Antiresorptive Therapy Use in Patients with Skeletal Metastases – Are We Under Prescribing?

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Patrick M. Mazza, Andrew Binder, Susana Coto, Adam S. Levin, Eric R. Henderson This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8913561/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Purpose: Antiresorptive therapy (AT) reduces risk of pathologic fractures (PF) in patients with osseous metastases (OM). Recent data show AT is prescribed to only 7.7% of patients with OM, suggesting under-prescription. This study aims to determine rates of AT use and PF in patients with OM using Epic’s comprehensive, practice-based database “COSMOS,” and to identify patient factors associated with AT use and PF. Methods: A retrospective review was conducted using “COSMOS” to identify patients diagnosed with OM from January 2005 to July 2022 with minimum two-year follow-up. Cox proportional hazards regression models were used to identify factors associated with AT use and risk of PF. Results: Of 678,073 patients included, AT was prescribed for 13.9%. 10.8% sustained PF, of whom 17.38% received AT before or after fracture and 82.6% never received AT. Age 25–34 and primary lymphoma patients were less likely to receive AT (p <.001). Risk of PF was higher for age 25–34 (HR 2.00, p <0.001), primary renal cancer and multiple myeloma (HRs 1.75 and 1.70, p <0.001), and lower for males (HR .89, p <.001) and primary prostate cancer (HR .69, p <.001). Modeling suggests that up to 35.5% of fractures may be preventable through universal use of AT. Conclusions: AT is prescribed at a lower-than-expected rate given its known efficacy in reducing PF risk in patients with OM. Younger age, female gender, primary renal cancer and multiple myeloma are associated with increased fracture risk, with implications for optimizing patient selection for AT. Antiresorptive medications Bisphosphonates Osseous metastasis Pathologic fracture Highlights • Antiresorptive therapy (AT) is prescribed at a lower-than-expected rate (14%; 7.7% in prior study) • The rate of pathologic fracture (PF) in patients with osseous metastasis is 10.8% • Younger patients and those with primary kidney cancer and multiple myeloma are at highest risk of PF • 35.5% of fractures may be preventable under universal treatment with AT 1. INTRODUCTION Osseous metastases are common sequelae of malignancy and incur substantial morbidity through skeletal-related events (SREs), including pathologic fractures, spinal cord compression, and the need for radiation and/or surgical stabilization [ 1 , 2 ]. Pathologic fractures are particularly consequential, often resulting in pain, loss of mobility, increased healthcare utilization, and reduced survival [ 3 , 4 ]. From an orthopedic oncology and supportive care standpoint, fracture prevention and early risk recognition are key opportunities to reduce mortality associated with metastatic bone disease. Antiresorptive therapies, including bisphosphonates and denosumab, are used to reduce osteoclast-mediated bone resorption and have demonstrated efficacy in decreasing skeletal-related events in patients with metastatic bone disease [ 1 , 5 , 6 ]. Translating these benefits into routine clinical practice depends on whether therapy is prescribed and when therapy is initiated following diagnosis. In real-world clinical practice, supportive therapies may be delayed due to factors such as care coordination challenges, uncertainty regarding prescribing responsibility, or competing clinical priorities [ 1 ]. Recent studies have raised concern that antiresorptive therapy may be underutilized among patients with osseous metastases, reporting low treatment rates within two years of diagnosis [ 7 ]. However, claims-based analyses may be sensitive to outpatient medication capture, insurance-driven utilization patterns, and other data artifacts that may not reflect prescribing behavior across broader health system settings [ 7 , 8 ]. Further study is warranted using a large, practice-derived electronic health record dataset, which may better characterize contemporary utilization patterns and provide further information on timing and patient factors associated with antiresorptive therapy use. Accordingly, we performed a retrospective cohort study using “COSMOS”, a large multi-institutional Epic-based electronic health record database, to evaluate use of antiresorptive therapy among patients with newly diagnosed osseous metastasis. Our primary objectives were (1) to evaluate the incidence of antiresorptive therapy initiation in patients with a new diagnosis of osseous metastatic disease, and (2) to evaluate the rate of pathologic fracture within two years of diagnosis. Secondary objectives were (1) to identify patient factors associated with antiresorptive therapy initiation and with risk of pathologic fracture, with the goal of informing future supportive-care and fracture-prevention strategies in this population, and (2) to estimate the percentage of pathologic fractures that may be preventable in this population with more widespread use of antiresorptive therapy. We hypothesized that antiresorptive therapy would prove to be under-prescribed in patients with osseous metastasis, highlighting an opportunity for clinical initiatives aimed at reducing the rate of pathologic fracture by prescribing therapy at a higher rate to appropriate patients. 2. METHODS 2.1 Patient selection Patients with a new diagnosis of osseous metastasis from January 2005 and July 2022 were retrospectively identified in the Epic-based COSMOS database. COSMOS is a large, de-identified, aggregated electronic health record (EHR) dataset derived from participating health systems using the Epic platform and includes routine, longitudinal clinical data such as diagnoses, medications, procedures, and encounter information across inpatient and outpatient settings [9]. Because COSMOS data is completely de-identified, study data is classified as non-human and Institutional Review Board (IRB) approval was not required. As our primary endpoints were to evaluate incidence of antiresorptive therapy use and pathologic fracture within two years of diagnosis of osseous metastasis, we collected the following data: 1) date of osseous metastasis diagnosis; 2) prescribing of antiresorptive therapy; 3) timing of antiresorptive therapy with respect to osseous metastasis diagnosis; 4) occurrence of pathologic fracture; 5) timing of pathologic fracture with respect to diagnosis. We defined antiresorptive medications as denosumab and the bisphosphonates class of drugs (Table S1). As our secondary endpoints were to identify potential factors associated with receiving antiresorptive therapies and with the risk of sustaining a pathologic fracture, we also collected the following data: 1) patient demographic data (age and sex); 2) history of diagnoses of the following primary cancer types (previous to the diagnosis of the osseous metastasis): breast, prostate, kidney, lung, lymphoma, multiple myeloma and thyroid. Sex was categorized as Female/Not female, while age was divided into the groups <25, 25-34, 35-44, 45-54, 55-64, 65-74 and +75 years. International Classification of Diseases ninth and tenth edition (ICD 9 and 10) codes were used to query all diagnoses (Table S2). These were treated as binary variables, with a ‘Yes’ value if the patient had the corresponding code recorded and ‘No’, otherwise. Patients with less than two years of follow-up after the osseous metastasis diagnosis were excluded. We also excluded patients who sustained a pathologic fracture before this diagnosis date and those with invalid values for any of the variables collected. 2.2 Statistical analysis Age, sex and primary cancer type variables were described by their absolute and relative frequencies. In order to address our primary objectives, we first calculated the prescription rate of antiresorptive therapies as the quotient between the number of patients who received a prescription and the total patients diagnosed with osseous metastasis. The median time (interquartile range, IQR) elapsed between the date of this diagnosis and the start of the prescription was also reported. Second, we calculated the rate of pathologic fractures within two years of diagnosis as the quotient between patients sustaining a pathologic fracture and the number of patients diagnosed with osseous metastasis. The rate of pathologic fractures is further specified differentiating between patients receiving antiresorptive therapies before the pathologic fracture, after experiencing it, and those who did not receive such therapies. We also reported the median time (IQR) elapsed from the osseous metastasis diagnosis to the date of the first diagnosis of a pathologic fracture. Our secondary objective was addressed by fitting separate Cox proportional hazards (PH) regression models. To assess the variables associated with the risk of being prescribed antiresorptive therapies within two years of osseous metastasis, we first fitted a multivariable model including age, sex and primary cancer type as risk factors. Patients younger than 25 years, female gender, and those without a prior diagnosis of the corresponding primary cancer type were considered as reference categories for each factor. In addition to these variables and aiming to assess the risk of sustaining a pathologic fracture, we included the timing of the initial prescription of antiresorptive therapies as a time-dependent risk factor, in a second multivariable PH regression model. Univariate models were also fitted to evaluate individual associations for the considered factors with both risks: being prescribed antiresorptive therapies and sustain pathologic fracture. Unadjusted (univariate case) and adjusted (multivariable case) hazard ratios together with confidence intervals at 95% confidence level were provided in both cases. All statistical analysis was performed using the R software (https://cran.r-project.org). 