1. RATE OF OSTEOPOROTIC FRACTURE OVER TIME AMONG WOMEN WITH AT LEAST ONE YEAR OF ADHERENCE TO OSTEOPOROSIS THERAPY Ankita Modi 1, Jackson Tang 2, Shuvayu Sen 1 1 Global Health Outcomes, Merck & Company 2 AsclepiusJT LLC Introduction Bisphosphonates such as alendronate, ibandronate, and risendronate have shown proven efficacy in randomized clinical trials for increasing bone mineral density (BMD) and reducing risk of osteoporosis-related (fragility) fractures. 1,2 Poor adherence with osteoporosis treatment regimens is a well- recognized problem, and the risk of having osteoporotic-related fractures increases among patients with poor adherence. 3,4 However, fractures may be recorded even in patients who are adherent to osteoporosis treatment. 5,6 Methods Study design A retrospective cohort study using the i3 InVision Data Mart (Ingenix, Eden Prairie, MN); a large U.S. claims database was conducted. The study window was January 1, 2001 to December 31, 2010. The date of first prescription of an oral bisphosphonate during the study window was the index date. There were three consecutive, one-year time periods during which fracture rates were determined (Figure 1): – Baseline period prior to the index date, – Adherence period during which adherence with osteoporosis treatment was calculated (Year 1 after index date), – Study period (Year 2 after index date). Adherence with bisphosphonate treatment was defined as having a medication possession ratio (MPR) of ≥0.6 during the adherence period (MPR = total number of days’ supply/365 days). A MPR of > 0.8 for definition of adherence was also conducted as a sensitivity analysis. Results Patient characteristics Of the 62,446 women who met eligibility criteria, 35,737 (57%) were compliant to osteoporosis therapy during year 2 with mean [SD] age of 60.7 [8.5] years). (Table 1) Hypertension (30.6%), chronic inflammatory joint disease (14.4%), and fatigue (12.8%) were the most common comorbidities. (Table 1) References 1.MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008;148(3):197-213. 2.Siris ES, Pasquale MK, Wang Y, Watts NB. Estimating bisphosphonate use and fracture reduction among US women aged 45 years and older, 2001-2008. J Bone Miner Res. 2011;26(1):3-11. 3.Kothawala P, Badamgarav E, Ryu S, Miller RM, Halbert RJ. Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin Proc. Dec 2007;82(12):1493- 1501. 4.Gallagher AM, Rietbrock S, Olson M, van Staa TP. Fracture outcomes related to persistence and adherence with oral bisphosphonates. J Bone Miner Res. Oct 2008;23(10):1569-1575. 5.Siris ES, Selby PL, Saag KG, Borgstrom F, Herings RM, Silverman SL. Impact of osteoporosis treatment adherence on fracture rates in North America and Europe. Am J Med. 2009;122(2 Suppl):S3-13. 6.Ross S, Samuels E, Gairy K, Iqbal S, Badamgarav E, Siris E. A meta-analysis of osteoporotic fracture risk with medication nonadherence. Value Health. 2011;14(4):571-581. 7.Kanis JA, Oden A, Johnell O. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporos Int. 2001;12(5):417-27. 8.Desai SS, Duncan BS, Sloan AS. The Cost of Treating Osteoporosis in a Managed Health Care Organization. J Manag Care Pharm. 2003 Mar-Apr;9(2):142-9. 9.David C, Confavreux CB, Mehsen N et al. Severity of osteoporosis: What is the impact of co- morbidities? Joint Bone Spine, 77 (2010) S103-S106. Percent patients with fractures in the Baseline, adherence, and Study periods Osteoporotic-related fractures were recorded in the baseline, adherence, and study periods for 1,507 (4.2%), 1,397 (3.9%), and 1,173 (3.3%) patients. The fracture rate during the study period was 52/1000 patient-years. (Table 2) Vertebral and other non-vertebral fractures were most common, representing over two thirds of all fractures during each of the three periods. (Table 2) Table 1. Patient characteristics in the Baseline period A Study sample Included osteoporotic women 50 years or older whose first osteoporosis treatment was an oral bisphosphonate from 2001- 2010 and continuously enrolled for three consecutive years -- one year before the index date and two years after the index date. Women were excluded if they had a diagnosis of malignant neoplasm or a Paget's disease. (Figure 2). Oral bisphosphonate treatment included alendronate, ibandronate, or risedronate. Medications were selected based on National Drug codes. Conclusions Among women 50 years and over on treatment with oral bisphosphonates, 3.9% experienced an osteoporotic-related fracture while being compliant to bisphosphonate treatment. Despite being compliant to bisphosphonate treatment for one year, 3.3% of patients experienced a fracture in the subsequent year. Additional interventions may be needed to manage osteoporosis in adherent patients who may not be well controlled with current therapies. Figure 2. Patient selection Objective To examine the rates of osteoporosis-related fractures over two years of treatment among patients who were adherent to oral bisphosphonates for at least one year. Osteoporosis-related fractures included non-traumatic fractures occurred at the hip, vertebral, and non-vertebral sites. 