Evaluate the renal system damage caused by zoledronic acid: A comprehensive analysis of adverse events from FAERS

Evaluate the renal system damage caused by zoledronic acid: A comprehensive analysis of adverse events from FAERS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluate the renal system damage caused by zoledronic acid: A comprehensive analysis of adverse events from FAERS Zhaojun Wang, Xin Su, Donglei Shi, Li Wei This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5106994/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Dec, 2024 Read the published version in BMC Cancer → Version 1 posted 4 You are reading this latest preprint version Abstract Background Zoledronic acid (ZA) is widely used for the treatment of osteolytic bone metastases in malignancies and osteoporosis, but it has been associated with renal impairment. In this study, we investigated adverse events (AEs) related to renal and urinary system diseases associated with ZA using the U.S. FDA’s Adverse Event Reporting System. Methods We collected FAERS data from Q1 2004 to Q1 2024 and used the reporting odds ratio to detect AEs related to renal and urinary system diseases associated with ZA. Additionally, we applied multiple algorithms, including ROR, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, to quantify renal and urinary AEs under different indications. Results A total of 52,495 AE reports involving ZA as the primary suspect drug were identified. Among renal and urinary system diseases, 25 distinct AEs were recognized, with renal tubular necrosis being the most frequently reported. For different indications, renal tubular necrosis was the most reported AE in breast cancer and osteoporosis; nephrogenic diabetes insipidus was both the most frequent and strongest signal in lung cancer; proteinuria was most common in multiple myeloma, and polyuria in prostate cancer. Furthermore, most AEs occurred in patients who had been on ZA for more than 360 days, followed by those within the first 30 days of use. Conclusion Based on pharmacovigilance data from FAERS, different renal and urinary system AEs should be closely monitored and addressed according to the specific indications for which ZA is used. zoledronic acid FDA adverse event reporting system adverse events Figures Figure 1 Figure 2 Figure 3 Background Zoledronic acid (ZA) is a third-generation bisphosphonate compound that was approved by the U.S. Food and Drug Administration (FDA) in 2001 for the treatment of hypercalcemia of malignancy and bone metastases in patients with solid tumors [ 1 ], with a dose of 4 mg. A 5 mg dose later became available for the treatment of postmenopausal osteoporosis and Paget's disease. The pharmacological action of ZA primarily involves inhibiting bone resorption by suppressing osteoclast activity and inducing osteoclast apoptosis [ 2 ]. Additionally, ZA can inhibit the enhanced osteoclast activity and bone calcium release caused by various factors released by tumors, thereby reducing tumor-induced osteolytic lesions, bone resorption, pain, and hypercalcemia due to bone metastasis [ 3 ]. However, during its use, several adverse reactions are commonly observed, such as fever, myalgia, gastrointestinal reactions, and renal function impairment. Although ZA is generally well-tolerated in clinical treatment of osteoporosis, preclinical studies found similar renal function effects between the experimental and control groups [ 4 ]. However, in January 2011, the FDA issued a drug safety communication highlighting new contraindications and updated warnings for Reclast (zoledronic acid) due to cases of acute renal failure, some with fatal outcomes, following its use [ 5 ]. ZA is primarily excreted intact through the kidneys, and studies have shown that it increases the risk of nephrotoxicity. The risk of renal function deterioration appears to be time-dependent, with renal impairment or progression to renal failure occurring even in patients with normal baseline renal function [ 4 ]. Nevertheless, comprehensive studies assessing the renal damage associated with the use of ZA are still lacking. Real-world data on drug use serves as a powerful tool for evaluating drug safety [ 6 ]. Recently, Su et al. published a study using FAERS data to investigate the indications and adverse event (AE) characteristics of denosumab and ZA. They compared the signal strength of AEs between denosumab and ZA and studied off-label use [ 7 ]. However, their study did not specifically focus on AEs related to renal and urinary system diseases. Therefore, this study also utilizes the FAERS database, with a specific focus on AEs related to renal and urinary system diseases associated with ZA, as well as the AEs in these systems across different indications. This research serves as a valuable complement to the study by Su et al. By conducting this study, we aim to provide more comprehensive insights into the safe clinical use of ZA, particularly regarding AEs related to renal and urinary system diseases. Methods Data source and collection The FAERS (FDA Adverse Event Reporting System) database is used to support FDA's post-marketing safety surveillance of drugs and therapeutic biologics. It contains reports of AEs, medication errors, and product quality complaints [ 8 ]. ZA was first approved by the FDA for clinical use in 2001. Therefore, this study utilized FAERS data from the second quarter of 2004 to the second quarter of 2024. The FAERS database consists of seven sub-datasets: demographics (DEMO), reactions (REAC), drugs (DRUG), indications (INDI), outcomes (OUTC), therapy start and end dates (THER), and report sources (RPSR). AEs in FAERS are coded using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PT), which are classified into 27 System Organ Classes (SOC). Drugs in FAERS are classified into four categories based on their involvement in the reported AEs: primary suspect, secondary suspect, concomitant, and interacting drugs [ 9 ]. To ensure accuracy, this study only included reports where ZA was the primary suspect drug. Data analysis Four commonly used disproportionality analysis methods were employed in this study: reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS) algorithms [ 10 ]. The specific formulas and criteria for positive signals for these four algorithms are provided in Supplementary Table 1. For this study, at the SOC level, we used the ROR positive signal criterion (95% CI > 1 and N ≥ 3) as the screening standard. At the PT level, we continued to use the ROR positive signal criterion to screen signals, with a primary focus on AEs under the SOC of renal and urinary system diseases. Additionally, we further analyzed the onset time of ZA-related AEs, calculated as the time interval in days between the EVENT_DT (adverse event date) and START_DT (drug start date). Finally, we conducted a subgroup analysis, focusing on renal and urinary system disease-related AEs in cases where ZA was used for indications such as breast cancer, lung cancer, osteoporosis, plasma cell myeloma, and prostate cancer. For these cases, an event was only considered a positive signal if it met the criteria of all four algorithms. The higher the score in the ROR algorithm, the more disproportionate the event is, indicating a stronger association between the drug and the AE [ 11 ]. All data processing and statistical analyses were conducted using R software, version 4.2.3, and data visualization was performed using the "ggplot2" package. Results Descriptive analysis Figure 1 shows the flowchart of the data selection process in this study. The FAERS database contains a total of 21,433,114 records. After removing duplicate entries based on the FDA's recommended method, 18,182,912 records were retained. Ultimately, 52,495 AE reports involving ZA as the primary suspect drug were identified. Table 1 presents the overall and subgroup-specific clinical characteristics of patients with ZA-induced AEs. The majority of cases involved females in the overall cohort (69.2%), breast cancer (94.9%), and osteoporosis (85.7%) groups, whereas males were predominant in lung cancer (57.4%), multiple myeloma (51.1%), and prostate cancer (96.9%) groups. In terms of reporting sources, consumers reported the highest percentage of cases in the total cohort (35.6%) and osteoporosis (47.2%) groups, while physicians were the primary reporters for breast cancer (32.8%), and other health professionals for lung cancer (33.1%), multiple myeloma (34.1%), and prostate cancer (30.1%) groups. Geographically, the United States had the highest number of reports. Among reported outcomes, the "other serious" category was the most common, while lung cancer had the highest mortality rate (31.5%), followed by prostate cancer (24.3%). The number of reports over the past five years showed minimal variation. Table 1 Clinical characteristics of reports with zoledronic acid from the FAERS database. Factors Number of events (%) Total Breast cancer Lung cancer Osteoporosis Multiple myeloma Prostate cancer Gender Female 36,289 (69.2) 4,740 (94.9) 215 (38.7) 14,898 (85.7) 1,442 (43.5) 14 (0.5) Male 13,374 (25.5) 46 (0.9) 319 (57.4) 2,055 (11.8) 1,694 (51.1) 2,675 (96.9) Unknown 2,810 (5.4) 211 (4.2) 22 (4) 423 (2.4) 176 (5.3) 72 (2.6) Age < 18 379 (0.7) 2 (0) 1 (0.2) 90 (0.5) - 4 (0.1) 18-64.9 11,608 (22.1) 2,024 (40.5) 206 (37.1) 3,119 (18) 876 (26.4) 379 (13.7) 65–85 17,167 (32.7) 1,359 (27.2) 199 (35.8) 6,543 (37.7) 1,468 (44.3) 1,350 (48.9) > 85 2,030 (3.9) 42 (0.8) - 1,012 (5.8) 56 (1.7) 91 (3.3) Unknown 21,289 (40.6) 1,570 (31.4) 150 (27) 6,612 (38.1) 912 (27.5) 937 (33.9) Reporter Consumer 18,670 (35.6) 1,027 (20.6) 106 (19.1) 8,201 (47.2) 444 (13.4) 790 (28.6) Physician 14,472 (27.6) 1,641 (32.8) 148 (26.6) 4,394 (25.3) 1,035 (31.3) 680 (24.6) Other health-professional 11,038 (21) 1,461 (29.2) 184 (33.1) 2,334 (13.4) 1,130 (34.1) 830 (30.1) Health Professional 2,842 (5.4) 373 (7.5) 66 (11.9) 995 (5.7) 213 (6.4) 181 (6.6) Pharmacist 1,572 (3.0) 120 (2.4) 19 (3.4) 432 (2.5) 79 (2.4) 63 (2.3) Reported countries United States 13,538 (25.8) 848 (16.9) 82 (15) 4,011 (23.1) 907 (27.4) 346 (12.5) Japan 3,343 (6.4) 407 (8.1) 59 (10.7) 293 (1.7) 190 (5.7) 215 (7.8) Canada 3,285 (6.3) 201 (4) 40 (7.2) 1,847 (10.7) 61 (1.9) 129 (4.7) Italy 2,425 (4.6) 483 (9.6) 46 (8.3) 124 (0.7) 437 (13.2) 204 (7.4) United Kingdom 2,330 (4.5) 214 (4.3) 10 (1.8) 744 (4.3) 128 (3.9) 125 (4.5) Outcome Other Serious 24,837 (47.3) 2,755 (55.1) 250 (45) 7,203 (41.5) 1,943 (58.7) 1,328 (48.1) Death 10,409 (19.8) 664 (13.3) 175 (31.5) 3,681 (21.2) 293 (8.8) 671 (24.3) Hospitalization 10,122 (19.3) 1,052 (21.1) 102 (18.3) 3,973 (22.9) 654 (19.7) 551 (20) Disability 2,416 (4.6) 266 (5.3) 8 (1.4) 898 (5.2) 226 (6.8) 107 (3.9) Life-Threatening 1,282 (2.4) 75 (1.5) 8 (1.4) 638 (3.7) 57 (1.7) 34 (1.2) Year (The last five years) 2020 2,192 (4.2) 283 (5.7) 30 (5.4) 657 (3.8) 118 (3.6) 122 (4.4) 2021 1,922 (3.7) 214 (4.3) 27 (4.9) 610 (3.5) 85 (2.6) 84 (3) 2022 1,566 (3) 198 (4) 15 (2.7) 583 (3.4) 67 (2) 53 (1.9) 2023 2,037 (3.9) 247 (4.9) 20 (3.6) 784 (4.5) 70 (2.1) 59 (2.1) 2024 1,143 (2.2) 144 (2.9) 22 (4) 409 (2.4) 31 (0.9) 40 (1.4) Signal of system organ class Figure 2 displays the signal strength of ZA-related AEs categorized by system organ class (SOC). A total of eight organ systems were affected by ZA-related AEs: musculoskeletal and connective tissue disorders, infections and infestations, neoplasms (benign, malignant, and unspecified), surgical and medical procedures, metabolism and nutrition disorders, eye disorders, renal and urinary disorders, ear and labyrinth disorders, and endocrine disorders. The musculoskeletal and connective tissue disorders category had both the highest number of reports (n = 46,560) and the strongest signal [ROR 4.21 (95% CI: 4.17–4.25)]. Signal of preferred terms Table 2 presents the related AEs at the PT level under the SOC of kidney and urinary system diseases. A total of 25 AEs were identified. The most reported was renal tubular necrosis (n = 166), while the strongest signal was for globulinuria [ROR 327.91 (95% CI: 54.79–1962.48)], followed by hyperuricosuria [ROR 32.15 (95% CI: 12.57–82.2)]. Table 3 outlines the AE signals within the SOC of renal and urinary system diseases in the ZA-related subgroups. In the breast cancer group, renal tubular necrosis was the most reported AE (n = 13), and urinary tract inflammation had the strongest signal [ROR 25.35 (95% CI: 10.01–64.24)]. In the lung cancer group, nephrogenic diabetes insipidus had both the highest number of reports (n = 7) and the strongest signal [ROR 57.44 (95% CI: 23.8–138.59)]. In the osteoporosis group, renal tubular necrosis had the most reports (n = 81), while haemoglobinuria had the strongest signal [ROR 22.85 (95% CI: 5.71–91.35)]. In the multiple myeloma group, proteinuria had the highest number of reports (n = 24), while glycosuria had the strongest signal [ROR 76.85 (95% CI: 18.37–321.61)]. In the prostate cancer group, polyuria was the most frequently reported AE (n = 11), and renal tubular acidosis had the strongest signal [ROR 31.47 (95% CI: 7.87–125.83)]. Table 2 Related AE signals of zoledronic acid based on SOC in FAERS for renal and urinary system diseases. PT Case reports ROR (95% Cl) PRR(χ2) EBGM (EBGM05) IC (IC025) Renal tubular necrosis 166 4.28 (3.67–4.99) 4.28 (408.75) 4.21 (3.71) 2.07 (0.41) Fanconi syndrome acquired 37 4.99 (3.6–6.91) 4.99 (115.4) 4.9 (3.73) 2.29 (0.63) Renal tubular acidosis 34 4.12 (2.94–5.79) 4.12 (78.92) 4.06 (3.06) 2.02 (0.36) Myoglobinuria 33 15.19 (10.67–21.62) 15.19 (408.94) 14.27 (10.62) 3.83 (2.16) Renal atrophy 27 5.27 (3.59–7.71) 5.27 (91.1) 5.16 (3.75) 2.37 (0.7) Renal tubular dysfunction 18 7.98 (4.99–12.78) 7.98 (106.05) 7.74 (5.22) 2.95 (1.28) Stress urinary incontinence 15 3.26 (1.96–5.43) 3.26 (23.19) 3.23 (2.11) 1.69 (0.02) Renal tubular atrophy 15 4.22 (2.53–7.03) 4.22 (36.16) 4.16 (2.71) 2.06 (0.39) Urinary tract inflammation 12 8.83 (4.96–15.73) 8.83 (80.11) 8.53 (5.26) 3.09 (1.42) Bladder outlet obstruction 11 16.58 (8.98–30.61) 16.58 (149.73) 15.48 (9.27) 3.95 (2.27) Urethral obstruction 8 4.73 (2.35–9.52) 4.73 (23.01) 4.65 (2.59) 2.22 (0.54) Renal glycosuria 8 29.64 (14.16–62.03) 29.64 (194.96) 26.22 (14.14) 4.71 (3.01) Hydroureter 8 5.79 (2.87–11.69) 5.79 (30.89) 5.67 (3.15) 2.5 (0.83) Postrenalfailure 8 4.21 (2.09–8.48) 4.21 (19.24) 4.15 (2.31) 2.05 (0.38) Ureteric dilatation 7 6.32 (2.98–13.41) 6.32 (30.49) 6.17 (3.29) 2.63 (0.95) Bladder hypertrophy 7 4.31 (2.04–9.11) 4.31 (17.45) 4.25 (2.27) 2.09 (0.41) Hyperphosphaturia 7 15.15 (7.04–32.59) 15.15 (86.52) 14.23 (7.5) 3.83 (2.14) Hyperuricosuria 5 32.15 (12.57–82.2) 32.15 (131.55) 28.15 (12.84) 4.82 (3.09) Urethral dilatation 5 20.24 (8.1–50.6) 20.24 (83.7) 18.61 (8.65) 4.22 (2.51) Bence jones proteinuria 4 30.15 (10.6-85.77) 30.15 (99.08) 26.62 (11.1) 4.73 (3) Mesangioproliferative Glomerulonephritis 4 6.83 (2.53–18.48) 6.83 (19.31) 6.65 (2.89) 2.73 (1.05) Renal hypertrophy 4 4.94 (1.83–13.31) 4.94 (12.29) 4.85 (2.12) 2.28 (0.6) Hyperkaliuria 3 13.38 (4.17–42.94) 13.38 (32.39) 12.67 (4.78) 3.66 (1.95) Pneumaturia 3 7.81 (2.47–24.7) 7.81 (17.19) 7.57 (2.89) 2.92 (1.23) Globulinuria 3 327.91 (54.79-1962.48) 327.9 (391.09) 131.76 (29.49) 7.04 (5) Abbreviations: PT, preferred term; ROR, reporting odds ratios; PRR, proportional reporting ratios; χ2, chi-squared; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of the 95% CI of EBGM; IC, information component; IC025, the lower limit of the 95% CI of the IC; CI, confidence interval. Table 3 AE signal AE of zoledronic acid related subgroups, SOC level for renal and urinary system diseases. Subgroup PT Case reports ROR (95% Cl) PRR (χ2) EBGM (EBGM05) IC (IC025) Breast cancer Renal tubular necrosis 13 4 (2.25–7.12) 4 (25.96) 3.66 (2.26) 1.87 (0.19) Urinary tract inflammation 8 25.35 (10.01–64.24) 25.35 (103.94) 14.53 (6.67) 3.86 (2.07) Renal atrophy 5 7.92 (2.97–21.11) 7.92 (24.19) 6.54 (2.88) 2.71 (0.95) Fanconi syndrome acquired 3 8.64 (2.41–30.98) 8.64 (15.93) 7 (2.41) 2.81 (0.98) Diabetic nephropathy 3 19.01 (4.54–79.56) 19.01 (31.99) 12.26 (3.7) 3.62 (1.69) Bladder hypertrophy 3 7.31 (2.08–25.66) 7.31 (13.28) 6.13 (2.14) 2.62 (0.81) Renal tubular acidosis 3 13.58 (3.51–52.52) 13.58 (24.47) 9.8 (3.16) 3.29 (1.41) Lung cancer Nephrogenic diabetes insipidus 7 57.44 (23.8-138.59) 57.33 (274.45) 40.9 (19.57) 5.35 (3.59) Renal tubular acidosis 7 46.5 (19.75-109.44) 46.41 (233.29) 35.06 (17.13) 5.13 (3.38) Osteoporosis Renal tubular necrosis 81 19.7 (13.75–28.23) 19.69 (527.58) 7.86 (5.82) 2.97 (1.29) Nephropathy toxic 24 6.53 (3.95–10.78) 6.53 (71.48) 4.52 (2.97) 2.18 (0.47) Anuria 19 4.34 (2.56–7.36) 4.34 (35.4) 3.42 (2.2) 1.77 (0.07) Oliguria 16 6.09 (3.32–11.18) 6.09 (44.41) 4.32 (2.6) 2.11 (0.39) Haemoglobinuria 6 22.85 (5.71–91.35) 22.84 (41.78) 8.28 (2.6) 3.05 (1.15) Multiple myeloma Proteinuria 24 6.84 (4.45–10.5) 6.83 (104.04) 6.08 (4.25) 2.6 (0.92) Tubulointerstitial nephritis 14 6.59 (3.76–11.54) 6.59 (58.05) 5.89 (3.68) 2.56 (0.87) Renal tubular necrosis 14 5.57 (3.2–9.69) 5.56 (46.77) 5.07 (3.19) 2.34 (0.66) Hydronephrosis 8 10.25 (4.76–22.05) 10.24 (54.61) 8.56 (4.51) 3.1 (1.38) Polyuria 7 4.97 (2.28–10.83) 4.96 (20.01) 4.58 (2.38) 2.2 (0.5) Azotaemia 7 4.82 (2.21–10.5) 4.82 (19.17) 4.46 (2.32) 2.16 (0.46) Fanconi syndrome acquired 6 27.67 (10.06–76.14) 27.66 (96.37) 17.66 (7.57) 4.14 (2.34) Urinary tract obstruction 6 5.53 (2.37–12.91) 5.53 (19.89) 5.05 (2.48) 2.34 (0.63) Glycosuria 5 76.85 (18.37-321.61) 76.84 (140.35) 29.44 (8.89) 4.88 (2.96) Renal atrophy 5 16.47 (5.93–45.73) 16.47 (53.52) 12.4 (5.27) 3.63 (1.85) Stress urinary incontinence 4 18.44 (5.78–58.81) 18.44 (47.13) 13.46 (5.1) 3.75 (1.93) Renal colic 4 26.35 (7.71–90.02) 26.34 (62.06) 17.13 (6.13) 4.1 (2.24) Renal tubular atrophy 4 16.77 (5.34–52.66) 16.76 (43.48) 12.56 (4.82) 3.65 (1.84) Kidney fibrosis 3 19.76 (5.11–76.42) 19.76 (37.4) 14.13 (4.56) 3.82 (1.94) Renal tubular disorder 3 9.88 (2.84–34.38) 9.88 (19.72) 8.31 (2.93) 3.06 (1.26) Renal tubular dysfunction 3 27.67 (6.61-115.77) 27.66 (48.18) 17.66 (5.33) 4.14 (2.22) Pneumaturia 3 23.05 (5.77–92.19) 23.05 (42.19) 15.7 (4.92) 3.97 (2.07) Prostate cancer Polyuria 11 6.79 (3.54–13.03) 6.78 (44.64) 5.76 (3.34) 2.53 (0.82) Renal tubular necrosis 8 11.45 (5.09–25.71) 11.44 (55.89) 8.66 (4.4) 3.11 (1.37) Renal tubular disorder 6 12.59 (4.88–32.45) 12.58 (45.7) 9.27 (4.2) 3.21 (1.44) Nephropathy 6 12.59 (4.88–32.45) 12.58 (45.7) 9.27 (4.2) 3.21 (1.44) Fanconi syndrome acquired 6 18.88 (6.86–51.96) 18.87 (63.48) 12.17 (5.22) 3.61 (1.8) Nephropathy Toxic 5 9.83 (3.6-26.85) 9.83 (30.22) 7.73 (3.34) 2.95 (1.17) Renal tubular acidosis 4 31.47 (7.87-125.83) 31.46 (58.98) 16.23 (5.09) 4.02 (2.1) Cystitis noninfective 4 6.29 (2.15–18.41) 6.29 (14.84) 5.41 (2.2) 2.44 (0.67) Hyperphosphaturia 3 31.46 (6.35-155.91) 31.46 (44.23) 16.23 (4.25) 4.02 (2.03) Neurogenic bladder 3 15.73 (3.93–62.91) 15.73 (27.59) 10.82 (3.39) 3.44 (1.54) Abbreviations: PT, preferred term; ROR, reporting odds ratios; PRR, proportional reporting ratios; χ2, chi-squared; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of the 95% CI of EBGM; IC, information component; IC025, the lower limit of the 95% CI of the IC; CI, confidence interval. Onset time of events The most common onset of AEs occurred in patients more than 360 days after starting ZA (38.84%), followed by those within 30 days (32.4%). The proportion of events between 30 and 180 days was small and showed a gradual decline. However, a clear upward trend emerged after 180 days (Fig. 3). Discussion The FAERS database is an important tool for post-marketing surveillance, collecting reports of adverse drug reactions that may not be evident under the controlled conditions of clinical trials [12]. This is crucial for ensuring medication safety. In this study, we comprehensively analyzed post-marketing reports of renal and urinary system AEs associated with ZA use from the FAERS database. We found that the most frequently reported renal and urinary system AE associated with ZA was renal tubular necrosis. Specifically, renal tubular necrosis was the most reported AE in patients treated for breast cancer and osteoporosis, while nephrogenic diabetes insipidus was most frequently reported in lung cancer, proteinuria in multiple myeloma, and polyuria in prostate cancer. The baseline distribution of AEs associated with ZA suggests that the majority of reports, especially for breast cancer and osteoporosis, came from female patients, which may be related to the drug's use in postmenopausal osteoporosis. Additionally, a higher percentage of AEs was reported in patients aged 65–85, likely due to age-related decline in renal function and decreased drug metabolism. Regarding outcomes, "Other Serious" events were the most common, while death was frequently reported in lung and prostate cancer patients, signaling a need to monitor for serious outcomes in these populations. Approximately 39–45% of ZA is excreted unchanged by the kidneys [13]. Previous studies have reported cases of acute kidney injury [14], including interstitial nephritis, acute tubular necrosis, and renal failure [15], following intravenous administration of ZA. In our study, renal tubular necrosis was the most frequently reported AE, with 166 cases, far exceeding reports of Fanconi syndrome. Osteoporosis was the leading indication for renal tubular necrosis (81 cases), which may be attributed to the widespread use of ZA in osteoporosis treatment. The nephrotoxic mechanism of ZA is thought to be similar to its pharmacological action in osteoclasts [16], likely involving inhibition of the mevalonate pathway [17]. ZA may also disrupt multiple pathways, including TGFβ/Smad3-mediated fibrosis, abnormal fatty acid metabolism, and small GTPase signaling [16]. Acute tubular necrosis and fibrosis are the primary pathological features observed in ZA-induced renal injury [18]. Thus, healthcare providers should remain vigilant for ZA-related renal toxicity, particularly renal tubular necrosis, during intravenous administration. Fanconi syndrome is characterized by phosphate depletion, aminoaciduria, and glucosuria [19]. Although rarely reported as a complication of ZA therapy [20, 21], our study identified 35 cases of acquired Fanconi syndrome, including 3 cases in breast cancer, 6 in multiple myeloma, and 6 in prostate cancer. Some reports suggest that ZA may trigger new-onset Fanconi syndrome [22], possibly through uptake into renal tubular cells via fluid-phase endocytosis [23]. Given the severity