2.3 Estimation of Preventable Fractures - Methodology We estimated the proportion of potentially preventable pathologic fractures using a potential impact fraction (PIF) approach, which quantifies the proportional change in outcome under a hypothetical shift in exposure prevalence [10-12]. Using data from the COSMOS cohort, the outcome was defined as pathologic fracture within two years of diagnosis, and the exposure was receipt of antiresorptive therapy (AT) within two-years of diagnosis. We modeled a counterfactual scenario in which 100% of patients received AT within two years ( P′ = 1.00). For a binary exposure to AT, PIF was calculated as: PIF = [( P′ − P ) × (1 − RR )] / [(1 − P ) + P × RR ], where P is the observed prevalence of AT in the cohort, P′ is the modeled prevalence under the counterfactual scenario, and RR is the risk ratio for pathologic fracture among treated versus untreated patients. [10-12]. The number of potentially preventable fractures was then calculated as Preventable fractures = F × PIF , where F represents the observed number of fractures within two years. The RR for fracture associated with AT was derived from a network meta-analysis of randomized trials comparing specific anti-resorptive agents versus placebo in patients with metastatic bone disease. To provide a conservative estimate, we used the reported relative risk reduction of 39% for zoledronate ( RR = 0.61) [12]. 3. RESULTS 3.1 Cohort Selection and Characteristics Of 725,869 patients with a diagnosis of osseous metastasis identified in COSMOS between January 2005 and July 2022, 678,073 met inclusion criteria above and were included in the final analytic cohort. The cohort was heterogeneous with respect to age, sex, and primary cancer type, which is expected given that COSMOS is representative of United Stated census data [9]. The largest age groups were 65–74 years and ≥75 years, and lung, lymphoma, breast, and prostate cancers comprised the majority of primary malignancies (Table 1). Table 1. Absolute and relative frequencies for categorized age, gender and primary cancer type CHARACTERISTIC (N = 678,073) Relative Frequency Absolute Frequency Age 75 29.95 203,068 Sex Female 45.36 307,546 Not female 54.64 370,527 Primary cancer type Breast 20.02 135,732 Prostate 21.01 142,461 Kidney 4.79 32,505 Lung 24.52 166,256 Lymphoma 32.22 218,494 Multiple Myeloma 3.01 20,431 Thyroid 1.24 8,388 3.2 Incidence and Timing Antiresorptive therapy was prescribed within two years of osseous metastasis diagnosis for 94,860 patients (13.99%). Among treated patients, the median time to therapy initiation was 40 days after diagnosis of skeletal metastasis (IQR 8–146 days). A total of 72,910 patients (10.75%) sustained a pathologic fracture within two years of diagnosis. Of these, 4,734 (6.49%) received antiresorptive therapy prior to fracture, 7,937 (10.89%) initiated therapy after fracture, and 60,239 (82.62%) never received therapy. The median time from diagnosis to fracture was 5 days (IQR 0–96 days). 3.3 Factors Associated with AT initiation On multivariable analysis, older age, female sex, and primary breast or prostate cancer were associated with higher likelihood of therapy initiation, whereas patients with lymphoma were less likely to receive therapy (Table 2). Table 2. Factors associated with receiving an antiresorptive therapy prescription within two years of osseous metastasis diagnosis (unadjusted and adjusted hazard ratios and 95 % C.I.) CHARACTERISTIC Unadjusted HR p-value Adjusted HR p-value Age < 25 Ref. Ref. 25 -34 5.85 (4.93, 6.95) <0.001 3.99 (3.36, 4.74) <0.001 35 - 44 7.55 (6.41, 8.89) <0.001 4.49 (3.81, 5.29) <0.001 45 -54 7.11 (6.05, 8.36) <0.001 4.53 (3.86, 5.33) <0.001 55 - 64 6.99 (5.95, 8.20) <0.001 4.75 (4.04, 5.57) <0.001 65 - 74 7.39 (6.29, 8.67) <0.001 4.95 (4.22, 5.82) 75 6.91 (5.89, 8.11) <0.001 4.41 (3.76, 5.18) <0.001 Sex Female Ref. Ref. Not female 0.70 (0.69, 0.71) <0.001 0.77 (0.75, 0.78) <0.001 Primary cancer type Breast - No Ref. Ref. - Yes 2.23 (2.22, 22.26) <0.001 2.43 (2.39, 2.48) <0.001 Prostate - No Ref. Ref. - Yes 1.34 (1.32, 1.36) <0.001 2.14 (2.10, 2.19) <0.001 Kidney - No Ref. Ref. - Yes 0.9 (0.87, 0.93) <0.001 1.25 (1.21, 1.29) <0.001 Lung - No Ref. Ref. - Yes 0.69 (0.68, 0.71) <0.001 1.02 (1.00, 1.04) 0.040 Lymphoma - No Ref. Ref. - Yes 0.84 (0.83, 0.85) <0.001 0.92 (0.90, 0.93) <0.001 Multiple Myeloma - No Ref. Ref. - Yes 1.23 (1.19, 1.27) <0.001 1.63 (1.57, 1.69) <0.001 Thyroid - No Ref. Ref. - Yes 0.89 (0.84, 0.94) <0.001 1.06 (1.00, 1.13) 0.044 3.4 Factors Associated with Pathological Fracture Younger age, primary kidney cancer, and multiple myeloma were independently associated with increased fracture risk, whereas male sex and primary prostate cancer were associated with lower fracture risk. Receipt of antiresorptive therapy was associated with a higher observed hazard of fracture (Table 3). Table 3. Factors associated with sustaining a PF within two years of follow-up after a new OM diagnosis (unadjusted and adjusted hazard ratios and 95 % C.I.): CHARACTERISTIC Unadjusted HR p-value Adjusted HR p-value Age < 25 Ref. Ref. 25 -34 1.92 (1.71, 2.15) <0.001 2.00 (1.73, 2.30) <0.001 35 - 44 1.97 (1.78, 2.18) <0.001 1.93 (1.70, 2.20) <0.001 45 -54 2.04 (1.85, 2.25) <0.001 1.94 (1.72, 2.19) <0.001 55 - 64 2.01 (1.83, 2.21) <0.001 1.86 (1.65, 2.10) <0.001 65 - 74 1.77 (1.61, 1.95) <0.001 1.63 (1.45, 1.84) 75 1.53 (1.39, 1.68) <0.001 1.30 (1.15, 1.46) <0.001 Sex Female Ref. Ref. Not female 0.82 (0.80, 0.83) <0.001 0.89 (0.86, 0.91) <0.001 Primary cancer type Breast - No Ref. Ref. - Yes 0.98 (0.96, 0.99) 0.012 0.86 (0.83, 0.89) <0.001 Prostate - No Ref. Ref. - Yes 0.55 (0.54, 0.56) <0.001 0.69 (0.67, 0.72) <0.001 Kidney - No Ref. Ref. - Yes 1.75 (1.70, 1.79) <0.001 1.75 (1.69,1.82) <0.001 Lung - No Ref. Ref. - Yes 1.10 (1.08, 1.12) <0.001 0.92 (0.89, 0.94) 0.040 Lymphoma - No Ref. Ref. - Yes 1.20 (1.18, 1.22) <0.001 0.98 (0.96, 1.00) 0.026 Multiple Myeloma - No Ref. Ref. - Yes 1.99 (1.93, 2.05) <0.001 1.70 (1.62, 1.78) <0.001 Thyroid - No Ref. Ref. - Yes 1.02 (0.95, 1.09) 0.594 1.10 (1.02, 1.20) 0.021 Received AT - No - Yes 1.34 (1.30, 1.38) <0.001 1.37 (1.32, 1.41) <0.001 3.5. Estimation of Preventable Fractures – Calculations A total of 72,910 patients (10.75%) sustained a pathologic fracture within two years of diagnosis. Using the standard PIF formulation for a binary protective exposure with P = 0.1399 (13.99% received AT within two years), P′ = 1.00, and RR = 0.61 ( RRR = 0.39), the PIF was: PIF = [(1.00 − 0.1399) × (1 − 0.61)] / [(1 − 0.1399) + (0.1399 × 0.61)] = 0.355 (35.5%). Therefore, the estimated number of potentially preventable fractures over two years under universal AT use within the follow-up period was: 72,910 × 0.355 = 25,868 fractures. The absolute reduction in fractures per 1,000 patients was: 25,868 / 678,073 × 1000 = 38.1 fractures prevented per 1,000 patients with osseous metastasis. 4. DISCUSSION In this large practice-based electronic health record cohort, antiresorptive therapy was prescribed in 13.99% of patients with osseous metastatic disease. Although utilization was higher than prior claims-based reports (7.7%), this rate appears modest relative to FDA-approved indications for denosumab and zoledronic acid for prevention of skeletal-related events in patients with metastatic bone disease and multiple myeloma [ 7 , 14 , 15 ]. We could not determine the exact proportion of patients who would be appropriate candidates for therapy in this dataset because COSMOS does not uniformly capture key clinical factors that influence eligibility and prescribing (e.g., renal function, baseline calcium/vitamin D status, dental risk, prognosis, and goals of care) [ 1 , 9 , 14 , 15 ]. Using a potential impact fraction modeling approach [ 8 , 10 , 11 ], we estimated that approximately 25,868 of the total 72,910 pathologic fractures in this cohort (35.5%) could potentially have been prevented over two years if antiresorptive therapy (specifically zoledronate or denosumab) [ 13 ] had been used universally in this population. Because COSMOS does not allow us to identify with confidence which patients met clinical eligibility criteria, we used a universal-treatment scenario to approximate the upper bound of potentially preventable fractures, while recognizing that universal therapy would not