Acute Phase Reactions in Osteoporotic Patients receiving Intravenous Zoledronic Acid: A Multi-Centre Retrospective Cohort Study

Acute Phase Reactions in Osteoporotic Patients receiving Intravenous Zoledronic Acid: A Multi-Centre Retrospective Cohort Study | 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 Acute Phase Reactions in Osteoporotic Patients receiving Intravenous Zoledronic Acid: A Multi-Centre Retrospective Cohort Study Samantha My-Linh Giang, Tripti Joshi, Flavian Joseph This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6650236/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background Intravenous Zoledronic Acid (IV ZA) is a third-generation bisphosphonates used for osteoporosis with once-yearly administration demonstrating benefits in improvement of bone mineral density and fracture risk reduction. However, acute phase reactions (APRs) pose challenges, often leading to treatment discontinuation. This study aims to assess APR incidence in osteoporotic patients who received IV ZA and associated risk factors. Methods A retrospective review of all patients aged over 50 years receiving IV ZA between the periods of May 2018 and May 2022 across Gosford and Wyong Hospitals, in NSW, Australia. Data on demographics, comorbidities, and adverse reactions were collected from electronic medical records. Logistic regression analysed associations between variables and APRs. Results Among 212 patients receiving IV ZA, 41% experienced APRs, predominantly in the form of flu-like symptoms. Patients starting IV ZA within 1–3 months of fracture onset were significantly more likely to develop APRs. Most APRs lasted 1–3 days, but 21% persisted over 1 week, with 15% resulting in a period of patient immobility. Despite APRs, 83% continued ZA treatment. Timing of ZA from fracture onset did not affect BMD improvement at 1 year. Conclusion This study highlights a higher APR risk with earlier ZA initiation from fracture onset. Notably, there are no significant BMD differences observed based on ZA timing at 1 year. In conclusion, early initiation of IV ZA post-fracture increased APR risk without affecting BMD outcomes, emphasising need for further prospective trials to optimise treatment protocols to reduce risk of APRs. Clinical Trial number: not applicable acute phase reactions osteoporosis zoledronic acid bone mineral density INTRODUCTION Zoledronic acid (ZA) is a highly potent, third-generation bisphosphonate used to treat osteoporosis, administered once yearly to inhibit bone resorption, and induce osteoclast apoptosis 1 – 3 . Evidence has demonstrated that once yearly intravenous zoledronic acid is associated with improvement in bone mineral density and reduced markers of bone turnover 4 . Furthermore, it has been shown to decrease risk of new clinical fractures and improve survival 4 – 5 . Acute phase reactions are the most common adverse effects experienced by patients who received zoledronic acid, often describing symptoms such as pyrexia, myalgias, headaches and influenza-like symptoms 5 – 8 . These symptoms are typically self-limiting in nature and generally occur within 3 days of treatment 5 – 6 , 9 . The incidence of acute phase reactions has been found to be widely variable, with major studies demonstrating incidences of roughly 30% 5 . With acute phase reactions, discontinuation of zoledronic acid has been observed, particularly in elderly patients 11 . Age, race, and prior use of bisphosphonates are factors that have been noted to determine adverse reactions to zoledronic acid. 12 – 13 . A retrospective multi-centre cohort study was performed to determine the incidence of acute phase reactions and associated risk factors in patients who are treated with IV ZA. METHODS Study design and population – This retrospective cohort study included men and women over the age of 50 years who received intravenous zoledronic acid between the period of May 2018 and May 2022 seen in the Central Coast Local Health District’s Osteoporosis Re-Fracture Prevention clinic (ORPC) at Gosford Hospital and Wyong Hospital, New South Wales, Australia (Supplementary Figure S1). Patients eligible for the ORPC were those who presented to the emergency department at Gosford Hospital and Wyong Hospital with a minimal trauma fracture and subsequently referred to ORPC. The observed age distribution reflects the cohort attending outpatient review, not a deliberate age-based inclusion criterion. At ORPC, decision to initiate IV ZA was made by the endocrinologist in consultation with the patient based off osteoporotic risk factors, prior anti-resorptive use, renal function and patient preference. The intended timing of IV ZA administration was 3–6 months post-fracture. However, delays beyond 6 months occurred from missed appointments, prolonged dental clearance, or patient preference. Data on time of fracture to IV ZA infusion were collected. Data collection – A list of patients who were referred to the ORPC were obtained through the ORPC patient list database collated from patients presenting with an acute fracture to the emergency department. Clinical data was extracted from the health system’s electronic medical records, (EMR). Data collection included the patient demographics, comorbidities, body mass index, previous anti-resorptive therapy use and duration, drug allergies, bone mineral density results, and number of minimal trauma fractures. Adverse effects were identified through clinician documentation in follow-up notes and supplemented by patient self-reporting during follow up calls or outpatient reviews, typically occurring 3–6 months post infusion, as well as unscheduled hospital presentations. There was no validated instrument used to systemically assess adverse effects. Data for acute phase reactions (flu-like symptoms); uveitis; atrial fibrillation; and other unexpected adverse effects occurring within the first week following zoledronic acid administration was collected. In patients that had an adverse reaction, further data was collected including the infusion number at which the reaction occurred at (i.e. first, second or third), duration of adverse reactions, severity of adverse reactions, self-management of adverse reactions, and the patient’s subsequent decision for continuing or cessation of IV ZA and switching to other therapeutic agents. Repeat BMD studies were reviewed which were typically scheduled 12 months after initial infusion. Data was stored in a password protected excel file accessible to researchers involved in the study. Data was analysed using descriptive statistics with results shown as number (%) or mean ± standard deviation. The primary outcome measured was the prevalence of adverse reactions 1 week post infusion in patients who received IV ZA and the cessation rates or decision to opt for alternative therapies due to adverse effects. Secondary outcomes measured included duration of adverse effects, susceptibility of acute phase reactions depending on several patient factors, timing of IV ZA from fracture onset and a change in BMD scores at 12months amongst patients with and without adverse reactions. Statistical analysis – Descriptive statistics were used to summarise demographic and clinical characteristics of the patient population. Binary