Trends and Factors Affecting the Initiation of Denosumab and Zoledronic Acid among Patients with Metastatic Lung, Breast, and Prostate Cancer in the United States

Trends and Factors Affecting the Initiation of Denosumab and Zoledronic Acid among Patients with Metastatic Lung, Breast, and Prostate Cancer in the United States | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trends and Factors Affecting the Initiation of Denosumab and Zoledronic Acid among Patients with Metastatic Lung, Breast, and Prostate Cancer in the United States Kaniz Afroz Tanni, Nedret Billor, Surachat Ngorsuraches, Salisa Westrick, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4223964/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Patients with Metastatic lung, breast, and prostate cancer (MLBPC) experience skeletal related events (SREs), which significantly decrease survival. Denosumab (DS) and Zoledronic acid (ZA) are recommended for these patients to prevent such SREs. However, there is a lack of evidence in the patterns and predictors of real-world initiation of DS versus ZA in older MLBPC patients in the United States. The objective of this study was to examine the trends and factors associated with DS or ZA initiation among older MLBPC patients in the US. Methods We used the Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data to identify patients diagnosed with MLBPC between 2012 and 2017 who initiated DS/ZA treatment within 12 months of cancer diagnosis. Demographics, healthcare utilization, comorbidities, disease, and treatment attributes of new users were evaluated. Trends in treatment initiation were assessed using Cochran-Armitage tests among all MLBPC patients and by cancer type. T-tests, Chi-squared tests and multiple logistic regressions were employed to identify factors influencing the choice between DS and ZA initiation. Results In 2012–2017, DS initiation trends increased across all individual cancer cohorts as well as the overall MLBPC sample, while ZA initiation notably decreased in the metastatic breast cancer and MLBPC cohorts (all P < 0.0001). Patients more likely to initiate DS over ZA were older at diagnosis, Hispanic, single, eligible for low-income subsidies, urban residents, had multiple comorbidities, impaired renal function, and prior chemotherapy use. Conclusions There are significant differences between the trends in DS and ZA initiation as well as in the factors affecting initiation among MLBPC patients. Skeletal-related events metastasis denosumab zoledronic acid utilization trend analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Lung, breast, and prostate cancers, the leading causes of cancer mortality, are estimated to cause 205,470 new deaths in 2023 in the United States (US). 1 The metastatic lung, breast, and prostate cancer (MLBPC) patients may develop a wide range of skeletal complications, commonly referred to as the skeletal-related events (SREs). SREs may include but not limited to conditions such as pathologic fracture, need for radiation or surgery to bone, spinal cord compression, or hypercalcemia. 2–4 SREs are known to significantly decrease patient’s survival (patients experiencing one SRE have a 10-fold higher risk of death than those without an SRE), mobility, and quality of life, as well as increase the cost burden for MLBPC patients. 5–7 The total cost per patient over a 12-month period are $ 22,000- $ 28,000 higher among patients with SREs than among patients without SREs. 8,9 To prevent SREs, the US clinical practice guidelines recommend the use of bone-modifying agents (BMAs) for patients with bone metastasis from solid cancers. 10–13 BMAs, including zoledronic acid (ZA) and denosumab (DS), modulate osteoclastic activity to suppress the decaying of bone. 14 Although these drugs have been marketed in the US for over a decade, real-world evidence (RWE) about their utilization in older MLBPC patients is limited. A few studies have examined the utilization of BMAs among patients with osteoporosis, 15,16 and one observational study evaluated the use of BMAs among patients with cancer in 2012 17 , but there is a lack of recent evidence regarding the patterns and predictors of BMA use among older MLBPC patients. Although randomized controlled trials (RCTs) are considered to be the gold standard for generating clinical evidence, the use of RWE, defined as the clinical evidence derived about the utilization of a medical product, serves important roles in healthcare decision-making. 18 RCTs have strict eligibility criteria and less generalizability to the overall US patients with cancer. For instance, the median age of MLBPC diagnosis varies between 63–70 years in the US. 19 In contrast, older patients are underrepresented in most of the registrational trials of oncologic products. 20 To date, post-marketing evaluation with comparisons of initiation of DS versus ZA in older MLBPC patients using RWD from the US is limited. DS treatment in standard dosing is known to cost much more compared to ZA treatment (the estimated drug and administration cost of ZA was $ 252 compared to $ 1,906 for DS every 4 weeks in 2021). 21–23 In addition, RCTs have shown superiority of DS over ZA in delaying the SREs in patients with breast and prostate cancer and noninferiority in patients with lung cancer. 24–26 Therefore, the objective of this study was to examine the trends and factors associated with DS and/or ZA initiation among older MLBPC patients in the US. 2. Methods 2.1 Data Source This retrospective study was conducted using the 2011–2019 Surveillance, Epidemiology and End Results (SEER)–Medicare linked database. The SEER-Medicare data reflect the linkage of two large population-based sources of data that provide detailed information about Medicare beneficiaries with cancer. 27 This study was reviewed and approved by the Auburn University Institutional Review Board. 2.2 Patient Cohort Patients with primary cancers of lung, breast, or prostate during 2012–2017 were identified using International Classification of Diseases for Oncology (ICD-O-3 site: C50.0-50.9 for breast, C61.9 for prostate, and C33.9, C34.0-34.3, C34.8, C34.9 for lung cancer) codes. 28 The full cohort of patients included those with stage IV disease according to the American Joint Committee on Cancer (AJCC) Staging Manual. 29 Next, we identified new users of DS and ZA (using a washout period of 12 months) among patients diagnosed with MLBPC. The inclusion criteria were: MLBPC patients who had at least one Medicare Part B claim based on Healthcare Common Procedure Coding System (HCPCS) J codes for BMAs of interest: DS (J0897) or ZA (J3487) within 12 months after their first observed MLBPC diagnosis (between January 2012-December 2018). The claims of DS/ZA were identified from the National Claims History (NCH), Outpatient, Home Health Agency (HHA), Hospice, and Durable Medical Equipment (DME) files. Exclusion criteria were: <66 years old at cancer diagnosis; cancer diagnosis date missing; cancer diagnosis was from autopsy/death; enrollment in Health Maintenance Organizations (HMOs), Part B claims of either of the BMAs during washout period i.e., within 12 months before index date (date of first prescription), and non-continuous Medicare Parts A and B coverage during the washout period. Finally, we did not exclude the users of other BMAs such as oral bisphosphonates in our study. 2.3 Factors/Independent Variables of Interest We collected patient’s information on the following 5 categories of variables during the pre-index washout period (12 months): 1) Demographic and socio-economic characteristics : age, sex, race/ethnicity, marital status, residence in urban/rural area, 30 SEER region (Northeast, Midwest, South, and West), and Medicare low-income subsidy 31 ; 2) Comorbidities : Charlson comorbidity index, 32 history of osteoporosis, 33 hypercalcemia, 34 impaired renal function 35 ; 3) Healthcare utilization : number of physician office visits, emergency department (ED) visits, and hospitalizations; 4) Disease characteristics : tumor type/grade (hormone receptor subtype for breast cancer), Gleason score for prostate cancers 36 , and lung cancer subtypes; 5) Treatment characteristics : receipt of chemotherapy, radiation, aromatase inhibitor (for MBC patients) use, 37 androgen deprivation therapy (for MPC patients) use 38 ; Supplementary Table 1 provides detailed information regarding the variables of interest. 2.4 Statistical Analysis 2.4.1 Trend Analysis The primary outcome of this study was the new initiation of BMAs, specifically DS and ZA, within 12 months following a diagnosis of MLBPC. The proportion of new DS/ZA users were calculated as those who initiated either therapy within one year of the first observed MLBPC diagnosis, relative to the total number of MLBPC patients in each calendar year (index years). The proportion of any BMA use was plotted by BMA type (DS/ZA) for the index years comprising the study period (2012-2017). For statistical analysis, we employed the Cochran-Armitage trend test to examine if there were significant increasing or decreasing trends in DS or ZA initiation across various disease cohorts, including metastatic lung cancer (MLC), metastatic breast cancer (MBC), metastatic prostate cancer (MPC), and MLBPC over the study time period. 39 In addition, sensitivity analyses were conducted focusing on DS/ZA initiation within 6 months post-diagnosis of MLBPC. 2.4.2 Regression Analysis For the assessment of factors influencing the initiation of DS or ZA, we pooled data from new users during January 2012-December 2018. To compare the distributions of variables of interest between DS and ZA initiators, we used two-sample t-tests for continuous variables and either Chi-squared tests or Fisher’s exact tests for categorical variables. Subsequently, multiple logistic regression models were fitted to explore predictors affecting the initiation of DS versus ZA (event=1 when DS is initiated and event=0 when ZA is initiated) across different patient cohorts: MLC, MBC, MPC, and MLBPC. All analyses were conducted using SAS version 9.4, with a significance level set at P<0.05. 3. Results 3.1 Sample Characteristics The detailed step-by-step process for including and excluding patients from these cohorts is elucidated in Fig. 1 . We identified a total of 99,262 patients with MLBPC diagnosis during January 2012 to December 2017 meeting the inclusion and exclusion criteria. Among them, 66,578 patients (67.07%) had MLC; 17,114 (17.24%) had MBC; and 15,570 (15.69%) had MPC. We found that 1.44%, 1.31%, and 0.42%, MLC, MBC, and MPC patients received both DS and ZA within the 12 months of their MLBPC diagnosis. The range of annual percentage of DS initiators within 12 months of the diagnosis in MLC cohort was between 22.90% and 32.81% across years and the ZA initiators ranged in 28.06%-29.81% (Table 1 ). The annual percentage of MBC patients who initiated DS ranged between 26.42% and 36.42%, while 15.71–25.07% of patients in the same cohort initiated ZA. In the MPC cohort, the range of percentage of DS initiation was 24.89–31.75% and it was 25.36–28.29% for ZA initiators. Table 1 Trend analysis of Denosumab and/or Zoledronic Acid initiation among metastatic lung, breast, and prostate cancer patients MLC Index Year P-Value* 2012 2013 2014 2015 2016 2017 DS (Yes %) 22.90 23.75 25.87 27.46 32.80 32.53 < 0.0001 ZA (Yes %) 28.07 29.81 28.76 28.15 28.58 28.06 0.097 MBC Index Year P-Value 2012 2013 2014 2015 2016 2017 DS (Yes %) 29.08 26.42 31.91 34.14 36.10 36.42 < 0.0001 ZA (Yes %) 24.53 25.07 21.28 20.74 17.62 15.72 < 0.0001 MPC Index Year P-Value 2012 2013 2014 2015 2016 2017 DS (Yes %) 24.89 25.55 27.46 27.90 30.95 31.75 < 0.0001 ZA (Yes %) 27.22 28.30 28.13 27.36 27.45 25.36 0.06 MLBPC Index Year P-Value 2012 2013 2014 2015 2016 2017 DS (Yes %) 24.29 24.51 27.15 28.69 33.09 33.06 < 0.0001 ZA (Yes %) 27.32 28.73 27.38 26.73 26.51 25.57 < 0.0001 [*p-values are derived from the Cochran-Armitage trend tests; MLC = metastatic lung cancer; MBC = metastatic breast cancer; MPC = metastatic prostate cancer; MLBPC = metastatic lung, breast, and prostate cancers; DS = denosumab; ZA = zoledronic acid] Figure 1 : Inclusion and Exclusion of Patient Cohort for Trend Analysis Table 1 : Trend analysis of Denosumab and/or Zoledronic Acid initiation among patients with metastatic lung, breast, and prostate cancer 