of Fanconi syndrome, clinicians should be vigilant in recognizing and managing this complication, especially in patients with breast cancer, multiple myeloma, and prostate cancer. Immediate discontinuation of ZA and continuous electrolyte replacement should be initiated if Fanconi syndrome is suspected. Regarding the time to onset, we found that these complications primarily occurred in patients who had used ZA for more than 360 days, followed by those who experienced AEs within the first 30 days of use. Some studies suggest that ZA-induced renal toxicity may be related to infusion time or dosage, with slower infusion rates potentially improving renal safety [24]. However, long-term studies have shown no significant differences in renal function between patients receiving ZA and control groups [25, 26]. In a study of elderly patients with osteoporosis, only 1.4% developed acute kidney injury in the following year [27]. Therefore, further clinical studies are needed to determine how soon renal impairment occurs following ZA administration. This study has several limitations. First, the FAERS database is a spontaneous reporting system, and the data may not be entirely accurate, with potential underreporting that could underestimate the true incidence of ZA-associated AEs. Second, we did not differentiate between the two available dosages of ZA (5 mg and 4 mg) or the indications for which they were used. Third, the majority of reports came from the United States, which may introduce geographic bias into the data distribution. Fourth, we did not analyze concomitant medications, which may affect the consistency of drug safety assessments. Finally, while disproportionality analysis methods are commonly used in pharmacovigilance research, establishing a causal relationship between ZA and AEs requires further clinical investigation. Despite these limitations, this study provides valuable insights into the renal and urinary system AEs associated with ZA in real-world clinical settings. Conclusion This study provides a comprehensive analysis of renal and urinary system AEs associated with ZA using the FAERS database. The findings highlight renal tubular necrosis as the most frequently reported AE across various indications, particularly in breast cancer and osteoporosis patients. Significant differences in the types of renal AEs were observed across different indications, such as nephrogenic diabetes insipidus in lung cancer and proteinuria in multiple myeloma. Additionally, prolonged use of ZA, especially beyond 360 days, appears to increase the risk of renal complications. Given the nephrotoxic potential of ZA, healthcare providers should be cautious during its administration, with particular attention to infusion rates and patient monitoring, especially in high-risk groups. Further clinical studies are needed to confirm these findings and guide safer use of ZA in clinical practice. Declarations Authors’ contributions Zhaojun Wang: Writing-original draft, Software, Methodology. Xin Su: Writing-original draft, Methodology, Formal analysis. Donglei Shi: Writing-review & editing, Validation, Data curation. Li Wei: Writing-review & editing, Data curation, Conceptualization. Funding None. Ethics approval and consent to participate This study was approved by the hospital’s ethics committee, and informed consent was obtained from all patients before treatment. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References FDA. Zoledronic Acid Injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203231s015s016s017lbl.pdf . Accessed Sep 1, 2024. Wang B, Zhan Y, Yan L, Hao D. How zoledronic acid improves osteoporosis by acting on osteoclasts. Front Pharmacol. 2022;13:961941. Liu L, Geng H, Mei C, Chen L. Zoledronic Acid Enhanced the Antitumor Effect of Cisplatin on Orthotopic Osteosarcoma by ROS-PI3K/AKT Signaling and Attenuated Osteolysis. Oxid Med Cell Longev. 2021;2021:6661534. Miller PD, Jamal SA, Evenepoel P, et al. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J Bone Min Res. 2013;28(10):2049–59. FDA. FDA Drug Safety Communication. New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-contraindication-and-updated-warning-kidney-impairment-reclast . Accessed Sep 1, 2024. Eshwar V, Kamath A. Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database. Sci Rep. 2024;14(1):1222. Su S, Wu L, Zhou G, et al. Indication and adverse event profiles of denosumab and zoledronic acid: based on U.S. FDA adverse event reporting system (FAERS). Front Pharmacol. 2023;14:1225919. FDA, Questions, and Answers on FDA's Adverse Event Reporting System (FAERS). https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers . Accessed Sep 1, 2024. Umetsu R, Tanaka M, Nakayama Y, et al. Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network. Front Pharmacol. 2021;12:764279. Wu X, Zhang L, Huang H, et al. Signal mining and analysis for central nervous system adverse events due to taking oxycodone based on FAERS database. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023;48(3):422–34. English, Chinese. Guo M, Shu Y, Chen G, et al. A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for niraparib. Sci Rep. 2022;12(1):20601. Kim HJ, Yoon JH, Park YH. Long-term hepatobiliary disorder associated with trastuzumab emtansine pharmacovigilance study using the FDA Adverse Event Reporting System database. Sci Rep. 2024;14(1):19587. Dhillon S. Zoledronic Acid (Reclast®, Aclasta®): A Review in Osteoporosis. Drugs. 2016;76(17):1683–97. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385–93. Yachoui R. Early onset acute tubular necrosis following single infusion of zoledronate. Clin Cases Min Bone Metab 2016 May-Aug;13(2):154–6. Cheng L, Ge M, Lan Z, et al. Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018;92(1):469–85. Wu Y, Ma T, Yu X, Su T. Severe Hypophosphatemia as the Initial Presentation of Renal Fanconi's Syndrome and Distal Renal Tubular Acidosis Related to Zoledronic Acid: A Case Report and Literature Review. Kidney Blood Press Res. 2023;48(1):18–27. Jennings P, Crean D, Aschauer L, et al. Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015;89(1):101–6. Igarashi T, Emma F, Hayes W. Pediatric Fanconi Syndrome. In: Emma F, Goldstein S, Bagga A, Bates CM, Shroff R, editors. Pediatric Nephrology. Berlin, Heidelberg: Springer; 2021. Gnanadeepan T, Mayilananthi K, Gaurav N, Durga K. Transient Renal tubular dysfunction following Zoledronic Acid treatment. Annals Trop Med Public Health. 2020;23(23):232–355. Oliveira M, Santos MT, Costa A. Fanconi syndrome related to zoledronic acid. Portuguese J Nephrol Hypertens. 2019;33(3):184–7. Portales-Castillo I, Mount DB, Nigwekar SU, Yu EW, Rennke HG, Gupta S. Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer. Am J Kidney Dis. 2022;80(4):555–9. 10.1053/j.ajkd.2021.12.015 . Epub 2022 Feb 24. Verhulst A, Sun S, McKenna CE, D’Haese PC. Endocytotic uptake of zoledronic acid by tubular cells may explain its renal effects in cancer patients receiving high doses of the compound. PLoS ONE. 2015;10(3):e0121861. Saad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458–68. Black DN, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. New Engl J Med. 2007;356:1809–22. Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int. 2008;74:641–8. Fixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022;33(11):2417–22. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 18 Dec, 2024 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 26 Sep, 2024 Editor assigned by journal 18 Sep, 2024 Submission checks completed at journal 18 Sep, 2024 First submitted to journal 18 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5106994","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":359213553,"identity":"6b634f73-0503-4e60-aa00-9e78b8b54e7c","order_by":0,"name":"Zhaojun Wang","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Zhaojun","middleName":"","lastName":"Wang","suffix":""},{"id":359213555,"identity":"46b99f03-8929-48bb-9178-af3fa80119fd","order_by":1,"name":"Xin Su","email":"","orcid":"","institution":"Hainan Hospital of PLA General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Su","suffix":""},{"id":359213556,"identity":"adde9559-14a2-4e9d-9d9f-4b9b6f60a166","order_by":2,"name":"Donglei Shi","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Donglei","middleName":"","lastName":"Shi","suffix":""},{"id":359213557,"identity":"9d1835d6-c6f1-4965-8c35-8728f070a52c","order_by":3,"name":"Li Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYFACxsYDCRU2DAzMzA0wIQNCWhoOJJxJA2phJFoLA8MBxrbDYL3EaTE43txw4MGZ89H87YwNjD/b6hIb2Ju3STDU3MGt5cxBoMMqbufOOMzYwMzbdjixgedYmQTDsWc4tZjdSAT55XZuA0gLY9uBxAaJHDMJxobDuLXcf9hwILHtXO78wzCHyb8hoOUGI0jLgdwNQC0MvG3MQFt48GuxPwN2WHLuRqCWwzznDhu38aQVWyQcw61Fsv34w4c/Kuxy550/fPDhj7I62X72wxtvfKjBrQUFHGBkY2BgA7ESiNMAAn+IVzoKRsEoGAUjBwAA3CBiPEKDYBwAAAAASUVORK5CYII=","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Li","middleName":"","lastName":"Wei","suffix":""}],"badges":[],"createdAt":"2024-09-18 05:08:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5106994/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5106994/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-024-13284-5","type":"published","date":"2024-12-18T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69837113,"identity":"a31d76ec-9bd1-4935-99a2-2e7f2bf25553","added_by":"auto","created_at":"2024-11-25 16:31:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":153395,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5106994/v1/d1001481547372b61536d290.png"},{"id":69837114,"identity":"05647a45-8d4a-4ed4-bf91-4cce0d8a7f97","added_by":"auto","created_at":"2024-11-25 16:31:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72316,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5106994/v1/3b4b2734844b05b835418ce3.png"},{"id":69836943,"identity":"282de38a-94ac-4f52-9223-01e7af4a17af","added_by":"auto","created_at":"2024-11-25 16:23:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86665,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5106994/v1/ae963bbc73036af50ebbd850.png"},{"id":72201707,"identity":"d9c1cbef-072b-48ac-a5c2-e5a7a3428094","added_by":"auto","created_at":"2024-12-23 16:10:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1178007,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5106994/v1/8ba6f4e8-bac4-411e-95c0-ffc341fdeae8.pdf"},{"id":69836941,"identity":"a4565f69-c36c-4984-af02-843ba8266671","added_by":"auto","created_at":"2024-11-25 16:23:55","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":21872,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5106994/v1/17a0c36bdaabdc7cf9c5ced0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluate the renal system damage caused by zoledronic acid: A comprehensive analysis of adverse events from FAERS","fulltext":[{"header":"Background","content":"\u003cp\u003eZoledronic acid (ZA) is a third-generation bisphosphonate compound that was approved by the U.S. Food and Drug Administration (FDA) in 2001 for the treatment of hypercalcemia of malignancy and bone metastases in patients with solid tumors [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e], with a dose of 4 mg. A 5 mg dose later became available for the treatment of postmenopausal osteoporosis and Paget's disease. The pharmacological action of ZA primarily involves inhibiting bone resorption by suppressing osteoclast activity and inducing osteoclast apoptosis [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additionally, ZA can inhibit the enhanced osteoclast activity and bone calcium release caused by various factors released by tumors, thereby reducing tumor-induced osteolytic lesions, bone resorption, pain, and hypercalcemia due to bone metastasis [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, during its use, several adverse reactions are commonly observed, such as fever, myalgia, gastrointestinal reactions, and renal function impairment.