4.3.2. This study used anonymized pharmacovigilance data and was deemed exempt from IRB review. Reporting followed STROBE protocols with consideration of RECORD-PE. RESULTS Baseline Characteristics A total of 282,143 adverse event reports involving ARPIs were identified: abiraterone (n = 73,590), apalutamide (n = 17,593), darolutamide (n = 3,771), and enzalutamide (n = 187,189). Overall, 1,140 reports (0.4% of the cohort) involved bone fractures, with counts ranging from 10 events with darolutamide to 778 with enzalutamide. Most reports originated from the Region of the Americas (78%), followed by Europe(17%). Reports increased over time, with abiraterone and enzalutamide dominating earlier years and apalutamide and darolutamide increasing in later years, consistent with the timing of approvals and availability. After regrouping into prespecified age categories, 8.3% were younger than 65 years, 21% were 65–74 years, and 38% were ≥ 75 years, while 33% had missing age data. Age distributions were similar across agents, with a notable concentration of reports in men ≥ 75 years for all ARPIs. Time-to-onset data were available in a minority of cases. Among those with non-missing values, median time to onset of any adverse events was 43 days overall, ranging from 32 days for enzalutamide to 56 days for abiraterone (Table 1 ). Table 1 Baseline characteristics of Vigibase adverse event reports for androgen receptor pathway inhibitors Overall, N = 282,143 1 Abiraterone, N = 73,590 1 Apalutamide, N = 17,593 1 Darolutamide, N = 3,771 1 Enzalutamide, N = 187,189 1 Region African Region 482 (0.2%) 427 (0.6%) 8 (< 0.1%) 0 (0%) 47 (< 0.1%) Eastern Mediterranean Region 1,239 (0.4%) 494 (0.7%) 284 (1.6%) 1 (< 0.1%) 460 (0.2%) European Region 46,654 (17%) 19,178 (26%) 8,046 (46%) 1,159 (31%) 18,271 (9.8%) Region of the Americas 221,021 (78%) 47,134 (64%) 9,027 (51%) 2,499 (66%) 162,361 (87%) South-East Asia Region 1,307 (0.5%) 470 (0.6%) 37 (0.2%) 17 (0.5%) 783 (0.4%) Western Pacific Region 11,440 (4.1%) 5,887 (8.0%) 191 (1.1%) 95 (2.5%) 5,267 (2.8%) Year 2009 32 (< 0.1%) 32 (< 0.1%) 0 (0%) 0 (0%) 0 (0%) 2010 22 (< 0.1%) 22 (< 0.1%) 0 (0%) 0 (0%) 0 (0%) 2011 122 (< 0.1%) 122 (0.2%) 0 (0%) 0 (0%) 0 (0%) 2012 1,206 (0.4%) 1,205 (1.6%) 0 (0%) 0 (0%) 1 (< 0.1%) 2013 1,682 (0.6%) 1,190 (1.6%) 0 (0%) 0 (0%) 492 (0.3%) 2014 10,140 (3.6%) 2,703 (3.7%) 0 (0%) 1 (< 0.1%) 7,436 (4.0%) 2015 20,189 (7.2%) 4,545 (6.2%) 0 (0%) 0 (0%) 15,644 (8.4%) 2016 14,130 (5.0%) 6,346 (8.6%) 0 (0%) 0 (0%) 7,784 (4.2%) 2017 35,158 (12%) 6,566 (8.9%) 0 (0%) 8 (0.2%) 28,584 (15%) 2018 48,241 (17%) 9,312 (13%) 85 (0.5%) 0 (0%) 38,844 (21%) 2019 53,699 (19%) 11,175 (15%) 1,398 (7.9%) 19 (0.5%) 41,107 (22%) 2020 18,895 (6.7%) 7,574 (10%) 1,867 (11%) 209 (5.5%) 9,245 (4.9%) 2021 20,535 (7.3%) 6,831 (9.3%) 1,973 (11%) 441 (12%) 11,290 (6.0%) 2022 20,452 (7.2%) 7,587 (10%) 3,713 (21%) 466 (12%) 8,686 (4.6%) 2023 23,449 (8.3%) 5,749 (7.8%) 5,386 (31%) 1,265 (34%) 11,049 (5.9%) 2024 14,191 (5.0%) 2,631 (3.6%) 3,171 (18%) 1,362 (36%) 7,027 (3.8%) Gender Male 282,143 (100%) 73,590 (100%) 17,593 (100%) 3,771 (100%) 187,189 (100%) Age group < 65 years 23,552 (8.4%) 7,147 (9.7%) 1,408 (8.0%) 656 (17%) 14,341 (7.7%) 65–74 years 58,279 (21%) 15,614 (21%) 4,060 (23%) 850 (23%) 37,755 (20%) ≥75 years 106,449 (38%) 26,601 (36%) 6,264 (36%) 1,370 (36%) 72,214 (39%) Unknown 93,863 (33%) 24,228 (33%) 5,861 (33%) 895 (24%) 62,879 (34%) Time to onset (days) 43 (2, 172) 56 (7, 216) 39 (4, 111) 40 (3, 139) 32 (0, 153) Unknown 248,109 58,012 13,272 3,118 173,707 Bone fractures 1,140 (0.4%) 278 (0.4%) 74 (0.4%) 10 (0.3%) 778 (0.4%) 1 n (%); Median (IQR) Primary Analysis In the primary disproportionality analysis ARPI therapy overall showed a signal of disproportionally higher reporting of fractures compared with all other drug–event pairs in adult men (ROR 1.87, 95% CI 1.77–1.98; EB05 1.77). Respectively, higher disproportionate reporting was observed for abiraterone (ROR 1.93, 95% CI 1.71–2.17; EB05 1.73), apalutamide (ROR 1.92, 95% CI 1.53–2.41; EB05 1.56), and enzalutamide (ROR 1.85, 95% CI 1.73–1.99; EB05 1.73), whereas no disproportionate reporting was detected for darolutamide (ROR 1.35, 95% CI 0.73–2.51; EB05 0.81) (Table 2 ). Table 2 Disproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor use Drug Count Expected Count ROR (95% CI) EB05 Abiraterone 278 145 1.93 (1.71, 2.17) 1.73 Apalutamide 74 39 1.92 (1.53, 2.41) 1.56 Darolutamide 10 7 1.35 (0.73, 2.51) 0.81 Enzalutamide 778 422 1.85 (1.73, 1.99) 1.73 Composite ARPI 1140 613 1.87 (1.77, 1.98) 1.77 Sensitivity Analysis Using ADT Comparator In sensitivity analysis with traditional ADT as the reference, ARPIs also demonstrated disproportionately higher ROR of fractures (ROR 1.43, 95% CI 1.29–1.58; EB05 1.08). Signals were evident for abiraterone (ROR 1.48, 95% CI 1.28–1.71; EB05 1.18), apalutamide (ROR 1.47, 95% CI 1.15–1.87; EB05 1.15), and enzalutamide (ROR 1.41, 95% CI 1.27–1.58; EB05 1.10), whereas darolutamide did not meet signal thresholds (ROR 1.03, 95% CI 0.55–1.93; EB05 0.59). (Table 3 ) Table 3 Disproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor use with reference to traditional androgen deprivation therapy Drug Count Expected Count ROR (95% CI) EB05 Abiraterone 278 212 1.48 (1.28, 1.71) 1.18 Apalutamide 74 52 1.47 (1.15, 1.87) 1.15 Darolutamide 10 10 1.03 (0.55, 1.93) 0.59 Enzalutamide 778 666 1.41 (1.27, 1.58) 1.10 Composite ARPI 1140 1004 1.43 (1.29, 1.58) 1.08 Sensitivity Analysis by Age Group In age-stratified analyses, ARPIs overall demonstrated signals of disproportionally higher reporting of fractures across all age groups: <65 years (ROR 1.57, 95% CI 1.24–1.97; EB05 1.26), 65–74 years (ROR 2.13, 95% CI 1.86–2.44; EB05 1.86), and ≥ 75 years (ROR 2.65, 95% CI 2.44–2.89; EB05 2.38). Abiraterone showed signals in all age categories, with RORs of 1.94 (95% CI 1.29–2.92; EB05 1.30) for men < 65 years, 1.82 (95% CI 1.35–2.46; EB05 1.38) for 65–74 years, and 3.06 (95% CI 2.60–3.60; EB05 2.60) for ≥ 75 years. For apalutamide, signals were not detected in younger men (< 65 years: ROR 2.10, 95% CI 0.94–4.68; EB05 0.93; 65–74 years: ROR 1.56, 95% CI 0.86–2.82; EB05 0.91), but a clear signal was observed in men ≥ 75 years (ROR 2.98, 95% CI 2.18–4.09; EB05 2.15). Darolutamide demonstrated a signal in men ≥ 75 years only (ROR 2.93, 95% CI 1.46–5.86; EB05 1.36), with inadequate numbers of reports available allowing analysis among other age groups. Enzalutamide demonstrated signals in all age categories, with RORs of 1.44 (95% CI 1.07–1.94; EB05 1.10) in men < 65 years, 2.34 (95% CI 1.99–2.74; EB05 2.00) in men 65–74 years, and 2.43 (95% CI 2.19–2.69; EB05 2.17) in men ≥ 75 years. (Table 4 ) Table 4 Disproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor by age groups Drug Count Expected Count ROR (95% CI) EB05 Composite ARPI < 65 72 46 1.57 (1.24, 1.97) 1.26 65–74 209 99 2.13 (1.86, 2.44) 1.86 ≥ 75 570 223 2.65 (2.44, 2.89) 2.38 Abiraterone < 65 23 12 1.94 (1.29, 2.92) 1.30 65–74 43 24 1.82 (1.35, 2.46) 1.38 ≥ 75 150 50 3.06 (2.60, 3.60) 2.60 Apalutamide < 65 6 3 2.10 (0.94, 4.68) 0.93 65–74 11 7 1.56 (0.86, 2.82) 0.91 ≥ 75 39 13 2.98 (2.18, 4.09) 2.15 Darolutamide ≥ 75 8 3 2.93 (1.46, 5.86) 1.36 Enzalutamide < 65 43 30 1.44 (1.07, 1.94) 1.10 65–74 155 67 2.34 (1.99, 2.74) 2.00 ≥ 75 373 157 2.43 (2.19, 2.69) 2.17 DISCUSSION In this global pharmacovigilance study using VigiBase, we evaluated the association between therapy with ARPIs and bone fractures in men with prostate cancer. We observed pharmacovigilance signals both for the class overall and for individual agents, confirmed across primary and sensitivity analyses. Signals persisted when androgen deprivation therapy served as the reference, underscoring the potential for additive skeletal toxicity with contemporary doublet and triplet regimens. Given that intensification is now standard in all states of advanced prostate cancer, these findings highlight the importance of ensuring appropriate bone health assessment and management strategies in the care of patients with prostate cancer. Our findings are consistent with data from randomized trials. Two earlier meta-analyses using trial data across different disease states of prostate cancer demonstrated that intensification with androgen receptor pathway inhibitors approximately doubled the risk of fractures and falls compared with androgen deprivation alone. 4 , 11 These effects were observed consistently across disease states, including metastatic hormone-sensitive, nonmetastatic hormone-resistant, and metastatic hormone-resistant disease. 