3.2 Trends in DS/ZA Initiation Results of the trend analysis are presented in Table 1 and illustrated in Figs. 2 to 4 . Across all three individual cancer cohorts, we observed statistically increasing trends in proportion of DS initiation during the study period (all P < 0.0001). Conversely, proportion of ZA initiation significantly declined in the MBC cohort (P < 0.0001), while remaining stable and non-significant for the MPC and MLC cohorts (P = 0.06 and P = 0.10, respectively). In addition, for the overall MLBPC cohort, proportion of DS initiation within 12 months of metastatic cancer diagnosis showed a significant upward trend (P < 0.0001), while ZA initiation correspondingly declined (P < 0.0001). For the sensitivity analyses of trends in DS/ZA initiation within 6 months of diagnosis ( Supplementary Fig. 1–3 ), results differed from the main analysis. Specifically, proportion of DS initiation continued to significantly increase in the MBC and MPC cohorts (P < 0.0001 and P = 0.03, respectively), but remained stable in the MLC cohort (P = 0.13). On the other hand, trends in ZA initiation among MBC and MLC patients did not change significantly (P = 0.25 and 0.38, respectively), but significantly declined among the MPC cohort (P = 0.03). Finally, in the overall MLBPC cohort, trend in DS initiation significantly increased (P < 0.0001) while the trend was stable for ZA initiation (P = 0.08). Figure 2 : Trend Analysis of Initiation of Denosumab within 12 months of MLBPC Diagnosis Figure 3 : Trend Analysis of Initiation of Zoledronic Acid within 12 months of MLBPC Diagnosis Figure 4 : Trend Analysis of Initiation of Denosumab or Zoledronic Acid within 12 months of MLBPC Diagnosis 3.3 Factors Associated with DS/ZA Initiation In our two-sample comparison analysis ( Supplementary Table 2 ), we discovered significant differences in several key variables among those who initiated DS vs. ZA treatments in various patient cohorts. In the MLC cohort, most studied variable, including age at diagnosis, sex, marital status, low-income subsidy, residential area, SEER-region, hospitalizations, physician office visits, Charlson Comorbidity Index (CCI), history of impaired renal function, and receipt of chemotherapy and radiation, showed statistically significant differences (all P < 0.0001). For the MBC cohort, variables like race/ethnicity, marital status, low-income subsidy, SEER-region, hospitalizations and ED visits, CCI, history of osteoporosis, and history of renal impairment had significant differences between DS and ZA users (all P < 0.0001). Additionally, receipt of aromatase inhibitor (P < 0.0001) and breast cancer subtypes (P = 0.02) were different between DS and ZA users. In the MPC cohort, the significant differences were found for variables including marital status, low-income subsidy, SEER-region, physician office visits, history of hypercalcemia and impaired renal function, as well as receipt of radiation and androgen deprivation therapy (all P < 0.05). Our findings for the overall MLBPC cohort (Table 2 , Supplementary Fig. 7 ) reveal that most of the variables were significantly different except for ED visits, history of osteoporosis, and history of hypercalcemia. From the multivariable analyses (Table 3 , Supplementary Figure − 4 ) in the MLC cohort, we found significant differences in odds of DS initiation for all the demographic factors. Compared to ZA initiators, the adjusted odds of initiation of DS significantly increases with increased age at diagnosis (OR = 1.13, 95% CI: 1.02–1.36). In contrast, we found that the odds of DS initiation decreased with age for the MBC patients (OR = 0.98, 95% CI: 0.96–0.99). Among MLC patients, females were less likely than males to initiated DS (OR = 0.71, 95% CI: 0.53–0.94). Black MLC patients were more likely to initiate with DS compared to White MLC patients (OR = 1.89, 95% CI: 1.29–3.70), whereas this association was opposite for the MBC and MPC patient cohorts, with White patients more likely to initiate DS than Black patients. However, in all 3 cancer cohorts, Hispanic patients were found to have significantly higher odds of DS initiation compared to White patients. Overall, we found that single patients had significantly higher likelihood of initiating with DS, while those who had low-income subsidy had significantly lower odds of initiating with DS. Residence also seemed to play a role in the use of DS and patients in rural areas were less likely to initiate DS than those residing in urban areas (OR = 0.79, 95% CI: 0.42–0.98; & OR = 0.78, 95% CI: 0.55–0.97 for MLC & MPC cohorts, respectively). Table 2 Bivariate and Multivariable analysis of factors affecting initiation of Denosumab or Zoledronic Acid in MLBPC Variables Categories Bivariate Analysis Multivariable Analysis DS (MLBPC) N = 27902 ZA (MLBPC) N = 26111 P-value DS (MLBPC) Age at Diagnosis 70.22 (1.97) a 69.77 (1.78) a < 0.0001 1.07 (1.01–1.12) Race/ethnicity White 19771 (70.86) 18189 (69.66) 0.002 REF Black 6118 (21.93) 6048 (23.16) 0.51 (0.44–0.58) Hispanic 882 (3.16) 880 (3.37) 1.52 (1.45–1.68) Other 876 (3.14) 742 (2.84) 0.95 (0.55–1.22) Missing/unknown 255 (0.91) 252 (0.97) 0.94 (0.69–1.32) Marital Status at diagnosis Single 5722 (20.51) 4942 (18.29) < 0.0001 1.28 (1.15–1.49) Married 20035 (71.80) 18854 (72.21) REF Divorced 1353 (4.85) 1753 (6.71) 0.92 (0.86–1.17) Other 361 (1.29) 266 (1.02) 1.45 (1.28–1.98) Unknown/Missing 431 (1.54) 296 (1.13) 0.77 (0.59–0.83) Low-income subsidy Yes 2032 (7.28) 2750 (10.53) < 0.0001 0.58 (0.44–0.69) No 25503 (91.40) 24149 (88.27) REF Unknown/Missing 367 (1.32) 312 (1.19) 1.02 (0.86–1.18) Residence Urban 23064 (82.66) 20649 (79.08) < 0.0001 REF Rural 4701 (16.85) 5295 (20.28) 0.82 (0.68–0.98) Unknown/Missing 137 (0.49) 167 (0.64) 0.66 (0.45–0.89) SEER Region West 8423 (30.19) 7652 (29.31) < 0.0001 REF Midwest 6298 (22.57) 5174 (19.82) 1.13 (1.01–1.45) Northeast 5883 (21.08) 6005 (23.00) 0.75 (0.59–1.22) South 7298 (26.16) 7280 (27.88) 0.69 (0.47–1.09) Hospitalizations 1.95 (0.51) a 1.93 (0.58) a < 0.0001 1.07 (1.01–1.64) ED Visits 1.69 (0.89) a 1.71 (0.88) a 0.104 1.12 (0.82–1.26) Physician Office Visits 8.55 (3.96) a 9.52 (4.13) a < 0.0001 0.86 (0.79–0.94) Charlson Comorbidity Index 0 1769 (6.34) 1457 (5.58) < 0.0001 REF 1 5717 (20.49) 5616 (21.51) 1.08 (1.03–1.14) 2 6582 (23.59) 5425 (20.78) 1.27 (1.16–1.41) ≥ 3 13834 (49.58) 13613 (52.14) 1.45 (1.36–1.71) History of Osteoporosis No 25098 (89.95) 23372 (89.51) 0.092 REF Yes 2804 (10.05) 2739 (10.49) 0.88 (0.79–1.06) History of Hypercalcemia No 25740 (92.25) 24078 (92.21) 0.871 REF Yes 2162 (7.75) 2033 (7.79) 0.85 (0.69–1.02) Impaired Renal Function No 22443 (80.44) 23635 (90.52) < 0.0001 REF Yes 5459 (19.56) 2476 (9.48) 1.22 (1.13–1.36) Receipt of chemotherapy No 21330 (76.45) 20165 (77.23) 0.032 REF Yes 6572 (23.55) 5946 (23.55) 1.07 (1.03–1.15) Receipt of Radiation No 24284 (87.03) 22067 (84.03) < 0.0001 REF Yes 3618 (12.97) 4044 (15.49) 0.73 (0.67–0.89) [values in bivariate analysis are presented as N (%); a = Mean (SD); p values are presented from the t-tests for continuous variables and chi-squared tests for the categorical variable. Logistic regression (multivariable analysis) results are presented as OR (95% CI); DS = Denosumab; MLC = Metastatic Lung Cancer; MBC = Metastatic Breast Cancer; MPC = Metastatic Prostate Cancer] Table 3 Multivariable analysis of factors affecting initiation of Denosumab vs. Zoledronic Acid DS (MLC) DS (MBC) DS (MPC) Age at Diagnosis 1.13 (1.02–1.36) 0.98 (0.96–0.99) 0.99 (0.68–1.54) Sex Male REF - - Female 0.71 (0.53–0.94) Missing/Unknown 1.47 (1.12–1.64) Race White REF REF REF Black 1.89 (1.29–3.70) 0.51 (0.45–0.58) 0.65 (0.59–0.88) Hispanic 2.06 (1.48–2.79) 2.00 (1.54–3.29) 1.82 (1.37–2.71) Other 1.59 (1.011–2.01) 2.94 (1.67–4.31) 2.02 (1.96–2.47) Missing/unknown 2.86 (1.76–3.56) 1.23 (0.79–1.91) 1.83 (1.04–3.01) Marital Status at diagnosis Married REF REF REF Single 1.45 (1.19–1.63) 1.21 (1.09–1.29) 1.17 (1.03–1.28) Divorced 1.07 (0.89–1.21) 0.77 (0.69–0.82) 0.59 (0.51–0.71) Other 1.29 (0.53–2.53) 1.11 (1.06–1.18) 1.87 (1.04–2.13) Unknown/Missing 0.69 (0.44–0.74) 0.81 (0.74–0.92) 0.88 (0.66–1.46) Low-income subsidy No REF REF REF Yes 0.64 (0.53–0.78) 0.52 (0.49–0.64) 0.59 (0.42–0.71) Unknown/Missing 0.86 (0.72–1.29) 1.09 (1.01–1.13) 0.78 (0.68–0.92) Residence Urban REF REF REF Rural 0.79 (0.42–0.98) 0.94 (0.83–1.09) 0.78 (0.55–0.97) Unknown/Missing 0.47 (0.23–0.77) 0.56 (0.31–1.03) 0.75 (0.66–1.01) SEER Region West REF REF REF Midwest 1.63 (1.42–1.83) 0.76 (0.65–0.84) 0.54 (0.37–0.78) Northeast 0.72 (0.54–0.90) 0.95 (0.84–1.52) 0.66 (0.49–0.84) South 0.91 (0.82–1.91) 0.46 (0.39–0.53) 0.77 (0.44–1.13) Hospitalizations 1.09 (1.02–1.16) 0.96 (0.92-1.00) 1.07 (0.86–1.55) ED Visits 1.52 (1.23–1.83) 1.99 (1.81–2.20) 1.07 (0.83–1.34) Physician Office Visits 0.69 (0.52–0.73) 1.01 (0.98–1.04) 1.26 (1.15–1.33) Charlson Comorbidity Index 0 REF REF REF 1 1.09 (1.04–1.15) 1.07 (1.01–1.12) 1.09 (0.98–1.13) 2 1.42 (1.36–1.49) 1.22 (1.17–1.29) 1.13 (0.99–1.26) ≥ 3 1.71 (1.58–1.84) 1.18 (1.09–1.26) 1.14 (1.01–1.21) History of Osteoporosis Yes 0.98 (0.87–1.10) 0.67 (0.55–0.73) 1.18 (0.91–1.22) History of Hypercalcemia Yes 0.92 (0.76–1.09) 0.68 (0.49–1.12) 0.98 (0.91–1.03) Impaired Renal Function Yes 1.37 (1.19–1.44) 1.29 (1.08–1.39) 1.06 (1.01–1.12) Receipt of chemotherapy Yes 1.15 (1.07–1.22) 1.03 (0.95–1.14) 1.12 (1.08–1.17) Receipt of Radiation Yes 0.71 (0.64–0.88) 0.81 (0.69–1.02) 0.67 (0.59–0.73) Receipt of Aromatase Inhibitor Yes - 1.10 (1.04–1.19) - Breast Tumor Subtype HER2+/HR+ - REF - HER2+/HR- 1.93 (1.07–2.45) HER2-/HR+ 1.45 (0.81–2.57) HER2-/HR- 1.18 (0.66–2.11) Unknown/Missing 1.52 (0.86–2.67) Receipt of Androgen Deprivation Therapy Yes - - 1.08 (1.01–1.16) Gleason Score ≤ 6 - - REF 7 0.88 (0.56–1.23) ≥ 8 1.12 (0.91–1.31) Missing/Unknown 0.76 (0.59–0.97) Lung cancer subtype Adenocarcinoma REF - - Squamous 0.88 (0.74–1.12) Other NSC 1.20 (0.89–1.48) Small cell 1.23 (0.85–1.67) Unknown/Missing 0.68 (0.48–0.88) [Logistic regression (multivariable analysis) results are presented as adjusted OR (95% CI); DS = Denosumab; MLC = Metastatic Lung Cancer; MBC = Metastatic Breast Cancer; MPC = Metastatic Prostate Cancer] Table 2 : Bivariate and Multivariable analysis of factors affecting initiation of Denosumab or Zoledronic Acid in MLBPC Table 3 : Multivariable analysis of factors affecting initiation of Denosumab vs. Zoledronic Acid We also found that the odds of DS initiation were higher among MLC patients with baseline hospitalizations & ED visits (OR = 1.09, 95% CI: 1.02–1.16 & OR = 1.52, 95% CI: 1.23–1.83), whereas those with physician office visits were less likely to initiate DS (OR = 0.69, 95% CI: 0.52–0.73). This finding was contrasting with MPC patients, where the likelihood of DS receipt was higher among those with physician office visits (OR = 1.26, 95% CI: 1.15–1.33). In addition, in all 3 cancer cohorts, higher CCI was associated with higher likelihood of DS initiation. It is also notable that patients with history of impaired renal function were more likely to receive DS compared to ZA (OR = 1.37, 95% CI: 1.19–1.44; OR = 1.29, 95% CI: 1.08–1.39; & OR = 1.06, 95% CI: 1.01–1.12, for MLC, MBC, & MPC, respectively). The receipt of chemotherapy was associated with a higher likelihood of receiving DS while the receipt of radiation was associated with lower odds of using DS in both MLC and MPC cohorts. In addition, MBC patients having a history of aromatase inhibitor use were more likely to initiate DS vs ZA (OR = 1.10, 95% CI: 1.04–1.19) and MPC patients who received androgen deprivation therapy tended to initiate DS rather than ZA (OR = 1.08, 95% CI: 1.01–1.16, Table 3 , Supplementary Fig. 6 ). Finally, a closer look at the breast tumor subtype indicated that MBC patients with HER2+/HR- subtype were more likely to initiate DS than those with HER2+/HR + subtype (OR = 1.93, 95% CI: 1.07–2.45, Table 3 , Supplementary Fig. 5 ). 4. Discussion Overall, we found significantly increasing trends in DS initiation within the 12 months of MLC, MBC, and MLC diagnosis during the study period (2012–2017). Correspondingly, we found significantly decreasing trend in ZA initiation within 12 months of MBC diagnosis during the same time period. Additionally, the trends in ZA initiation within 12 months of diagnosis among MPC and MLC patients also decreased, although not statistically significant. ZA (Brand: Zometa®), approved in 2002, has been available in the US market long before DS entry. DS (Brand: Xgeva®) was approved by the FDA in late 2010 and subsequently became available in the US market to be used for the prevention of SREs in patients with bone metastases from solid cancers. 