be clinically appropriate for all patients [ 1 , 14 , 15 ]. This estimate assumes immediate antiresorptive therapy treatment effect and therapy utilization in 100% of patients with osseous metastasis, and therefore likely overstates real-world benefit given biologic lag as well as clinical contraindications and logistical barriers to prescribing AT in certain patients. Additionally, it is important to note that the model for estimating the number of preventable fractures used in this study was based on use of zoledronate specifically, given that the meta-analysis of randomized trials comparing AT to placebo in this patient population showed zoledronate to have the more conservative pathologic fracture RRR (.39) compared to denosumab (.5) and other bisphosphonates (no effect) [ 13 ]. Despite the known limitations of this statistical modeling, clinical value remains in considering 35.5% as a potential upper end for the proportion of fractures that are preventable under a hypothetical scenario of universal-treatment, recognizing that most fractures in this study occurred early after diagnosis and therefore in real-world practice effective prevention would require near-immediate initiation of therapy following diagnosis. From a clinical perspective, these findings suggest a potential gap in supportive oncologic care. Additionally, the early occurrence of fractures following diagnosis (median 5 days) indicates that delays in care coordination, uncertainty regarding prescribing responsibility, or pre-treatment requirements may cause patients to miss the narrow window whereby they can benefit from antiresorptive therapy and underscores the timely administration of these medications [ 1 ]. Identification of high-risk patient subsets, particularly younger patients (specifically < 64) and those with primary kidney cancer or multiple myeloma based on the findings in this study, may enable earlier intervention and improved fracture prevention. A key finding of this study is the marked temporal mismatch between fracture occurrence and therapy initiation. Pathologic fractures occurred very early following diagnosis of osseous metastasis (median 5 days), whereas antiresorptive therapy was typically initiated later (median 40 days). This pattern suggests that fractures frequently precede initiation of supportive therapy, indicating that antiresorptive treatment is often reactive rather than preventive in real-world practice. This again may represent an opportunity for the multidisciplinary care team involved in managing these complex patients to recognize the significant risk of pathologic fracture immediately upon diagnosis of osseous metastatic disease and to prioritize early, proactive initiation of antiresorptive therapy in an effort to decrease the rate of highly morbid fracture events. Additionally, although receipt of antiresorptive therapy was associated with a higher observed hazard of pathologic fracture in this study, this is unlikely to be due to a harmful effect of therapy given the known efficacy of these medications in reducing risk of pathologic fracture [ 1 , 5 , 6 , 13 ]. Rather, it likely reflects reverse temporal sequencing inherent to observational analyses in which treatment initiation commonly follows fracture events. Because exposure was modeled as a time-fixed variable in this study (“ever received antiresorptive therapy”), patients who fractured early and were subsequently treated contributed to an apparent positive association between therapy and fracture risk. Several limitations warrant consideration. As a large, retrospective analysis of electronic health record data, this study is subject to potential misclassification related to diagnostic coding and medication capture, which may influence both fracture risk and treatment ascertainment. While we were able to capture objective data on prescribing trends, the large patient cohort (n = 678,073) and de-identified nature of the data in COSMOS prevented us from contacting patients or using manual chart review to confirm patients were actually taking the medications. COSMOS also does not uniformly capture disease severity, tumor burden, or functional status, factors that likely affect both fracture risk and clinical decision-making around therapy initiation. Additionally, as discussed, modeling antiresorptive therapy exposure as a time-fixed variable introduces potential for reverse causation and bias related to fractures occurring before therapy initiation, limiting causal inference. Next, AT was queried as a binary variable based on the assembled list of medications (Table S1), and we did not investigate the rates of utilization or fracture for each specific form of AT in the present study. This would be clinically valuable as an area for future investigation based on the known differential efficacies of the various forms of AT in the setting of osseous metastasis [ 13 ]. Finally, although COSMOS represents a large, multi-institutional dataset in the United States, prescribing practices and care pathways may differ across healthcare systems abroad, which may affect generalizability. In summary, in this large COSMOS-based cohort of patients with osseous metastatic disease, antiresorptive therapy was prescribed in 13.99% of patients. This suggests possible underutilization given the relatively broad FDA-approved indications for antiresorptive therapy use in the setting of metastatic bone disease [ 14 , 15 ]. Fractures frequently occurred shortly after diagnosis and often before therapy initiation, underscoring a narrow window for preventive intervention. Notably, modeling using a universal-treatment scenario suggests that up to 35.5% of pathologic fractures may be potentially preventable with antiresorptive therapy (zoledronate or denosumab), but this should be interpreted as an upper bound given biologic lag and contraindications to prescribing these medications in certain patients. Overall, the findings in this study highlight an opportunity to improve supportive oncologic care through more widespread, timely initiation of antiresorptive therapy in appropriately selected patients with osseous metastatic disease. Abbreviation AT = Antiresorptive therapy, PF= Pathologic fracture, OM = Osseous Metastasis, PIF = Population/Potential Impact Fraction Declarations Ethics approval, Consent to participate, Consent to publish This study used de-identified data from the Epic COSMOS database and was deemed exempt from full institutional review board (IRB) review. As such, no consent to participate or consent to publish is needed. Full institutional approval was obtained to proceed with this study and to utilize the data herein. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Competing interests The authors declare no competing financial interests or personal relationships that could have influenced this paper. Availability of data and materials The data that support the findings of this study are available from Epic COSMOS but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. Full institutional approval was obtained to proceed with this study and to utilize the data herein. CRediT authorship contribution statement Patrick Mazza: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Andrew Binder: Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization. Susana Coto: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Adam S. Levin: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. Eric R. Henderson: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. References Coleman RE, Hadji P, Body JJ, Santini D, Chow E, Terpos E, et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(12):1650–1663. doi:10.1016/j.annonc.2020.07.019 Ryan C, Stoltzfus KC, Horn S, Chen H, Louie AV, Lehrer EJ, Trifiletti DM, Fox EJ, Abraham JA, Zaorsky NG. Epidemiology of bone metastases. Bone. 2022;158:115783. doi:10.1016/j.bone.2020.115783 Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer. 2007;110(8):1860–1867. doi:10.1002/cncr.22991 von Moos R, Body JJ, Egerdie B, Stopeck A, Brown J, Fallowfield L, et al. Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases. Support Care Cancer. 2016;24(3):1327–1337. doi:10.1007/s00520-015-2908-1 Wajda BG, Ferrie LE, Abbott AG, Elmi Assadzadeh G, Monument MJ, Kendal JK. Denosumab vs. zoledronic acid for metastatic bone disease: a comprehensive systematic review and meta-analysis of randomized controlled trials. Cancers (Basel). 2025;17(3):388. doi:10.3390/cancers17030388 D'Oronzo S, Wood S, Brown JE. The use of bisphosphonates to treat skeletal complications in solid tumours. Bone. 2021;147:115907. doi:10.1016/j.bone.2021.115907 Agarwal AR, LiBrizzi CL, Wessel L, Thakkar SC, Levin AS. The low and disproportionate utilization of antiresorptive therapy in patients with osseous metastasis. J Bone Oncol. 2023;43:100507. doi:10.1016/j.jbo.2023.100507 Dahlen A, Charu V. Analysis of sampling bias in large health care claims databases. JAMA Netw Open. 2023;6(1):e2249804. doi:10.1001/jamanetworkopen.2022.49804 Epic Systems Corporation. COSMOS data platform overview. Verona, WI: Epic Systems Corporation; 2024. Available at: https://cosmos.epic.com. Accessed February 18, 2026. Askari M, Namayandeh SM. “The Difference between the Population Attributable Risk (PAR) and the Potential Impact Fraction (PIF).” Iran J Public Health . 