4 , 11 While our pharmacovigilance analysis did not include falls as an outcome, the fracture signals we identified align closely with these pooled trial-level data, underscoring the robustness of the skeletal toxicity signal across study designs. Specifically, darolutamide has been suggested in clinical trial data to carry a comparatively favorable skeletal safety profile, possibly due to its limited central nervous system penetration and reudced dizziness and balance-related complications that can predispose to falls. 4 , 11 , 19 Our analysis likewise did not detect a composite signal for darolutamide in the primary analysis, though a signal appeared among men 75 years and older. Importantly, darolutamide was the last ARPI to receive approval compared to other ARPIs, accounting for the lower absolute number of reports in the current edition of VigiBase and limiting the statistical power. Darolutamide is also first approved in non-metastatic hormone-resistant prostate cancer, which could represent a group of patients with inherently lower fracture risk compared to those with metastatic disease. Caution is warranted in interpreting these findings. Our results also add to a small body of evidence from “real world” practice on bone health. For example, In an earlier (US-based) analysis among Medicare beneficiaries (> 65 with public insurance), the two-year cumulative incidence of skeletal related events approached 12–14% in men treated with abiraterone or enzalutamide, with even higher rates among those with prior fracture. 20 Our pharmacovigilance signals echo these observations and further support the additional skeletal toxicity in real-world settings. Additionally, our data included additional ARPIs in global practice settings and a wider age range than the 65 + population in Medicare claims. Mechanistic explanations—accelerated bone mineral density loss with androgen deprivation, glucocorticoid-associated fragility with abiraterone, and central nervous system adverse effects that may predispose to falls with enzalutamide and apalutamide—have been described. 5 , 21 , 22 However, it should be noted that in current practice these agents are layered on top of androgen deprivation, and the risk we observed reflects the added burden of intensification rather than monotherapy. Combination regimens, particularly those involving additional therapy, may further magnify fracture risk if bone-protective agents and other mitigation strategies are not used, as demonstrated by the sharp risk reduction once prophylactic bone health agent use was mandated in PEACE-III in which radium was added to the ADT and enzalutamide combination therapy. 23 We also observed pharmacovigilance signals across all age strata, with numerically larger disproportionality estimates among older men. While we cannot directly compare subgroups within this framework, the absolute values suggest that older adults may be more vulnerable to skeletal complications—a finding consistent with prior evidence. For example, secondary analysis of the PREVAIL trial of enzalutamide in metastatic hormone-resistant prostate cancer patients has reported falls and fractures in 19% and 16% of men ≥ 75 years, compared to 7% and 10% in younger patients. 24 Two recent meta-analysis of clinical trials of treatment intensification in metastatic hormone sensitive prostate cancer reported that older men above 70 or 75 years old may gain much little survival benefit from treatment intensification, compared to their younger counterparts. 25 , 26 Our pharmacovigilance signals, alongside existing data, suggest that skeletal safety may warrant particular consideration when weighing ARPI intensification in older or frail populations. This study has several limitations. First, pharmacovigilance analyses detect disproportionate reporting, not incidence or causality. VigiBase relies on voluntary reports, subject to underreporting, selective reporting, and regional heterogeneity in data quality. Second, clinical details such as disease stage, bone metastasis burden, comorbidities, and bone-protective agent use were not codified into the database. We could not distinguish osteoporotic from pathologic fractures, as some trial data suggest that ARPI may confer protection against pathologic fractures. 27 Likewise, medDRA terminology lacks the specificity needed to identify malignant spinal cord compression and therefore does not fully capture the spectrum of skeletal-related events in prostate cancer. Third, although the number of ARPI reports was large overall, darolutamide was more recently added to the treatment armamentarium and would be expected to have a significantly lower number of reported complications. Fourth, while age-stratified analyses were informative, pharmacovigilance methods preclude formal comparisons of magnitude across groups. Finally, as with all pharmacovigilance research, these results are hypothesis-generating and best interpreted alongside trial and epidemiologic data. CONCLUSION In this global pharmacovigilance analysis, androgen receptor pathway inhibitors were consistently associated with disproportionate reporting of bone fractures across agents and age groups, reinforcing concerns about additive skeletal toxicity with treatment intensification. These findings complement evidence from randomized trials and limited real-world cohorts, and underscore the need for careful attention to bone health assessment and management, particularly for older men. Proactive bone health strategies, including guideline-based screening and preventive measures, remain essential as ARPI-based regimens continue to expand in prostate cancer care. Declarations Disclosures: AKM reports consulting fees from Astellas, AstraZeneca, Bayer, Curium, Dendreon, Exact Sciences, Johnson & Johnson, Lantheus, Merck, Novartis, Pfizer, Sumitomo Pharma, Inc., Telix, Tolmar. Q-DT reports consulting fees from Astellas, Bayer, Intuitive Surgical, Janssen, Novartis, Pfizer, and research funding from the American Cancer Society, Pfizer Global Medical Grants (Prostate Cancer Disparities #63354905). Q-DT reports funding from Health Disparity Research Award from the Department of Defense Congressionally Directed Medical Research Program (#PC220551). APC reports research funding from the Bruce A Beal and Robert L Beal surgical fellowship of the BWH Department of Surgery, from the Prostate Cancer Foundation and American Cancer Society (#23YOUN25) and from a Physician Research Award from the Department of Defense Congressionally Directed Medical Research Program (#PC220342). Conflict of Interests: The authors have no conflict of interests that may influence the outcomes of this study. References Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. Ca . 2025;75(1):10. Kratzer TB, Mazzitelli N, Star J, Dahut WL, Jemal A, Siegel RL. Prostate cancer statistics, 2025. CA: A Cancer Journal for Clinicians . 2025; Raychaudhuri R, Lin DW, Montgomery RB. Prostate cancer: a review. JAMA . 2025; Fazekas T, Miszczyk M, Giesen A, et al. Androgen Receptor Pathway Inhibitor Monotherapy in Prostate Cancer: Safety, Oncologic Outcomes, and Quality of Life—A Systematic Review and Meta-analysis. European Urology Focus . 2025; Nowakowska MK, Ortega RM, Wehner MR, Nead KT. Association of second-generation antiandrogens with cognitive and functional toxic effects in randomized clinical trials: a systematic review and meta-analysis. JAMA oncology . 2023;9(7):930-937. Miller K, Steger GG, Niepel D, Lüftner D. Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. Prostate cancer and prostatic diseases . 2018;21(4):461-472. Schaeffer EM, Srinivas S, Adra N, et al. Prostate cancer, version 3.2024 featured updates to the NCCN guidelines. JNCCN Journal of the National Comprehensive Cancer Network . 2024;22(3):140-150. Fischer S, Clements S, McWilliam A, et al. Influence of abiraterone and enzalutamide on body composition in patients with metastatic castration resistant prostate cancer. Cancer Treatment and Research Communications . 2020;25:100256. Baldessari C, Pipitone S, Molinaro E, et al. Bone metastases and health in prostate cancer: From pathophysiology to clinical implications. Cancers . 2023;15(5):1518. Jones C, Gray S, Brown M, et al. Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials. European Urology Oncology . 2024/10/01/ 2024;7(5):993-1004. doi:https://doi.org/10.1016/j.euo.2024.01.016 Myint ZW, Momo HD, Otto DE, Yan D, Wang P, Kolesar JM. Evaluation of Fall and Fracture Risk Among Men With Prostate Cancer Treated With Androgen Receptor Inhibitors: A Systematic Review and Meta-analysis. JAMA Network Open . 2020;3(11):e2025826-e2025826. doi:10.1001/jamanetworkopen.2020.25826 Lindquist M. VigiBase, the WHO global ICSR database system: basic facts. Drug Information Journal . 