logistic regression was used to identify predictors of APRs. Variables included in the model were time to IV ZA, BMI, history of allergic reactions, prior antiresorptive therapy, and presence of comorbidities. A stepwise backward elimination using log-likelihood ratio was used to derive the final parsimonious model. For BMD analysis, the Kruskal-Wallis H test was used to compare percentage changes across timing groups. A p-value of < 0.05 was considered statistically significant. RESULTS During the period of May 2018 to May 2022, 769 patients were seen in the ORPC, with 212 patients receiving intravenous zoledronic acid during this time. Of the 212 patients who received IV ZA, 189 were female and 23 were male. The average age of the patients was 64.8years (± 6.18). The majority of patients, 202 were of Caucasian ethnicity (n = 202, 95%). Other ethnicities included 6 Australian Indigenous patients, 3 East Asian patients and 1 South Asian patient. (Table 1 ) Table 1 Patient demographics Abbreviations: SD, standard deviation; ZA, zoledronic acid Baseline characteristics Variable Patients who received IV ZA (n = 212) Age Mean – years (SD) 64.8(± 6.18) Range 50–76 Sex – no. (%) Female 189 (89) Male 23 (11) Ethnicity – no. (%) Caucasian 202 (95) Australian Indigenous 6 (2) East Asian 3 (1.4) South Asian 1 (0.4) Among the 212 patients who received IV ZA cohort of patients, 87 (41%) experienced an APR (Table 2 ). The most commonly reported symptom were flu-like symptoms, occurring in 83/87 (94.5%) patients. Less commonly experienced symptoms included uveitis (n = 2), swollen knee (n = 1) and periorbital swelling (n = 1) (Table 3 ). No cases of atrial fibrillation were observed in this patient group. Amongst affected cohort, majority of the patients developed side-effects following the first infusion (n = 85, 98%). On subsequent infusions, 1 patient developed flu-like symptoms with the second infusion and another patient developed flu-like symptoms with the third infusion. Notably, 2 patients did not experience flu-like symptoms with the first infusion. Table 2 Patient characteristics in adverse reactions vs no adverse reactions Abbreviations: SD, standard deviation; ZA, zoledronic acid Characteristics of patients with adverse reactions vs no adverse reactions Variable Adverse reaction (n = 87) No adverse reaction (n = 125) Total patients (n = 212) Age - year Mean (SD) 64.3 ± 6.3 65.2 ± 6.1 Median 64 66 Sex – no. (%) Female 80 (92) 109 (87) 189 Male 7 (8.) 16 (13) 23 Timing of IV ZA from fracture onset – no. (%) 1–3 months 27 (31) 21 (17) 48 4–6 months 38 (44) 48 (38) 86 7 + months 22 (25) 56 (45) 78 Table 3 Adverse events in patients who received intravenous zoledronic acid Abbreviations – IV, intravenous; ZA, zoledronic acid Adverse events in patients who received IV ZA Variable Number of patients who received IV ZA with adverse reactions (n = 87) (%) Flu-like symptoms ∫ 83(95) Fevers 7 (8) Myalgias and arthralgias 20 (22) Headaches 1 (1.2) Uveitis 2 (2.2) Periorbital swelling 1 (1.2) Swollen knee 1 (1.2) Duration – no. (%) 0–1 day 11 (13) 1–3 days 47 (54) 4–7 days 8 (9.2) > 7 days 18 (20.7) Unknown 3 (3.5) Immobile or bed bound – no. (%) No 74 (85) Yes 13 (15) Decision for ongoing treatment– no. (%) Cease all treatment including other proposed options 3 (3.5) Cease treatment and discuss alternate options 2 (2.2) Change to alternate treatment 10 (12) Continue treatment 72 (83) ∫ Includes fevers, myalgia and arthralgia, headaches Amongst the patients who experienced acute phase reactions, 47 (54%) reported a symptom duration of 1–3 days and 18 (21%) reported symptoms for over 7 days. Furthermore, 13 (17%) patients reported acute phase reactions resulting in being bed bound or immobile (Table 3 ). Despite this, 72 (83%) patients continued intravenous zoledronic acid, 10 (12%) patients were changed to an alternative treatment and 5 (6%) patients decided to cease treatment completely (Table 3 ). Binary logistic regression was conducted to assess predictors of APR development. The overall model was statistically significant (p = 0.0141), but individual predictors varied in significance when adjusted for covariates. A stepwise backward elimination approach was used to derive a parsimonious model. In the final model (Table 4 ), timing of IV ZA infusion remained a single predictor of APR (p = 0.0055). Table 4 Binary logistic regression of variables against acute phase reactions development. Abbreviations – OR, odds ratio; IV, intravenous; ZA, zoledronic acid; BMI, body mass index Adverse reaction IV ZA OR Std. err. Z P > |z| 95% confidence interval of OR Reference BMI low/normal BMI obese 0.8211875 0.2678006 -0.60 0.546 0.4333649 1.556076 Frac to first disease Reference = 1–3 months 4–6 months 0.6254871 0.237505 -1.27 0.203 0.303528 1.288955 7 months + 0.3195978 0.1249464 -2.92 0.004 0.1485345 0.68767 Previous antiresorptive Reference = no 0.7604142 0.262267 -0.79 0.427 0.386786 1.494961 History of allergic reaction Reference = no Yes 1.372141 0.409117 1.06 0.289 0.7649006 2.461459 Risk factors Reference = None or 1 2+ 0.5263922 0.1768465 -1.91 0.056 0.2724834 1.016901 _cons 1.977813 0.8238941 1.64 0.102 0.8741816 4.47475 Log likelihood − 135.55488 Number of observations = 212 LR chi2(6) = 15.94 Pron > chi2 = 0.0141 Pseudo R2 = 0.0555 Patients who received IV ZA within 1–3 months post-fracture were 3.3 times more likely to develop an APR compared to those treated after 7 months (p = 0.002). Those treated within 4–6 months also had an elevated risk (OR 2.0, p = 0.035) The percentage change in BMD from baseline to one-year post treatment were assessed using Kruskal-Wallis H test, revealing no significant differences in BMD percentage change across three time intervals of when IV ZA was administered post fracture (1–3 months; 4–6 months; >7 months) at the total left hip (p = 0.4), total right hip (p = 0.5), lumbar spine (p = 0.7) or radius (p = 0.3). A significant change was determined as a change in BMD of 0.05g/cm2 or a 4% or more difference at the measured bone sites over a 1 year period. To assess factors associated with APR development, binary logistic regression was performed, incorporating the following predictors: BMI, prior use of antiresorptive therapy, history of allergic drug reactions, comorbidities (chronic kidney disease, liver disease), and time from fracture to first IV ZOL administration. The overall model was statistically significant (p = 0.0141), but individual predictors varied in significance when adjusted for covariates. A parsimonious model was derived using stepwise backward elimination and log-likelihood ratio testing. In the final model (Table 4 ), shorter time from fracture to ZOL infusion was independently associated with increased odds of APR. Patients who received ZOL within 1–3 months post-fracture were 3.3 times more likely to develop an APR compared to those treated after 7 months (p = 0.002). Those treated within 4–6 months also had higher odds (OR 2.0, p = 0.035). Bone mineral density (BMD) changes from baseline to one-year post-treatment was also assessed, stratified by time from fracture to ZOL initiation. A Kruskal-Wallis H test revealed no significant differences in BMD percentage change across the three-time intervals (1–3 months; 