40 In our study, we observed that at the start of the study period (index year 2012) proportions of MPC and MLC patients initiating the ZA were much higher than that of the proportions of DS initiators when DS just entered US market. Moving forward in the study period, the proportions of ZA initiators gradually decreased while the proportion of DS initiators increased at the same time. One potential explanation of this increase in DS uptake can be that the RCTs showing DS to be superior to ZA in delaying time to first on-study SRE in MBC and MPC patients and non-inferior to ZA for the same outcome in MLC patients. 24–26 DS is administered as a subcutaneous injection which can be convenient compared to the intravenously given ZA for the same indication. Importantly, DS is not excreted through the kidney which is a potential advantage compared to ZA for patients with metastatic solid cancer and chronic kidney disease. 41 We found the highest proportion of DS uptake in the MBC patient cohort, while the uptake was lower overall in the MLC cohort. This finding aligns with an earlier study which reported an overall higher BMA uptake among Medicare beneficiaries with breast cancer in 2012. 17 Although the RCTs have shown superiority of DS over ZA in delaying the SREs in patients with breast and prostate cancer, DS was only found to be noninferior to ZA in patients with lung cancer. 24–26 This can potentially explain the overall lower uptake of DS in MLC patients. It is also noticeable from the trends in overall MLBPC cohort that, up until 2014, proportion of ZA initiators were higher in comparison to DS initiators. Interestingly, the only significant trend in DS initiation within 6 months of diagnosis was observed for the MBC cohort only, whereas, only the trend in ZA initiation among MPC patient decreased significantly. It is also noteworthy that, overall a quarter of MLBPC patients received the BMAs (DS or ZA) treatment within the first 6-month of diagnosis, while the proportion almost doubled for the 12-month period. Even at this rate, it is possible that approximately half of the MLBPC patients did not receive optimal treatment to prevent SREs. However, our study cohort was not limited to patients with bone metastasis only, so it is possible that many of these patients who didn’t receive either of the treatments did not have bone metastasis and therefore might not need to initiate these treatments. Another possible explanation is that they could have initiated with BMAs other than DS or ZA. We did not include other bisphosphonates in our analysis as ZA is found to be superior in delaying SREs among the bisphosphonates. 42 In the bivariate and multivariable analyses, demographic characteristics were found to play important roles in DS or ZA initiation. Overall, age was found to be a significant factor affecting the initiation among the MBC patients, with younger patients more likely to initiate DS compared to the ZA. Again, we found that compared to White MLBPC patients, Black/African American MBC and MPC patients had significantly lower likelihood of uptake of DS than White patients. A recent study conducted among MPC patients found higher incidence rate of first SRE among White males compared to Black/African American males. 43 This disparity can be partially explained by the fact that Black/African American men have higher bone density than White men. 44 It is possible that the Black patients who have lower risk of SREs tend to have an overall lower uptake BMAs, be it DS or ZA. However, currently there is no strong evidence to support the lower use of either of the BMAs as seen in the MBC and MPC patient cohort in our study. It was also noticed from our analysis that for the MLC cohort, Black patients were more likely to initiate DS than ZA. Regardless of this contrasting finding for the Black patients, Hispanic patients are revealed to have significantly higher odds of receiving DS compared to White patients. This finding is interesting and should be explored further in future studies. Again, for all the three cancer cohorts, it is noticeable that the patients in rural areas are significantly less likely to receive DS compared to ZA. Another common predictor of DS initiation in the individual cohorts and the overall MLBPC cohort was ineligible for low-income subsidy. This can be due to the potential higher cost associated with DS treatment than ZA as mentioned earlier. 21–23 The healthcare utilization and comorbidities prior to cancer diagnosis were also found to be important factors affecting DS/ZA initiation. Overall, patients who initiated with DS rather than ZA had higher number of comorbidities, supported by the fact that they also had overall higher hospitalization, ED visits, and physician office visits. In addition, patients who had underlying impaired renal function were more likely to initiate with DS compared to ZA, which can be explained since DS is safe to be used in patients with chronic kidney disease. In the overall MLBPC cohort, history of osteoporosis wasn’t found to significantly impact the uptake of either DS/ZA. Moreover, from the drug utilization factors, we found that, MBC patients with history of aromatase inhibitor and MPC patients with androgen deprivation therapy were more likely to initiate DS compared to ZA. This aligns with the fact that denosumab treatment is indicated to increase bone mass in women at high risk for fracture from aromatase inhibitor therapy for breast cancer. 40,45 Again, denosumab was also associated with increased bone mineral density and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. 46 Our study has some limitations. First, causality cannot be established for identified factors and initiation of DS/ZA among MLBPC patients due to observational study design. However, the new user approach may minimize biases from modification of variables on the causal pathway that usually occur in observational studies. 47 In addition, we did not limit our study sample to those who only has bone metastasis diagnosis as currently there is no validated algorithm to identify patients with bone metastasis from SEER-Medicare data. 48 SEER started to document metastases to the bone, brain, liver, and lung among all patients from 2010. A population-based study comparing bone metastasis diagnosis codes in the Medicare claims with bone metastasis collected by the SEER registries revealed that the Medicare claims had only 58.8% sensitivity and 54.1% specificity for identifying bone metastasis at diagnosis. 48 It is possible that the trends and characteristics of initiators vary according to the site of metastasis. Again, our study was limited to new users of DS or ZA after the MLBPC diagnosis and we did not analyze the impact of prior bisphosphonate use on the trend of DS/ZA initiation. Next, due to the nature of the claims data, we did not have access to any biological markers or laboratory values of important biological factors that can potentially drive the decision for DS versus ZA uptake. Last but not least, our results may not be generalizable to populations not represented in SEER-Medicare data, such as younger individuals or those who did not have breast, lung, and prostate cancer. However, the methods used in this study can be applied to other RWD sources. 5. Conclusion This study revealed important differences in the trends in DS and ZA initiation among the older MLBPC patients. In addition, differences in demographic and clinical characteristics of new DS and ZA users indicate potential disparity in usage of the treatments among different patient subgroups. Findings serve as a basis to build evidence regarding comparative benefits and assist clinicians and policymakers in decision-making in treatment uptake. Further research is warranted with focus on patients having bone metastasis and assess information on important biomarkers and clinical characteristics related to BMA use. Declarations Funding : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgement : This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Centers for Medicare & Medicaid Services, Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors. IRB Statement: This study was reviewed and approved by the Auburn University Institutional Review Board (IRB). Data Availability Statement: The datasets used to conduct this study are available upon approval of a research protocol from the National Cancer Institute. Instructions for obtaining these data are available at https://healthcaredelivery.cancer.gov/seermedicare/obtain/ Author Contributions: Kaniz Afroz Tanni - Conceptualization, Methodology, Formal Analysis, Manuscript Writing & Editing Nedret Billor- Supervision, Methodology, Manuscript Writing & Editing Surachat Ngorsuraches- Supervision, Methodology, Manuscript Writing & Editing Salisa Westrick- Supervision, Methodology, Manuscript Writing & Editing Pei Xu- Supervision, Methodology, Manuscript Writing & Editing Brandon Johnson- Supervision, Methodology, Manuscript Writing & Editing Jingjing Qian- Supervision, Methodology, Manuscript Writing & Editing Conflict of interest : No conflicts of interest to report for all authors. References Cancer Stat Facts: Common Cancer Sites. 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The treatment of metastatic carcinoma and myeloma of the femur: Clinical practice guideline. http://msts.org/view/download.php/education/mbd-cpg-amended. Published 2020. Accessed 22 November 2022. Network NCC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer. https://www2.tri-kobe.org/nccn/guideline/lung/english/non_small.pdf. Published 2021. Accessed 22 November 2022. Network NCC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published 2021. Accessed 22 November 2022. Network NCC. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Published 2021. Accessed 22 November 2022. Heeke A, Nunes MR, Lynce F. Bone-Modifying Agents in Early-Stage and Advanced Breast Cancer. Current Breast Cancer Reports. 2018;10(4):241-250. Borek DM, Smith RC, Gruber CN, Gruber BL. Long-term persistence in patients with osteoporosis receiving denosumab in routine practice: 36-month non-interventional, observational study. Osteoporos Int. 2019;30(7):1455-1464. Singer AJ, Liu J, Yan H, Stad RK, Gandra SR, Yehoshua A. Treatment patterns and long-term persistence with osteoporosis therapies in women with Medicare fee-for-service (FFS) coverage. Osteoporos Int. 2021;32(12):2473-2484. Hernandez RK, Adhia A, Wade SW, et al. Prevalence of bone metastases and bone-targeting agent use among solid tumor patients in the United States. Clin Epidemiol. 2015;7:335-345. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-World Evidence - What Is It and What Can It Tell Us? N Engl J Med. 2016;375(23):2293-2297. Institute NC. Cancer Stat Facts: Common Cancer Sites. https://seer.cancer.gov/statfacts/html/common.html. Published 2021. Accessed 22 November 2022. Tack L, Lefebvre T, Lycke M, et al. Underrepresentation of vulnerable older patients with cancer in phase II and III oncology registration trials: A case-control study. J Geriatr Oncol. 2020;11(2):320-326. Shapiro CL. Bone-modifying Agents (BMAs) in Breast Cancer. Clinical Breast Cancer. 2021;21(5):e618-e630. Koo K, Lam K, Mittmann N, et al. Comparing cost-effectiveness analyses of denosumab versus zoledronic acid for the treatment of bone metastases. Supportive Care in Cancer. 2013;21(6):1785-1791. Shapiro CL, Moriarty JP, Dusetzina S, et al. Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance). J Clin Oncol. 2017;35(35):3949-3955. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132-5139. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125-1132. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822. Weir HK, Johnson CJ, Mariotto AB, et al. Evaluation of North American Association of Central Cancer Registries' (NAACCR) data for use in population-based cancer survival studies. J Natl Cancer Inst Monogr. 