2008;42(5):409-419. Qian Z, Song J, Jones A, et al. SGLT2 inhibitor and urinary tract infection in men at risk for voiding dysfunction: a VigiBase analysis. Urology Practice . 2025;12(1):131-137. Song JJ, Qian Z, Cho M, Nguyen D-D, Trinh Q-D, Wollin DA. Disproportionality Analysis of Hypotension-Related Adverse Drug Reactions Associated With Type 1a Selective Alpha-Blockers in VigiBase. Urology Practice . 2025:10.1097/UPJ. 0000000000000790. Nguyen DD, Marchese M, Cone EB, et al. Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. JAMA Dermatol . Jan 1 2021;157(1):35-42. doi:10.1001/jamadermatol.2020.3385 Tregunno PM, Fink DB, Fernandez-Fernandez C, Lázaro-Bengoa E, Norén GN. Performance of probabilistic method to detect duplicate individual case safety reports. Drug safety . 2014;37(4):249-258. Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf . Jun 2009;18(6):427-36. doi:10.1002/pds.1742 Salem J-E, Manouchehri A, Bretagne M, et al. Cardiovascular toxicities associated with ibrutinib. Journal of the American College of Cardiology . 2019;74(13):1667-1678. Turco F, Gillessen S, Treglia G, et al. Safety profile of darolutamide versus placebo: a systematic review and meta-analysis. Prostate cancer and prostatic diseases . 2024;27(3):385-392. Kwon DH, Paciorek A, Zhang L, et al. Skeletal-related events after abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer: A population-based study using the SEER-Medicare linked dataset. Urol Oncol . Aug 2022;40(8):379.e17-379.e24. doi:10.1016/j.urolonc.2022.05.025 Halabi S, Jiang S, Terasawa E, et al. Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer. J Urol . Aug 2021;206(2):298-307. doi:10.1097/ju.0000000000001767 Fukuokaya W, Mori K, Urabe F, et al. Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate. JAMA Network Open . 2024;7(3):e242467-e242467. doi:10.1001/jamanetworkopen.2024.2467 Gillessen S, Tombal B, Turco F, et al. Decrease in fracture rate with mandatory bone-protecting agents in the EORTC 1333/PEACE-3 trial comparing radium-223 combined with enzalutamide versus enzalutamide alone: a safety analysis. European Urology . 2025;87(3):285-288. Graff JN, Baciarello G, Armstrong AJ, et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Annals of Oncology . 2016;27(2):286-294. Fisher DJ, Vale CL, Rydzewska LH, et al. Which patients with metastatic hormone-sensitive prostate cancer (mHSPC) benefit more from androgen receptor pathway inhibitors (ARPIs)? STOPCAP meta-analyses of individual participant data (IPD). American Society of Clinical Oncology; 2025. Morgans AK, Roy S, Jia AY, et al. Age and Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer. NEJM Evidence . 2025;4(11):EVIDoa2500109. doi:doi:10.1056/EVIDoa2500109 Logothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol . Dec 2012;13(12):1210-7. doi:10.1016/s1470-2045(12)70473-4 Additional Declarations Yes there is potential conflict of interest. Supplementary Files jq121825suppfiles.docx Supplemental Materials Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 09 Mar, 2026 Review # 2 received at journal 20 Feb, 2026 Reviewer # 2 agreed at journal 02 Feb, 2026 Review # 1 received at journal 01 Feb, 2026 Reviewer # 1 agreed at journal 01 Feb, 2026 Reviewers invited by journal 28 Jan, 2026 Editor assigned by journal 26 Jan, 2026 Submission checks completed at journal 26 Jan, 2026 First submitted to journal 22 Jan, 2026 Unknown event 21 Jan, 2026 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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Cole","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYDACdjDJDONaMPCDqIQCPFqYUbVIMEg2gLQYkKLF4ACIxqOFv5n5mMTPHdZy5g28Bxh+VEjIGZ9fnfjhgQGDPL/YAaxaJA6zJRv2nkk3ljnAl8DYc0bC2OzG280SQIcZzpydgN2awzyGD3jbDifOYOAxYGZsk0jcduPsBpCWBIPb2LXIH+b/cPBv2+F6mJb6zTPObv6BT4vBYR7Gx0BbEiSgWhIM+Hu34bXF8DCbsbFsW7rhDGa+hINAvxjOuMG7zSLBQAKnX+SONz+TfNtmLS/B3nvwwY8KG3n+/rObb4IZ0ji8DwfMPAwHwAwJsEoJAsrBgAdK8x8gRvUoGAWjYBSMIAAAm9RWyx54emkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0049-8529","institution":"Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women�","correspondingAuthor":true,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Cole","suffix":""},{"id":581979515,"identity":"b3d6da17-ae44-4542-9376-1d4e7521d3b0","order_by":1,"name":"Zhiyu Qian","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Zhiyu","middleName":"","lastName":"Qian","suffix":""},{"id":581979516,"identity":"c664699c-0f5e-415f-96d7-dcef822f7f3d","order_by":2,"name":"Mansoo Cho","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mansoo","middleName":"","lastName":"Cho","suffix":""},{"id":581979517,"identity":"5e0fe708-84a3-43af-8df4-b1b4290e1924","order_by":3,"name":"Stephan Korn","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Korn","suffix":""},{"id":581979518,"identity":"66e25f5f-663a-4c26-8465-3de0744e3517","order_by":4,"name":"Hanna Zurl","email":"","orcid":"https://orcid.org/0009-0007-1255-9337","institution":"Medical University of Graz","correspondingAuthor":false,"prefix":"","firstName":"Hanna","middleName":"","lastName":"Zurl","suffix":""},{"id":581979519,"identity":"b80701ab-51eb-4c14-9b29-25729f811901","order_by":5,"name":"Pietro Brin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Pietro","middleName":"","lastName":"Brin","suffix":""},{"id":581979520,"identity":"373cf5a3-a1ec-44ca-823d-0a882b2fe218","order_by":6,"name":"Kerry Kilbridge","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Kerry","middleName":"","lastName":"Kilbridge","suffix":""},{"id":581979521,"identity":"f2a68cff-fc5e-4b6a-bd0a-1cec82905a04","order_by":7,"name":"Alicia Morgans","email":"","orcid":"https://orcid.org/0000-0002-6563-4587","institution":"Dana-Farber Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Alicia","middleName":"","lastName":"Morgans","suffix":""},{"id":581979522,"identity":"d5636646-7a7c-411b-8813-0b4d60fa4d51","order_by":8,"name":"Matthew Smith","email":"","orcid":"","institution":"Massachusetts General Hospital Cancer Center and Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Smith","suffix":""},{"id":581979523,"identity":"83661ea0-3da3-4359-86ca-7ea3a0fe042f","order_by":9,"name":"Mutlay Sayan","email":"","orcid":"https://orcid.org/0000-0002-0101-0951","institution":"Brigham and Women's Hospital and Dana Farber Cancer Institute","correspondingAuthor":false,"prefix":"","firstName":"Mutlay","middleName":"","lastName":"Sayan","suffix":""},{"id":581979524,"identity":"541ef082-02af-45f5-83ed-7b5ac0462313","order_by":10,"name":"Stuart Lipsitz","email":"","orcid":"https://orcid.org/0000-0003-2619-1389","institution":"Brigham and Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stuart","middleName":"","lastName":"Lipsitz","suffix":""},{"id":581979525,"identity":"36fab1a5-3a00-4128-9085-5c199ed8ca97","order_by":11,"name":"Adam Kibel","email":"","orcid":"","institution":"Urology Division, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Kibel","suffix":""},{"id":581979526,"identity":"2026303c-bc6b-4437-b714-f9dbd98faf6d","order_by":12,"name":"Quoc-Dien Trinh","email":"","orcid":"https://orcid.org/0000-0003-3857-9276","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Quoc-Dien","middleName":"","lastName":"Trinh","suffix":""}],"badges":[],"createdAt":"2026-01-21 11:11:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8658712/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8658712/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101752465,"identity":"ec3e1bb0-7c80-441c-8467-db104dad7617","added_by":"auto","created_at":"2026-02-03 10:27:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":899536,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8658712/v1/ce276f95-6367-43b7-b984-f0352b62419f.pdf"},{"id":101525070,"identity":"8c958a34-3fe5-4961-9d28-a8bbb93502b0","added_by":"auto","created_at":"2026-01-30 18:10:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17170,"visible":true,"origin":"","legend":"Supplemental Materials","description":"","filename":"jq121825suppfiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-8658712/v1/d74ea41444b6daed4a6a0e66.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eProstate cancer is the most common non-skin malignancy among men in the United States, with approximately 313,780 new diagnoses and 35,770 deaths projected in 2025.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Nearly one in four men present with metastatic disease at diagnosis. For metastatic hormone-sensitive prostate cancer, contemporary standards rely on intensified ADT which includes an androgen receptor pathway inhibitor (ARPI), such as enzalutamide, apalutamide, darolutamide, or abiraterone with or without taxane agents.