NEW YORK (Reuters Health) – Thiazolidinediones (TZDs) are linked to an increased risk for extremity fractures in women over age 65, findings from a large retrospective cohort study indicate.
Mainly used in diabetics, TZDs are agonists of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear transcription factor. PPAR-gamma is expressed in fat cells, where activation by TZDs improves insulin sensitivity.
But PPAR-gamma is also expressed in osteoblasts, osteoclasts, and bone marrow stromal cells, where activation by TZDs can contribute to bone loss, according to a report of the study in the February Journal of Clinical Endocrinology and Metabolism.
“Given the prevalent use of TZDs in patients with diabetes and that this patient population is already at risk for fractures, it is important to assess the effect of these drugs on fracture risk,” senior author Dr. L. Keoki Williams and her associates write.
The researchers, from Henry Ford Hospital in Detroit, studied claims data and medical records for 19,070 diabetic patients (50% female; mean age 58 years) enrolled at a health maintenance organization between 2000 and 2007. All the patients used oral diabetes medication, and 4511 had filled at least one prescription for a TZD (rosiglitazone and/or pioglitazone).
Ninety-five patients in the TZD group and 382 not treated with a TZD developed a fracture. The unadjusted first event rates were 7.0 and 5.3 per 1000 patient-years. At about a year and a half, the Kaplan-Meier curves began to separate and remained separated for the rest of the study period.
TZD use was associated with an adjusted hazard ratio of 1.34 in analyses controlling for sociodemographics, other medication use, HbA1c levels, and comorbidities.
However, after stratification by age and sex, only women over age 65 were at significantly elevated risk for fracture with TZD use (aHR 1.72). The increased risk was not apparent until after a year of TZD therapy, the researchers note.
A post hoc analysis indicated that TZD use affected fractures of the upper extremity and distal lower extremity, but not fractures of the femur and vertebrae.
Although theirs is one of the largest cohort studies to examine the longitudinal relationship between TZD use and fractures, the investigators note that their analyses did not take into account other important risk factors, including body mass index, smoking, nephropathy, and bone mineral density.
Given that older women are already at risk for fractures, the new findings complicate decisions for when and how to screen for bone density deficits in patients who’ve been taking these drugs.
“For example,” the authors caution, “the increase in bone marrow fat caused by TZDs may result in underestimating dual-energy x-ray absorptiometry-measured bone mineral density.”
J Clin Endocrinol Metab 2010.