4–6 months; ≥7 months) at the total left hip (p = 0.4), total right hip (p = 0.5), lumbar spine (p = 0.7), or radius (p = 0.3). DISCUSSION Among the 212 patients who received IV ZA at Gosford and Wyong Hospital during the period of May 2018 to May 2022, 41% experienced APRs, predominantly in the form of flu-like symptoms. Those who received IV ZA within 1–3 months of fracture onset were found to be more likely to develop APRs. Most APRs last 1–3 days, however 21% were found to persist for over 1 week, with 15% resulting in a period of immobility. Despite this, 83% of patients who experienced APRs continued IV ZA. Notably timing of IV ZA administration did not influence changes in BMD at 1 year post treatment. The biological correlation between IV ZA and APRs is thought to occur as a result of activation of the immune system through induction of inflammatory marker expression, specifically tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL‐6), interferon-gamma (IFN‐γ) and interleukin-1 beta (IL‐1β) 21 . The cytokine surge post bisphosphonate administration provides biological plausibility for the increased APRs observed, especially in patients administered IV ZA early post-fracture, a period associated with heightened systemic inflammatory responses and immune activation 22 . Consistent with findings from larger clinical trials 4 – 5 , we observed a relatively high rate of APRs in patients who received IV ZA, particularly following first infusions. However, our findings suggest an influence of timing of IV ZA post fracture on rates of APRs. This is a post hoc observation, and it should be acknowledged that our study was not designed to review this specific hypothesis. These results raise important clinical consideration for timing of bisphosphonate initiation after fracture onset. Prior studies 14 – 17 have demonstrated that early zoledronic acid treatment – particularly between 2 weeks and 3 months following fracture onset - has been associated with reduction in rates of new clinical fractures and BMD scores. As such, early administration of bisphosphonates is encouraged for secondary fracture prevention. However, the occurrence of APRs raises the risk of non-adherence to osteoporosis treatment, thereby reducing effectiveness of osteoporosis therapy and increased healthcare burden. The consideration of reducing APR risks may positively affect adherence and patient satisfaction, particularly in the frail and elderly populations 11 . Our findings that early IV ZA administration may increase risk of APRs must be weighed against evidence that supports early intervention. High APR rates following inpatient administration of IV ZA post-fracture have been observed, highlighting that timing and setting may influence side effect profiles 18 .Strategies to mitigate APR risk that have been explored, such as appropriate patient education and pre-medication protocols 19 – 20 , which should be considered to optimise adherence and outcomes. This study draws on real life clinical data across two regional hospital sites, providing insights into the practical application of IV ZA in a heterogenous patient population. The inclusion of data on treatment adherence following APRs also provides valuable information on patient counselling and clinical decisions. However, there are several limitations of our study that should be acknowledged. Firstly, the retrospective cohort study design limits the ability to establish causality between IV ZA timing and occurrence of APRs. Secondary, as our study is reliant on retrospective chart review and patient reports, there is susceptibility of recall bias and no consistent measure of nature or severity of patient’s acute phase reactions. Thirdly, due to our modest sample size, there is limitations in its power to detect smaller BMD differences based on treatment timing. In summary, our study demonstrates that APRs are a common occurrence following IV ZA administration, particularly in patients treated at an earlier time frame post fracture onset. Whilst early IV ZA administration remains important for reducing refracture risk and improving BMD, there is potential impact of APRs on patient adherence that should be considered. Prospective studies specifically designed to investigate the relationship between fracture timing, systemic inflammation, APR risk following bisphosphonate administration is warranted. Conclusion This retrospective study highlights the potential for delayed administration of zoledronic acid to reduce APRs; however, this post-hoc findings warrants further investigations with larger, more controlled studies. The timing of infusion should be balanced with the need to provide effective re-fracture prevention. Future larger scale research should focus on optimising treatment protocols to minimise APRs whilst maximising bone protective benefits of IV ZA. Abbreviations zoledronic acid (ZA), acute phase reactions (APRs), intravenous (IV), bone mineral density (BMD), Osteoporosis Re-fracture Prevention clinic (ORPC), body mass index (BMI) Declarations Ethics Approval: This study was approved by the Northern Sydney Local Health District Human Research and Ethics Committee (Reference Number: PID01587) and conducted in accordance with the Declaration of Helsinki 23 . Consent to participate: This study was approved by the Northern Sydney Local Health District Human Research and Ethics Committee (Reference Number: PID01587). The requirement for individual informed consent was waived by the committee due to the retrospective nature of the audit and minimal risk to participants. All data was de-identified prior to analysis and no identifiable information was used or published. Consent for publication: Not applicable. Availability of data: The datasets generated and/or analysed during the current study are not publicly available due to privacy concerns but are available from the corresponding author on reasonable request. Conflicts of Interest: The author declare that they have no competing interests. Funding: Not applicable. Authors’ contribution: All authors contributed to the study design. SG collected the data. TJ and FJ contributed to data analysis and interpretation. SG drafted the initial manuscript, which TJ and FJ revised. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6650236","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473300059,"identity":"2135b0ac-3dc9-4146-8ba4-3a5cb32d6ad2","order_by":0,"name":"Samantha My-Linh Giang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABTUlEQVRIie2Sv2vCQBTHXwg0y5OskVD8F1KELlrzr+QIuKVYXASHXggkizRrSsf+A4Lg6slBHVoq3YQ4GAQ3QXCR6tBT+wOV1o6F5gP3OI734X25O4CUlL8LE0uiohQtAJnKxw3rUykLRXK9Xyob+HElFzyS+dVimAP13p1XXvuXqtINxhUYmgZTXsYIJUJ3FePJaemRNTmjWuLptzdxNdsgrhfBhDQZVvMI9oECTlNHi0tU61I904hFp1BQJDxnWM5GIO8ruXDaWgrFFIq3zDSeSaefbBTzXbneV2DgtNdTCFVdX8cFI01tO0VqM+VBmwE/CDaYtgtY5ravSX4hQ20SDRL3Dg1OOhxlY2b08gfBnFaMRX4Rqr1xjKsSCUObzbHGzWwQJCOrVj/dD/bBibZ+Ef/rWsQvQGO7+Q6VibLaOVJGP/SnpKSk/B/eALECf/Gn92J8AAAAAElFTkSuQmCC","orcid":"","institution":"Concord Repatriation General Hospital, Sydney Local Health District, NSW Health. Hospital Rd, Concord, 2139","correspondingAuthor":true,"prefix":"","firstName":"Samantha","middleName":"My-Linh","lastName":"Giang","suffix":""},{"id":473300060,"identity":"03f431df-8bca-4758-b183-6c97654ea16f","order_by":1,"name":"Tripti Joshi","email":"","orcid":"","institution":"Department of Endocrinology, Gosford Hospital, Central Coast Local Health District, NSW Health. 