2020;49(10):2018-2019. doi:10.18502/ijph.v49i10.4713. Rockhill B, Newman B, Weinberg C. Use and misuse of population attributable fractions. Am J Public Health. 1998;88(1):15–19. doi:10.2105/AJPH.88.1.15. Murray CJL, Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S. Comparative quantification of health risks: Conceptual framework and methodological issues. Lancet. 2003;362(9387):717–725. doi:10.1016/S0140-6736(03)14203-0. Wang Z, Qiao D, Lu Y, Curtis D, Wen X, Yao Y, Zhao H. Systematic literature review and network meta-analysis comparing bone-targeted agents for the prevention of skeletal-related events in cancer patients with bone metastasis. The Oncologist. 2015;20(4):440–449. doi:10.1634/theoncologist.2014-0328 U.S. Food and Drug Administration. Xgeva (denosumab) prescribing information. Silver Spring, MD: FDA. Accessed via Drugs@FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125320s168lbl.pdf. Accessed February 18, 2026. U.S. Food and Drug Administration. Zometa (zoledronic acid) prescribing information. Silver Spring, MD: FDA. Accessed via Drugs@FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021223s006lbl.pdf. Accessed February 18, 2026. Additional Declarations No competing interests reported. Supplementary Files SupplementarytablesS12SupportiveCareinCancer.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 06 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 11 Apr, 2026 Reviewers invited by journal 01 Apr, 2026 Editor assigned by journal 01 Apr, 2026 Submission checks completed at journal 26 Feb, 2026 First submitted to journal 18 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Mazza","email":"data:image/png;base64,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","orcid":"","institution":"Dartmouth-Hitchcock Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Patrick","middleName":"M.","lastName":"Mazza","suffix":""},{"id":617532719,"identity":"99ac87a1-00f8-42e2-b106-a517155a60c1","order_by":1,"name":"Andrew Binder","email":"","orcid":"","institution":"Dartmouth-Hitchcock Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Binder","suffix":""},{"id":617532720,"identity":"26905d67-3fae-4f53-8e2b-5d5bd680a503","order_by":2,"name":"Susana Coto","email":"","orcid":"","institution":"Dartmouth-Hitchcock Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Susana","middleName":"","lastName":"Coto","suffix":""},{"id":617532721,"identity":"77925a9f-b2a2-4051-8dd2-d46394723214","order_by":3,"name":"Adam S. Levin","email":"","orcid":"","institution":"Johns Hopkins Medicine","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"S.","lastName":"Levin","suffix":""},{"id":617532722,"identity":"a1a8a31f-1d33-4e36-86c8-180bec9b3ed5","order_by":4,"name":"Eric R. Henderson","email":"","orcid":"","institution":"Dartmouth-Hitchcock Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"R.","lastName":"Henderson","suffix":""}],"badges":[],"createdAt":"2026-02-19 03:39:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8913561/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8913561/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106403823,"identity":"86ae9cd8-462a-4e02-9366-a73c505ab7dc","added_by":"auto","created_at":"2026-04-08 09:15:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":879799,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8913561/v1/37e407af-bf2a-4997-afb2-065aeb9831f6.pdf"},{"id":106311153,"identity":"f92e7ea0-c36b-42b1-8528-4fcc944a5f78","added_by":"auto","created_at":"2026-04-07 10:28:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15060,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarytablesS12SupportiveCareinCancer.docx","url":"https://assets-eu.researchsquare.com/files/rs-8913561/v1/96c677e72f844ddd1e0042fb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Antiresorptive Therapy Use in Patients with Skeletal Metastases – Are We Under Prescribing?","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Antiresorptive therapy (AT) is prescribed at a lower-than-expected rate (14%; 7.7% in prior study)\u003c/p\u003e\u003cp\u003e\u0026bull; The rate of pathologic fracture (PF) in patients with osseous metastasis is 10.8%\u003c/p\u003e\u003cp\u003e\u0026bull; Younger patients and those with primary kidney cancer and multiple myeloma are at highest risk of PF\u003c/p\u003e\u003cp\u003e\u0026bull; 35.5% of fractures may be preventable under universal treatment with AT\u003c/p\u003e"},{"header":"1. INTRODUCTION","content":"\u003cp\u003eOsseous metastases are common sequelae of malignancy and incur substantial morbidity through skeletal-related events (SREs), including pathologic fractures, spinal cord compression, and the need for radiation and/or surgical stabilization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pathologic fractures are particularly consequential, often resulting in pain, loss of mobility, increased healthcare utilization, and reduced survival [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. From an orthopedic oncology and supportive care standpoint, fracture prevention and early risk recognition are key opportunities to reduce mortality associated with metastatic bone disease.\u003c/p\u003e \u003cp\u003eAntiresorptive therapies, including bisphosphonates and denosumab, are used to reduce osteoclast-mediated bone resorption and have demonstrated efficacy in decreasing skeletal-related events in patients with metastatic bone disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Translating these benefits into routine clinical practice depends on whether therapy is prescribed and when therapy is initiated following diagnosis. In real-world clinical practice, supportive therapies may be delayed due to factors such as care coordination challenges, uncertainty regarding prescribing responsibility, or competing clinical priorities [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have raised concern that antiresorptive therapy may be underutilized among patients with osseous metastases, reporting low treatment rates within two years of diagnosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, claims-based analyses may be sensitive to outpatient medication capture, insurance-driven utilization patterns, and other data artifacts that may not reflect prescribing behavior across broader health system settings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Further study is warranted using a large, practice-derived electronic health record dataset, which may better characterize contemporary utilization patterns and provide further information on timing and patient factors associated with antiresorptive therapy use.\u003c/p\u003e \u003cp\u003eAccordingly, we performed a retrospective cohort study using \u0026ldquo;COSMOS\u0026rdquo;, a large multi-institutional Epic-based electronic health record database, to evaluate use of antiresorptive therapy among patients with newly diagnosed osseous metastasis. Our primary objectives were (1) to evaluate the incidence of antiresorptive therapy initiation in patients with a new diagnosis of osseous metastatic disease, and (2) to evaluate the rate of pathologic fracture within two years of diagnosis. Secondary objectives were (1) to identify patient factors associated with antiresorptive therapy initiation and with risk of pathologic fracture, with the goal of informing future supportive-care and fracture-prevention strategies in this population, and (2) to estimate the percentage of pathologic fractures that may be preventable in this population with more widespread use of antiresorptive therapy. We hypothesized that antiresorptive therapy would prove to be under-prescribed in patients with osseous metastasis, highlighting an opportunity for clinical initiatives aimed at reducing the rate of pathologic fracture by prescribing therapy at a higher rate to appropriate patients.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003e\u003cstrong\u003e2.1\u0026nbsp;\u003c/strong\u003ePatient selection\u003c/p\u003e\n\u003cp\u003ePatients with a new diagnosis of osseous metastasis from January 2005 and July 2022 were retrospectively identified in the Epic-based COSMOS database. COSMOS is a large, de-identified, aggregated electronic health record (EHR) dataset derived from participating health systems using the Epic platform and includes routine, longitudinal clinical data such as diagnoses, medications, procedures, and encounter information across inpatient and outpatient settings [9]. Because COSMOS data is completely de-identified, study data is classified as non-human and Institutional Review Board (IRB) approval was not required.\u003c/p\u003e\n\u003cp\u003eAs our primary endpoints were to evaluate incidence of antiresorptive therapy use and pathologic fracture within two years of diagnosis of osseous metastasis, we collected the following data: 1) date of osseous metastasis diagnosis; 2) prescribing of antiresorptive therapy; 3) timing of antiresorptive therapy with respect to osseous metastasis diagnosis; 4) occurrence of pathologic fracture; 5) timing of pathologic fracture with respect to diagnosis. We defined antiresorptive medications as denosumab and the bisphosphonates class of drugs (Table S1).