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Clinical trials and real-world studies consistently show substantial survival benefits with ARPI-based regimens, establishing them as the current guideline-endorsed first-line therapy across all stages of advanced prostate cancer.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough effective, ARPI-based regimens are accompanied by a spectrum of adverse effects, including hot flashes, fatigue, hypertension, hypokalemia, cardiovascular complications, central nervous system effects, rashes, and drug-specific toxicities.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Among these, bone fractures and skeletal related events are especially concerning, as they contribute to declines in quality of life, increased morbidity, mortality, and higher healthcare utilization.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Current guidelines recommend preventive measures such as baseline and serial bone density assessment, calcium and vitamin D supplementation, and use of bone-modifying agents when appropriate.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Despite these efforts, residual risk remains, reflecting the complex mechanisms underlying skeletal fragility in this setting. ADT induces hypogonadism, lowering testosterone and estrogen levels, which accelerates bone turnover and reduces bone mineral density. The addition of ARPIs\u0026mdash;particularly when combined with glucocorticoids, as with abiraterone plus prednisone\u0026mdash;may further compromise bone integrity compared to ADT along.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In men with preexisting bone metastases, these effects are compounded by disrupted bone remodeling, leaving patients especially vulnerable to fractures and other skeletal-related events.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLittle is known about the real-world effects of ARPIs on bone health. Randomized trials have generally reported higher rates of fractures and other skeletal complications in men receiving ARPIs compared with ADT alone, raising concerns about additive toxicity.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Yet beyond these controlled settings, real-world data are limited, making it unclear whether these risks translate consistently into routine practice. Such limitations highlight a critical evidence gap in understanding skeletal safety in everyday care. A global pharmacovigilance study thus offers a valuable opportunity to systematically assess real-world bone fracture signals associated with ARPIs, compare patterns among agents, and evaluate consistency across demographic and clinical subgroups. This study aims to leverage the World Health Organization\u0026rsquo;s global safety database Vigibase to address this question. We hypothesize that ARPI therapy is associated with increased reporting of fractures compared with ADT alone, and that the strength of this signal may vary across individual ARPI agents.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Source\u003c/h2\u003e \u003cp\u003eWe used VigiBase, the World Health Organization (WHO)\u0026rsquo;s global database of adverse drug reaction reports, maintained by the Uppsala Monitoring Centre. VigiBase is the largest pharmacovigilance database in the world, with more than 30\u0026nbsp;million reports submitted by over 150 national drug safety centers since 1968.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Reports are contributed by healthcare professionals, patients, and pharmaceutical companies, and are standardized using the WHO Drug Dictionary and the Medical Dictionary for Regulatory Activities (MedDRA). Each entry includes information on patient demographics, suspected and concomitant drugs, treatment indication, reported adverse events, seriousness, and event timing. VigiBase has been used extensively in prior pharmacovigilance studies to identify clinically important safety concerns such as mental health, infections, and cardiovascular side effects, many of which were later substantiated through dedicated epidemiologic or clinical investigations.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eWe included individual case safety reports for adult men (\u0026ge;\u0026thinsp;18 years) in which an androgen receptor pathway inhibitor (ARPI) was identified as a suspected or interacting drug. ARPIs of interest were abiraterone, enzalutamide, apalutamide, and darolutamide, identified through WHO Drug Dictionary preferred base names and synonyms. To ensure relevance to contemporary clinical practice, we restricted the analytic period to reports submitted between 2011 (the year of the first ARPI approval: abiraterone) and the most recent database at the time of analysis (cutoff date September 2024). Reports were excluded if temporality fields indicated that the adverse event occurred before initiation of the ARPI, or if data quality checks suggested implausible entries. Suspected duplicate reports were handled using the standard VigiMatch algorithm applied by the Uppsala Monitoring Centre, which designates the most complete report as preferred while retaining all others in the database.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was bone fracture, defined using MedDRA preferred terms encompassing all fracture types. The full list of MedDRA terms is provided in Supplementary File 1.\u003c/p\u003e\n\u003ch3\u003eStudy Design and Comparators\u003c/h3\u003e\n\u003cp\u003eWe conducted a disproportionality analysis to assess whether fractures were reported more frequently with ARPIs than would be expected by chance.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e The primary analysis compared ARPI reports with all other drug\u0026ndash;event pairs submitted for adult men. Agent-specific analyses were performed to examine heterogeneity of signals across abiraterone, enzalutamide, apalutamide, and darolutamide. Two prespecified sensitivity analyses were performed. First, we redefined the comparator group as men receiving ADT alone. These included luteinizing hormone\u0026ndash;releasing hormone modifiers and androgen receptor antagonists (Supplementary File 2). This sensitivity analysis aimed to address the question of whether ARPI intensification increases the risk of fractures beyond that of ADT alone, consistent with standard doublet or triplet regimens. Second, we stratified analyses by age group (\u0026lt;\u0026thinsp;65, 65\u0026ndash;74, and \u0026ge;\u0026thinsp;75 years) to assess whether older patients may experience disproportionate risks. This was motivated by prior evidence suggesting that intensified therapy may confer greater toxicity in older men.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eWe first summarized the descriptive characteristics using frequencies and proportions for categorical variables and medians with interquartile ranges for continuous variables. We then conducted disproportionality analyses to quantify associations between ARPI exposure and fractures. Two-by-two contingency tables were constructed to compare the reporting of fractures with ARPIs versus comparator groups. Reporting odds ratios (RORs) with 95% confidence intervals were calculated as the primary disproportionality measure. To address statistical instability with rare events, we also applied Bayesian shrinkage estimates (EB05). A statistically significant signal for an association between drug and the adverse event was considered present if the EB05 was greater than 1.0.\u003csup\u003e17\u003c/sup\u003e All analyses were conducted using R version 4.3.2. This study used anonymized pharmacovigilance data and was deemed exempt from IRB review. Reporting followed STROBE protocols with consideration of RECORD-PE.