1. Utrecht Institute for Pharmaceutical Sciences Use of thiazolidinediones and risk of osteoporotic fracture: disease or drugs? Frank de Vries, PharmD,PhD Marloes Bazelier MSc –Universiteit Utrecht, NL –University of Southampton, UK

2. Utrecht Institute for Pharmaceutical Sciences Conflict of Interest This work was funded by a grant from the European Calcified Tissue Society, and the Dutch Organisation for Scientific Research

3. Utrecht Institute for Pharmaceutical Sciences Introduction Glitazones Antidiabetic treatment Linked with low bone density and fracture

4. Utrecht Institute for Pharmaceutical Sciences Are glitazones useless?

5. Utrecht Institute for Pharmaceutical Sciences Introduction Type 2 diabetes mellitus is a risk factor for osteoporotic fracture Epidemiological studies have not been clear about confounding by disease severity

6. Utrecht Institute for Pharmaceutical Sciences Objective To study the association between thiazolidinedione use, severity of diabetes mellitus and fracture risk

7. Utrecht Institute for Pharmaceutical Sciences Methods Dutch PHARMO database 1998 – 2008 Hospitalisations linked to longitudinal drug prescribing 3 million patients Population-based cohort study Index date: first antidiabetic drug prescription Cox Regression analysis

8. Utrecht Institute for Pharmaceutical Sciences Results: baseline characteristics Diabetes patientsNon-diabetes patients N=123,452N=451,388 Duration of follow-up, mean 4.5 yrs4.0 yrs Females53% Mean age, yrs64.0 History of fracture 1.4%2.0% Use of oral steroids 13.7%14.3%

9. Utrecht Institute for Pharmaceutical Sciences Results: risk of fracture in glitazone users Fractures (n)Fully adjusted Hazard ratio (95% CI) Unexposed to antidiabetics 10,882referent Glitazone exposed Any fracture2151.5 (1.4-1.8) Osteoporotic1601.6 (1.4-1.9) Hip861.5 (1.2-1.8) Vertebral172.1 (1.3-3.4)

10. Utrecht Institute for Pharmaceutical Sciences Risk of osteoporotic fracture by disease stage Fully adjusted Hazard ratio (95% CI) Unexposed to antidiabetics referent Diabetes severity stage 1. Metformin or sulphonurea 1.1 (1.0-1.2) 2. Metformin and sulphonurea 1.0 (1.0-1.1) 3. Glitazone1.6 (1.3-1.8) 4. Insulin1.2 (1.1-1.3)

11. Utrecht Institute for Pharmaceutical Sciences Limitations No data on BMI, alcohol or smoking Insulin use may have anabolic effects on bone

12. Utrecht Institute for Pharmaceutical Sciences Conclusion Risk of fracture is 1.5-fold increased in users of glitazones Severity of the underlying disease plays a minor role Fracture risk assessment may be considered in patients taking pioglitazone

13. Utrecht Institute for Pharmaceutical Sciences Thank you very much for your attention www.pharm.uu.nl/epithera F.devries@uu.nl