\u003c/p\u003e\n\u003cp\u003eAs our secondary endpoints were to identify potential factors associated with receiving antiresorptive therapies and with the risk of sustaining a pathologic fracture, we also collected the following data: 1) patient demographic data (age and sex); 2) history of diagnoses of the following primary cancer types (previous to the diagnosis of the osseous metastasis): breast, prostate, kidney, lung, lymphoma, multiple myeloma and thyroid.\u003c/p\u003e\n\u003cp\u003eSex was categorized as Female/Not female, while age was divided into the groups \u0026lt;25, 25-34, 35-44, 45-54, 55-64, 65-74 and +75 years. International Classification of Diseases ninth and tenth edition (ICD 9 and 10) codes were used to query all diagnoses (Table S2). These were treated as binary variables, with a \u0026lsquo;Yes\u0026rsquo; value if the patient had the corresponding code recorded and \u0026lsquo;No\u0026rsquo;, otherwise.\u003c/p\u003e\n\u003cp\u003ePatients with less than two years of follow-up after the osseous metastasis diagnosis were excluded. We also excluded patients who sustained a pathologic fracture before this diagnosis date and those with invalid values for any of the variables collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2\u0026nbsp;\u003c/strong\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eAge, sex and primary cancer type variables were described by their absolute and relative frequencies.\u003c/p\u003e\n\u003cp\u003eIn order to address our primary objectives, we first calculated the prescription rate of antiresorptive therapies as the quotient between the number of patients who received a prescription and the total patients diagnosed with osseous metastasis. The median time (interquartile range, IQR) elapsed between the date of this diagnosis and the start of the prescription was also reported. Second, we calculated the rate of pathologic fractures within two years of diagnosis as the quotient between patients sustaining a pathologic fracture and the number of patients diagnosed with osseous metastasis. The rate of pathologic fractures is further specified differentiating between patients receiving antiresorptive therapies before the pathologic fracture, after experiencing it, and those who did not receive such therapies. We also reported the median time (IQR) elapsed from the osseous metastasis diagnosis to the date of the first diagnosis of a pathologic fracture.\u003c/p\u003e\n\u003cp\u003eOur secondary objective was addressed by fitting separate Cox proportional hazards (PH) regression models. To assess the variables associated with the risk of being prescribed antiresorptive therapies within two years of osseous metastasis, we first fitted a multivariable model including age, sex and primary cancer type as risk factors. Patients younger than 25 years, female gender, and those without a prior diagnosis of the corresponding primary cancer type were considered as reference categories for each factor.\u003c/p\u003e\n\u003cp\u003eIn addition to these variables and aiming to assess the risk of sustaining a pathologic fracture, we included the timing of the initial prescription of antiresorptive therapies as a time-dependent risk factor, in a second multivariable PH regression model.\u003c/p\u003e\n\u003cp\u003eUnivariate models were also fitted to evaluate individual associations for the considered factors with both risks: being prescribed antiresorptive therapies and sustain pathologic fracture. Unadjusted (univariate case) and adjusted (multivariable case) hazard ratios together with confidence intervals at 95% confidence level were provided in both cases. All statistical analysis was performed using the R software (https://cran.r-project.org).\u003c/p\u003e\n\u003cp\u003e2.3 Estimation of Preventable Fractures - Methodology\u003c/p\u003e\n\u003cp\u003eWe estimated the proportion of potentially preventable pathologic fractures using a potential impact fraction (PIF) approach, which quantifies the proportional change in outcome under a hypothetical shift in exposure prevalence [10-12].\u003c/p\u003e\n\u003cp\u003eUsing data from the COSMOS cohort, the outcome was defined as pathologic fracture within two years of diagnosis, and the exposure was receipt of antiresorptive therapy (AT) within two-years of diagnosis. We modeled a counterfactual scenario in which 100% of patients received AT within two years (\u003cem\u003eP\u0026prime;\u003c/em\u003e = 1.00).\u003c/p\u003e\n\u003cp\u003eFor a binary exposure to AT, PIF was calculated as: PIF = [(\u003cem\u003eP\u0026prime;\u003c/em\u003e \u0026minus; \u003cem\u003eP\u003c/em\u003e) \u0026times; (1 \u0026minus; \u003cem\u003eRR\u003c/em\u003e)] / [(1 \u0026minus; \u003cem\u003eP\u003c/em\u003e) + \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026times; \u003cem\u003eRR\u003c/em\u003e], where \u003cem\u003eP\u003c/em\u003e is the observed prevalence of AT in the cohort, \u003cem\u003eP\u0026prime;\u003c/em\u003e is the modeled prevalence under the counterfactual scenario, and \u003cem\u003eRR\u003c/em\u003e is the risk ratio for pathologic fracture among treated versus untreated patients. [10-12].\u003c/p\u003e\n\u003cp\u003eThe number of potentially preventable fractures was then calculated as Preventable fractures = \u003cem\u003eF\u003c/em\u003e \u0026times; \u003cem\u003ePIF\u003c/em\u003e, where \u003cem\u003eF\u003c/em\u003e represents the observed number of fractures within two years.\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003eRR\u003c/em\u003e for fracture associated with AT was derived from a network meta-analysis of randomized trials comparing specific anti-resorptive agents versus placebo in patients with metastatic bone disease. To provide a conservative estimate, we used the reported relative risk reduction of 39% for zoledronate (\u003cem\u003eRR\u003c/em\u003e = 0.61) [12].\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e3.1 Cohort Selection and Characteristics\u003c/p\u003e\n\u003cp\u003eOf 725,869 patients with a diagnosis of osseous metastasis identified in COSMOS between January 2005 and July 2022, 678,073 met inclusion criteria above and were included in the final analytic cohort. The cohort was heterogeneous with respect to age, sex, and primary cancer type, which is expected given that COSMOS is representative of United Stated census data [9]. The largest age groups were 65\u0026ndash;74 years and \u0026ge;75 years, and lung, lymphoma, breast, and prostate cancers comprised the majority of primary malignancies (Table 1).\u003c/p\u003e\n\u003cp\u003eTable 1. Absolute and relative frequencies for categorized age, gender and primary cancer type\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" valign=\"bottom\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCHARACTERISTIC\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e(N = 678,073)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelative Frequency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbsolute Frequency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026lt; 25\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7,066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;25 -34\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7,976\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;35 - 44\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e3.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e23,317\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;45 -54\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e9.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e66,731\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;55 - 64\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e23.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e161,109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;65 - 74\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e30.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e208,806\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026gt; 75\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e29.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e203,068\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e45.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e307,546\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Not female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e54.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e370,527\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary cancer type\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Breast\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e20.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e135,732\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Prostate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e21.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e142,461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Kidney\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e4.