\u003c/p\u003e\n\u003cp\u003eAlthough ZA is generally well-tolerated in clinical treatment of osteoporosis, preclinical studies found similar renal function effects between the experimental and control groups [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, in January 2011, the FDA issued a drug safety communication highlighting new contraindications and updated warnings for Reclast (zoledronic acid) due to cases of acute renal failure, some with fatal outcomes, following its use [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. ZA is primarily excreted intact through the kidneys, and studies have shown that it increases the risk of nephrotoxicity. The risk of renal function deterioration appears to be time-dependent, with renal impairment or progression to renal failure occurring even in patients with normal baseline renal function [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. Nevertheless, comprehensive studies assessing the renal damage associated with the use of ZA are still lacking.\u003c/p\u003e\n\u003cp\u003eReal-world data on drug use serves as a powerful tool for evaluating drug safety [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recently, Su et al. published a study using FAERS data to investigate the indications and adverse event (AE) characteristics of denosumab and ZA. They compared the signal strength of AEs between denosumab and ZA and studied off-label use [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, their study did not specifically focus on AEs related to renal and urinary system diseases. Therefore, this study also utilizes the FAERS database, with a specific focus on AEs related to renal and urinary system diseases associated with ZA, as well as the AEs in these systems across different indications. This research serves as a valuable complement to the study by Su et al. By conducting this study, we aim to provide more comprehensive insights into the safe clinical use of ZA, particularly regarding AEs related to renal and urinary system diseases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eData source and collection\u003c/h2\u003e\n\u003cp\u003eThe FAERS (FDA Adverse Event Reporting System) database is used to support FDA's post-marketing safety surveillance of drugs and therapeutic biologics. It contains reports of AEs, medication errors, and product quality complaints [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. ZA was first approved by the FDA for clinical use in 2001. Therefore, this study utilized FAERS data from the second quarter of 2004 to the second quarter of 2024. The FAERS database consists of seven sub-datasets: demographics (DEMO), reactions (REAC), drugs (DRUG), indications (INDI), outcomes (OUTC), therapy start and end dates (THER), and report sources (RPSR). AEs in FAERS are coded using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PT), which are classified into 27 System Organ Classes (SOC). Drugs in FAERS are classified into four categories based on their involvement in the reported AEs: primary suspect, secondary suspect, concomitant, and interacting drugs [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. To ensure accuracy, this study only included reports where ZA was the primary suspect drug.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eData analysis\u003c/h2\u003e\n\u003cp\u003eFour commonly used disproportionality analysis methods were employed in this study: reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS) algorithms [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. The specific formulas and criteria for positive signals for these four algorithms are provided in Supplementary Table\u0026nbsp;1. For this study, at the SOC level, we used the ROR positive signal criterion (95% CI\u0026thinsp;\u0026gt;\u0026thinsp;1 and N\u0026thinsp;\u0026ge;\u0026thinsp;3) as the screening standard. At the PT level, we continued to use the ROR positive signal criterion to screen signals, with a primary focus on AEs under the SOC of renal and urinary system diseases. Additionally, we further analyzed the onset time of ZA-related AEs, calculated as the time interval in days between the EVENT_DT (adverse event date) and START_DT (drug start date). Finally, we conducted a subgroup analysis, focusing on renal and urinary system disease-related AEs in cases where ZA was used for indications such as breast cancer, lung cancer, osteoporosis, plasma cell myeloma, and prostate cancer. For these cases, an event was only considered a positive signal if it met the criteria of all four algorithms. The higher the score in the ROR algorithm, the more disproportionate the event is, indicating a stronger association between the drug and the AE [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eAll data processing and statistical analyses were conducted using R software, version 4.2.3, and data visualization was performed using the \"ggplot2\" package.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eDescriptive analysis\u003c/h2\u003eFigure 1 shows the flowchart of the data selection process in this study. The FAERS database contains a total of 21,433,114 records. After removing duplicate entries based on the FDA\u0026apos;s recommended method, 18,182,912 records were retained. Ultimately, 52,495 AE reports involving ZA as the primary suspect drug were identified. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e presents the overall and subgroup-specific clinical characteristics of patients with ZA-induced AEs. The majority of cases involved females in the overall cohort (69.2%), breast cancer (94.9%), and osteoporosis (85.7%) groups, whereas males were predominant in lung cancer (57.4%), multiple myeloma (51.1%), and prostate cancer (96.9%) groups. In terms of reporting sources, consumers reported the highest percentage of cases in the total cohort (35.6%) and osteoporosis (47.2%) groups, while physicians were the primary reporters for breast cancer (32.8%), and other health professionals for lung cancer (33.1%), multiple myeloma (34.1%), and prostate cancer (30.1%) groups. Geographically, the United States had the highest number of reports. Among reported outcomes, the \u0026quot;other serious\u0026quot; category was the most common, while lung cancer had the highest mortality rate (31.5%), followed by prostate cancer (24.3%). The number of reports over the past five years showed minimal variation.\u003cbr\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical characteristics of reports with zoledronic acid from the FAERS database.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth colspan=\"6\" align=\"left\"\u003e\n \u003cp\u003eNumber of events (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBreast cancer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLung cancer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOsteoporosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMultiple myeloma\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProstate cancer\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36,289 (69.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,740 (94.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e215 (38.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14,898 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,442 (43.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13,374 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e319 (57.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,055 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,694 (51.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,675 (96.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,810 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e211 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e423 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e176 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e379 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18-64.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11,608 (22.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,024 (40.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e206 (37.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,119 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e876 (26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e379 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u0026ndash;85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17,167 (32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,359 (27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e199 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6,543 (37.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,468 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,350 (48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,030 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,012 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21,289 (40.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,570 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6,612 (38.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e912 (27.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e937 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eReporter\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConsumer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18,670 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,027 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8,201 (47.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e444 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e790 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14,472 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,641 (32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e148 (26.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,394 (25.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,035 (31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e680 (24.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther health-professional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11,038 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,461 (29.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e184 (33.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,334 (13.