2014;2014(49):198-209. World Health Organization. International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). https://www.who.int/standards/classifications/other-classifications/international-classification-of-diseases-for-oncology. Published 2013. Accessed 7 January 2022. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471-1474. Osazuwa-Peters N, Barnes JM, Okafor SI, et al. Incidence and Risk of Suicide Among Patients With Head and Neck Cancer in Rural, Urban, and Metropolitan Areas. JAMA Otolaryngol Head Neck Surg. 2021;147(12):1045-1052. Melony E. Sorbero PMSMPH, Susan M. Paddock P, Cheryl L. Damberg P, et al. Adjusting Medicare Advantage Star Ratings for Socioeconomic Status and Disability. The American Journal of Managed Care. 2018;24(9). Möller S, Bliddal M, Rubin KH. Methodical considerations on adjusting for Charlson Comorbidity Index in epidemiological studies. Eur J Epidemiol. 2021;36(11):1123-1128. Osteoporosis ICD-9-CM & ICD-10-CM Codes. https://www.boneandjointburden.org/fourth-edition/iva8/icd-9-cm-and-icd-10-cm-codes. Published 2015. Accessed 3 January 2022. ICD-9 & 10-CM Diagnosis Code: Hypercalcemia. http://www.icd9data.com/2015/Volume1/240-279/270-279/275/275.42.htm. Published 2015. Accessed 3 January 2022. Tremblay É, Perreault S, Dorais M. Persistence with denosumab and zoledronic acid among older women: a population-based cohort study. Arch Osteoporos. 2016;11(1):30. Satkunasivam R, Kim AE, Desai M, et al. Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis. J Urol. 2015;194(2):378-385. Matthews AA, Peacock Hinton S, Stanway S, et al. Endocrine therapy use and cardiovascular risk in postmenopausal breast cancer survivors. Heart. 2021;107(16):1327-1335. Trogdon JG, Falchook AD, Basak R, Carpenter WR, Chen RC. Total Medicare Costs Associated With Diagnosis and Treatment of Prostate Cancer in Elderly Men. JAMA Oncology. 2019;5(1):60-66. Liu H. Cochran-Armitage Trend Test Using SAS. PharmaSUG Conference Proceedings Web site. https://www.lexjansen.com/pharmasug/2007/sp/SP05.pdf. Accessed 2 March 2022. Highlights of prescribing information: Xgeva (denosumab). US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf. Published 2013. Accessed 24 August 2023. Peddi P, Lopez-Olivo MA, Pratt GF, Suarez-Almazor ME. Denosumab in patients with cancer and skeletal metastases: a systematic review and meta-analysis. Cancer Treat Rev. 2013;39(1):97-104. Raghu Subramanian C, Talluri S, Mullangi S, Lekkala MR, Moftakhar B. Review of Bone Modifying Agents in Metastatic Breast Cancer. Cureus. 2021;13(2):e13332. Kawai AT, Martinez D, Saltus CW, Vassilev ZP, Soriano-Gabarró M, Kaye JA. Incidence of Skeletal-Related Events in Patients with Castration-Resistant Prostate Cancer: An Observational Retrospective Cohort Study in the US. Prostate cancer. 2019;2019:5971615-5971615. Aloia JF. African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox. Am J Clin Nutr. 2008;88(2):545s-550s. Highlights of prescribing information: Denosumab US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125320s5s6lbl.pdf. Published 2011. Accessed 13 September 2023. Smith MR, Egerdie B, Toriz NH, et al. Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer. New England Journal of Medicine. 2009;361(8):745-755. Yoshida K, Solomon DH, Kim SC. Active-comparator design and new-user design in observational studies. Nat Rev Rheumatol. 2015;11(7):437-441. Program NCIHDR. Measures that are Limited or not Available in the Data. https://healthcaredelivery.cancer.gov/seermedicare/considerations/measures.html. Published 2023. Accessed 13 September 2023. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4223964","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":291588121,"identity":"059094b8-5a35-460a-8e7b-b158867c9868","order_by":0,"name":"Kaniz Afroz Tanni","email":"","orcid":"","institution":"Auburn University","correspondingAuthor":false,"prefix":"","firstName":"Kaniz","middleName":"Afroz","lastName":"Tanni","suffix":""},{"id":291588122,"identity":"eff40e8f-9381-4c15-a8c7-3bf137d83729","order_by":1,"name":"Nedret Billor","email":"","orcid":"","institution":"Auburn 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Cancer]\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/032b90ec0e859eb744bcd9ab.png"},{"id":55112961,"identity":"8a1ce835-5335-49e2-b05b-152285d8fda5","added_by":"auto","created_at":"2024-04-22 19:10:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":25828,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrend Analysis of Initiation of Denosumab within 12 months of MLBPC Diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[MLC= Metastatic Lung Cancer, MBC= Metastatic Breast Cancer, MPC= Metastatic Prostate Cancer, DS= Denosumab]\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/25b191165db5154aea64e894.png"},{"id":55112965,"identity":"c30dba9c-6d23-40ab-b94f-444efe7302cf","added_by":"auto","created_at":"2024-04-22 19:10:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23279,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrend Analysis of Initiation of Zoledronic Acid within 12 months of MLBPC Diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[MLC= Metastatic Lung Cancer, MBC= Metastatic Breast Cancer, MPC= Metastatic Prostate Cancer, ZA= Zoledronic Acid]\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/4545228ba0258b920d13df85.png"},{"id":55112963,"identity":"a5978de5-63f6-4809-ae77-8403ecc7b476","added_by":"auto","created_at":"2024-04-22 19:10:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":20518,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrend Analysis of Initiation of Denosumab or Zoledronic Acid within 12 months of MLBPC Diagnosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[MLBPC= Metastatic Lung, Breast, and Prostate Cancer, DS= Denosumab. ZA= Zoledronic Acid]\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/8f035dbb26750093d30947bb.png"},{"id":60606102,"identity":"67cde623-d581-4255-8558-3df681af99da","added_by":"auto","created_at":"2024-07-18 16:59:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1557899,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/54583f19-7dcc-45d3-a097-a2222e52d6cb.pdf"},{"id":55112972,"identity":"1e0aa664-6507-475d-a7b8-2603ec062c28","added_by":"auto","created_at":"2024-04-22 19:10:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":202910,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile.docx","url":"https://assets-eu.researchsquare.com/files/rs-4223964/v1/dc36c1f190134790b5269f4c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Trends and Factors Affecting the Initiation of Denosumab and Zoledronic Acid among Patients with Metastatic Lung, Breast, and Prostate Cancer in the United States","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eLung, breast, and prostate cancers, the leading causes of cancer mortality, are estimated to cause 205,470 new deaths in 2023 in the United States (US).\u003csup\u003e1\u003c/sup\u003e The metastatic lung, breast, and prostate cancer (MLBPC) patients may develop a wide range of skeletal complications, commonly referred to as the skeletal-related events (SREs). SREs may include but not limited to conditions such as pathologic fracture, need for radiation or surgery to bone, spinal cord compression, or hypercalcemia.\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e SREs are known to significantly decrease patient\u0026rsquo;s survival (patients experiencing one SRE have a 10-fold higher risk of death than those without an SRE), mobility, and quality of life, as well as increase the cost burden for MLBPC patients.\u003csup\u003e5\u0026ndash;7\u003c/sup\u003e The total cost per patient over a 12-month period are \u003cspan\u003e$\u003c/span\u003e22,000-\u003cspan\u003e$\u003c/span\u003e28,000 higher among patients with SREs than among patients without SREs.\u003csup\u003e8,9\u003c/sup\u003e \u003c/p\u003e \u003cp\u003eTo prevent SREs, the US clinical practice guidelines recommend the use of bone-modifying agents (BMAs) for patients with bone metastasis from solid cancers.\u003csup\u003e10\u0026ndash;13\u003c/sup\u003e BMAs, including zoledronic acid (ZA) and denosumab (DS), modulate osteoclastic activity to suppress the decaying of bone.\u003csup\u003e14\u003c/sup\u003e Although these drugs have been marketed in the US for over a decade, real-world evidence (RWE) about their utilization in older MLBPC patients is limited. A few studies have examined the utilization of BMAs among patients with osteoporosis,\u003csup\u003e15,16\u003c/sup\u003e and one observational study evaluated the use of BMAs among patients with cancer in 2012\u003csup\u003e17\u003c/sup\u003e, but there is a lack of recent evidence regarding the patterns and predictors of BMA use among older MLBPC patients. Although randomized controlled trials (RCTs) are considered to be the gold standard for generating clinical evidence, the use of RWE, defined as the clinical evidence derived about the utilization of a medical product, serves important roles in healthcare decision-making.\u003csup\u003e18\u003c/sup\u003e RCTs have strict eligibility criteria and less generalizability to the overall US patients with cancer. For instance, the median age of MLBPC diagnosis varies between 63\u0026ndash;70 years in the US.\u003csup\u003e19\u003c/sup\u003e In contrast, older patients are underrepresented in most of the registrational trials of oncologic products.\u003csup\u003e20\u003c/sup\u003e To date, post-marketing evaluation with comparisons of initiation of DS versus ZA in older MLBPC patients using RWD from the US is limited. DS treatment in standard dosing is known to cost much more compared to ZA treatment (the estimated drug and administration cost of ZA was \u003cspan\u003e$\u003c/span\u003e252 compared to \u003cspan\u003e$\u003c/span\u003e1,906 for DS every 4 weeks in 2021).\u003csup\u003e21\u0026ndash;23\u003c/sup\u003e In addition, RCTs have shown superiority of DS over ZA in delaying the SREs in patients with breast and prostate cancer and noninferiority in patients with lung cancer.\u003csup\u003e24\u0026ndash;26\u003c/sup\u003e Therefore, the objective of this study was to examine the trends and factors associated with DS and/or ZA initiation among older MLBPC patients in the US.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data Source\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted using the 2011\u0026ndash;2019 Surveillance, Epidemiology and End Results (SEER)\u0026ndash;Medicare linked database. The SEER-Medicare data reflect the linkage of two large population-based sources of data that provide detailed information about Medicare beneficiaries with cancer.\u003csup\u003e27\u003c/sup\u003e This study was reviewed and approved by the Auburn University Institutional Review Board.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Patient Cohort\u003c/h2\u003e \u003cp\u003ePatients with primary cancers of lung, breast, or prostate during 2012\u0026ndash;2017 were identified using International Classification of Diseases for Oncology (ICD-O-3 site: C50.0-50.9 for breast, C61.9 for prostate, and C33.9, C34.0-34.3, C34.8, C34.9 for lung cancer) codes.\u003csup\u003e28\u003c/sup\u003e The full cohort of patients included those with stage IV disease according to the American Joint Committee on Cancer (AJCC) Staging Manual.