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e32,505\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lung\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e24.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e166,256\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lymphoma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e32.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e218,494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Multiple Myeloma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e3.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e20,431\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 231px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Thyroid\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e8,388\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e3.2 Incidence and Timing\u003c/p\u003e\n\u003cp\u003eAntiresorptive therapy was prescribed within two years of osseous metastasis diagnosis for 94,860 patients (13.99%). Among treated patients, the median time to therapy initiation was 40 days after diagnosis of skeletal metastasis (IQR 8\u0026ndash;146 days).\u003c/p\u003e\n\u003cp\u003eA total of 72,910 patients (10.75%) sustained a pathologic fracture within two years of diagnosis. Of these, 4,734 (6.49%) received antiresorptive therapy prior to fracture, 7,937 (10.89%) initiated therapy after fracture, and 60,239 (82.62%) never received therapy. The median time from diagnosis to fracture was 5 days (IQR 0\u0026ndash;96 days).\u003c/p\u003e\n\u003cp\u003e3.3 Factors Associated with AT initiation\u003c/p\u003e\n\u003cp\u003eOn multivariable analysis, older age, female sex, and primary breast or prostate cancer were associated with higher likelihood of therapy initiation, whereas patients with lymphoma were less likely to receive therapy (Table 2).\u003c/p\u003e\n\u003cp\u003eTable 2. Factors associated with receiving an antiresorptive therapy prescription within two years of osseous metastasis diagnosis (unadjusted and adjusted hazard ratios and 95 % C.I.)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCHARACTERISTIC\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnadjusted HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026lt; 25\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;25 -34\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e5.85 (4.93, 6.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e3.99 (3.36, 4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;35 - 44\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e7.55 (6.41, 8.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e4.49 (3.81, 5.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;45 -54\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e7.11 (6.05, 8.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e4.53 (3.86, 5.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;55 - 64\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e6.99 (5.95, 8.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e4.75 (4.04, 5.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;65 - 74\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e7.39 (6.29, 8.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.95 (4.22, 5.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026gt; 75\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e6.91 (5.89, 8.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e4.41 (3.76, 5.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Not female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.70 (0.69, 0.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.77 (0.75, 0.78)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary cancer type\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Breast\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e2.23 (2.22, 22.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.43 (2.39, 2.48)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Prostate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.34 (1.32, 1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.14 (2.10, 2.19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Kidney\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.9 (0.87, 0.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.25 (1.21, 1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lung\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.69 (0.68, 0.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.02 (1.00, 1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lymphoma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.84 (0.83, 0.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.92 (0.90, 0.93)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Multiple Myeloma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.23 (1.19, 1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.63 (1.57, 1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Thyroid\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 191px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e0.89 (0.84, 0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 122px;\"\u003e\n \u003cp\u003e1.06 (1.00, 1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;3.4 Factors Associated with Pathological Fracture\u003c/p\u003e\n\u003cp\u003eYounger age, primary kidney cancer, and multiple myeloma were independently associated with increased fracture risk, whereas male sex and primary prostate cancer were associated with lower fracture risk. Receipt of antiresorptive therapy was associated with a higher observed hazard of fracture (Table 3).\u003c/p\u003e\n\u003cp\u003eTable 3. Factors associated with sustaining a PF within two years of follow-up after a new OM diagnosis (unadjusted and adjusted hazard ratios and 95 % C.I.):\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"540\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCHARACTERISTIC\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnadjusted HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026lt; 25\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;25 -34\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.92 (1.71, 2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.00 (1.73, 2.30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;35 - 44\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.97 (1.78, 2.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.93 (1.70, 2.20)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;45 -54\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2.04 (1.85, 2.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.94 (1.72, 2.19)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;55 - 64\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2.01 (1.83, 2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.86 (1.65, 2.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;65 - 74\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.77 (1.61, 1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.63 (1.45, 1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u0026gt; 75\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.53 (1.39, 1.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.30 (1.15, 1.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Not female\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.82 (0.80, 0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.89 (0.86, 0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary cancer type\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Breast\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.98 (0.96, 0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.86 (0.83, 0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Prostate\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.55 (0.54, 0.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.69 (0.67, 0.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Kidney\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.75 (1.70, 1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.75 (1.69,1.82)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lung\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.10 (1.08, 1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.92 (0.89, 0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.040\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Lymphoma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.20 (1.18, 1.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.98 (0.96, 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Multiple Myeloma\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.99 (1.93, 2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.70 (1.62, 1.78)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;Thyroid\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; - Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.02 (0.95, 1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.594\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.10 (1.02, 1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;Received AT\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;- No\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd nowrap=\"\" style=\"width: 171px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;- Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.34 (1.30, 1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1.37 (1.32, 1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;3.5. Estimation of Preventable Fractures \u0026ndash; Calculations\u003c/p\u003e\n\u003cp\u003eA total of 72,910 patients (10.75%) sustained a pathologic fracture within two years of diagnosis.