75 Holden St, Gosford, NSW, 2250.","correspondingAuthor":false,"prefix":"","firstName":"Tripti","middleName":"","lastName":"Joshi","suffix":""},{"id":473300061,"identity":"9160a1cc-b3a8-479c-bca3-5a83c81eab91","order_by":2,"name":"Flavian Joseph","email":"","orcid":"","institution":"Department of Endocrinology, Gosford Hospital, Central Coast Local Health District, NSW Health. 75 Holden St, Gosford, NSW, 2250.","correspondingAuthor":false,"prefix":"","firstName":"Flavian","middleName":"","lastName":"Joseph","suffix":""}],"badges":[],"createdAt":"2025-05-13 01:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6650236/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6650236/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85074156,"identity":"254f6f64-82f2-4382-b6d6-c04c67aa2b47","added_by":"auto","created_at":"2025-06-20 16:12:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1145643,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6650236/v1/7929f725-6284-4b04-bd0f-37a842a8e1fc.pdf"},{"id":85072850,"identity":"d7df3f83-0a41-4cc8-aca3-2c20faca3089","added_by":"auto","created_at":"2025-06-20 15:56:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":171180,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6650236/v1/7fa71d259e7989c93e072515.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Acute Phase Reactions in Osteoporotic Patients receiving Intravenous Zoledronic Acid: A Multi-Centre Retrospective Cohort Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eZoledronic acid (ZA) is a highly potent, third-generation bisphosphonate used to treat osteoporosis, administered once yearly to inhibit bone resorption, and induce osteoclast apoptosis\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Evidence has demonstrated that once yearly intravenous zoledronic acid is associated with improvement in bone mineral density and reduced markers of bone turnover\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Furthermore, it has been shown to decrease risk of new clinical fractures and improve survival\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAcute phase reactions are the most common adverse effects experienced by patients who received zoledronic acid, often describing symptoms such as pyrexia, myalgias, headaches and influenza-like symptoms\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. These symptoms are typically self-limiting in nature and generally occur within 3 days of treatment\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The incidence of acute phase reactions has been found to be widely variable, with major studies demonstrating incidences of roughly 30%\u003csup\u003e5\u003c/sup\u003e. With acute phase reactions, discontinuation of zoledronic acid has been observed, particularly in elderly patients\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Age, race, and prior use of bisphosphonates are factors that have been noted to determine adverse reactions to zoledronic acid. \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA retrospective multi-centre cohort study was performed to determine the incidence of acute phase reactions and associated risk factors in patients who are treated with IV ZA.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population \u0026ndash;\u003c/h2\u003e \u003cp\u003e This retrospective cohort study included men and women over the age of 50 years who received intravenous zoledronic acid between the period of May 2018 and May 2022 seen in the Central Coast Local Health District\u0026rsquo;s Osteoporosis Re-Fracture Prevention clinic (ORPC) at Gosford Hospital and Wyong Hospital, New South Wales, Australia (Supplementary Figure S1).\u003c/p\u003e \u003cp\u003ePatients eligible for the ORPC were those who presented to the emergency department at Gosford Hospital and Wyong Hospital with a minimal trauma fracture and subsequently referred to ORPC. The observed age distribution reflects the cohort attending outpatient review, not a deliberate age-based inclusion criterion.\u003c/p\u003e \u003cp\u003eAt ORPC, decision to initiate IV ZA was made by the endocrinologist in consultation with the patient based off osteoporotic risk factors, prior anti-resorptive use, renal function and patient preference.\u003c/p\u003e \u003cp\u003eThe intended timing of IV ZA administration was 3\u0026ndash;6 months post-fracture. However, delays beyond 6 months occurred from missed appointments, prolonged dental clearance, or patient preference. Data on time of fracture to IV ZA infusion were collected.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection –\u003c/h3\u003e\n\u003cp\u003eA list of patients who were referred to the ORPC were obtained through the ORPC patient list database collated from patients presenting with an acute fracture to the emergency department. Clinical data was extracted from the health system\u0026rsquo;s electronic medical records, (EMR). Data collection included the patient demographics, comorbidities, body mass index, previous anti-resorptive therapy use and duration, drug allergies, bone mineral density results, and number of minimal trauma fractures.\u003c/p\u003e \u003cp\u003eAdverse effects were identified through clinician documentation in follow-up notes and supplemented by patient self-reporting during follow up calls or outpatient reviews, typically occurring 3\u0026ndash;6 months post infusion, as well as unscheduled hospital presentations. There was no validated instrument used to systemically assess adverse effects. Data for acute phase reactions (flu-like symptoms); uveitis; atrial fibrillation; and other unexpected adverse effects occurring within the first week following zoledronic acid administration was collected. In patients that had an adverse reaction, further data was collected including the infusion number at which the reaction occurred at (i.e. first, second or third), duration of adverse reactions, severity of adverse reactions, self-management of adverse reactions, and the patient\u0026rsquo;s subsequent decision for continuing or cessation of IV ZA and switching to other therapeutic agents. Repeat BMD studies were reviewed which were typically scheduled 12 months after initial infusion.\u003c/p\u003e \u003cp\u003eData was stored in a password protected excel file accessible to researchers involved in the study. Data was analysed using descriptive statistics with results shown as number (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e \u003cp\u003eThe primary outcome measured was the prevalence of adverse reactions 1 week post infusion in patients who received IV ZA and the cessation rates or decision to opt for alternative therapies due to adverse effects. Secondary outcomes measured included duration of adverse effects, susceptibility of acute phase reactions depending on several patient factors, timing of IV ZA from fracture onset and a change in BMD scores at 12months amongst patients with and without adverse reactions.