Real-World Effectiveness of Denosumab in Prevention of Fracture among Postmenopausal Osteoporotic Women with FREEDOM Baseline Characteristics

Date of Approval
Application Number
20_165
Technical Summary

OBJECTIVES:
This study will aim to assess whether available analytical methods could obtain comparable findings to those from the FREEDOM Randomized Clinical Trial (RCT) in primary care real world data (RWD) using CPRD. For each method, we will specifically analyze the association between denosumab use (compared to no anti-osteoporosis drug therapy) and fracture risk amongst postmenopausal osteoporotic women meeting FREEDOM eligibility criteria.
METHODS:
Data source: CPRD-GOLD and CPRD-AURUM, linked to HES-ONS
Source Population: postmenopausal women aged 60-90, who at during the identification period (01/01/2011-31/12/2018) had evidence of osteoporosis, defined as either a ‘history of (non-traumatic) fracture’ or a ‘diagnosis of osteoporosis’ and were registered in CPRD for 1+ years in up-to-standard practices. Exclusion criteria will be applied to reflect FREEDOM eligibility criteria to the most possible extent.
Exposure: Denosumab 60mg for s.c. administration
Outcomes: Non-vertebral (incl. hip) fracture (primary outcome), overall fracture, clinical vertebral fracture and hip fracture (secondary outcomes).
ANALYSES:
This study will employ a cohort design. Risk for non-vertebral (incl. hip) 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. Expert-based propensity score (PS)
o Matching
o Stratification
o Inverse probability weighting (IPW)
2. High-dimensional propensity score (HDPS)
o Matching
o Stratification
o Inverse probability weighting (IPW)
3. Disease risk score
4. Instrumental variables

For each of the methods, we will report its outcome analysis finding and compare it with the FREEDOM trial findings individually. Results from the individual datasets will then be pooled in meta-analyses, and the pooled estimate compared with the FREEDOM RCT results using a set of pre-specified criteria for agreement.

Sensitivity analyses including negative control outcomes will be conducted.

Health Outcomes to be Measured

Non-vertebral fracture (incl. hip fractures); overall fracture; clinical vertebral fracture; hip fracture

Collaborators

Daniel Prieto-Alhambra - Chief Investigator - University of Oxford
Victoria Y Strauss - Corresponding Applicant - University of Oxford
Annika Jodicke - Collaborator - University of Oxford
Antonella Delmestri - Collaborator - University of Oxford
Eng Hooi Tan - Collaborator - University of Oxford
Joe Maskell - Collaborator - Amgen Ltd

Linkages

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