\u003c/p\u003e\n\u003cp\u003eUsing the standard PIF formulation for a binary protective exposure with \u003cem\u003eP\u003c/em\u003e = 0.1399 (13.99% received AT within two years), \u003cem\u003eP\u0026prime;\u003c/em\u003e = 1.00, and \u003cem\u003eRR\u003c/em\u003e = 0.61 (\u003cem\u003eRRR\u003c/em\u003e = 0.39), the PIF was:\u003c/p\u003e\n\u003cp\u003ePIF = [(1.00 \u0026minus; 0.1399) \u0026times; (1 \u0026minus; 0.61)] / [(1 \u0026minus; 0.1399) + (0.1399 \u0026times; 0.61)] = 0.355 (35.5%).\u003c/p\u003e\n\u003cp\u003eTherefore, the estimated number of potentially preventable fractures over two years under universal AT use within the follow-up period was: 72,910 \u0026times; 0.355 = 25,868 fractures.\u003c/p\u003e\n\u003cp\u003eThe absolute reduction in fractures per 1,000 patients was: 25,868 / 678,073 \u0026times; 1000 = 38.1 fractures prevented per 1,000 patients with osseous metastasis.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eIn this large practice-based electronic health record cohort, antiresorptive therapy was prescribed in 13.99% of patients with osseous metastatic disease. Although utilization was higher than prior claims-based reports (7.7%), this rate appears modest relative to FDA-approved indications for denosumab and zoledronic acid for prevention of skeletal-related events in patients with metastatic bone disease and multiple myeloma [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. We could not determine the exact proportion of patients who would be appropriate candidates for therapy in this dataset because COSMOS does not uniformly capture key clinical factors that influence eligibility and prescribing (e.g., renal function, baseline calcium/vitamin D status, dental risk, prognosis, and goals of care) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUsing a potential impact fraction modeling approach [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], we estimated that approximately 25,868 of the total 72,910 pathologic fractures in this cohort (35.5%) could potentially have been prevented over two years if antiresorptive therapy (specifically zoledronate or denosumab) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] had been used universally in this population. Because COSMOS does not allow us to identify with confidence which patients met clinical eligibility criteria, we used a universal-treatment scenario to approximate the upper bound of potentially preventable fractures, while recognizing that universal therapy would not be clinically appropriate for all patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This estimate assumes immediate antiresorptive therapy treatment effect and therapy utilization in 100% of patients with osseous metastasis, and therefore likely overstates real-world benefit given biologic lag as well as clinical contraindications and logistical barriers to prescribing AT in certain patients. Additionally, it is important to note that the model for estimating the number of preventable fractures used in this study was based on use of zoledronate specifically, given that the meta-analysis of randomized trials comparing AT to placebo in this patient population showed zoledronate to have the more conservative pathologic fracture \u003cem\u003eRRR\u003c/em\u003e (.39) compared to denosumab (.5) and other bisphosphonates (no effect) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite the known limitations of this statistical modeling, clinical value remains in considering 35.5% as a potential upper end for the proportion of fractures that are preventable under a hypothetical scenario of universal-treatment, recognizing that most fractures in this study occurred early after diagnosis and therefore in real-world practice effective prevention would require near-immediate initiation of therapy following diagnosis.\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, these findings suggest a potential gap in supportive oncologic care. Additionally, the early occurrence of fractures following diagnosis (median 5 days) indicates that delays in care coordination, uncertainty regarding prescribing responsibility, or pre-treatment requirements may cause patients to miss the narrow window whereby they can benefit from antiresorptive therapy and underscores the timely administration of these medications [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Identification of high-risk patient subsets, particularly younger patients (specifically\u0026thinsp;\u0026lt;\u0026thinsp;64) and those with primary kidney cancer or multiple myeloma based on the findings in this study, may enable earlier intervention and improved fracture prevention.\u003c/p\u003e \u003cp\u003eA key finding of this study is the marked temporal mismatch between fracture occurrence and therapy initiation. Pathologic fractures occurred very early following diagnosis of osseous metastasis (median 5 days), whereas antiresorptive therapy was typically initiated later (median 40 days). This pattern suggests that fractures frequently precede initiation of supportive therapy, indicating that antiresorptive treatment is often reactive rather than preventive in real-world practice. This again may represent an opportunity for the multidisciplinary care team involved in managing these complex patients to recognize the significant risk of pathologic fracture immediately upon diagnosis of osseous metastatic disease and to prioritize early, proactive initiation of antiresorptive therapy in an effort to decrease the rate of highly morbid fracture events.\u003c/p\u003e \u003cp\u003eAdditionally, although receipt of antiresorptive therapy was associated with a higher observed hazard of pathologic fracture in this study, this is unlikely to be due to a harmful effect of therapy given the known efficacy of these medications in reducing risk of pathologic fracture [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Rather, it likely reflects reverse temporal sequencing inherent to observational analyses in which treatment initiation commonly follows fracture events. Because exposure was modeled as a time-fixed variable in this study (\u0026ldquo;ever received antiresorptive therapy\u0026rdquo;), patients who fractured early and were subsequently treated contributed to an apparent positive association between therapy and fracture risk.\u003c/p\u003e \u003cp\u003eSeveral limitations warrant consideration. As a large, retrospective analysis of electronic health record data, this study is subject to potential misclassification related to diagnostic coding and medication capture, which may influence both fracture risk and treatment ascertainment. While we were able to capture objective data on prescribing trends, the large patient cohort (n\u0026thinsp;=\u0026thinsp;678,073) and de-identified nature of the data in COSMOS prevented us from contacting patients or using manual chart review to confirm patients were actually taking the medications. COSMOS also does not uniformly capture disease severity, tumor burden, or functional status, factors that likely affect both fracture risk and clinical decision-making around therapy initiation. Additionally, as discussed, modeling antiresorptive therapy exposure as a time-fixed variable introduces potential for reverse causation and bias related to fractures occurring before therapy initiation, limiting causal inference. Next, AT was queried as a binary variable based on the assembled list of medications (Table S1), and we did not investigate the rates of utilization or fracture for each specific form of AT in the present study. This would be clinically valuable as an area for future investigation based on the known differential efficacies of the various forms of AT in the setting of osseous metastasis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Finally, although COSMOS represents a large, multi-institutional dataset in the United States, prescribing practices and care pathways may differ across healthcare systems abroad, which may affect generalizability.\u003c/p\u003e \u003cp\u003eIn summary, in this large COSMOS-based cohort of patients with osseous metastatic disease, antiresorptive therapy was prescribed in 13.99% of patients. This suggests possible underutilization given the relatively broad FDA-approved indications for antiresorptive therapy use in the setting of metastatic bone disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Fractures frequently occurred shortly after diagnosis and often before therapy initiation, underscoring a narrow window for preventive intervention. Notably, modeling using a universal-treatment scenario suggests that up to 35.5% of pathologic fractures may be potentially preventable with antiresorptive therapy (zoledronate or denosumab), but this should be interpreted as an upper bound given biologic lag and contraindications to prescribing these medications in certain patients. Overall, the findings in this study highlight an opportunity to improve supportive oncologic care through more widespread, timely initiation of antiresorptive therapy in appropriately selected patients with osseous metastatic disease.