\u003c/p\u003e\n\u003ch3\u003eStatistical analysis –\u003c/h3\u003e\n\u003cp\u003eDescriptive statistics were used to summarise demographic and clinical characteristics of the patient population. Binary logistic regression was used to identify predictors of APRs. Variables included in the model were time to IV ZA, BMI, history of allergic reactions, prior antiresorptive therapy, and presence of comorbidities. A stepwise backward elimination using log-likelihood ratio was used to derive the final parsimonious model. For BMD analysis, the Kruskal-Wallis H test was used to compare percentage changes across timing groups. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eDuring the period of May 2018 to May 2022, 769 patients were seen in the ORPC, with 212 patients receiving intravenous zoledronic acid during this time. Of the 212 patients who received IV ZA, 189 were female and 23 were male. The average age of the patients was 64.8years (\u0026plusmn;\u0026thinsp;6.18). The majority of patients, 202 were of Caucasian ethnicity (n\u0026thinsp;=\u0026thinsp;202, 95%). Other ethnicities included 6 Australian Indigenous patients, 3 East Asian patients and 1 South Asian patient. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePatient demographics\u003c/b\u003e Abbreviations: SD, standard deviation; ZA, zoledronic acid\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients who received IV ZA (n\u0026thinsp;=\u0026thinsp;212)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean \u0026ndash; years (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.8(\u0026plusmn;\u0026thinsp;6.18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u0026ndash;76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e189 (89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCaucasian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e202 (95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAustralian Indigenous\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEast Asian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSouth Asian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 212 patients who received IV ZA cohort of patients, 87 (41%) experienced an APR (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The most commonly reported symptom were flu-like symptoms, occurring in 83/87 (94.5%) patients. Less commonly experienced symptoms included uveitis (n\u0026thinsp;=\u0026thinsp;2), swollen knee (n\u0026thinsp;=\u0026thinsp;1) and periorbital swelling (n\u0026thinsp;=\u0026thinsp;1) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No cases of atrial fibrillation were observed in this patient group. Amongst affected cohort, majority of the patients developed side-effects following the first infusion (n\u0026thinsp;=\u0026thinsp;85, 98%). On subsequent infusions, 1 patient developed flu-like symptoms with the second infusion and another patient developed flu-like symptoms with the third infusion. Notably, 2 patients did not experience flu-like symptoms with the first infusion.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePatient characteristics in adverse reactions vs no adverse reactions\u003c/b\u003e Abbreviations: SD, standard deviation; ZA, zoledronic acid\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics of patients with adverse reactions vs no adverse reactions\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdverse reaction\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo adverse reaction\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;125)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;212)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge - year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.3\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.2\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109 (87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (8.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTiming of IV ZA from fracture onset \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u0026ndash;3 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u0026ndash;6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u0026thinsp;+\u0026thinsp;months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eAdverse events in patients who received intravenous zoledronic acid\u003c/b\u003e Abbreviations \u0026ndash; IV, intravenous; ZA, zoledronic acid\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAdverse events in patients who received IV ZA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients who received IV ZA with adverse reactions (n\u0026thinsp;=\u0026thinsp;87) (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFlu-like symptoms\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026int;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83(95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFevers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMyalgias and arthralgias\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeadaches\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUveitis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePeriorbital swelling\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSwollen knee\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDuration \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1 day\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u0026ndash;3 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u0026ndash;7 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (9.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;7 days\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (20.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnknown\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImmobile or bed bound \u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecision for ongoing treatment\u0026ndash; no. (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCease all treatment including other proposed options\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCease treatment and discuss alternate options\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChange to alternate treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eContinue treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e\u0026int;\u003c/sup\u003eIncludes fevers, myalgia and arthralgia, headaches\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmongst the patients who experienced acute phase reactions, 47 (54%) reported a symptom duration of 1\u0026ndash;3 days and 18 (21%) reported symptoms for over 7 days. Furthermore, 13 (17%) patients reported acute phase reactions resulting in being bed bound or immobile (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite this, 72 (83%) patients continued intravenous zoledronic acid, 10 (12%) patients were changed to an alternative treatment and 5 (6%) patients decided to cease treatment completely (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBinary logistic regression was conducted to assess predictors of APR development. The overall model was statistically significant (p\u0026thinsp;=\u0026thinsp;0.0141), but individual predictors varied in significance when adjusted for covariates. A stepwise backward elimination approach was used to derive a parsimonious model. In the final model (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), timing of IV ZA infusion remained a single predictor of APR (p\u0026thinsp;=\u0026thinsp;0.0055).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eBinary logistic regression of variables against acute phase reactions development.\u003c/b\u003e Abbreviations \u0026ndash; OR, odds ratio; IV, intravenous; ZA, zoledronic acid; BMI, body mass index\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse reaction IV ZA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStd. err.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP \u0026gt; |z|\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e95% confidence interval of OR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eReference BMI low/normal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI obese\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.8211875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.2678006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.4333649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.556076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFrac to first disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eReference\u0026thinsp;=\u0026thinsp;1\u0026ndash;3 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u0026ndash;6 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6254871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.237505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.303528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.288955\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7 months +\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3195978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1249464\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.1485345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.68767\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious antiresorptive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eReference\u0026thinsp;=\u0026thinsp;no\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7604142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.262267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.386786\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.494961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of allergic reaction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eReference\u0026thinsp;=\u0026thinsp;no\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.372141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.409117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.7649006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.461459\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRisk factors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eReference\u0026thinsp;=\u0026thinsp;None or 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2+\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5263922\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1768465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.2724834\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.016901\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e_cons\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.977813\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.8238941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.8741816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.47475\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eLog likelihood \u0026minus;\u0026thinsp;135.55488\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNumber of observations\u0026thinsp;=\u0026thinsp;212\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eLR chi2(6)\u0026thinsp;=\u0026thinsp;15.94\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003ePron\u0026thinsp;\u0026gt;\u0026thinsp;chi2\u0026thinsp;=\u0026thinsp;0.0141\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003ePseudo R2\u0026thinsp;=\u0026thinsp;0.0555\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients who received IV ZA within 1\u0026ndash;3 months post-fracture were 3.3 times more likely to develop an APR compared to those treated after 7 months (p\u0026thinsp;=\u0026thinsp;0.002). Those treated within 4\u0026ndash;6 months also had an elevated risk (OR 2.0, p\u0026thinsp;=\u0026thinsp;0.035)\u003c/p\u003e \u003cp\u003eThe percentage change in BMD from baseline to one-year post treatment were assessed using Kruskal-Wallis H test, revealing no significant differences in BMD percentage change across three time intervals of when IV ZA was administered post fracture (1\u0026ndash;3 months; 4\u0026ndash;6 months; \u0026gt;7 months) at the total left hip (p\u0026thinsp;=\u0026thinsp;0.4), total right hip (p\u0026thinsp;=\u0026thinsp;0.5), lumbar spine (p\u0026thinsp;=\u0026thinsp;0.7) or radius (p\u0026thinsp;=\u0026thinsp;0.3). A significant change was determined as a change in BMD of 0.05g/cm2 or a 4% or more difference at the measured bone sites over a 1 year period.\u003c/p\u003e \u003cp\u003eTo assess factors associated with APR development, binary logistic regression was performed, incorporating the following predictors: BMI, prior use of antiresorptive therapy, history of allergic drug reactions, comorbidities (chronic kidney disease, liver disease), and time from fracture to first IV ZOL administration. The overall model was statistically significant (p\u0026thinsp;=\u0026thinsp;0.0141), but individual predictors varied in significance when adjusted for covariates. A parsimonious model was derived using stepwise backward elimination and log-likelihood ratio testing.\u003c/p\u003e \u003cp\u003eIn the final model (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), shorter time from fracture to ZOL infusion was independently associated with increased odds of APR. Patients who received ZOL within 1\u0026ndash;3 months post-fracture were 3.3 times more likely to develop an APR compared to those treated after 7 months (p\u0026thinsp;=\u0026thinsp;0.002). Those treated within 4\u0026ndash;6 months also had higher odds (OR 2.0, p\u0026thinsp;=\u0026thinsp;0.035).\u003c/p\u003e \u003cp\u003eBone mineral density (BMD) changes from baseline to one-year post-treatment was also assessed, stratified by time from fracture to ZOL initiation. A Kruskal-Wallis H test revealed no significant differences in BMD percentage change across the three-time intervals (1\u0026ndash;3 months; 4\u0026ndash;6 months; \u0026ge;7 months) at the total left hip (p\u0026thinsp;=\u0026thinsp;0.4), total right hip (p\u0026thinsp;=\u0026thinsp;0.5), lumbar spine (p\u0026thinsp;=\u0026thinsp;0.7), or radius (p\u0026thinsp;=\u0026thinsp;0.3).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAmong the 212 patients who received IV ZA at Gosford and Wyong Hospital during the period of May 2018 to May 2022, 41% experienced APRs, predominantly in the form of flu-like symptoms. Those who received IV ZA within 1\u0026ndash;3 months of fracture onset were found to be more likely to develop APRs. Most APRs last 1\u0026ndash;3 days, however 21% were found to persist for over 1 week, with 15% resulting in a period of immobility. Despite this, 83% of patients who experienced APRs continued IV ZA. Notably timing of IV ZA administration did not influence changes in BMD at 1 year post treatment.