\u003csup\u003e29\u003c/sup\u003e Next, we identified new users of DS and ZA (using a washout period of 12 months) among patients diagnosed with MLBPC. The inclusion criteria were: MLBPC patients who had at least one Medicare Part B claim based on Healthcare Common Procedure Coding System (HCPCS) J codes for BMAs of interest: DS (J0897) or ZA (J3487) within 12 months after their first observed MLBPC diagnosis (between January 2012-December 2018). The claims of DS/ZA were identified from the National Claims History (NCH), Outpatient, Home Health Agency (HHA), Hospice, and Durable Medical Equipment (DME) files. Exclusion criteria were: \u0026lt;66 years old at cancer diagnosis; cancer diagnosis date missing; cancer diagnosis was from autopsy/death; enrollment in Health Maintenance Organizations (HMOs), Part B claims of either of the BMAs during washout period i.e., within 12 months before index date (date of first prescription), and non-continuous Medicare Parts A and B coverage during the washout period. Finally, we did not exclude the users of other BMAs such as oral bisphosphonates in our study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Factors/Independent Variables of Interest\u003c/h2\u003e \u003cp\u003eWe collected patient\u0026rsquo;s information on the following 5 categories of variables during the pre-index washout period (12 months):\u003c/p\u003e \u003cp\u003e\u003cstrong\u003e\u003cem\u003e1)\u003c/em\u003e\u003c/strong\u003e \u003cstrong\u003e\u003cem\u003eDemographic and socio-economic characteristics\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e age, sex, race/ethnicity, marital status, residence in urban/rural area,\u003csup\u003e30\u003c/sup\u003e SEER region (Northeast, Midwest, South, and West), and Medicare low-income subsidy\u003csup\u003e31\u003c/sup\u003e;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2) Comorbidities\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e Charlson comorbidity index,\u003csup\u003e32\u003c/sup\u003e history of osteoporosis,\u003csup\u003e33\u003c/sup\u003e hypercalcemia,\u003csup\u003e34\u003c/sup\u003e impaired renal function\u003csup\u003e35\u003c/sup\u003e;\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3) Healthcare utilization\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e number of physician office visits, emergency department (ED) visits, and hospitalizations;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e4) Disease characteristics\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003c/em\u003e tumor type/grade (hormone receptor subtype for breast cancer), Gleason score for prostate cancers\u003csup\u003e36\u003c/sup\u003e, and lung cancer subtypes;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e5) Treatment characteristics\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/em\u003ereceipt of chemotherapy, radiation, aromatase inhibitor (for MBC patients) use,\u003csup\u003e37\u003c/sup\u003e androgen deprivation therapy (for MPC patients) use\u003csup\u003e38\u003c/sup\u003e;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary\u003c/strong\u003e \u003cstrong\u003eTable 1\u003c/strong\u003e provides detailed information regarding the variables of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Statistical Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.1 Trend Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome of this study was the new initiation of BMAs, specifically DS and ZA,\u0026nbsp;within 12 months following a diagnosis of MLBPC. \u0026nbsp;The proportion of new DS/ZA users were calculated as those who initiated either therapy within one year of the first observed MLBPC diagnosis, relative to the total number of MLBPC patients in each calendar year (index years). The proportion of any BMA use was plotted by BMA type (DS/ZA) for the index years comprising the study period (2012-2017). For statistical analysis, we employed the Cochran-Armitage trend test to examine if there were significant increasing or decreasing trends in DS or ZA initiation across various disease cohorts, including metastatic lung cancer (MLC), metastatic breast cancer (MBC), metastatic prostate cancer (MPC), and MLBPC over the study time period.\u003csup\u003e39\u003c/sup\u003e\u0026nbsp; In addition, sensitivity analyses were conducted focusing on \u0026nbsp;DS/ZA initiation within 6 months post-diagnosis of \u0026nbsp;MLBPC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.2 Regression Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the assessment of factors influencing the initiation of DS or ZA, we pooled data from new users during January 2012-December 2018. To compare the distributions of variables of interest between DS and ZA initiators, we used two-sample t-tests for continuous variables and either Chi-squared tests or Fisher\u0026rsquo;s exact tests for categorical variables. Subsequently, multiple logistic regression models were fitted to explore predictors affecting the initiation of DS versus ZA (event=1 when DS is initiated and event=0 when ZA is initiated) across different patient cohorts: MLC, MBC, MPC, and MLBPC. All analyses were conducted using SAS version 9.4, with a significance level set at P\u0026lt;0.05.\u0026nbsp;\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Sample Characteristics\u003c/h2\u003e \u003cp\u003eThe detailed step-by-step process for including and excluding patients from these cohorts is elucidated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We identified a total of 99,262 patients with MLBPC diagnosis during January 2012 to December 2017 meeting the inclusion and exclusion criteria. Among them, 66,578 patients (67.07%) had MLC; 17,114 (17.24%) had MBC; and 15,570 (15.69%) had MPC. We found that 1.44%, 1.31%, and 0.42%, MLC, MBC, and MPC patients received both DS and ZA within the 12 months of their MLBPC diagnosis. The range of annual percentage of DS initiators within 12 months of the diagnosis in MLC cohort was between 22.90% and 32.81% across years and the ZA initiators ranged in 28.06%-29.81% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The annual percentage of MBC patients who initiated DS ranged between 26.42% and 36.42%, while 15.71\u0026ndash;25.07% of patients in the same cohort initiated ZA. In the MPC cohort, the range of percentage of DS initiation was 24.89\u0026ndash;31.75% and it was 25.36\u0026ndash;28.29% for ZA initiators.\u003c/p\u003e\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTrend analysis of Denosumab and/or Zoledronic Acid initiation among metastatic lung, breast, and prostate cancer patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eMLC\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eIndex Year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP-Value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDS (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZA (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMBC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIndex Year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eP-Value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDS (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZA (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMPC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIndex Year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eP-Value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDS (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZA (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMLBPC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIndex Year\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eP-Value\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDS (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZA (Yes %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e[*p-values are derived from the Cochran-Armitage trend tests;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eMLC\u0026thinsp;=\u0026thinsp;metastatic lung cancer; MBC\u0026thinsp;=\u0026thinsp;metastatic breast cancer; MPC\u0026thinsp;=\u0026thinsp;metastatic prostate cancer; MLBPC\u0026thinsp;=\u0026thinsp;metastatic lung, breast, and prostate cancers; DS\u0026thinsp;=\u0026thinsp;denosumab; ZA\u0026thinsp;=\u0026thinsp;zoledronic acid]\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eInclusion and Exclusion of Patient Cohort for Trend Analysis\u003c/span\u003e\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eTrend analysis of Denosumab and/or Zoledronic Acid initiation among patients with metastatic lung, breast, and prostate cancer\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Trends in DS/ZA Initiation\u003c/h2\u003e \u003cp\u003eResults of the trend analysis are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and illustrated in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e to \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Across all three individual cancer cohorts, we observed statistically increasing trends in proportion of DS initiation during the study period (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Conversely, proportion of ZA initiation significantly declined in the MBC cohort (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), while remaining stable and non-significant for the MPC and MLC cohorts (P\u0026thinsp;=\u0026thinsp;0.06 and P\u0026thinsp;=\u0026thinsp;0.10, respectively). In addition, for the overall MLBPC cohort, proportion of DS initiation within 12 months of metastatic cancer diagnosis showed a significant upward trend (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), while ZA initiation correspondingly declined (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). For the sensitivity analyses of trends in DS/ZA initiation within 6 months of diagnosis (\u003cb\u003eSupplementary Fig.\u0026nbsp;1\u0026ndash;3\u003c/b\u003e), results differed from the main analysis. Specifically, proportion of DS initiation continued to significantly increase in the MBC and MPC cohorts (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 and P\u0026thinsp;=\u0026thinsp;0.03, respectively), but remained stable in the MLC cohort (P\u0026thinsp;=\u0026thinsp;0.13). On the other hand, trends in ZA initiation among MBC and MLC patients did not change significantly (P\u0026thinsp;=\u0026thinsp;0.25 and 0.38, respectively), but significantly declined among the MPC cohort (P\u0026thinsp;=\u0026thinsp;0.03). Finally, in the overall MLBPC cohort, trend in DS initiation significantly increased (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) while the trend was stable for ZA initiation (P\u0026thinsp;=\u0026thinsp;0.08).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eTrend Analysis of Initiation of Denosumab within 12 months of MLBPC Diagnosis\u003c/span\u003e\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eTrend Analysis of Initiation of Zoledronic Acid within 12 months of MLBPC Diagnosis\u003c/span\u003e\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eTrend Analysis of Initiation of Denosumab or Zoledronic Acid within 12 months of MLBPC Diagnosis\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Factors Associated with DS/ZA Initiation\u003c/h2\u003e \u003cp\u003eIn our two-sample comparison analysis (\u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e), we discovered significant differences in several key variables among those who initiated DS vs. ZA treatments in various patient cohorts. In the MLC cohort, most studied variable, including age at diagnosis, sex, marital status, low-income subsidy, residential area, SEER-region, hospitalizations, physician office visits, Charlson Comorbidity Index (CCI), history of impaired renal function, and receipt of chemotherapy and radiation, showed statistically significant differences (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). For the MBC cohort, variables like race/ethnicity, marital status, low-income subsidy, SEER-region, hospitalizations and ED visits, CCI, history of osteoporosis, and history of renal impairment had significant differences between DS and ZA users (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Additionally, receipt of aromatase inhibitor (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and breast cancer subtypes (P\u0026thinsp;=\u0026thinsp;0.02) were different between DS and ZA users. In the MPC cohort, the significant differences were found for variables including marital status, low-income subsidy, SEER-region, physician office visits, history of hypercalcemia and impaired renal function, as well as receipt of radiation and androgen deprivation therapy (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Our findings for the overall MLBPC cohort (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplementary Fig.\u0026nbsp;7\u003c/b\u003e) reveal that most of the variables were significantly different except for ED visits, history of osteoporosis, and history of hypercalcemia.