Adherence to osteoporosis drugs and fracture prevention: no evidence of healthy adherer bias in a frail cohort of seniors

Abstract

We examined new users of osteoporosis drugs among seniors in Pennsylvania and found no evidence of healthy adherer bias on observed associations between adherence to treatment and non-vertebral fracture risk; we document fracture reduction with better adherence to bisphosphonates, yet no fracture reduction with better adherence to calcitonin or raloxifene.

Introduction: We examined the potential for "healthy adherer bias" when studying the effects of adherence to osteoporosis pharmacotherapy on fracture risk. Based on clinical trial evidence, bisphosphonates, calcitonin, and raloxifene reduce vertebral fracture risk; yet only bisphosphonates are documented to reduce non-vertebral fracture risk.

Methods: This is a cohort study of older women in Pennsylvania who initiated osteoporosis drugs between 1995 and 2005. We included new users of bisphosphonates, calcitonin, and raloxifene. Adherence was categorized based on a measure of compliance as high [proportion of days covered (PDC) ≥ 80%], intermediate (50% < PDC < 80%), or low (PDC ≤ 50%) according to a 180-day ascertainment period. Non-vertebral fracture rates within 365 days after the ascertainment period were compared between adherence categories (reference = low) using Cox proportional hazard models and adjusting for fracture risk factors. Primary and secondary prevention cohorts were examined separately. Adherence to calcitonin and raloxifene were control analyses.

Results: We found little difference in fracture rates between levels of adherence to calcitonin, bisphosphonates for primary prevention, or raloxifene for secondary prevention. We document lower fracture rates among high versus low adherent bisphosphonate users for secondary prevention (HR = 0.53, 95%CI = 0.38-0.74) and higher fracture rates among high versus low adherent raloxifene users for primary prevention (HR = 2.01, 95%CI = 1.04-3.87).

Conclusions: We document little evidence of healthy adherer bias when studying the association between better adherence to osteoporosis drugs and fracture risk reduction, with only better adherence to bisphosphonates reducing fracture risk. The higher fracture risk among highly adherent raloxifene users for primary prevention is likely due to residual confounding.

Fig. 1

Study design. *Index date; at the time of analysis, we had complete Medicare data from January 1, 1994 through to December 31, 2005. Inclusion was limited to those with at least one Medicare and pharmacy claim in each of the three 6-month intervals prior to treatment initiation (system activity); therefore, July 1, 1995 is the first possible date of treatment initiation. Baseline period: 1-year lookback to define new users and to assess covariates. Adherence ascertainment period: Eligibility restricted to new users with complete drug coverage during the ascertainment period (drug coverage, survive, community-dwelling). Patients experiencing a hip, humerus, radius, or ulna fracture or spending 50% or more days in hospital during the ascertainment period were excluded. Adherence based on a measure of compliance and calculated as proportion of days covered, adjusting for number of days in hospital [20] = total days supply/(total number of days evaluated – number of days in hospital); capped at 1.0. Follow-up for outcome assessment: maximum length of follow-up was 365 days from the end of the 180-day ascertainment period or December 31, 2005

Fig. 2

Adjusted risk (hazard ratio and 95% confidence intervals) for non-vertebral fracture and preventive healthcare services for highly adherent versus low adherent users of oral bisphosphonates, calcitonin and raloxifene in primary prevention (a) and secondary prevention (b) cohorts. FX hip, humerus, radius, or ulna fracture (adjusts for fracture risk factors), HIP hip fracture (adjusts for fracture risk factors), FLU influenza vaccination (adjusts for age, hospitalization, comorbidity, number of drugs, and prior influenza vaccinations), PNE pneumoccocal vaccination (adjusts for age, hospitalization, comorbidity, number of drugs and prior pneumoccocal vaccination), MAM mammography (adjusts for age, hospitalization, comorbidity, number of drugs, and prior mammography), PAP Papanicolaou testing (adjusts for age, hospitalization, comorbidity, number of drugs, and prior PAP testing)

Fig. 3

Flow diagram of participant inclusion—enrollees in the Pennsylvania Pharmaceutical Assistance Contract for the Elderly (PACE). *subcategories for exclusion are not mutually exclusive