\u003c/p\u003e \u003cp\u003eThe biological correlation between IV ZA and APRs is thought to occur as a result of activation of the immune system through induction of inflammatory marker expression, specifically tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL‐6), interferon-gamma (IFN‐γ) and interleukin-1 beta (IL‐1β)\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The cytokine surge post bisphosphonate administration provides biological plausibility for the increased APRs observed, especially in patients administered IV ZA early post-fracture, a period associated with heightened systemic inflammatory responses and immune activation\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eConsistent with findings from larger clinical trials\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, we observed a relatively high rate of APRs in patients who received IV ZA, particularly following first infusions. However, our findings suggest an influence of timing of IV ZA post fracture on rates of APRs. This is a post hoc observation, and it should be acknowledged that our study was not designed to review this specific hypothesis.\u003c/p\u003e \u003cp\u003eThese results raise important clinical consideration for timing of bisphosphonate initiation after fracture onset. Prior studies\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e have demonstrated that early zoledronic acid treatment \u0026ndash; particularly between 2 weeks and 3 months following fracture onset - has been associated with reduction in rates of new clinical fractures and BMD scores. As such, early administration of bisphosphonates is encouraged for secondary fracture prevention. However, the occurrence of APRs raises the risk of non-adherence to osteoporosis treatment, thereby reducing effectiveness of osteoporosis therapy and increased healthcare burden. The consideration of reducing APR risks may positively affect adherence and patient satisfaction, particularly in the frail and elderly populations\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur findings that early IV ZA administration may increase risk of APRs must be weighed against evidence that supports early intervention. High APR rates following inpatient administration of IV ZA post-fracture have been observed, highlighting that timing and setting may influence side effect profiles\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.Strategies to mitigate APR risk that have been explored, such as appropriate patient education and pre-medication protocols\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, which should be considered to optimise adherence and outcomes.\u003c/p\u003e \u003cp\u003eThis study draws on real life clinical data across two regional hospital sites, providing insights into the practical application of IV ZA in a heterogenous patient population. The inclusion of data on treatment adherence following APRs also provides valuable information on patient counselling and clinical decisions.\u003c/p\u003e \u003cp\u003eHowever, there are several limitations of our study that should be acknowledged. Firstly, the retrospective cohort study design limits the ability to establish causality between IV ZA timing and occurrence of APRs. Secondary, as our study is reliant on retrospective chart review and patient reports, there is susceptibility of recall bias and no consistent measure of nature or severity of patient\u0026rsquo;s acute phase reactions. Thirdly, due to our modest sample size, there is limitations in its power to detect smaller BMD differences based on treatment timing.\u003c/p\u003e \u003cp\u003eIn summary, our study demonstrates that APRs are a common occurrence following IV ZA administration, particularly in patients treated at an earlier time frame post fracture onset. Whilst early IV ZA administration remains important for reducing refracture risk and improving BMD, there is potential impact of APRs on patient adherence that should be considered. Prospective studies specifically designed to investigate the relationship between fracture timing, systemic inflammation, APR risk following bisphosphonate administration is warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis retrospective study highlights the potential for delayed administration of zoledronic acid to reduce APRs; however, this post-hoc findings warrants further investigations with larger, more controlled studies. The timing of infusion should be balanced with the need to provide effective re-fracture prevention. Future larger scale research should focus on optimising treatment protocols to minimise APRs whilst maximising bone protective benefits of IV ZA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ezoledronic acid (ZA), acute phase reactions (APRs), intravenous (IV), bone mineral density (BMD),\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eOsteoporosis Re-fracture Prevention clinic (ORPC), body mass index (BMI)\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Northern Sydney Local Health District Human Research and Ethics Committee (Reference Number: PID01587) and conducted in accordance with the Declaration of Helsinki\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Northern Sydney Local Health District Human Research and Ethics Committee (Reference Number: PID01587). The requirement for individual informed consent was waived by the committee due to the retrospective nature of the audit and minimal risk to participants. All data was de-identified prior to analysis and no identifiable information was used or published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to privacy concerns but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study design. SG collected the data. TJ and FJ contributed to data analysis and interpretation. SG drafted the initial manuscript, which TJ and FJ revised. All authors contributed to the critical review of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDhillon S. Zoledronic acid (Reclast\u0026reg;, Aclasta\u0026reg;): a review in osteoporosis. Drugs. 2016;76(17):1683\u0026ndash;97.\u003c/li\u003e\n\u003cli\u003eTherapeutic Goods Administration. Australian public assessment report for zoledronic acid [Internet]. Woden (AU): Therapeutic Goods Administration; 2011 [cited 2022 Apr 16]. Available from: https://www.tga.gov.au/sites/default/files/auspar-aclasta.pdf\u003c/li\u003e\n\u003cli\u003eLambrinoudaki I, Vlachou S, Galapi F, Papadimitriou D, Papadias K. Once-yearly zoledronic acid in the prevention of osteoporotic bone fractures in postmenopausal women. Clin Interv Aging. 2008;3:445\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eBlack D, Delmas P, Eastell R, Reid I. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809\u0026ndash;22. \u003c/li\u003e\n\u003cli\u003eLyles K, Col\u0026oacute;n-Emeric C, Magaziner J, Adachi J, Pieper C, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357(18):1799\u0026ndash;809. \u003c/li\u003e\n\u003cli\u003eKotian P, Boloor A, Sreenivasan S. Study of adverse effect profile of parenteral zoledronic acid in female patients with osteoporosis. J Clin Diagn Res. 2016; 10(1). \u003c/li\u003e\n\u003cli\u003eLopez L, Cacheda A, Salman-Monte T, Padr\u0026ograve; I, Ciria M, Blanch-Rubi\u0026oacute; J. Side effects associated with the use of zoledronic acid. Ann Rheum Dis. 2013;71(3):697.3\u0026ndash;697.