\u003c/p\u003e"},{"header":"Abbreviation","content":"\u003cp\u003eAT = Antiresorptive therapy, PF= Pathologic fracture, OM = Osseous Metastasis, PIF = Population/Potential Impact Fraction\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval, Consent to participate, Consent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study used de-identified data from the Epic COSMOS database and was deemed exempt from full institutional review board (IRB) review. As such, no consent to participate or consent to publish is needed. Full institutional approval was obtained to proceed with this study and to utilize the data herein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests or personal relationships that could have influenced this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from Epic COSMOS but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. Full institutional approval was obtained to proceed with this study and to utilize the data herein.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatrick Mazza:\u0026nbsp;\u003c/strong\u003eConceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization. \u003cstrong\u003eAndrew Binder:\u0026nbsp;\u003c/strong\u003eFormal analysis, Investigation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization. \u003cstrong\u003eSusana Coto:\u003c/strong\u003e Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization. \u003cstrong\u003eAdam S. Levin:\u003c/strong\u003e Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization. \u003cstrong\u003eEric R. Henderson:\u003c/strong\u003e Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing \u0026ndash; original draft, Writing \u0026ndash; review \u0026amp; editing, Visualization.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eColeman RE, Hadji P, Body JJ, Santini D, Chow E, Terpos E, et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(12):1650\u0026ndash;1663. doi:10.1016/j.annonc.2020.07.019\u003c/li\u003e\n\u003cli\u003eRyan C, Stoltzfus KC, Horn S, Chen H, Louie AV, Lehrer EJ, Trifiletti DM, Fox EJ, Abraham JA, Zaorsky NG. Epidemiology of bone metastases. Bone. 2022;158:115783. doi:10.1016/j.bone.2020.115783\u003c/li\u003e\n\u003cli\u003eSaad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer. 2007;110(8):1860\u0026ndash;1867. doi:10.1002/cncr.22991\u003c/li\u003e\n\u003cli\u003evon Moos R, Body JJ, Egerdie B, Stopeck A, Brown J, Fallowfield L, et al. Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases. Support Care Cancer. 2016;24(3):1327\u0026ndash;1337. doi:10.1007/s00520-015-2908-1\u003c/li\u003e\n\u003cli\u003eWajda BG, Ferrie LE, Abbott AG, Elmi Assadzadeh G, Monument MJ, Kendal JK. Denosumab vs. zoledronic acid for metastatic bone disease: a comprehensive systematic review and meta-analysis of randomized controlled trials. Cancers (Basel). 2025;17(3):388. doi:10.3390/cancers17030388\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Oronzo S, Wood S, Brown JE. The use of bisphosphonates to treat skeletal complications in solid tumours. Bone. 2021;147:115907. doi:10.1016/j.bone.2021.115907\u003c/li\u003e\n\u003cli\u003eAgarwal AR, LiBrizzi CL, Wessel L, Thakkar SC, Levin AS. The low and disproportionate utilization of antiresorptive therapy in patients with osseous metastasis. J Bone Oncol. 2023;43:100507. doi:10.1016/j.jbo.2023.100507\u003c/li\u003e\n\u003cli\u003eDahlen A, Charu V. Analysis of sampling bias in large health care claims databases. JAMA Netw Open. 2023;6(1):e2249804. doi:10.1001/jamanetworkopen.2022.49804\u003c/li\u003e\n\u003cli\u003eEpic Systems Corporation. COSMOS data platform overview. Verona, WI: Epic Systems Corporation; 2024. Available at: https://cosmos.epic.com. Accessed February 18, 2026.\u003c/li\u003e\n\u003cli\u003eAskari M, Namayandeh SM. \u0026ldquo;The Difference between the Population Attributable Risk (PAR) and the Potential Impact Fraction (PIF).\u0026rdquo; \u003cem\u003eIran J Public Health\u003c/em\u003e. 2020;49(10):2018-2019. doi:10.18502/ijph.v49i10.4713.\u003c/li\u003e\n\u003cli\u003eRockhill B, Newman B, Weinberg C. Use and misuse of population attributable fractions. Am J Public Health. 1998;88(1):15\u0026ndash;19. doi:10.2105/AJPH.88.1.15.\u003c/li\u003e\n\u003cli\u003eMurray CJL, Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S. Comparative quantification of health risks: Conceptual framework and methodological issues. Lancet. 2003;362(9387):717\u0026ndash;725. doi:10.1016/S0140-6736(03)14203-0.\u003c/li\u003e\n\u003cli\u003eWang Z, Qiao D, Lu Y, Curtis D, Wen X, Yao Y, Zhao H. Systematic literature review and network meta-analysis comparing bone-targeted agents for the prevention of skeletal-related events in cancer patients with bone metastasis. The Oncologist. 2015;20(4):440\u0026ndash;449. doi:10.1634/theoncologist.2014-0328\u003c/li\u003e\n\u003cli\u003eU.S. Food and Drug Administration. Xgeva (denosumab) prescribing information. Silver Spring, MD: FDA. Accessed via Drugs@FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125320s168lbl.pdf. Accessed February 18, 2026.\u003c/li\u003e\n\u003cli\u003eU.S. Food and Drug Administration. Zometa (zoledronic acid) prescribing information. Silver Spring, MD: FDA. Accessed via Drugs@FDA: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021223s006lbl.pdf. Accessed February 18, 2026.\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":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Antiresorptive medications, Bisphosphonates, Osseous metastasis, Pathologic fracture","lastPublishedDoi":"10.21203/rs.3.rs-8913561/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8913561/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003cbr\u003e\nAntiresorptive therapy (AT) reduces risk of pathologic fractures (PF) in patients with osseous metastases (OM). Recent data show AT is prescribed to only 7.7% of patients with OM, suggesting under-prescription. This study aims to determine rates of AT use and PF in patients with OM using Epic’s comprehensive, practice-based database “COSMOS,” and to identify patient factors associated with AT use and PF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nA retrospective review was conducted using “COSMOS” to identify patients diagnosed with OM from January 2005 to July 2022 with minimum two-year follow-up. Cox proportional hazards regression models were used to identify factors associated with AT use and risk of PF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nOf 678,073 patients included, AT was prescribed for 13.9%. 10.8% sustained PF, of whom 17.38% received AT before or after fracture and 82.6% never received AT. Age 25–34 and primary lymphoma patients were less likely to receive AT (p \u0026lt;.001). Risk of PF was higher for age 25–34 (HR 2.00, p \u0026lt;0.001), primary renal cancer and multiple myeloma (HRs 1.75 and 1.70, p \u0026lt;0.001), and lower for males (HR .89, p \u0026lt;.001) and primary prostate cancer (HR .69, p \u0026lt;.001). Modeling suggests that up to 35.5% of fractures may be preventable through universal use of AT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003cbr\u003e\nAT is prescribed at a lower-than-expected rate given its known efficacy in reducing PF risk in patients with OM. Younger age, female gender, primary renal cancer and multiple myeloma are associated with increased fracture risk, with implications for optimizing patient selection for AT.\u003c/p\u003e","manuscriptTitle":"Antiresorptive Therapy Use in Patients with Skeletal Metastases – Are We Under Prescribing?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 10:28:00","doi":"10.21203/rs.3.rs-8913561/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"155366370168242260344475992979055649271","date":"2026-05-06T12:30:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T21:03:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"319891976318794405904388918244438892350","date":"2026-04-11T11:33:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-01T15:44:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-01T15:42:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-27T00:36:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2026-02-19T03:28:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0dfd7eda-776c-4322-9fdc-3ab47e5b14d2","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"155366370168242260344475992979055649271","date":"2026-05-06T12:30:57+00:00","index":20,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T21:03:18+00:00","index":17,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T10:28:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 10:28:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8913561","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8913561","identity":"rs-8913561","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}