Introduction 1 2 3 4 5 6 7 8 10 11 12 13 14 15 16 17 18 19 20 21 Since the once-a-week dosing regimens of both risedronate and alendronate have been available in the US since 2002, there is now an opportunity to observe their effect on reducing fractures in a large population of patients seen in clinical practice. Hence, we conducted an observational study across multiple US health plans to observe the incidence of hip and nonvertebral fractures among women ages 65 and over following initiation of therapy with once-a-week dosing of either risedronate or alendronate. Methods 22 23 24 Data source The data source was commercially available datasets of healthcare utilization from the 1 health plan within Ingenix Lab/Rx (Eden Prairie, MN; data through June 2004) and the 100 health plans of employers within MedStat Marketscan (Ann Arbor, MI; data through September 2004). These datasets contain a longitudinal history of patient-specific data including demographic information (sex, age, dates of dataset inclusion), clinical encounters (inpatient and outpatient services by associated procedures and diagnoses specified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)), and outpatient pharmaceutical dispensations (retail and mail order specified by the national drug code (NDC)). To maximize sample size, the two datasets were combined for all analyses. At the time of data extraction for the current study, the combined datasets contained 12 million persons across 34 states in the US. Study population 1 12 14 Fig. 1 Identification of the study population  Length of observation 25 Fracture outcomes 12 1 Table 1 Identification of fractures outcomes in the study population (n = 33,830)   a b Subjects with a medical claim for fracture during the observation period after initial bisphosphonate. 135 923 Exclusion of medical claim if a fracture at the same site both before and after start of bisphosphonate therapy; in order to increase the likelihood of including only new fractures. −16 −368 c −2 −6 d −3 −11 e −5 −31 Subjects with a fracture outcome 109 507 a b c d e Statistical analyses 2 Table 2 Comparison of baseline characteristics between cohorts in study   Cohorts Characteristic Risedronate Alendronate p-value Number of women subjects 12,215 21,615  Duration of observation period     Days (mean) 226 238 < 0.001 Age at study entry    Years & months (mean) 74 & 10 74 & 7 < 0.001  Ages 65 – 74 (%) 53.5 52.4   Ages 75 – 84 (%) 36.8 36.7   Ages 85 and over (%) 9.7 11.0  Medications – 6 month history a    b 4.0 3.6 < 0.001 c 26.2 20.1 < 0.001 d 17.2 16.5 0.08 e 15.6 11.0 < 0.001 f 10.3 8.5 < 0.001 Medical encounters – 6 month history a     Office visits (mean) 5.6 5.1 < 0.001  Hospitalization (%) 8.2 8.2 0.87 g 37.7 33.8 < 0.001 h 12.5 10.5 < 0.001 i 47.4 41.5 < 0.001 j 15.4 12.3 < 0.001 k 2.7 2.3 0.01 a b 34 c 35 d e f g h i j 36 k For the primary analysis, the main outcome measures were the 6 and 12 month incidence of nonvertebral fractures and hip fractures. Cox proportional hazard modeling (PROC PHREG, SAS Institute, Cary, NC) was used to compare the incidence of fractures between risedronate and alendronate cohorts, adjusting for potential differences in measurable risk factors for fractures. A parsimonious model for each outcome was developed to enhance precision of the parameter estimates and interpretation of results. The selection of variables to be included in the model was based on forward selection. These models were checked against models based on backward selection. The appropriateness of the proportional hazard assumption was assessed by graphical and numerical methods (ASSESS statement, SAS Institute). 5 Results 2 2 Fig. 2 1 2 3 4  During the 12 months of observation after the start of bisphosphonate therapy, 507 subjects had nonvertebral fractures. The site of nonvertebral fracture was wrist (30%), hip (21%), leg (17%), pelvis (15%), humerus (14%), and clavicle (3%). For the 109 women hospitalized with a hip fracture, the skeletal sites were intertrochanteric (46%), transcervical (28%), unspecified (20%), and trochanteric or subtrochanteric (6%). 3 3 Fig. 3 Cumulative incidence of nonvertebral fractures in patients treated with alendronate or risedronate for up to 1 year  Table 3 Cumulative incidence of fractures during therapy Fracture type Cohort size Number of women with a fracture a b b 95% CI p-value Time on therapy                Cohort               Nonvertebral 6 Months  Alendronate 21,615 253 1.31 – – – –  Risedronate 12,215 123 1.14 0.87 0.81 0.65–1.00 0.05 12 Months  Alendronate 21,615 343 2.30 – – – –  Risedronate 12,215 164 1.99 0.88 0.82 0.68–0.98 0.03 Hip 6 Months  Alendronate 21,615 54 0.29 – – – –  Risedronate 12,215 19 0.17 0.63 0.54 0.32–0.91 0.02 12 Months  Alendronate 21,615 80 0.58 – – – –  Risedronate 12,215 29 0.37 0.68 0.57 0.37–0.87 0.01 CI = confidence interval of adjusted rate ratio a b c 4 3 Fig. 4 Cumulative incidence of hip fractures in patients treated with alendronate or risedronate for up to 1 year  5 Fig. 5 Sensitivity analysis: Rate ratio for fracture in the first year of therapy between patients on risedronate and patients on alendronate; results of the primary analysis and 4 other methods of analyses  Discussion In this observational study across multiple US health plans, we observed that patients on once-a-week dosing of risedronate had a lower incidence of hip and nonvertebral fractures than patients on once-a-week dosing of alendronate. Differences in fracture incidence between these two cohorts of patients were observed at 6 and 12 months after initiating therapy. 26 2 3 4 12 14 6 10 27 28 29 30 31 32 33 In conclusion, within this observational study of clinical practice, a cohort of patients receiving risedronate had lower rates of hip and nonvertebral fractures during their first year of therapy than a cohort of patients receiving alendronate. These results do not appear to be explained by baseline differences in fracture risk between cohorts. In addition, the observed rates of fracture were consistent with the fracture rates in clinical trials. Thus it appears, patients receiving risedronate are better protected from hip and nonvertebral fractures during their first year of therapy than patients receiving alendronate.