\u003c/p\u003e \u003cp\u003eFrom the multivariable analyses (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eSupplementary Figure \u0026minus;\u0026thinsp;4\u003c/b\u003e ) in the MLC cohort, we found significant differences in odds of DS initiation for all the demographic factors. Compared to ZA initiators, the adjusted odds of initiation of DS significantly increases with increased age at diagnosis (OR\u0026thinsp;=\u0026thinsp;1.13, 95% CI: 1.02\u0026ndash;1.36). In contrast, we found that the odds of DS initiation decreased with age for the MBC patients (OR\u0026thinsp;=\u0026thinsp;0.98, 95% CI: 0.96\u0026ndash;0.99). Among MLC patients, females were less likely than males to initiated DS (OR\u0026thinsp;=\u0026thinsp;0.71, 95% CI: 0.53\u0026ndash;0.94). Black MLC patients were more likely to initiate with DS compared to White MLC patients (OR\u0026thinsp;=\u0026thinsp;1.89, 95% CI: 1.29\u0026ndash;3.70), whereas this association was opposite for the MBC and MPC patient cohorts, with White patients more likely to initiate DS than Black patients. However, in all 3 cancer cohorts, Hispanic patients were found to have significantly higher odds of DS initiation compared to White patients. Overall, we found that single patients had significantly higher likelihood of initiating with DS, while those who had low-income subsidy had significantly lower odds of initiating with DS. Residence also seemed to play a role in the use of DS and patients in rural areas were less likely to initiate DS than those residing in urban areas (OR\u0026thinsp;=\u0026thinsp;0.79, 95% CI: 0.42\u0026ndash;0.98; \u0026amp; OR\u0026thinsp;=\u0026thinsp;0.78, 95% CI: 0.55\u0026ndash;0.97 for MLC \u0026amp; MPC cohorts, respectively).\u003c/p\u003e \n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBivariate and Multivariable analysis of factors affecting initiation of Denosumab or Zoledronic Acid in MLBPC\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCategories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eBivariate Analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMultivariable Analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDS (MLBPC)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;27902\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eZA (MLBPC)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;26111\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDS (MLBPC)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at Diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.22 (1.97)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.77 (1.78)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.07 (1.01\u0026ndash;1.12)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace/ethnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19771 (70.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18189 (69.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6118 (21.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6048 (23.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.51 (0.44\u0026ndash;0.58)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e882 (3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e880 (3.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.52 (1.45\u0026ndash;1.68)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e876 (3.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e742 (2.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95 (0.55\u0026ndash;1.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing/unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e255 (0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e252 (0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.94 (0.69\u0026ndash;1.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMarital Status at diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5722 (20.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4942 (18.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.28 (1.15\u0026ndash;1.49)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20035 (71.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18854 (72.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1353 (4.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1753 (6.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.92 (0.86\u0026ndash;1.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e361 (1.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e266 (1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.45 (1.28\u0026ndash;1.98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e431 (1.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e296 (1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.77 (0.59\u0026ndash;0.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLow-income subsidy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2032 (7.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2750 (10.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.58 (0.44\u0026ndash;0.69)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25503 (91.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24149 (88.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e367 (1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e312 (1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.02 (0.86\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eResidence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUrban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23064 (82.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20649 (79.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4701 (16.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5295 (20.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.82 (0.68\u0026ndash;0.98)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137 (0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e167 (0.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.66 (0.45\u0026ndash;0.89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSEER Region\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8423 (30.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7652 (29.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMidwest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6298 (22.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5174 (19.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.13 (1.01\u0026ndash;1.45)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5883 (21.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6005 (23.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.75 (0.59\u0026ndash;1.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7298 (26.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7280 (27.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.69 (0.47\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospitalizations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.95 (0.51)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.93 (0.58)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.07 (1.01\u0026ndash;1.64)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eED Visits\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.69 (0.89)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.71 (0.88)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.12 (0.82\u0026ndash;1.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhysician Office Visits\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.55 (3.96)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.52 (4.13)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.86 (0.79\u0026ndash;0.94)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCharlson Comorbidity Index\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1769 (6.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1457 (5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5717 (20.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5616 (21.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.08 (1.03\u0026ndash;1.14)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6582 (23.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5425 (20.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.27 (1.16\u0026ndash;1.41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13834 (49.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13613 (52.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.45 (1.36\u0026ndash;1.71)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of Osteoporosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25098 (89.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23372 (89.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2804 (10.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2739 (10.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.88 (0.79\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of Hypercalcemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25740 (92.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24078 (92.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2162 (7.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2033 (7.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.85 (0.69\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpaired Renal Function\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22443 (80.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23635 (90.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5459 (19.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2476 (9.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.22 (1.13\u0026ndash;1.36)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21330 (76.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20165 (77.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6572 (23.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5946 (23.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e1.07 (1.03\u0026ndash;1.15)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of Radiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24284 (87.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22067 (84.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3618 (12.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4044 (15.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.73 (0.67\u0026ndash;0.89)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e[values in bivariate analysis are presented as N (%); a\u0026thinsp;=\u0026thinsp;Mean (SD); p values are presented from the t-tests for continuous variables and chi-squared tests for the categorical variable. Logistic regression (multivariable analysis) results are presented as OR (95% CI); DS\u0026thinsp;=\u0026thinsp;Denosumab; MLC\u0026thinsp;=\u0026thinsp;Metastatic Lung Cancer; MBC\u0026thinsp;=\u0026thinsp;Metastatic Breast Cancer; MPC\u0026thinsp;=\u0026thinsp;Metastatic Prostate Cancer]\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable analysis of factors affecting initiation of Denosumab vs. Zoledronic Acid\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDS (MLC)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDS (MBC)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDS (MPC)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at Diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.13 (1.02\u0026ndash;1.36)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.98 (0.96\u0026ndash;0.99)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99 (0.68\u0026ndash;1.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.71 (0.53\u0026ndash;0.94)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing/Unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.47 (1.12\u0026ndash;1.64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.89 (1.29\u0026ndash;3.70)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.51 (0.45\u0026ndash;0.58)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.65 (0.59\u0026ndash;0.88)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2.06 (1.48\u0026ndash;2.79)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2.00 (1.54\u0026ndash;3.29)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.82 (1.37\u0026ndash;2.71)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.59 (1.011\u0026ndash;2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.94 (1.67\u0026ndash;4.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.02 (1.96\u0026ndash;2.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing/unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.86 (1.76\u0026ndash;3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.23 (0.79\u0026ndash;1.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.83 (1.04\u0026ndash;3.