7.8 Osteoporosis-related fractures were identified by the ICD-9-CM codes which were recorded in the primary and/or secondary diagnoses in medical claims. Data analysis The main analysis was conducted among patients who met the study inclusion criteria and who were adherent (MPR > 0.6) in the adherence period. – A sensitivity analysis using adherence defined as MPR >= 0.8 was also conducted. The primary outcome was the frequency of osteoporotic fractures during the baseline, adherence, and study period. The number of osteoporosis-related fractures was defined as the total number of distinct fractures. History of fracture is defined as an occurrence of osteoporotic- related fracture during the baseline or adherence period. Rate of osteoporotic-related fracture during the study period was computed as number of osteoporotic fractures per 1,000 patient years among adherent patients. Rate of osteoporotic-related fracture during the study period was also compared between those with a history of fracture and those without, and those who remained adherent in the study period and those who did not. Table 2. Percentage of patients with osteoporotic fractures in the Baseline, adherence, and Study periods A Table 3. Fracture rates in the Study period by fracture history and by adherence in the Study period A Figure 1. Study time periods N = 3,021,390 Patients with osteoporosis diagnosis, fracture or treatment Patients whose first treatment is a bisphosphonate during study window. N = 845,091 N = 106,105 Patients with at least 12-month continuous eligibility before and 24- month of continuous eligibility after the index date N = 35,737 (57%) Patients who were adherent N = 26,709 (43%) Patients who were non-adherent N = 67,463 Patients without Paget's disease or diagnoses of malignant neoplasm Women > 50 years of age as of index date N = 62,446 Index Date Adherence period (12-months) Study period (12-months) MPR being calculated Baseline period (12-months) adherence measured Naive to all osteoporosis treatment Adherent patients Characteristic (N=35,737) Age at index date (years), mean (SD)60.7 (8.5) 50-5919,883 (55.6) 60-6910,023 (28.0) 70-793,853 (10.8) ≥801,978 (5.5) Charlson index, mean (SD)0.37 (0.82) Comorbidities 9 Chronic inflammatory bowel disease284 (0.8) Chronic inflammatory joint disease5,142 (14.4) Diabetes2,411 (6.8) Depression1,636 (4.6) Chronic kidney disease206 (0.6) Hypertension10.948 (30.6) ____________________________________________________________ A Values are presented as N (%) unless otherwise indicated. Baseline periodadherence periodStudy period Experienced fractures1,507 (4.2)1,397 (3.9)1,173 (3.3) Hip265 (0.7)218 (0.6)171 (0.5) Vertebral459 (1.3)391 (1.1)312 (0.9) Non-vertebral974 (2.7)919 (2.6)821 (2.3) Rib132 (0.4)126 (0.4)148 (0.4) Clavicle, scapula, and sternum33 (0.1)34 (0.1)43 (0.1) Pelvis104 (0.3)84 (0.2)69 (0.2) Humerus185 (0.5)147 (0.4)124 (0.4) Forearm378 (1.1)357 (1.0)315 (0.9) Femur105 (0.3)82 (0.2)80 (0.2) Tibia and fibula169 (0.5)162 (0.5)129 (0.4) Number of distinct fractures 11,007 (2.8)853 (2.4)783 (2.2) 2303 (0.9)302 (0.9)242 (0.7) 3115 (0.3)132 (0.4)84 (0.2) ≥482 (0.2)110 (0.3)64 (0.2) Number of distinct fracture sites 11,329 (3.7)1,273 (3.6)1,054 (3.0) 2165 (0.5)117 (0.3)107 (0.3) 313 (0.0)7 (0.0)12 (0.0) A Values are presented as N (%) unless otherwise indicated. Definition of adherence Study period outcomes MPR > 0.6 (Main analysis) MPR > 0.8 (Sensitivity analysis) All Fracture history All Fracture history YesNoYesNo Number of patients 35,737 (100) 2,350 (6.6) 33,387 (93.4) 26,852 (100) 1,776 (6.6) 25,076 (93.4) Number of patients with osteoporotic- related fracture 1,173 (3.3) 423 (18.0) 750 (2.2) 871 (3.2) 319 (18.0) 552 (2.2) Number of fractures1,8517371,1141,389556833 Number of fractures/1,000 patient-years 52314335231333 All Compliant for another year (study period) All Compliant for another year (study period) YesNoYesNo Number of patients 35,737 (100) 24,342 (68.1) 11,395 (31.9) 26,852 (100) 14,364 (53.5) 12,488 (46.5) Number of patients with osteoporotic- related fracture 1,173 (3.3) 784 (3.2) 389 (3.4) 871 (3.2) 457 (3.2) 414 (3.3) Number of fractures18511,2336181389700689 Number of fractures/1,000 patient-years 525154524955 A Values are presented as N (%) unless otherwise indicated. Fracture rates during the study period by history of fracture or by adherence in the study period Patients with a history of fracture experienced a higher rate of fracture during the study period (18.0%) compared to those without (2.2%). (Table 3) For the 24,342 (68.1%) patients who remained adherent for 2 years (in the adherence and study period), 784 (3.2%) experienced osteoporotic-related fractures during the study period. (Table 3) The fracture rate during the study period was 3.2% among those who remained adherent and 3.4 % among those who didn’t. (Table 3) A sensitivity analysis using MPR > 0.8 as a definition of adherence yielded similar results, indicating that robustness of the definition and study results. European Congress on Osteoporosis and Osteoarthritis Bordeaux, France March 21-24, 2012