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,130 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e830 (30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHealth Professional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,842 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e373 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e995 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e213 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e181 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePharmacist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,572 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e120 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e432 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eReported countries\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnited States\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13,538 (25.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e848 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4,011 (23.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e907 (27.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e346 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,343 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e407 (8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e293 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e190 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e215 (7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,285 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e201 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,847 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e129 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,425 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e483 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e124 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e437 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e204 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnited Kingdom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,330 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e214 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e744 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e128 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e125 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther Serious\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24,837 (47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,755 (55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7,203 (41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,943 (58.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,328 (48.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10,409 (19.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e664 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e175 (31.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,681 (21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e293 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e671 (24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10,122 (19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,052 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e102 (18.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3,973 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e654 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e551 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,416 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e266 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e898 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e226 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e107 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLife-Threatening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,282 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e638 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eYear (The last five years)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,192 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e283 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e657 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e118 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e122 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,922 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e214 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e610 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,566 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e198 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e583 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2,037 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e247 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e784 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,143 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e144 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e409 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eSignal of system organ class\u003c/h3\u003e\n\u003cp\u003eFigure 2 displays the signal strength of ZA-related AEs categorized by system organ class (SOC). A total of eight organ systems were affected by ZA-related AEs: musculoskeletal and connective tissue disorders, infections and infestations, neoplasms (benign, malignant, and unspecified), surgical and medical procedures, metabolism and nutrition disorders, eye disorders, renal and urinary disorders, ear and labyrinth disorders, and endocrine disorders. The musculoskeletal and connective tissue disorders category had both the highest number of reports (n\u0026thinsp;=\u0026thinsp;46,560) and the strongest signal [ROR 4.21 (95% CI: 4.17\u0026ndash;4.25)].\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eSignal of preferred terms\u003c/h2\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e presents the related AEs at the PT level under the SOC of kidney and urinary system diseases. A total of 25 AEs were identified. The most reported was renal tubular necrosis (n\u0026thinsp;=\u0026thinsp;166), while the strongest signal was for globulinuria [ROR 327.91 (95% CI: 54.79\u0026ndash;1962.48)], followed by hyperuricosuria [ROR 32.15 (95% CI: 12.57\u0026ndash;82.2)].\u003cbr\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e outlines the AE signals within the SOC of renal and urinary system diseases in the ZA-related subgroups. In the breast cancer group, renal tubular necrosis was the most reported AE (n\u0026thinsp;=\u0026thinsp;13), and urinary tract inflammation had the strongest signal [ROR 25.35 (95% CI: 10.01\u0026ndash;64.24)]. In the lung cancer group, nephrogenic diabetes insipidus had both the highest number of reports (n\u0026thinsp;=\u0026thinsp;7) and the strongest signal [ROR 57.44 (95% CI: 23.8\u0026ndash;138.59)]. In the osteoporosis group, renal tubular necrosis had the most reports (n\u0026thinsp;=\u0026thinsp;81), while haemoglobinuria had the strongest signal [ROR 22.85 (95% CI: 5.71\u0026ndash;91.35)]. In the multiple myeloma group, proteinuria had the highest number of reports (n\u0026thinsp;=\u0026thinsp;24), while glycosuria had the strongest signal [ROR 76.85 (95% CI: 18.37\u0026ndash;321.61)]. In the prostate cancer group, polyuria was the most frequently reported AE (n\u0026thinsp;=\u0026thinsp;11), and renal tubular acidosis had the strongest signal [ROR 31.47 (95% CI: 7.87\u0026ndash;125.83)].\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRelated AE signals of zoledronic acid based on SOC in FAERS for renal and urinary system diseases.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCase reports\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eROR (95% Cl)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePRR(\u0026chi;2)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEBGM (EBGM05)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIC (IC025)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.28 (3.67\u0026ndash;4.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.28 (408.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.21 (3.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.07 (0.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFanconi syndrome acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.99 (3.6\u0026ndash;6.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.99 (115.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.9 (3.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.29 (0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.12 (2.94\u0026ndash;5.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.12 (78.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.06 (3.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.02 (0.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMyoglobinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.19 (10.67\u0026ndash;21.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.19 (408.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.27 (10.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.83 (2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.27 (3.59\u0026ndash;7.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.27 (91.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.16 (3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.37 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.98 (4.99\u0026ndash;12.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.98 (106.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.74 (5.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.95 (1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStress urinary incontinence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.26 (1.96\u0026ndash;5.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.26 (23.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.23 (2.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.69 (0.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.22 (2.53\u0026ndash;7.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.22 (36.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.16 (2.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.06 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrinary tract inflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.83 (4.96\u0026ndash;15.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.83 (80.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.53 (5.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.09 (1.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBladder outlet obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.58 (8.98\u0026ndash;30.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.58 (149.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.48 (9.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.95 (2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrethral obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.73 (2.35\u0026ndash;9.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.73 (23.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.65 (2.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.22 (0.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal glycosuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29.64 (14.16\u0026ndash;62.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29.64 (194.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.22 (14.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.71 (3.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydroureter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.79 (2.87\u0026ndash;11.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.79 (30.