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMarital Status at diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarried\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.45 (1.19\u0026ndash;1.63)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.21 (1.09\u0026ndash;1.29)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.17 (1.03\u0026ndash;1.28)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDivorced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.07 (0.89\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.77 (0.69\u0026ndash;0.82)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.59 (0.51\u0026ndash;0.71)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.29 (0.53\u0026ndash;2.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.11 (1.06\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.87 (1.04\u0026ndash;2.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.69 (0.44\u0026ndash;0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81 (0.74\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.88 (0.66\u0026ndash;1.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLow-income subsidy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.64 (0.53\u0026ndash;0.78)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.52 (0.49\u0026ndash;0.64)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.59 (0.42\u0026ndash;0.71)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86 (0.72\u0026ndash;1.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.09 (1.01\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78 (0.68\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eResidence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUrban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.79 (0.42\u0026ndash;0.98)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.94 (0.83\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.78 (0.55\u0026ndash;0.97)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47 (0.23\u0026ndash;0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56 (0.31\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.75 (0.66\u0026ndash;1.01)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSEER Region\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMidwest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.63 (1.42\u0026ndash;1.83)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.76 (0.65\u0026ndash;0.84)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.54 (0.37\u0026ndash;0.78)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNortheast\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.72 (0.54\u0026ndash;0.90)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95 (0.84\u0026ndash;1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.66 (0.49\u0026ndash;0.84)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSouth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.91 (0.82\u0026ndash;1.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.46 (0.39\u0026ndash;0.53)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77 (0.44\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHospitalizations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.09 (1.02\u0026ndash;1.16)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96 (0.92-1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.07 (0.86\u0026ndash;1.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eED Visits\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.52 (1.23\u0026ndash;1.83)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.99 (1.81\u0026ndash;2.20)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.07 (0.83\u0026ndash;1.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhysician Office Visits\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.69 (0.52\u0026ndash;0.73)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 (0.98\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.26 (1.15\u0026ndash;1.33)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCharlson Comorbidity Index\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.09 (1.04\u0026ndash;1.15)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.07 (1.01\u0026ndash;1.12)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.09 (0.98\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.42 (1.36\u0026ndash;1.49)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.22 (1.17\u0026ndash;1.29)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13 (0.99\u0026ndash;1.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.71 (1.58\u0026ndash;1.84)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.18 (1.09\u0026ndash;1.26)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.14 (1.01\u0026ndash;1.21)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of Osteoporosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98 (0.87\u0026ndash;1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.67 (0.55\u0026ndash;0.73)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.18 (0.91\u0026ndash;1.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of Hypercalcemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.92 (0.76\u0026ndash;1.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68 (0.49\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98 (0.91\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eImpaired Renal Function\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.37 (1.19\u0026ndash;1.44)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.29 (1.08\u0026ndash;1.39)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.06 (1.01\u0026ndash;1.12)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of chemotherapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1.15 (1.07\u0026ndash;1.22)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.03 (0.95\u0026ndash;1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.12 (1.08\u0026ndash;1.17)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of Radiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.71 (0.64\u0026ndash;0.88)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81 (0.69\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.67 (0.59\u0026ndash;0.73)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of Aromatase Inhibitor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.10 (1.04\u0026ndash;1.19)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBreast Tumor Subtype\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHER2+/HR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHER2+/HR-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.93 (1.07\u0026ndash;2.45)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHER2-/HR+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.45 (0.81\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHER2-/HR-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.18 (0.66\u0026ndash;2.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.52 (0.86\u0026ndash;2.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceipt of Androgen Deprivation Therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.08 (1.01\u0026ndash;1.16)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGleason Score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.88 (0.56\u0026ndash;1.23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.12 (0.91\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMissing/Unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.76 (0.59\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung cancer subtype\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eREF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSquamous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.88 (0.74\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther NSC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.20 (0.89\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSmall cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.23 (0.85\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown/Missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.68 (0.48\u0026ndash;0.88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e[Logistic regression (multivariable analysis) results are presented as adjusted OR (95% CI); DS\u0026thinsp;=\u0026thinsp;Denosumab; MLC\u0026thinsp;=\u0026thinsp;Metastatic Lung Cancer; MBC\u0026thinsp;=\u0026thinsp;Metastatic Breast Cancer; MPC\u0026thinsp;=\u0026thinsp;Metastatic Prostate Cancer]\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eBivariate and Multivariable analysis of factors affecting initiation of Denosumab or Zoledronic Acid in MLBPC\u003c/span\u003e\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e: \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eMultivariable analysis of factors affecting initiation of Denosumab vs. Zoledronic Acid\u003c/span\u003e\u003c/p\u003e \u003cp\u003eWe also found that the odds of DS initiation were higher among MLC patients with baseline hospitalizations \u0026amp; ED visits (OR\u0026thinsp;=\u0026thinsp;1.09, 95% CI: 1.02\u0026ndash;1.16 \u0026amp; OR\u0026thinsp;=\u0026thinsp;1.52, 95% CI: 1.23\u0026ndash;1.83), whereas those with physician office visits were less likely to initiate DS (OR\u0026thinsp;=\u0026thinsp;0.69, 95% CI: 0.52\u0026ndash;0.73). This finding was contrasting with MPC patients, where the likelihood of DS receipt was higher among those with physician office visits (OR\u0026thinsp;=\u0026thinsp;1.26, 95% CI: 1.15\u0026ndash;1.33). In addition, in all 3 cancer cohorts, higher CCI was associated with higher likelihood of DS initiation. It is also notable that patients with history of impaired renal function were more likely to receive DS compared to ZA (OR\u0026thinsp;=\u0026thinsp;1.37, 95% CI: 1.19\u0026ndash;1.44; OR\u0026thinsp;=\u0026thinsp;1.29, 95% CI: 1.08\u0026ndash;1.39; \u0026amp; OR\u0026thinsp;=\u0026thinsp;1.06, 95% CI: 1.01\u0026ndash;1.12, for MLC, MBC, \u0026amp; MPC, respectively).\u003c/p\u003e \u003cp\u003eThe receipt of chemotherapy was associated with a higher likelihood of receiving DS while the receipt of radiation was associated with lower odds of using DS in both MLC and MPC cohorts. In addition, MBC patients having a history of aromatase inhibitor use were more likely to initiate DS vs ZA (OR\u0026thinsp;=\u0026thinsp;1.10, 95% CI: 1.04\u0026ndash;1.19) and MPC patients who received androgen deprivation therapy tended to initiate DS rather than ZA (OR\u0026thinsp;=\u0026thinsp;1.08, 95% CI: 1.01\u0026ndash;1.16, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eSupplementary Fig.\u0026nbsp;6\u003c/b\u003e). Finally, a closer look at the breast tumor subtype indicated that MBC patients with HER2+/HR- subtype were more likely to initiate DS than those with HER2+/HR\u0026thinsp;+\u0026thinsp;subtype (OR\u0026thinsp;=\u0026thinsp;1.93, 95% CI: 1.07\u0026ndash;2.45, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eSupplementary Fig.\u0026nbsp;5\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOverall, we found significantly increasing trends in DS initiation within the 12 months of MLC, MBC, and MLC diagnosis during the study period (2012\u0026ndash;2017). Correspondingly, we found significantly decreasing trend in ZA initiation within 12 months of MBC diagnosis during the same time period. Additionally, the trends in ZA initiation within 12 months of diagnosis among MPC and MLC patients also decreased, although not statistically significant. ZA (Brand: Zometa\u0026reg;), approved in 2002, has been available in the US market long before DS entry. DS (Brand: Xgeva\u0026reg;) was approved by the FDA in late 2010 and subsequently became available in the US market to be used for the prevention of SREs in patients with bone metastases from solid cancers.\u003csup\u003e40\u003c/sup\u003e In our study, we observed that at the start of the study period (index year 2012) proportions of MPC and MLC patients initiating the ZA were much higher than that of the proportions of DS initiators when DS just entered US market. Moving forward in the study period, the proportions of ZA initiators gradually decreased while the proportion of DS initiators increased at the same time. One potential explanation of this increase in DS uptake can be that the RCTs showing DS to be superior to ZA in delaying time to first on-study SRE in MBC and MPC patients and non-inferior to ZA for the same outcome in MLC patients.\u003csup\u003e24\u0026ndash;26\u003c/sup\u003e DS is administered as a subcutaneous injection which can be convenient compared to the intravenously given ZA for the same indication. Importantly, DS is not excreted through the kidney which is a potential advantage compared to ZA for patients with metastatic solid cancer and chronic kidney disease.