Thiazolidinediones Linked to Risk for Osteoporotic Fracture

Ricki Lewis, PhD

March 08, 2012

March 8, 2012 — Thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus, are associated with a 1.3-fold elevation in risk for osteoporotic fracture compared with other antidiabetic medications, according to a report published online March 6 in Pharmacoepidemiology and Drug Safety.

Two randomized controlled clinical trials implicated TZDs in decreased bone density in the hip and lumbar spine in women, and a meta-analysis of 10 studies found increased risk for fracture in the upper arm, hand, and foot.

TZDs decrease bone mineral density by activating peroxisome proliferator–activated receptors, which shifts the fates of mesenchymal stem cells in bone marrow toward the adipocyte lineage and away from producing osteoblasts. Diabetes can also affect bone remodeling by altering vitamin D metabolism, glycosylating collagen, and increasing output of calcium in urine.

In the current study, Marloes T. Bazelier, PhD, from the Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands, and colleagues aimed to tease apart the role the drug plays in loss of bone density and osteoporotic fracture risk versus the role the underlying metabolic derangement of diabetes plays.

The team evaluated 123,452 patients who were taking oral antidiabetic medication from the Dutch PHARMO database, covering 1998 to 2008 for drug use and hospitalization. They compared each patient with 4 control patients matched for year of birth and sex. The 451,388 control patients had no history of antidiabetic medication use.

The researchers used a "proxy indicator of disease severity." Stage 1 was use of either biguanide or sulfonylureum, stage 2 was use of both of these diabetes drugs, stage 3 was use of TZDs, and stage 4 was use of insulin. The patients with diabetes were followed for a mean duration of 4.5 years, and the control patients were followed for a mean of 4.0 years.

The researchers calculated a 1.5-fold increased risk for osteoporotic fracture in patients taking TZDs (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.28 - 1.73), and a 1.2-fold increase for those taking insulin (HR, 1.24; 95% CI, 1.14 - 1.36), compared with control patients. Those patients with less severe diabetes were at much lower risk for fracture (stage 1: HR, 1.11; 95% CI, 1.06 - 1.17; stage 2: HR, 1.03; 95% CI, 0.96 - 1.11).

When patients taking TZDs were compared with patients taking any other antidiabetic medication, the overall risk was 1.25-fold higher (95% CI, 1.09 - 1.43) in patients receiving TZDs. However, the elevation was statistically significant in women (HR, 1.36; 95% CI, 1.16 - 1.60), but not in men (HR, 1.04; 95% CI, 0.80 - 1.34).

"The risk with current TZD use (stage 3) was significantly different from the risk in stages 1, 2 and 4," the investigators write. However, they caution, the underlying disease could be a confounding factor. In addition, "[s]ix months after discontinuation of TZD, osteoporotic fracture risk returned to baseline levels." If severity of disease were the only factor, stage 4 would have had the highest fracture risk, and the risk would not have diminished after cessation of drug use.

Three factors may have contributed to an underestimate of risk, according to the researchers: use of a proxy metric for disease severity, not considering body mass index because heavier weight lowers risk for fracture, and the protective effect of insulin on bone.

This study was supported by a grant from the European Calcified Tissue Society and by the Dutch Organisation of Scientific Research. The Department of Pharmacoepidemiology and Clinical Pharmacology, which employs Dr. Bazelier and 3 coauthors, has received unrestricted funding for pharmacoepidemiologic research from GlaxoSmithKline, Novo Nordisk, the private–public-funded Top Institute Pharma, the Dutch Medicines Evaluation Board and the Dutch Ministry of Health. Two coauthors also work for the General Practice Research Database in the United Kingdom.

Pharmacoepidemiol Drug Saf. Published online March 6, 2012. Abstract

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