Osteoporosis International

, Volume 29, Issue 9, pp 2079–2086 | Cite as

Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case–control study

  • E. Losada
  • B. Soldevila
  • M.S. Ali
  • D. Martínez-Laguna
  • X. Nogués
  • M. Puig-Domingo
  • A. Díez-Pérez
  • D. MauricioEmail author
  • D. Prieto-Alhambra
Original Article



We conducted a nested case–control study to study the association between antidiabetic treatments (alone or in combination) use and fracture risk among incident type 2 Diabetes mellitus patients. We found an increased risk of bone fracture with insulin therapy compared to metformin monotherapy.


Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures, to which antidiabetic therapies may contribute. We aimed to characterize the risk of fracture associated with different antidiabetic treatments as usually prescribed to T2DM patients in actual practice conditions.


A case–control study was nested within a cohort of incident T2DM patients registered in 2006–2012 in the Information System for Research Development in Primary Care (Catalan acronym, SIDIAP), a database which includes records for > 5.5 million patients in Catalonia (Spain). Each case (incident major osteoporotic fracture) was risk-set matched with up to five same-sex controls by calendar year of T2DM diagnosis and year of birth (± 10 years). Study exposure included previous use of all antidiabetic medications (alone or in combination), as dispensed in the 6 months before the index date, with metformin (MTF) monotherapy, the most commonly used drug, as a reference group (active comparator).


Data on 12,277 T2DM patients (2049 cases and 10,228 controls) were analyzed. Insulin use was associated with increased fracture risk (adjusted OR 1.63 (95% CI 1.30–2.04)), as was the combination of MTF and sulfonylurea (SU) (adjusted OR 1.29 (1.07–1.56)), compared with MTF monotherapy. Sensitivity analyses suggest possible causality for insulin therapy but not for the MTF + SU combination association. No significant association was found with any other antidiabetic medications.


Insulin monotherapy was associated with an increased fracture risk compared to MTF monotherapy in T2DM patients. Fracture risk should be taken into account when starting a glucose-lowering drug as part of T2DM treatment.


Epidemiology Fracture risk General population Type 2 diabetes mellitus 



This work has been carried out as a part of the PhD program of the Department of Medicine, Universitat Autònoma de Barcelona. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III, Spain.

The authors thank Elaine Lilly, Ph.D., for revising the manuscript for English language usage.

Compliance with ethical standards

Conflict of interest

D.P.A. declares that his department/research group has received unrestricted research grants from Amgen, Servier Laboratoires, and Bioiberica; XN has been paid by Amgen and Lilly for developing and delivering educational presentations; D.M. declares receipt of honoraria from Abbott, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Ferrer, GlaxoSmithKline, Eli Lilly, Medtronic, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi for consulting and presentations. ADP has been a speaker or advisory board member for Lilly, Amgen, GSK, and UCB and owns stocks of Active Life Scientific; E.L.G., B.S., M.S.A., M.P.D., and D.M.L. have no conflicts of interest.


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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • E. Losada
    • 1
    • 2
  • B. Soldevila
    • 3
    • 4
    • 5
  • M.S. Ali
    • 6
    • 7
  • D. Martínez-Laguna
    • 8
    • 9
    • 10
  • X. Nogués
    • 10
    • 11
  • M. Puig-Domingo
    • 2
    • 3
    • 4
    • 5
  • A. Díez-Pérez
    • 10
    • 11
  • D. Mauricio
    • 2
    • 3
    • 4
    • 5
    Email author
  • D. Prieto-Alhambra
    • 6
    • 8
    • 10
  1. 1.Department of Endocrinology and NutritionHospital Can MissesEivissaSpain
  2. 2.Department of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Department of Endocrinology and NutritionHospital Universitari Germans Trias i PujolBarcelonaSpain
  4. 4.Fundació Institut d’Investigació Germans Trias i PujolUniversitat Autònoma de BarcelonaBarcelonaSpain
  5. 5.CiBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)Instituto de Salud Carlos IIIMadridSpain
  6. 6.Musculoskeletal Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, NDORMSUniversity of OxfordOxfordUK
  7. 7.Faculty of Epidemiology and Population Health, Department of Infectious Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK
  8. 8.GREMPAL Research Group, IDIAP Jordi GolUniversitat Autònoma de BarcelonaBarcelonaSpain
  9. 9.Primary Care BarcelonaInstitut Català de la SalutBarcelonaSpain
  10. 10.CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES)Instituto de Salud Carlos IIIMadridSpain
  11. 11.Department of Internal MedicineHospital del Mar, Universitat Autònoma de BarcelonaBarcelonaSpain

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