\u003csup\u003e41\u003c/sup\u003e We found the highest proportion of DS uptake in the MBC patient cohort, while the uptake was lower overall in the MLC cohort. This finding aligns with an earlier study which reported an overall higher BMA uptake among Medicare beneficiaries with breast cancer in 2012.\u003csup\u003e17\u003c/sup\u003e Although the RCTs have shown superiority of DS over ZA in delaying the SREs in patients with breast and prostate cancer, DS was only found to be noninferior to ZA in patients with lung cancer.\u003csup\u003e24\u0026ndash;26\u003c/sup\u003e This can potentially explain the overall lower uptake of DS in MLC patients. It is also noticeable from the trends in overall MLBPC cohort that, up until 2014, proportion of ZA initiators were higher in comparison to DS initiators. Interestingly, the only significant trend in DS initiation within 6 months of diagnosis was observed for the MBC cohort only, whereas, only the trend in ZA initiation among MPC patient decreased significantly. It is also noteworthy that, overall a quarter of MLBPC patients received the BMAs (DS or ZA) treatment within the first 6-month of diagnosis, while the proportion almost doubled for the 12-month period. Even at this rate, it is possible that approximately half of the MLBPC patients did not receive optimal treatment to prevent SREs. However, our study cohort was not limited to patients with bone metastasis only, so it is possible that many of these patients who didn\u0026rsquo;t receive either of the treatments did not have bone metastasis and therefore might not need to initiate these treatments. Another possible explanation is that they could have initiated with BMAs other than DS or ZA. We did not include other bisphosphonates in our analysis as ZA is found to be superior in delaying SREs among the bisphosphonates.\u003csup\u003e42\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the bivariate and multivariable analyses, demographic characteristics were found to play important roles in DS or ZA initiation. Overall, age was found to be a significant factor affecting the initiation among the MBC patients, with younger patients more likely to initiate DS compared to the ZA. Again, we found that compared to White MLBPC patients, Black/African American MBC and MPC patients had significantly lower likelihood of uptake of DS than White patients. A recent study conducted among MPC patients found higher incidence rate of first SRE among White males compared to Black/African American males.\u003csup\u003e43\u003c/sup\u003e This disparity can be partially explained by the fact that Black/African American men have higher bone density than White men.\u003csup\u003e44\u003c/sup\u003e It is possible that the Black patients who have lower risk of SREs tend to have an overall lower uptake BMAs, be it DS or ZA. However, currently there is no strong evidence to support the lower use of either of the BMAs as seen in the MBC and MPC patient cohort in our study. It was also noticed from our analysis that for the MLC cohort, Black patients were more likely to initiate DS than ZA. Regardless of this contrasting finding for the Black patients, Hispanic patients are revealed to have significantly higher odds of receiving DS compared to White patients. This finding is interesting and should be explored further in future studies. Again, for all the three cancer cohorts, it is noticeable that the patients in rural areas are significantly less likely to receive DS compared to ZA. Another common predictor of DS initiation in the individual cohorts and the overall MLBPC cohort was ineligible for low-income subsidy. This can be due to the potential higher cost associated with DS treatment than ZA as mentioned earlier.\u003csup\u003e21\u0026ndash;23\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe healthcare utilization and comorbidities prior to cancer diagnosis were also found to be important factors affecting DS/ZA initiation. Overall, patients who initiated with DS rather than ZA had higher number of comorbidities, supported by the fact that they also had overall higher hospitalization, ED visits, and physician office visits. In addition, patients who had underlying impaired renal function were more likely to initiate with DS compared to ZA, which can be explained since DS is safe to be used in patients with chronic kidney disease. In the overall MLBPC cohort, history of osteoporosis wasn\u0026rsquo;t found to significantly impact the uptake of either DS/ZA. Moreover, from the drug utilization factors, we found that, MBC patients with history of aromatase inhibitor and MPC patients with androgen deprivation therapy were more likely to initiate DS compared to ZA. This aligns with the fact that denosumab treatment is indicated to increase bone mass in women at high risk for fracture from aromatase inhibitor therapy for breast cancer.\u003csup\u003e40,45\u003c/sup\u003e Again, denosumab was also associated with increased bone mineral density and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.\u003csup\u003e46\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur study has some limitations. First, causality cannot be established for identified factors and initiation of DS/ZA among MLBPC patients due to observational study design. However, the new user approach may minimize biases from modification of variables on the causal pathway that usually occur in observational studies.\u003csup\u003e47\u003c/sup\u003e In addition, we did not limit our study sample to those who only has bone metastasis diagnosis as currently there is no validated algorithm to identify patients with bone metastasis from SEER-Medicare data.\u003csup\u003e48\u003c/sup\u003e SEER started to document metastases to the bone, brain, liver, and lung among all patients from 2010. A population-based study comparing bone metastasis diagnosis codes in the Medicare claims with bone metastasis collected by the SEER registries revealed that the Medicare claims had only 58.8% sensitivity and 54.1% specificity for identifying bone metastasis at diagnosis.\u003csup\u003e48\u003c/sup\u003e It is possible that the trends and characteristics of initiators vary according to the site of metastasis. Again, our study was limited to new users of DS or ZA after the MLBPC diagnosis and we did not analyze the impact of prior bisphosphonate use on the trend of DS/ZA initiation. Next, due to the nature of the claims data, we did not have access to any biological markers or laboratory values of important biological factors that can potentially drive the decision for DS versus ZA uptake. Last but not least, our results may not be generalizable to populations not represented in SEER-Medicare data, such as younger individuals or those who did not have breast, lung, and prostate cancer. However, the methods used in this study can be applied to other RWD sources.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study revealed important differences in the trends in DS and ZA initiation among the older MLBPC patients. In addition, differences in demographic and clinical characteristics of new DS and ZA users indicate potential disparity in usage of the treatments among different patient subgroups. Findings serve as a basis to build evidence regarding comparative benefits and assist clinicians and policymakers in decision-making in treatment uptake. Further research is warranted with focus on patients having bone metastasis and assess information on important biomarkers and clinical characteristics related to BMA use.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This 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\u003eAcknowledgement\u003c/strong\u003e: This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Centers for Medicare \u0026amp; Medicaid Services, Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention\u0026rsquo;s (CDC) National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the National Cancer Institute\u0026rsquo;s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIRB Statement:\u0026nbsp;\u003c/strong\u003eThis study was reviewed and approved by the Auburn University Institutional Review Board (IRB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe datasets used to conduct this study are available upon approval of a research protocol from the National Cancer Institute. Instructions for obtaining these data are available at https://healthcaredelivery.cancer.gov/seermedicare/obtain/\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions: \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaniz Afroz Tanni - Conceptualization, Methodology, Formal Analysis, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eNedret Billor- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eSurachat Ngorsuraches- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eSalisa Westrick- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003ePei Xu- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eBrandon Johnson- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eJingjing Qian- Supervision, Methodology, Manuscript Writing \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e: No conflicts of interest to report for all authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCancer Stat Facts: Common Cancer Sites. 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Accessed 13 September 2023.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Skeletal-related events, metastasis, denosumab, zoledronic acid, utilization, trend analysis","lastPublishedDoi":"10.21203/rs.3.rs-4223964/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4223964/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePatients with Metastatic lung, breast, and prostate cancer (MLBPC) experience skeletal related events (SREs), which significantly decrease survival. Denosumab (DS) and Zoledronic acid (ZA) are recommended for these patients to prevent such SREs. However, there is a lack of evidence in the patterns and predictors of real-world initiation of DS versus ZA in older MLBPC patients in the United States. The objective of this study was to examine the trends and factors associated with DS or ZA initiation among older MLBPC patients in the US.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe used the Surveillance, Epidemiology, and End Results (SEER)-linked Medicare data to identify patients diagnosed with MLBPC between 2012 and 2017 who initiated DS/ZA treatment within 12 months of cancer diagnosis. Demographics, healthcare utilization, comorbidities, disease, and treatment attributes of new users were evaluated. Trends in treatment initiation were assessed using Cochran-Armitage tests among all MLBPC patients and by cancer type. T-tests, Chi-squared tests and multiple logistic regressions were employed to identify factors influencing the choice between DS and ZA initiation.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn 2012\u0026ndash;2017, DS initiation trends increased across all individual cancer cohorts as well as the overall MLBPC sample, while ZA initiation notably decreased in the metastatic breast cancer and MLBPC cohorts (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Patients more likely to initiate DS over ZA were older at diagnosis, Hispanic, single, eligible for low-income subsidies, urban residents, had multiple comorbidities, impaired renal function, and prior chemotherapy use.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThere are significant differences between the trends in DS and ZA initiation as well as in the factors affecting initiation among MLBPC patients.\u003c/p\u003e","manuscriptTitle":"Trends and Factors Affecting the Initiation of Denosumab and Zoledronic Acid among Patients with Metastatic Lung, Breast, and Prostate Cancer in the United States","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-22 19:10:35","doi":"10.21203/rs.3.rs-4223964/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9996bbcc-5d06-44ce-80b1-71744725199b","owner":[],"postedDate":"April 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-18T16:51:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-22 19:10:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4223964","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4223964","identity":"rs-4223964","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}