\u003c/li\u003e\n\u003cli\u003eElsalem L, Basheer H, Alshoh A, Abu-Aqoulah A, Alsa\u0026apos;di H, Bayyari S, et al. Study of adverse effect profile of zoledronic acid infusion among patients with cancer: a retrospective analysis. Int J Cancer Manag. 2020;13(10).\u003c/li\u003e\n\u003cli\u003eReid I, Gamble G, Mesenbrink P, Lakatos P, Black D. Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab. 2010;95(9):4380\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eStopeck A, Lipton A, Campbell-Baird C, von Moos R, Fan M, Haddock B, et al. Abstract P6-14-09: Acute-phase reactions following treatment with zoledronic acid or denosumab: results from a randomized, controlled phase 3 study in patients with breast cancer and bone metastases. Cancer Res. 2010;70(24 Suppl). doi:10.1158/0008-5472.sabcs10-p6-14-09\u003c/li\u003e\n\u003cli\u003eSp\u0026aring;ngeus A, Johansson S, Woisetschl\u0026auml;ger M. Adherence to and persistence with zoledronic acid treatment for osteoporosis\u0026mdash;reasons for early discontinuation. Arch Osteoporos. 2020;15(1):58.\u003c/li\u003e\n\u003cli\u003eEastell R, Black DM, Boonen S, Adami S, Felsenberg D, Lippuner K, et al. Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. Obstet Gynecol Surv. 2010;65(3):177\u0026ndash;8. doi:10.1097/01.ogx.0000369680.41957.f9\u003c/li\u003e\n\u003cli\u003eChen D. Characterization and risk factors of acute-phase response following a first-dose administration of zoledronic acid for treatment of osteoporosis. Bone Abstr. 2013. doi:10.1530/boneabs.1.pp396\u003c/li\u003e\n\u003cli\u003eReid I, Horne A, Mihov B et al. Effects of Zoledronic on Cancer, Cardiac Events, and Mortality in Osteopenic Older Women. Journal of Bone Mineral Research. 2020 Jan; 35(1):20-27\u003c/li\u003e\n\u003cli\u003eReid I, Horne A, Mihov B et al. Fracture Prevention with Zoledronate in Older Women with Osteopenia. NEJM. 2018 Oct; 379: 2407-2416\u003c/li\u003e\n\u003cli\u003eLi Y-T, Cai H-F, Zhang Z-L. Timing of the initiation of bisphosphonates after surgery for fracture healing: A systematic review and meta-analysis of randomized controlled trials. Osteoporosis International. 2014;26(2):431\u0026ndash;41. doi:10.1007/s00198-014-2903-2 \u003c/li\u003e\n\u003cli\u003eShiraki M, Kuroda T, Takeuchi Y, Sugimoto T, Tanaka S, Suzuki H, et al. Acute phase reactions after intravenous infusion of zoledronic acid in Japanese patients with osteoporosis: Sub-analyses of the Phase III Zone Study. Calcified Tissue International. 2021;109(6):666\u0026ndash;74. doi:10.1007/s00223-021-00884-7 \u003c/li\u003e\n\u003cli\u003eFan WQ, Sun X, Leder BZ et al. Zoledronic acid for hip fracture during initial hospitalisation. Journal of Bone Mineral Search. 2024 Aug 21; 39(8):1061-70\u003c/li\u003e\n\u003cli\u003eChen C, Yeap EK, Hsu C et al. Novel combined pharmacological strategy to alleviate acute phase response following zoledronic acid treatment. Arch Osteoporosis. 2024 Oct 15; 19(1): 97\u003c/li\u003e\n\u003cli\u003eChen FP, Fu TS, Lin YC et al. Addition of dexamethasone to manage acute phase responses following initial zoledronic acid infusion. Osteoporosis International. 2021 Apr; 32(4):663-670\u003c/li\u003e\n\u003cli\u003eTakimoto R, Suzawa T, Yamada A et al. Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in presence of \u0026gamma;\u0026delta; T cells. Immunology. 2021 Mar; 162(3): 306-313\u003c/li\u003e\n\u003cli\u003eEvans AR, Giannoudis PV, Leucht P et al. The local and systemic effects of immune function on fracture healing. OTA Int. 2024 Mar 11; 7(2 Suppl)\u003c/li\u003e\n\u003cli\u003eWorld Medical Association. \u003cem\u003eWorld Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects\u003c/em\u003e. JAMA. 2013;310(20):2191\u0026ndash;4.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"acute phase reactions, osteoporosis, zoledronic acid, bone mineral density","lastPublishedDoi":"10.21203/rs.3.rs-6650236/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6650236/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntravenous Zoledronic Acid (IV ZA) is a third-generation bisphosphonates used for osteoporosis with once-yearly administration demonstrating benefits in improvement of bone mineral density and fracture risk reduction. However, acute phase reactions (APRs) pose challenges, often leading to treatment discontinuation. This study aims to assess APR incidence in osteoporotic patients who received IV ZA and associated risk factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective review of all patients aged over 50 years receiving IV ZA between the periods of May 2018 and May 2022 across Gosford and Wyong Hospitals, in NSW, Australia. Data on demographics, comorbidities, and adverse reactions were collected from electronic medical records. Logistic regression analysed associations between variables and APRs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 212 patients receiving IV ZA, 41% experienced APRs, predominantly in the form of flu-like symptoms. Patients starting IV ZA within 1–3 months of fracture onset were significantly more likely to develop APRs. Most APRs lasted 1–3 days, but 21% persisted over 1 week, with 15% resulting in a period of patient immobility. Despite APRs, 83% continued ZA treatment. Timing of ZA from fracture onset did not affect BMD improvement at 1 year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study highlights a higher APR risk with earlier ZA initiation from fracture onset. Notably, there are no significant BMD differences observed based on ZA timing at 1 year. In conclusion, early initiation of IV ZA post-fracture increased APR risk without affecting BMD outcomes, emphasising need for further prospective trials to optimise treatment protocols to reduce risk of APRs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial number: \u003c/strong\u003enot applicable\u003c/p\u003e","manuscriptTitle":"Acute Phase Reactions in Osteoporotic Patients receiving Intravenous Zoledronic Acid: A Multi-Centre Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-20 15:56:02","doi":"10.21203/rs.3.rs-6650236/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-06-29T13:57:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102953941813096048145474577276365614857","date":"2025-06-25T16:15:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284512594685922476496743355799078326455","date":"2025-06-25T15:50:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-18T13:31:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-16T16:11:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-15T14:34:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-15T14:31:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2025-05-13T01:09:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6dcf8661-ac86-4e1c-b609-7f1c445e00b9","owner":[],"postedDate":"June 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-06-20T15:56:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-20 15:56:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6650236","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6650236","identity":"rs-6650236","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}