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 282,143 adverse event reports involving ARPIs were identified: abiraterone (n\u0026thinsp;=\u0026thinsp;73,590), apalutamide (n\u0026thinsp;=\u0026thinsp;17,593), darolutamide (n\u0026thinsp;=\u0026thinsp;3,771), and enzalutamide (n\u0026thinsp;=\u0026thinsp;187,189). Overall, 1,140 reports (0.4% of the cohort) involved bone fractures, with counts ranging from 10 events with darolutamide to 778 with enzalutamide. Most reports originated from the Region of the Americas (78%), followed by Europe(17%). Reports increased over time, with abiraterone and enzalutamide dominating earlier years and apalutamide and darolutamide increasing in later years, consistent with the timing of approvals and availability. After regrouping into prespecified age categories, 8.3% were younger than 65 years, 21% were 65\u0026ndash;74 years, and 38% were \u0026ge;\u0026thinsp;75 years, while 33% had missing age data. Age distributions were similar across agents, with a notable concentration of reports in men\u0026thinsp;\u0026ge;\u0026thinsp;75 years for all ARPIs. Time-to-onset data were available in a minority of cases. Among those with non-missing values, median time to onset of any adverse events was 43 days overall, ranging from 32 days for enzalutamide to 56 days for abiraterone (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of Vigibase adverse event reports for androgen receptor pathway inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall, N\u0026thinsp;=\u0026thinsp;282,143\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbiraterone, N\u0026thinsp;=\u0026thinsp;73,590\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eApalutamide, N\u0026thinsp;=\u0026thinsp;17,593\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDarolutamide, N\u0026thinsp;=\u0026thinsp;3,771\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEnzalutamide, N\u0026thinsp;=\u0026thinsp;187,189\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfrican Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e482 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e427 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEastern Mediterranean Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,239 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e494 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e284 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e460 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEuropean Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46,654 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19,178 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8,046 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,159 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18,271 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion of the Americas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e221,021 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47,134 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9,027 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2,499 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e162,361 (87%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth-East Asia Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,307 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e470 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e783 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWestern Pacific Region\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11,440 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5,887 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e191 (1.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95 (2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5,267 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYear\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,206 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,205 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,682 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,190 (1.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e492 (0.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10,140 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,703 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (\u0026lt;\u0026thinsp;0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7,436 (4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20,189 (7.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4,545 (6.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15,644 (8.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14,130 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6,346 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7,784 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35,158 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6,566 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28,584 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48,241 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9,312 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38,844 (21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53,699 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11,175 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,398 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41,107 (22%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18,895 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7,574 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,867 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e209 (5.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9,245 (4.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20,535 (7.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6,831 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,973 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e441 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11,290 (6.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20,452 (7.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7,587 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3,713 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e466 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8,686 (4.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23,449 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5,749 (7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5,386 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,265 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11,049 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14,191 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,631 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3,171 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,362 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7,027 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e282,143 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73,590 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17,593 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3,771 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e187,189 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23,552 (8.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7,147 (9.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,408 (8.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e656 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14,341 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;74 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58,279 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15,614 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4,060 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e850 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37,755 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;75 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106,449 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26,601 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6,264 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,370 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72,214 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93,863 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24,228 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5,861 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e895 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62,879 (34%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to onset (days)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (2, 172)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (7, 216)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (4, 111)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 (3, 139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32 (0, 153)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e248,109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58,012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13,272\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3,118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e173,707\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone fractures\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,140 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e278 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (0.