PERSISTENCE WITH BISPHOSPHONATE THERAPY IN OLDER PEOPLE

To the Editor: Bisphosphonates increase bone mineral density and reduce fracture rates.1 Randomized clinical trials of bisphosphonate therapy generally document high adherence rates (50–86% with risedronate2-4 and 84–89% with alendronate5, 6), although information on adherence in the clinical setting is sparse. The present study investigated persistence with bisphosphonate therapy in a large population of approximately 1.5 million older adults. A retrospective cohort study was conducted using the Ontario Drug Benefit Program database, which records prescription drugs dispensed to all Ontario residents aged 65 and older. Eligible individuals were Ontario residents aged 66 and older who redeemed their first prescription for any bisphosphonate (etidronate, alendronate, or risedronate) between January 1, 1999, and June 30, 2004. At least 1 full year had to have passed before the first prescription during which no bisphosphonate was dispensed. Continual persistence, defined as ongoing bisphosphonate refills within an interval composed of the days of drug supply plus a grace period of 50%, was examined. Each new period of drug use commenced on the day of the subsequent claim, and any remaining drug from the previous claim was added to the new interval. If the claim was dispensed outside the days' supply period but within the grace period, no extra days were added to the subsequent interval. Discontinuation of bisphosphonate therapy was defined as no renewal during the interval defined above. Observation ended when subjects temporarily or permanently discontinued their study drug. Switches from one bisphosphonate to another were allowed. A sensitivity analysis was conducted in which the grace period was extended to 300%, and sporadic persistence, defined as the receipt of a bisphosphonate prescription within 180 days before the end of observation, was also examined. Kaplan-Meier analysis was used to calculate the cumulative risk of persisting with treatment as a function of time since baseline. Patients were censored at the end of the study (December 31, 2004) or date of death, whichever came first. For sporadic persistence, three cohorts (1-year, 3-year, and 5-year cohort survivors) were further assembled, and the proportion of those who had filled a prescription for a bisphosphonate within the 180 days before the end of observation, regardless of intervening persistence, was determined. Analyses were conducted using SAS version 8.2 (SAS Institute, Inc., Cary, NC). During the 5-year study period, 222,311 patients entered the cohort. The majority were women (86.1%), and the median age was 75. The percentage of patients with continual persistence to therapy at 180 days, 1 year, 3 years, and 5 years was 63.9%, 49.1%, 26.6%, and 16.9%, respectively. The median time for persisting with therapy was 11 months (Figure 1). When the exposure grace period was extended to 300%, the percentage of patients persisting with bisphosphonate therapy at 180 days, 1 year, 3 years, and 5 years after cohort entry was 91.4%, 75.8%, 52.1%, and 40.6%, respectively. Sporadic persistence at 1 year, 3 years, and 5 years was 75.3%, 66.6%, and 64.4%, respectively. Cumulative rate of persistence with bisphosphonate therapy for Ontario residents aged 66 and older for January 1999 to June 2004. Persistence was defined as the renewal of prescriptions within the period of drug use, which consisted of the days of drug supply plus a 50% grace period. This study found that half of patients treated with bisphosphonates did not persist with therapy for more than 1 year after their first prescription and that only about 27% persisted with treatment for more than 3 years, in contrast to rates of up to 89% seen in the tightly controlled setting of clinical trials.3-6 One possible explanation for the low persistence rates found in the current study is that physicians might be prescribing intermittent regimens of bisphosphonates. Another reason may be that patients do not persist with treatment because of gastrointestinal intolerance, or because they do not perceive a benefit from the treatment.7 The sporadic approach to persistence rates provided much higher persistence rates than the ones obtained with the continual-use approach (66.6% vs 26.6% at 3 years, 64.4% vs 16.9% at 5 years), suggesting that some patients temporarily interrupt their medication. The clinical implications of such erratic drug use for population-based fracture rates are uncertain. It was not possible to characterize 3-year and 5-year persistence rates for once-weekly formulations of alendronate and risedronate, because these were introduced as provincial formulary benefits only in November 2002 and March 2003, respectively. Future research should compare persistence with the different regimens for the three bisphosphonates, their respective costs, and effectiveness of therapy. In conclusion, in Ontario residents, long-term persistence with bisphosphonates is poor, although the majority of new users exhibit sporadic use during the initial years of therapy. The clinical and economic consequences of suboptimal persistence require further study. Financial Disclosure: None of the authors have any conflict of interest or financial disclosures. Author Contributions: Magda Melo: design, interpretation of data, and drafting of the manuscript. Feng Qiu and Kathy Sykora: design, acquisition of data, statistical analysis and interpretation of data, and critical revision of the manuscript. David Juurlink and Andreas Laupacis: design, interpretation of data, and critical revision of the manuscript. Muhammad Mamdani: conception and design, acquisition of data, analysis and interpretation of data, critical revision of the manuscript, and study supervision. Sponsor's Role: Not applicable.

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