The association between fracture risk and diabetes duration, complications and regulation in diabetes mellitus

Date of ISAC Approval: 
22/02/2019
Lay Summary: 
Diabetes Mellitus (DM) is a chronic disease, wherein the regulation of the blood sugar (glucose) level is disturbed resulting in high glucose levels. On the long-term patients with DM might develop microvascular complications such as; eye damage (retinopathy), kidney damage (nephropathy), and nerve damage (neuropathy). DM patients may also have an increased fracture risk due to bone deterioration or fall risk. Current studies focus on the question whether fracture risk in patients with DM is increased compared to people without DM. Results of these studies differ and most studies only focus on all fractures or on one specific fracture type. Therefore, it is not clear which fracture types are more common in DM. Fracture risk might also differ between patients with DM. Some studies suggested that patients with a long DM duration, with diabetic complications or poor DM regulation have an increased fracture risk compared to patients with a shorter DM duration, without complications or healthy blood glucose levels. However, the results of these previous studies are not concordant and difficult to compare due to different study designs. Obtaining this information is important to better understand if and why fracture risk is increased and inform preventative strategies. Therefore, the aim of our study is first to determine whether fracture risk is increased for specific fracture types in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) compared to people without DM. Secondly, we will determine whether a long DM duration, DM complications and a poor DM regulation increase fracture risk in DM.
Technical Summary: 
The objective of this study is to determine whether fracture risk is increased in patients with diabetes mellitus (DM) compared to matched controls, broken down by fracture type and to identify risk factors per fracture type. In addition, we will investigate diabetes specific risk factors within patients with DM. The study population will consist of all patients with diabetes within the full CPRD cohort. Diabetes will be identified by a prescription for an insulin, or a non-insulin anti-diabetic drug (NIAD). The date of the prescription will define the index date. In order to identify incident diabetics, patients will need to have at least one year of valid data collection before the index date. Patients with diabetes will be matched by year of birth, sex and practice to 1 control patient without diabetes, using incidence density sampling. Control patients will be assigned the index date of their matched control. The study period for this study will be 1987 - 2017. Cox regression will be used to compare fracture risk in patients with DM (T1DM/T2DM) to healthy controls. For each fracture type we will investigate what potential risk factors are. We identified these possible risk factors based on literature and we will use them as potential confounders. We will also do this for T1DM and T2DM separately. Within the DM cohort we will investigate whether regulation of DM, presence of complications and duration of DM are specific risk factors for the different fracture types. For aim 1 the following confounders are considered: Age, Charlson comorbidity index, A history of: fall and hypoglycaemia related hospitalizations and use of the following drugs in de 6 months before an interval: anti-epileptics, oral glucocorticoids, antidepressants, anxiolytics or hypnotics, antipsychotics, anti-Parkinson drugs, opposed hormone replacement therapy, calcium, bisphosphonates, vitamin D, raloxifene, strontium ranelate, calcitonin, and parathyroid hormone. For aim 2+3 main confounders are, depending on the outcome, DM duration, DM regulation or presence of microvascular complications. Other confounders are antidiabetic medication, other medication, educational level, Anti-depressive use and history of cardiovascular disease.
Health Outcomes to be Measured: 
- Risk factors for fracture Risk in patients with T1DM or T2DM compared to healthy matched controls, broken down by fracture type. - The association of diabetes duration, quality of glycaemic control and microvascular complications with fracture Risk in patients with T1DM or T2DM. - The association of diabetes duration with fracture Risk in T1DM or T2DM, stratified for quality of glycaemic control and The presence of microvascular complications.
Collaborators: 

Frank de Vries - Chief Investigator - Utrecht University
Cindy Sarodnik - Collaborator - Maastricht University
Frank de Vries - Corresponding Applicant - Utrecht University
Johanna Annemariek Driessen - Collaborator - Utrecht University
Joop van den Bergh - Collaborator - Maastricht University
Dr Morten Jensen - Collaborator - Aalborg University Hospital
Dr Nicklas Rasmussen - Collaborator - Aalborg University Hospital
Nicolaas Schaper - Collaborator - Maastricht University
Mr Patrick C Souverein - Collaborator - Utrecht University
Peter Vestergaard - Collaborator - Aalborg University Hospital
Sandrine Bours - Collaborator - Maastricht University