Study Title:

Actos, Avandia, and Increased Bone Fracture Risk

Study Abstract

Context: Thiazolidinedione (TZD) use has recently been associated with an increased risk of fractures.

Objective: The aim of this study was to determine the time-dependent relationship between TZD use and fracture risk.

Design: We conducted a retrospective cohort study in a large health system in southeast Michigan.

Patients: Patients who received care from the health system were included if they were at least 18 yr of age, had a diagnosis of diabetes, and had at least one prescription for an oral diabetes medication. These criteria identified 19,070 individuals (9,620 women and 9,450 men).

Intervention: This study compared patients treated with TZDs to patients without TZD treatment. Cox proportional hazard models were used to assess the relationship between exposure and outcomes.

Main Outcome Measures: The primary outcome was the time to fracture. Secondary analyses examined the risk of fractures in subgroups defined by sex and age.

Results: TZD use was associated with an increased risk of fracture in the cohort overall [adjusted hazard ratio (aHR), 1.35; 95% confidence interval (CI), 1.05–1.71] and in women (aHR, 1.57; 95% CI, 1.16–2.14), but not in men (aHR, 1.05; 95% CI, 0.70–1.58). Women more than 65 yr of age appeared to be at greatest risk for fracture (aHR, 1.72; 95% CI, 1.17–2.52). Among women, the increased fracture risk was not apparent until after 1 yr of TZD treatment.

Conclusions: TZD use was associated with an increased risk for fractures in women, particularly at ages above 65 yr. Clinicians should be aware of this association when considering TZD therapy so as to appropriately manage and counsel their patients.

From press release:

A Henry Ford Hospital study finds women with type 2 diabetes who take a commonly prescribed class of medications to treat insulin resistance may be at a higher risk for developing bone fractures.

After taking a thiazolidinedione (TZD) for one year, women are 50 percent more likely to have a bone fracture than patients not taking TZDs, according to study results. And those at the greatest risk for fractures from TZD use are women older than 65.

"Older women are already at a higher risk of osteoporosis and osteoporosis-related fractures, which might explain why they appeared to be the most affected by TZDs," says study senior author L. Keoki Williams, M.D., MPH, Center for Health Services Research and Department of Internal Medicine at Henry Ford Hospital.

The study -- one of the largest groups to examine the longitudinal relationship between TZD use and fractures -- appears in this month's issue of The Journal of Clinical Endocrinology & Metabolism.

TZDs such as pioglitazone and rosiglitazone help keep blood glucose levels on target by decreasing insulin resistance and making body tissues more sensitive to insulin's effects. TZDs also cut down on the amount of glucose made by the liver in patients with type 2 diabetes.

But in recent years, TZDs have been linked to bone loss and increasing fracture risk. Complicating matters, type 2 diabetes and insulin use are also associated with an increased risk for fractures.

To determine the relationship between TZD use and fracture risk in patients with type 2 diabetes, Dr. Williams and his colleagues conducted a retrospective study from Jan. 2, 2000 to May 31, 2007 of 19,070 Henry Ford patients. Among the study group, 9,620 were women and 9,450 were men.

During the study period, 4,511 patients had at least one prescription fill for a TZD. The researchers used electronically maintained medical claims data to identify non-traumatic bone fractures. The increased risk in women appeared after approximately one year of TZD use.

The location of the fractures in this group also was unique. Typically, osteoporosis-related fractures involve the vertebra and hip. This study, however, found TZD use in women to be associated with fractures of the upper extremity and distal lower extremity. Similar findings were observed in treated women older than 65, who were shown to have a 70 percent increased risk for developing fractures. Men, regardless of age, were not at an increased risk for fractures.

"Although two recent studies suggest that men may also be at increased risk for fractures after TZD exposure, we did not observe this association for men, despite having nearly equal numbers of men and women in our study," says study co-author Zeina A. Habib, M.D.

African-American race-ethnicity was protective for fractures when compared with other race-ethnic groups, which were predominately Caucasian.

"Fractures are just one of a growing number of problems associated with these medications. Henry Ford and other researchers have previously found that this class of medications also can increase risk of congestive heart failure hospitalization," says Dr. Williams.

Dr. Williams notes that there are other medication options available to treat insulin resistance in patients with type 2 diabetes.

"TZDs may put some patients at increased risk for other health issues, and I encourage patients to talk with their physician about other suitable options," says Dr. Williams. "If the physician feels the patient should be placed on a TZD, routine screening for bone loss and prophylactic therapy to prevent bone loss and fractures may also be needed."

Study Information

Zeina A. Habib, Suzanne L. Havstad, Karen Wells, George Divine, Manel Pladevall and L. Keoki Williams
Thiazolidinedione Use and the Longitudinal Risk of Fractures in Patients with Type 2 Diabetes Mellitus
Journal of Clinical Endocrinology & Metabolism
2010 February
Henry Ford Hospital, Detroit, Michigan.

Full Study