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.67 (3.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.5 (0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostrenalfailure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.21 (2.09\u0026ndash;8.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.21 (19.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.15 (2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.05 (0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUreteric dilatation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.32 (2.98\u0026ndash;13.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.32 (30.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.17 (3.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.63 (0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBladder hypertrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.31 (2.04\u0026ndash;9.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.31 (17.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.25 (2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.09 (0.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperphosphaturia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.15 (7.04\u0026ndash;32.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.15 (86.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.23 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.83 (2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperuricosuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.15 (12.57\u0026ndash;82.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32.15 (131.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28.15 (12.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.82 (3.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrethral dilatation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.24 (8.1\u0026ndash;50.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.24 (83.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.61 (8.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.22 (2.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBence jones proteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.15 (10.6-85.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.15 (99.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.62 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.73 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMesangioproliferative Glomerulonephritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.83 (2.53\u0026ndash;18.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.83 (19.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.65 (2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.73 (1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal hypertrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.94 (1.83\u0026ndash;13.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.94 (12.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.85 (2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.28 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperkaliuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.38 (4.17\u0026ndash;42.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.38 (32.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.67 (4.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.66 (1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePneumaturia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.81 (2.47\u0026ndash;24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.81 (17.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.57 (2.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.92 (1.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlobulinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e327.91 (54.79-1962.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e327.9 (391.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e131.76 (29.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.04 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eAbbreviations: PT, preferred term; ROR, reporting odds ratios; PRR, proportional reporting ratios; \u0026chi;2, chi-squared; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of the 95% CI of EBGM; IC, information component; IC025, the lower limit of the 95% CI of the IC; CI, confidence interval.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAE signal AE of zoledronic acid related subgroups, SOC level for renal and urinary system diseases.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubgroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCase reports\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eROR (95% Cl)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePRR (\u0026chi;2)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEBGM (EBGM05)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIC (IC025)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eBreast cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (2.25\u0026ndash;7.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (25.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.66 (2.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.87 (0.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrinary tract inflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.35 (10.01\u0026ndash;64.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.35 (103.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.53 (6.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.86 (2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.92 (2.97\u0026ndash;21.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.92 (24.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.54 (2.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.71 (0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFanconi syndrome acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.64 (2.41\u0026ndash;30.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.64 (15.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (2.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.81 (0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetic nephropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.01 (4.54\u0026ndash;79.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.01 (31.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.26 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.62 (1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBladder hypertrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.31 (2.08\u0026ndash;25.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.31 (13.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.13 (2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.62 (0.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.58 (3.51\u0026ndash;52.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.58 (24.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.8 (3.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.29 (1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eLung cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephrogenic diabetes insipidus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57.44 (23.8-138.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57.33 (274.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.9 (19.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.35 (3.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46.5 (19.75-109.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46.41 (233.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35.06 (17.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.13 (3.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" align=\"left\"\u003e\n \u003cp\u003eOsteoporosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.7 (13.75\u0026ndash;28.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.69 (527.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.86 (5.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.97 (1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephropathy toxic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.53 (3.95\u0026ndash;10.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.53 (71.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.52 (2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.18 (0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.34 (2.56\u0026ndash;7.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.34 (35.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.42 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.77 (0.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOliguria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.09 (3.32\u0026ndash;11.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.09 (44.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.32 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.11 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHaemoglobinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.85 (5.71\u0026ndash;91.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.84 (41.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.28 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.05 (1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"17\" align=\"left\"\u003e\n \u003cp\u003eMultiple myeloma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.84 (4.45\u0026ndash;10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.83 (104.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.08 (4.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.6 (0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTubulointerstitial nephritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.59 (3.76\u0026ndash;11.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.59 (58.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.89 (3.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.56 (0.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.57 (3.2\u0026ndash;9.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.56 (46.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.07 (3.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.34 (0.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydronephrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.25 (4.76\u0026ndash;22.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.24 (54.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.56 (4.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.1 (1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePolyuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.97 (2.28\u0026ndash;10.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.96 (20.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.58 (2.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAzotaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.82 (2.21\u0026ndash;10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.82 (19.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.46 (2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.16 (0.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFanconi syndrome acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27.67 (10.06\u0026ndash;76.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27.66 (96.