Comparability and Relative Effectiveness of Osteoporosis Treatment Groups in European Clinical Practice

Date of Approval: 
2021-01-15 00:00:00
Lay Summary: 
Osteoporosis weakens bones, making them more likely to break (fracture). Treatment options for osteoporosis have been effective to reduce fracture risk but it is unknown which type of treatment is better. There may be differences in characteristics (age, medical condition, fracture history etc) amongst patients receiving different treatments. The differences in patient characteristics that may affect the type of treatment they receive and also their risk of fracture are known as confounders. These confounders need to be accounted for to allow the treatment groups to be comparable. Our study has the following aims: (1) To describe the characteristics of patients on two types of treatments for osteoporosis; (2) To balance the characteristics between these two groups; (3) To compare the rate of fracture in these two groups after accounting for the rate of negative control outcomes (events that are related to unmeasured confounders but not known effects of treatment [e.g. traffic accident, colon screening, burn injury]) Patients will be included based on their use of osteoporosis treatments in primary care records. The rate of fracture after starting treatment will be calculated. We will compare the rates of fracture between the two treatment groups before and after balancing patient characteristics and accounting for negative control outcomes. Our results will inform which methods should be used to balance patient characteristics in future studies when the effectiveness of different treatment options shall be compared.
Technical Summary: 
Objectives This study aims to assess the comparability between patients on denosumab and patients on oral bisphosphonates. This will be achieved with the following objectives: 1. To describe osteoporosis treatment groups with respect to demographics, clinical history, and prior medication use 2. To determine whether osteoporosis treatment groups are “adequately comparable” after adjusting for confounding 3. To compare the incidence of fractures between treatment groups accounting for residual confounding as identified using negative control outcome analyses Population Postmenopausal women aged 50 and above, who were prescribed denosumab or oral bisphosphonates between 01 January 2011 and 31 December 2018 and were registered in the Clinical Practice Research Datalink (CPRD) for 1+ years in up-to-standard practices Exposure The exposure of interest is denosumab 60mg for subcutaneous administration. Comparator exposures are oral bisphosphonates with the indicated doses for treatment of osteoporosis: - Alendronate (10mg daily or 70mg weekly) - Ibandronate (150mg once monthly) - Risedronate (5mg once daily, 35mg once weekly, 75 mg on 2 consecutive days, or 150 mg once monthly) Outcomes Primary outcome • Any fragility fracture (including hip, vertebral, radius, ulna, wrist, humerus, tibia, fibula, ankle, foot, pelvis, clavicle, shoulder, rib, limb) Secondary outcomes • Hip fracture • Vertebral fracture • Non-hip non-vertebral fracture Non-fracture negative control outcomes • Outcomes unrelated to exposure and study outcome (full list in Section N) Methods This study will employ a retrospective cohort design. Summary statistics on demographics, clinical factors, and treatment history in each treatment cohort of interest will be described. Risk for fractures will be calculated via Cox-proportional hazard model over the course of a maximum of 36 months. The following methods to account for measures/unmeasured confounding will be applied: 1) Propensity score (PS) based methods (matching, stratification, and inverse probability of treatment weighting) 2) Negative control outcomes analysis
Health Outcomes to be Measured: 
Primary: • Any fragility fracture (including hip, vertebral, radius, ulna, wrist, humerus, tibia, fibula, ankle, foot, pelvis, clavicle, shoulder, rib, limb) Secondary: • Hip fracture • Vertebral fracture • Non-hip non-vertebral fracture Non-fracture negative control outcomes • Outcomes unrelated to exposure and study outcome (full list in Section N: Exposures, outcomes, and covariates)
Application Number: 
20_000206
Collaborators: 

James O'Kelly - Chief Investigator - Amgen Ltd
Eng Hooi Tan - Corresponding Applicant - University of Oxford
Clement Erhard - Collaborator - Amgen Ltd
Daniel Prieto-Alhambra - Collaborator - University of Oxford
Joe Maskell - Collaborator - Amgen Ltd
Victoria Y Strauss - Collaborator - University of Oxford

Linkages: 
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation