Short summary

Longitudinal population-based study using Danish national radiology, pharmacy and other health care data, with expert radiograph review and classification of every subtrochanteric and femoral shaft fracture during 2010-2014, to elucidate risk factors for Atypical Femur Fractures(AFF). Fractures are a common and debilitating consequence of osteoporosis, and bisphosphonates (BPs) are the most widely used anti-fracture treatment worldwide. Unfortunately, accumulating evidence from observational studies point towards a relationship between BP use and the development of unusual subtrochanteric and femoral diaphyseal fractures, now referred to atypical femoral fracture (AFF), which are radiographically distinct from typical spiral and comminuted femoral shaft fractures.1 Compared to the millions of individuals treated with BPs worldwide, the number of suspected or confirmed AFFs is quite small but there is increasing patient and clinician concern that the indications for BP use and duration of use should account for AFF risk.

Rationale

Studies to date have generated inconsistent estimates of the incidence of AFF and the magnitude of the association with BP use, perhaps a result of differing study designs, comparators and definitions of AFF. Now that a specific case definition and objective radiographic AFF criteria have been agreed upon, future studies of AFF must include expert radiograph review and confirmation of suspected cases of AFF. Because there are few adequately powered large prospective studies, critical areas of uncertainty include the relationships with BP exposure, particularly the duration of treatment, and importantly, the resolution of risk after discontinuation. Uncertainty also exists regarding additional risk factors, such as the effects of age and gender, severity of osteoporosis, concurrent medical conditions (such as rheumatoid arthritis), and other medication use (such as corticosteroids and proton pump inhibitors). Given the relative infrequency of AFF, randomized designs are not feasible and very large population-based cohorts with complete drug exposure and objective fracture ascertainment are needed. Population-based longitudinal data from Denmark, with longstanding centralized health records and nearly two decades of drug exposure information, are ideal for such analyses. In additional to the large number of BP users and accurate information about initiation and discontinuation of medications, additional advantages of the Danish data not available in previous studies include access to digital radiographs for all reported fractures, comprehensive information about previous fractures and other comorbidities, and availability of pre-treatment bone density measurements.  We therefore propose a longitudinal population-based study using Danish national radiology, pharmacy and other health care data, with expert radiograph review and classification of every subtrochanteric and femoral shaft fracture during 2010-2014, to elucidate risk factors for AFF and to address the following 3 aims:

Aims:

1. To describe the rates of radiographically confirmed AFF according to strata defined by age, gender and duration of BP use. This will enable comparisons with the rates of typical subtrochanteric/femoral shaft fracture and typical hip fracture for analyses comparing the benefits and risks of BP use.
2. To determine the independent effect of BP use as a risk factor for sustaining a confirmed AFF by duration of use and cumulative dose, and to determine whether other factors, such as severity of osteoporosis, co-morbid conditions and use of other medications, are associated with AFF.
3. To determine if AFF risk declines after discontinuation of bisphosphonates, and to determine patient and treatment characteristics that influence AFF risk after discontinuation.

Description of the cohort

1. Cases: Every subtrochanteric and femoral shaft fracture (about 6,500) in the Danish population ages 50 and older over a 5 year period (2010-14).
2. Comparator cohort: A randomly selected cohort of Danes >50 (N=40,000).
3. A random sample of typical subtrochanteric and femoral shaft fractures (TFF, N=500)
4. A separate random sample of typical hip fractures (THF, N=500).

Data and biological material

Radiology images will be retrieved and subjected to blinded expert review and the outcome of this transferred to the study database for merging at Statistics Denmark with drug prescription data and data from the Danish National Hospital Discharge Register (Landspatientregistret).
The study does not collect biological material.

Collaborating researchers and departments

OPEN Odense Patient Data Explorative Network, Odense University Hospital & Department of Medicine, Holbaek Hospital

• Professor Bo Abrahamsen

Department of Medicine, University of California San Francisco, USA

• Professor Doug Bauer

Department of Biostatistics, University of California San Francisco, USA

• Professor Dennis Black

Department of Radiology, San Francisco Coordinating Center, USA

• Professor emeritus Harry Genant

OPEN Odense Patient Data Explorative Network, Odense University Hospital

• Associate professor Katrine Hass Rubin

Deparmentt of Medicine, Aalborg University Hospital

• Professor Peter Vestergaard