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.66 (7.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.14 (2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrinary tract obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.53 (2.37\u0026ndash;12.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.53 (19.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.05 (2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.34 (0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlycosuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76.85 (18.37-321.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76.84 (140.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29.44 (8.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.88 (2.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.47 (5.93\u0026ndash;45.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.47 (53.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.4 (5.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.63 (1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStress urinary incontinence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.44 (5.78\u0026ndash;58.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.44 (47.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.46 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.75 (1.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal colic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.35 (7.71\u0026ndash;90.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.34 (62.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.13 (6.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1 (2.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.77 (5.34\u0026ndash;52.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.76 (43.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.56 (4.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.65 (1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKidney fibrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.76 (5.11\u0026ndash;76.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19.76 (37.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.13 (4.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.82 (1.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.88 (2.84\u0026ndash;34.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.88 (19.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.31 (2.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.06 (1.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27.67 (6.61-115.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27.66 (48.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.66 (5.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.14 (2.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePneumaturia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23.05 (5.77\u0026ndash;92.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23.05 (42.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.7 (4.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.97 (2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"10\" align=\"left\"\u003e\n \u003cp\u003eProstate cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePolyuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.79 (3.54\u0026ndash;13.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.78 (44.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.76 (3.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.53 (0.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.45 (5.09\u0026ndash;25.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.44 (55.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.66 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.11 (1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.59 (4.88\u0026ndash;32.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.58 (45.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.27 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.21 (1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.59 (4.88\u0026ndash;32.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.58 (45.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.27 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.21 (1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFanconi syndrome acquired\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.88 (6.86\u0026ndash;51.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18.87 (63.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12.17 (5.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.61 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNephropathy Toxic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.83 (3.6-26.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.83 (30.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.73 (3.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.95 (1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal tubular acidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31.47 (7.87-125.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31.46 (58.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.23 (5.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.02 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCystitis noninfective\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.29 (2.15\u0026ndash;18.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.29 (14.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.41 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.44 (0.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperphosphaturia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31.46 (6.35-155.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31.46 (44.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.23 (4.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.02 (2.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeurogenic bladder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.73 (3.93\u0026ndash;62.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.73 (27.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.82 (3.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.44 (1.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eAbbreviations: PT, preferred term; ROR, reporting odds ratios; PRR, proportional reporting ratios; \u0026chi;2, chi-squared; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of the 95% CI of EBGM; IC, information component; IC025, the lower limit of the 95% CI of the IC; CI, confidence interval.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eOnset time of events\u003c/h3\u003e\n\u003cp\u003eThe most common onset of AEs occurred in patients more than 360 days after starting ZA (38.84%), followed by those within 30 days (32.4%). The proportion of events between 30 and 180 days was small and showed a gradual decline. However, a clear upward trend emerged after 180 days (Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe FAERS database is an important tool for post-marketing surveillance, collecting reports of adverse drug reactions that may not be evident under the controlled conditions of clinical trials [12]. This is crucial for ensuring medication safety. In this study, we comprehensively analyzed post-marketing reports of renal and urinary system AEs associated with ZA use from the FAERS database. We found that the most frequently reported renal and urinary system AE associated with ZA was renal tubular necrosis. Specifically, renal tubular necrosis was the most reported AE in patients treated for breast cancer and osteoporosis, while nephrogenic diabetes insipidus was most frequently reported in lung cancer, proteinuria in multiple myeloma, and polyuria in prostate cancer.\u003c/p\u003e\n\u003cp\u003eThe baseline distribution of AEs associated with ZA suggests that the majority of reports, especially for breast cancer and osteoporosis, came from female patients, which may be related to the drug's use in postmenopausal osteoporosis. Additionally, a higher percentage of AEs was reported in patients aged 65\u0026ndash;85, likely due to age-related decline in renal function and decreased drug metabolism. Regarding outcomes, \"Other Serious\" events were the most common, while death was frequently reported in lung and prostate cancer patients, signaling a need to monitor for serious outcomes in these populations.\u003c/p\u003e\n\u003cp\u003eApproximately 39\u0026ndash;45% of ZA is excreted unchanged by the kidneys [13]. Previous studies have reported cases of acute kidney injury [14], including interstitial nephritis, acute tubular necrosis, and renal failure [15], following intravenous administration of ZA. In our study, renal tubular necrosis was the most frequently reported AE, with 166 cases, far exceeding reports of Fanconi syndrome. Osteoporosis was the leading indication for renal tubular necrosis (81 cases), which may be attributed to the widespread use of ZA in osteoporosis treatment. The nephrotoxic mechanism of ZA is thought to be similar to its pharmacological action in osteoclasts [16], likely involving inhibition of the mevalonate pathway [17]. ZA may also disrupt multiple pathways, including TGF\u0026beta;/Smad3-mediated fibrosis, abnormal fatty acid metabolism, and small GTPase signaling [16]. Acute tubular necrosis and fibrosis are the primary pathological features observed in ZA-induced renal injury [18]. Thus, healthcare providers should remain vigilant for ZA-related renal toxicity, particularly renal tubular necrosis, during intravenous administration.\u003c/p\u003e\n\u003cp\u003eFanconi syndrome is characterized by phosphate depletion, aminoaciduria, and glucosuria [19]. Although rarely reported as a complication of ZA therapy [20, 21], our study identified 35 cases of acquired Fanconi syndrome, including 3 cases in breast cancer, 6 in multiple myeloma, and 6 in prostate cancer. Some reports suggest that ZA may trigger new-onset Fanconi syndrome [22], possibly through uptake into renal tubular cells via fluid-phase endocytosis [23]. Given the severity of Fanconi syndrome, clinicians should be vigilant in recognizing and managing this complication, especially in patients with breast cancer, multiple myeloma, and prostate cancer. Immediate discontinuation of ZA and continuous electrolyte replacement should be initiated if Fanconi syndrome is suspected.\u003c/p\u003e\n\u003cp\u003eRegarding the time to onset, we found that these complications primarily occurred in patients who had used ZA for more than 360 days, followed by those who experienced AEs within the first 30 days of use. Some studies suggest that ZA-induced renal toxicity may be related to infusion time or dosage, with slower infusion rates potentially improving renal safety [24]. However, long-term studies have shown no significant differences in renal function between patients receiving ZA and control groups [25, 26]. In a study of elderly patients with osteoporosis, only 1.4% developed acute kidney injury in the following year [27]. Therefore, further clinical studies are needed to determine how soon renal impairment occurs following ZA administration.