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e778 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003en (%); Median (IQR)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePrimary Analysis\u003c/h3\u003e\n\u003cp\u003eIn the primary disproportionality analysis ARPI therapy overall showed a signal of disproportionally higher reporting of fractures compared with all other drug\u0026ndash;event pairs in adult men (ROR 1.87, 95% CI 1.77\u0026ndash;1.98; EB05 1.77). Respectively, higher disproportionate reporting was observed for abiraterone (ROR 1.93, 95% CI 1.71\u0026ndash;2.17; EB05 1.73), apalutamide (ROR 1.92, 95% CI 1.53\u0026ndash;2.41; EB05 1.56), and enzalutamide (ROR 1.85, 95% CI 1.73\u0026ndash;1.99; EB05 1.73), whereas no disproportionate reporting was detected for darolutamide (ROR 1.35, 95% CI 0.73\u0026ndash;2.51; EB05 0.81) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor use\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExpected Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEB05\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbiraterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.93 (1.71, 2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApalutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.92 (1.53, 2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDarolutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.35 (0.73, 2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnzalutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e778\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e422\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.85 (1.73, 1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComposite ARPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.87 (1.77, 1.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity Analysis Using ADT Comparator\u003c/h2\u003e \u003cp\u003eIn sensitivity analysis with traditional ADT as the reference, ARPIs also demonstrated disproportionately higher ROR of fractures (ROR 1.43, 95% CI 1.29\u0026ndash;1.58; EB05 1.08). Signals were evident for abiraterone (ROR 1.48, 95% CI 1.28\u0026ndash;1.71; EB05 1.18), apalutamide (ROR 1.47, 95% CI 1.15\u0026ndash;1.87; EB05 1.15), and enzalutamide (ROR 1.41, 95% CI 1.27\u0026ndash;1.58; EB05 1.10), whereas darolutamide did not meet signal thresholds (ROR 1.03, 95% CI 0.55\u0026ndash;1.93; EB05 0.59). (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor use with reference to traditional androgen deprivation therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExpected Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEB05\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbiraterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.48 (1.28, 1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApalutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.47 (1.15, 1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDarolutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.03 (0.55, 1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnzalutamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e778\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.41 (1.27, 1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComposite ARPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.43 (1.29, 1.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity Analysis by Age Group\u003c/h2\u003e \u003cp\u003eIn age-stratified analyses, ARPIs overall demonstrated signals of disproportionally higher reporting of fractures across all age groups: \u0026lt;65 years (ROR 1.57, 95% CI 1.24\u0026ndash;1.97; EB05 1.26), 65\u0026ndash;74 years (ROR 2.13, 95% CI 1.86\u0026ndash;2.44; EB05 1.86), and \u0026ge;\u0026thinsp;75 years (ROR 2.65, 95% CI 2.44\u0026ndash;2.89; EB05 2.38). Abiraterone showed signals in all age categories, with RORs of 1.94 (95% CI 1.29\u0026ndash;2.92; EB05 1.30) for men\u0026thinsp;\u0026lt;\u0026thinsp;65 years, 1.82 (95% CI 1.35\u0026ndash;2.46; EB05 1.38) for 65\u0026ndash;74 years, and 3.06 (95% CI 2.60\u0026ndash;3.60; EB05 2.60) for \u0026ge;\u0026thinsp;75 years. For apalutamide, signals were not detected in younger men (\u0026lt;\u0026thinsp;65 years: ROR 2.10, 95% CI 0.94\u0026ndash;4.68; EB05 0.93; 65\u0026ndash;74 years: ROR 1.56, 95% CI 0.86\u0026ndash;2.82; EB05 0.91), but a clear signal was observed in men\u0026thinsp;\u0026ge;\u0026thinsp;75 years (ROR 2.98, 95% CI 2.18\u0026ndash;4.09; EB05 2.15). Darolutamide demonstrated a signal in men\u0026thinsp;\u0026ge;\u0026thinsp;75 years only (ROR 2.93, 95% CI 1.46\u0026ndash;5.86; EB05 1.36), with inadequate numbers of reports available allowing analysis among other age groups. Enzalutamide demonstrated signals in all age categories, with RORs of 1.44 (95% CI 1.07\u0026ndash;1.94; EB05 1.10) in men\u0026thinsp;\u0026lt;\u0026thinsp;65 years, 2.34 (95% CI 1.99\u0026ndash;2.74; EB05 2.00) in men 65\u0026ndash;74 years, and 2.43 (95% CI 2.19\u0026ndash;2.69; EB05 2.17) in men\u0026thinsp;\u0026ge;\u0026thinsp;75 years. (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDisproportionality analysis of bone fractures reporting associated with androgen receptor pathway inhibitor by age groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCount\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eExpected Count\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEB05\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComposite ARPI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.57 (1.24, 1.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.13 (1.86, 2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e570\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.65 (2.44, 2.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbiraterone\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.94 (1.29, 2.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.82 (1.35, 2.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.06 (2.60, 3.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eApalutamide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.10 (0.94, 4.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.56 (0.86, 2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.98 (2.18, 4.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDarolutamide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.93 (1.46, 5.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEnzalutamide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.44 (1.07, 1.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.34 (1.99, 2.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.43 (2.19, 2.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this global pharmacovigilance study using VigiBase, we evaluated the association between therapy with ARPIs and bone fractures in men with prostate cancer. We observed pharmacovigilance signals both for the class overall and for individual agents, confirmed across primary and sensitivity analyses. Signals persisted when androgen deprivation therapy served as the reference, underscoring the potential for additive skeletal toxicity with contemporary doublet and triplet regimens. Given that intensification is now standard in all states of advanced prostate cancer, these findings highlight the importance of ensuring appropriate bone health assessment and management strategies in the care of patients with prostate cancer.\u003c/p\u003e \u003cp\u003eOur findings are consistent with data from randomized trials. Two earlier meta-analyses using trial data across different disease states of prostate cancer demonstrated that intensification with androgen receptor pathway inhibitors approximately doubled the risk of fractures and falls compared with androgen deprivation alone.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e These effects were observed consistently across disease states, including metastatic hormone-sensitive, nonmetastatic hormone-resistant, and metastatic hormone-resistant disease.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e While our pharmacovigilance analysis did not include falls as an outcome, the fracture signals we identified align closely with these pooled trial-level data, underscoring the robustness of the skeletal toxicity signal across study designs. Specifically, darolutamide has been suggested in clinical trial data to carry a comparatively favorable skeletal safety profile, possibly due to its limited central nervous system penetration and reudced dizziness and balance-related complications that can predispose to falls.