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Background: Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.
Methods: To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.
Results: Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).
Conclusion: The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.
Trial registration: ClincalTrials.gov registration number NCT00523341; registered August 30, 2007
Summary: Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture.
Purpose: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence.
Methods: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression.
Results: The 24-month analyses included 1479 women (mean age 66.3–72.5 years) from 140 sites; persistence with denosumab was 75.1–86.0%, adherence 62.9–70.1%, and mean MCR 87.4–92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3–6.9% patients.
Conclusions: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.