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the FAERS database is a spontaneous reporting system, and the data may not be entirely accurate, with potential underreporting that could underestimate the true incidence of ZA-associated AEs. Second, we did not differentiate between the two available dosages of ZA (5 mg and 4 mg) or the indications for which they were used. Third, the majority of reports came from the United States, which may introduce geographic bias into the data distribution. Fourth, we did not analyze concomitant medications, which may affect the consistency of drug safety assessments. Finally, while disproportionality analysis methods are commonly used in pharmacovigilance research, establishing a causal relationship between ZA and AEs requires further clinical investigation. Despite these limitations, this study provides valuable insights into the renal and urinary system AEs associated with ZA in real-world clinical settings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides a comprehensive analysis of renal and urinary system AEs associated with ZA using the FAERS database. The findings highlight renal tubular necrosis as the most frequently reported AE across various indications, particularly in breast cancer and osteoporosis patients. Significant differences in the types of renal AEs were observed across different indications, such as nephrogenic diabetes insipidus in lung cancer and proteinuria in multiple myeloma. Additionally, prolonged use of ZA, especially beyond 360 days, appears to increase the risk of renal complications. Given the nephrotoxic potential of ZA, healthcare providers should be cautious during its administration, with particular attention to infusion rates and patient monitoring, especially in high-risk groups. Further clinical studies are needed to confirm these findings and guide safer use of ZA in clinical practice.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhaojun Wang: Writing-original draft, Software, Methodology. Xin Su: Writing-original draft, Methodology, Formal analysis. Donglei Shi: Writing-review \u0026amp; editing, Validation, Data curation. Li Wei: Writing-review \u0026amp; editing, Data curation, Conceptualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the hospital\u0026rsquo;s ethics committee, and informed consent was obtained from all patients before treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFDA. Zoledronic Acid Injection. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203231s015s016s017lbl.pdf\u003c/span\u003e\u003cspan address=\"https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203231s015s016s017lbl.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed Sep 1, 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang B, Zhan Y, Yan L, Hao D. How zoledronic acid improves osteoporosis by acting on osteoclasts. Front Pharmacol. 2022;13:961941.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu L, Geng H, Mei C, Chen L. Zoledronic Acid Enhanced the Antitumor Effect of Cisplatin on Orthotopic Osteosarcoma by ROS-PI3K/AKT Signaling and Attenuated Osteolysis. Oxid Med Cell Longev. 2021;2021:6661534.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller PD, Jamal SA, Evenepoel P, et al. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J Bone Min Res. 2013;28(10):2049\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFDA. FDA Drug Safety Communication. New contraindication and updated warning on kidney impairment for Reclast (zoledronic acid). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-contraindication-and-updated-warning-kidney-impairment-reclast\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-contraindication-and-updated-warning-kidney-impairment-reclast\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed Sep 1, 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEshwar V, Kamath A. Assessment of safety profile of secukinumab in real-world scenario using United States food and drug administration adverse event reporting system database. Sci Rep. 2024;14(1):1222.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSu S, Wu L, Zhou G, et al. Indication and adverse event profiles of denosumab and zoledronic acid: based on U.S. FDA adverse event reporting system (FAERS). Front Pharmacol. 2023;14:1225919.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFDA, Questions, and Answers on FDA's Adverse Event Reporting System (FAERS). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-adverse-event-reporting-system-faers\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed Sep 1, 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUmetsu R, Tanaka M, Nakayama Y, et al. Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network. Front Pharmacol. 2021;12:764279.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu X, Zhang L, Huang H, et al. Signal mining and analysis for central nervous system adverse events due to taking oxycodone based on FAERS database. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023;48(3):422\u0026ndash;34. English, Chinese.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo M, Shu Y, Chen G, et al. A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for niraparib. Sci Rep. 2022;12(1):20601.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim HJ, Yoon JH, Park YH. Long-term hepatobiliary disorder associated with trastuzumab emtansine pharmacovigilance study using the FDA Adverse Event Reporting System database. Sci Rep. 2024;14(1):19587.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDhillon S. Zoledronic Acid (Reclast\u0026reg;, Aclasta\u0026reg;): A Review in Osteoporosis. Drugs. 2016;76(17):1683\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYachoui R. Early onset acute tubular necrosis following single infusion of zoledronate. Clin Cases Min Bone Metab 2016 May-Aug;13(2):154\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng L, Ge M, Lan Z, et al. Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018;92(1):469\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Ma T, Yu X, Su T. Severe Hypophosphatemia as the Initial Presentation of Renal Fanconi's Syndrome and Distal Renal Tubular Acidosis Related to Zoledronic Acid: A Case Report and Literature Review. Kidney Blood Press Res. 2023;48(1):18\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJennings P, Crean D, Aschauer L, et al. Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015;89(1):101\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIgarashi T, Emma F, Hayes W. Pediatric Fanconi Syndrome. In: Emma F, Goldstein S, Bagga A, Bates CM, Shroff R, editors. Pediatric Nephrology. Berlin, Heidelberg: Springer; 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGnanadeepan T, Mayilananthi K, Gaurav N, Durga K. Transient Renal tubular dysfunction following Zoledronic Acid treatment. Annals Trop Med Public Health. 2020;23(23):232\u0026ndash;355.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliveira M, Santos MT, Costa A. Fanconi syndrome related to zoledronic acid. Portuguese J Nephrol Hypertens. 2019;33(3):184\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePortales-Castillo I, Mount DB, Nigwekar SU, Yu EW, Rennke HG, Gupta S. Zoledronic Acid-Associated Fanconi Syndrome in Patients With Cancer. Am J Kidney Dis. 2022;80(4):555\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.ajkd.2021.12.015\u003c/span\u003e\u003cspan address=\"10.1053/j.ajkd.2021.12.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2022 Feb 24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerhulst A, Sun S, McKenna CE, D\u0026rsquo;Haese PC. Endocytotic uptake of zoledronic acid by tubular cells may explain its renal effects in cancer patients receiving high doses of the compound. PLoS ONE. 2015;10(3):e0121861.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaad F, Gleason DM, Murray R, et al. Zoledronic Acid Prostate Cancer Study Group. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlack DN, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. New Engl J Med. 2007;356:1809\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int. 2008;74:641\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022;33(11):2417\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"zoledronic acid, FDA adverse event reporting system, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-5106994/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5106994/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eZoledronic acid (ZA) is widely used for the treatment of osteolytic bone metastases in malignancies and osteoporosis, but it has been associated with renal impairment. In this study, we investigated adverse events (AEs) related to renal and urinary system diseases associated with ZA using the U.S. FDA\u0026rsquo;s Adverse Event Reporting System.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe collected FAERS data from Q1 2004 to Q1 2024 and used the reporting odds ratio to detect AEs related to renal and urinary system diseases associated with ZA. Additionally, we applied multiple algorithms, including ROR, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, to quantify renal and urinary AEs under different indications.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 52,495 AE reports involving ZA as the primary suspect drug were identified. Among renal and urinary system diseases, 25 distinct AEs were recognized, with renal tubular necrosis being the most frequently reported. For different indications, renal tubular necrosis was the most reported AE in breast cancer and osteoporosis; nephrogenic diabetes insipidus was both the most frequent and strongest signal in lung cancer; proteinuria was most common in multiple myeloma, and polyuria in prostate cancer. Furthermore, most AEs occurred in patients who had been on ZA for more than 360 days, followed by those within the first 30 days of use.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBased on pharmacovigilance data from FAERS, different renal and urinary system AEs should be closely monitored and addressed according to the specific indications for which ZA is used.\u003c/p\u003e","manuscriptTitle":"Evaluate the renal system damage caused by zoledronic acid: A comprehensive analysis of adverse events from FAERS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-25 16:23:50","doi":"10.21203/rs.3.rs-5106994/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-26T06:43:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-18T10:05:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-18T10:03:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-09-18T05:05:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b10370ff-6a4d-47c9-83b3-05f52668380c","owner":[],"postedDate":"November 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:01:18+00:00","versionOfRecord":{"articleIdentity":"rs-5106994","link":"https://doi.org/10.1186/s12885-024-13284-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2024-12-18 15:56:51","publishedOnDateReadable":"December 18th, 2024"},"versionCreatedAt":"2024-11-25 16:23:50","video":"","vorDoi":"10.1186/s12885-024-13284-5","vorDoiUrl":"https://doi.org/10.1186/s12885-024-13284-5","workflowStages":[]},"version":"v1","identity":"rs-5106994","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5106994","identity":"rs-5106994","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}