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Our analysis likewise did not detect a composite signal for darolutamide in the primary analysis, though a signal appeared among men 75 years and older. Importantly, darolutamide was the last ARPI to receive approval compared to other ARPIs, accounting for the lower absolute number of reports in the current edition of VigiBase and limiting the statistical power. Darolutamide is also first approved in non-metastatic hormone-resistant prostate cancer, which could represent a group of patients with inherently lower fracture risk compared to those with metastatic disease. Caution is warranted in interpreting these findings.\u003c/p\u003e \u003cp\u003eOur results also add to a small body of evidence from “real world” practice on bone health. For example, In an earlier (US-based) analysis among Medicare beneficiaries (\u0026gt; 65 with public insurance), the two-year cumulative incidence of skeletal related events approached 12–14% in men treated with abiraterone or enzalutamide, with even higher rates among those with prior fracture.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Our pharmacovigilance signals echo these observations and further support the additional skeletal toxicity in real-world settings. Additionally, our data included additional ARPIs in global practice settings and a wider age range than the 65 + population in Medicare claims. Mechanistic explanations—accelerated bone mineral density loss with androgen deprivation, glucocorticoid-associated fragility with abiraterone, and central nervous system adverse effects that may predispose to falls with enzalutamide and apalutamide—have been described.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e However, it should be noted that in current practice these agents are layered on top of androgen deprivation, and the risk we observed reflects the added burden of intensification rather than monotherapy. Combination regimens, particularly those involving additional therapy, may further magnify fracture risk if bone-protective agents and other mitigation strategies are not used, as demonstrated by the sharp risk reduction once prophylactic bone health agent use was mandated in PEACE-III in which radium was added to the ADT and enzalutamide combination therapy.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe also observed pharmacovigilance signals across all age strata, with numerically larger disproportionality estimates among older men. While we cannot directly compare subgroups within this framework, the absolute values suggest that older adults may be more vulnerable to skeletal complications—a finding consistent with prior evidence. For example, secondary analysis of the PREVAIL trial of enzalutamide in metastatic hormone-resistant prostate cancer patients has reported falls and fractures in 19% and 16% of men ≥ 75 years, compared to 7% and 10% in younger patients.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Two recent meta-analysis of clinical trials of treatment intensification in metastatic hormone sensitive prostate cancer reported that older men above 70 or 75 years old may gain much little survival benefit from treatment intensification, compared to their younger counterparts.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Our pharmacovigilance signals, alongside existing data, suggest that skeletal safety may warrant particular consideration when weighing ARPI intensification in older or frail populations.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, pharmacovigilance analyses detect disproportionate reporting, not incidence or causality. VigiBase relies on voluntary reports, subject to underreporting, selective reporting, and regional heterogeneity in data quality. Second, clinical details such as disease stage, bone metastasis burden, comorbidities, and bone-protective agent use were not codified into the database. We could not distinguish osteoporotic from pathologic fractures, as some trial data suggest that ARPI may confer protection against pathologic fractures.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Likewise, medDRA terminology lacks the specificity needed to identify malignant spinal cord compression and therefore does not fully capture the spectrum of skeletal-related events in prostate cancer. Third, although the number of ARPI reports was large overall, darolutamide was more recently added to the treatment armamentarium and would be expected to have a significantly lower number of reported complications. Fourth, while age-stratified analyses were informative, pharmacovigilance methods preclude formal comparisons of magnitude across groups. Finally, as with all pharmacovigilance research, these results are hypothesis-generating and best interpreted alongside trial and epidemiologic data.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn this global pharmacovigilance analysis, androgen receptor pathway inhibitors were consistently associated with disproportionate reporting of bone fractures across agents and age groups, reinforcing concerns about additive skeletal toxicity with treatment intensification. These findings complement evidence from randomized trials and limited real-world cohorts, and underscore the need for careful attention to bone health assessment and management, particularly for older men. Proactive bone health strategies, including guideline-based screening and preventive measures, remain essential as ARPI-based regimens continue to expand in prostate cancer care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures:\u003c/strong\u003e AKM reports consulting fees from Astellas, AstraZeneca, Bayer, Curium, Dendreon, Exact Sciences, Johnson \u0026amp; Johnson, Lantheus, Merck, Novartis, Pfizer, Sumitomo Pharma, Inc., Telix, Tolmar. Q-DT reports consulting fees from Astellas, Bayer, Intuitive Surgical, Janssen, Novartis, Pfizer, and research funding from the American Cancer Society, Pfizer Global Medical Grants (Prostate Cancer Disparities #63354905). Q-DT reports funding from Health Disparity Research Award from the Department of Defense Congressionally Directed Medical Research Program (#PC220551). APC reports research funding from the Bruce A Beal and Robert L Beal surgical fellowship of the BWH Department of Surgery, from the Prostate Cancer Foundation and American Cancer Society (#23YOUN25) and from a Physician Research Award from the Department of Defense Congressionally Directed Medical Research Program (#PC220342).\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no conflict of interests that may influence the outcomes of this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. \u003cem\u003eCa\u003c/em\u003e. 2025;75(1):10. \u003c/li\u003e\n\u003cli\u003eKratzer TB, Mazzitelli N, Star J, Dahut WL, Jemal A, Siegel RL. Prostate cancer statistics, 2025. \u003cem\u003eCA: A Cancer Journal for Clinicians\u003c/em\u003e. 2025;\u003c/li\u003e\n\u003cli\u003eRaychaudhuri R, Lin DW, Montgomery RB. Prostate cancer: a review. \u003cem\u003eJAMA\u003c/em\u003e. 2025;\u003c/li\u003e\n\u003cli\u003eFazekas T, Miszczyk M, Giesen A, et al. Androgen Receptor Pathway Inhibitor Monotherapy in Prostate Cancer: Safety, Oncologic Outcomes, and Quality of Life\u0026mdash;A Systematic Review and Meta-analysis. \u003cem\u003eEuropean Urology Focus\u003c/em\u003e. 2025;\u003c/li\u003e\n\u003cli\u003eNowakowska MK, Ortega RM, Wehner MR, Nead KT. Association of second-generation antiandrogens with cognitive and functional toxic effects in randomized clinical trials: a systematic review and meta-analysis. \u003cem\u003eJAMA oncology\u003c/em\u003e. 2023;9(7):930-937. \u003c/li\u003e\n\u003cli\u003eMiller K, Steger GG, Niepel D, L\u0026uuml;ftner D. Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. \u003cem\u003eProstate cancer and prostatic diseases\u003c/em\u003e. 2018;21(4):461-472. \u003c/li\u003e\n\u003cli\u003eSchaeffer EM, Srinivas S, Adra N, et al. Prostate cancer, version 3.2024 featured updates to the NCCN guidelines. \u003cem\u003eJNCCN Journal of the National Comprehensive Cancer Network\u003c/em\u003e. 2024;22(3):140-150. \u003c/li\u003e\n\u003cli\u003eFischer S, Clements S, McWilliam A, et al. Influence of abiraterone and enzalutamide on body composition in patients with metastatic castration resistant prostate cancer. \u003cem\u003eCancer Treatment and Research Communications\u003c/em\u003e. 2020;25:100256. \u003c/li\u003e\n\u003cli\u003eBaldessari C, Pipitone S, Molinaro E, et al. Bone metastases and health in prostate cancer: From pathophysiology to clinical implications. \u003cem\u003eCancers\u003c/em\u003e. 2023;15(5):1518. \u003c/li\u003e\n\u003cli\u003eJones C, Gray S, Brown M, et al. Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials. \u003cem\u003eEuropean Urology Oncology\u003c/em\u003e. 2024/10/01/ 2024;7(5):993-1004. doi:https://doi.org/10.1016/j.euo.2024.01.016\u003c/li\u003e\n\u003cli\u003eMyint ZW, Momo HD, Otto DE, Yan D, Wang P, Kolesar JM. Evaluation of Fall and Fracture Risk Among Men With Prostate Cancer Treated With Androgen Receptor Inhibitors: A Systematic Review and Meta-analysis. \u003cem\u003eJAMA Network Open\u003c/em\u003e. 2020;3(11):e2025826-e2025826. doi:10.1001/jamanetworkopen.2020.25826\u003c/li\u003e\n\u003cli\u003eLindquist M. VigiBase, the WHO global ICSR database system: basic facts. \u003cem\u003eDrug Information Journal\u003c/em\u003e. 2008;42(5):409-419. \u003c/li\u003e\n\u003cli\u003eQian Z, Song J, Jones A, et al. SGLT2 inhibitor and urinary tract infection in men at risk for voiding dysfunction: a VigiBase analysis. \u003cem\u003eUrology Practice\u003c/em\u003e. 2025;12(1):131-137. \u003c/li\u003e\n\u003cli\u003eSong JJ, Qian Z, Cho M, Nguyen D-D, Trinh Q-D, Wollin DA. Disproportionality Analysis of Hypotension-Related Adverse Drug Reactions Associated With Type 1a Selective Alpha-Blockers in VigiBase. \u003cem\u003eUrology Practice\u003c/em\u003e. 2025:10.1097/UPJ. 0000000000000790. \u003c/li\u003e\n\u003cli\u003eNguyen DD, Marchese M, Cone EB, et al. Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. \u003cem\u003eJAMA Dermatol\u003c/em\u003e. Jan 1 2021;157(1):35-42. doi:10.1001/jamadermatol.2020.3385\u003c/li\u003e\n\u003cli\u003eTregunno PM, Fink DB, Fernandez-Fernandez C, L\u0026aacute;zaro-Bengoa E, Nor\u0026eacute;n GN. Performance of probabilistic method to detect duplicate individual case safety reports. \u003cem\u003eDrug safety\u003c/em\u003e. 2014;37(4):249-258. \u003c/li\u003e\n\u003cli\u003eBate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. \u003cem\u003ePharmacoepidemiol Drug Saf\u003c/em\u003e. Jun 2009;18(6):427-36. doi:10.1002/pds.1742\u003c/li\u003e\n\u003cli\u003eSalem J-E, Manouchehri A, Bretagne M, et al. Cardiovascular toxicities associated with ibrutinib. \u003cem\u003eJournal of the American College of Cardiology\u003c/em\u003e. 2019;74(13):1667-1678. \u003c/li\u003e\n\u003cli\u003eTurco F, Gillessen S, Treglia G, et al. Safety profile of darolutamide versus placebo: a systematic review and meta-analysis. \u003cem\u003eProstate cancer and prostatic diseases\u003c/em\u003e. 2024;27(3):385-392. \u003c/li\u003e\n\u003cli\u003eKwon DH, Paciorek A, Zhang L, et al. Skeletal-related events after abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer: A population-based study using the SEER-Medicare linked dataset. \u003cem\u003eUrol Oncol\u003c/em\u003e. Aug 2022;40(8):379.e17-379.e24. doi:10.1016/j.urolonc.2022.05.025\u003c/li\u003e\n\u003cli\u003eHalabi S, Jiang S, Terasawa E, et al. Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer. \u003cem\u003eJ Urol\u003c/em\u003e. Aug 2021;206(2):298-307. doi:10.1097/ju.0000000000001767\u003c/li\u003e\n\u003cli\u003eFukuokaya W, Mori K, Urabe F, et al. Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate. \u003cem\u003eJAMA Network Open\u003c/em\u003e. 2024;7(3):e242467-e242467. doi:10.1001/jamanetworkopen.2024.2467\u003c/li\u003e\n\u003cli\u003eGillessen S, Tombal B, Turco F, et al. Decrease in fracture rate with mandatory bone-protecting agents in the EORTC 1333/PEACE-3 trial comparing radium-223 combined with enzalutamide versus enzalutamide alone: a safety analysis. \u003cem\u003eEuropean Urology\u003c/em\u003e. 2025;87(3):285-288. \u003c/li\u003e\n\u003cli\u003eGraff JN, Baciarello G, Armstrong AJ, et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. \u003cem\u003eAnnals of Oncology\u003c/em\u003e. 2016;27(2):286-294. \u003c/li\u003e\n\u003cli\u003eFisher DJ, Vale CL, Rydzewska LH, et al. Which patients with metastatic hormone-sensitive prostate cancer (mHSPC) benefit more from androgen receptor pathway inhibitors (ARPIs)? STOPCAP meta-analyses of individual participant data (IPD). American Society of Clinical Oncology; 2025.\u003c/li\u003e\n\u003cli\u003eMorgans AK, Roy S, Jia AY, et al. Age and Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer. \u003cem\u003eNEJM Evidence\u003c/em\u003e. 2025;4(11):EVIDoa2500109. doi:doi:10.1056/EVIDoa2500109\u003c/li\u003e\n\u003cli\u003eLogothetis CJ, Basch E, Molina A, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. \u003cem\u003eLancet Oncol\u003c/em\u003e. Dec 2012;13(12):1210-7. doi:10.1016/s1470-2045(12)70473-4\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Prostate Cancer, Androgen Receptor Pathway Inhibitor, Skeletal Related Event, VigiBase, Disproportionality Analysis, Pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-8658712/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8658712/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAndrogen receptor pathway inhibitors (ARPIs) improve the survival of men with various states of advanced prostate cancer, but complications, including bone fractures, have been associated with treatment. Although rates of SREs are reported in ARPI registration trials, real-world data describing SRE rates during treatment with ARPIs is lacking.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe conducted a global pharmacovigilance study using VigiBase, the World Health Organization\u0026rsquo;s international database of adverse drug reaction reports. All reports involving abiraterone, enzalutamide, apalutamide, or darolutamide in adult men from 2011 to September 2024 were included. Fractures were defined using standardized MedDRA terms, and disproportionality analyses quantified reporting odds ratios (RORs) with 95% confidence intervals and Bayesian shrinkage estimates (EB05). Two prespecified sensitivity analyses were performed, redefining the reference group as men on androgen deprivation therapy (ADT) alone and stratifying results by age groups.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAmong 282,143 VigiBase reports involving ARPIs, 1,140 (0.4%) included fractures. In primary analysis, ARPI therapy demonstrated a pharmacovigilance signal for increased SRE reporting (ROR 1.87, 95% CI 1.77\u0026ndash;1.98; EB05 1.77). Signals were consistent for abiraterone, enzalutamide, and apalutamide, but not for darolutamide. Using ADT as reference, ARPIs remained associated with higher reporting of fractures (ROR 1.43, 95% CI 1.29\u0026ndash;1.58; EB05 1.08). Age-stratified analyses demonstrated signals across all categories, with numerically larger disproportionality estimates among older men.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn this global pharmacovigilance analysis, ARPIs were consistently associated with increased reporting of fractures, including when compared with ADT alone. This highlights the potentially additive skeletal toxicity of treatment intensification, and underscore the importance of bone health monitoring and preventive strategies, particularly among older patients.\u003c/p\u003e","manuscriptTitle":"Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-30 18:09:21","doi":"10.21203/rs.3.rs-8658712/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-03-09T16:39:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-20T10:40:26+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-02T20:16:33+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-01T16:29:46+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-01T16:08:21+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-01-28T17:38:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-26T19:07:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-26T18:24:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Prostate Cancer and Prostatic Diseases","date":"2026-01-22T21:54:02+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-01-21T15:35:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"prostate-cancer-and-prostatic-diseases","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"pcan","sideBox":"Learn more about [Prostate Cancer and Prostatic Diseases](http://www.nature.com/pcan/)","snPcode":"41391","submissionUrl":"https://mts-pcan.nature.com/cgi-bin/main.plex","title":"Prostate Cancer and Prostatic Diseases","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0f097d98-96c4-4975-90e2-981c4fb595f5","owner":[],"postedDate":"January 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61919036,"name":"Health sciences/Diseases/Urogenital diseases/Urological cancer/Prostate cancer"},{"id":61919037,"name":"Health sciences/Medical research/Outcomes research"}],"tags":[],"updatedAt":"2026-04-27T09:42:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-30 18:09:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8658712","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8658712","identity":"rs-8658712","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}