Basel, Switzerland - Further evidence that long-term use of the thiazolidinediones rosiglitazone and pioglitazone may increase risk of fractures (particularly of the hip and wrist) has come from a new case-control study [1].

The study, published in the April 28, 2008, issue of the Archives of Internal Medicine, was conducted by a team led by Dr Christoph Meier (University Hospital Basel, Switzerland).

They note that patients with type 2 diabetes have higher bone density than normal and thus might be expected to be at lower risk for fracture, but studies have actually suggested an increased risk of fragility fractures, predominantly at nonvertebral sites, independent of age, body-mass index, and bone density for such patients, suggesting that this might be related to other factors, such as diabetic complications, risk of falls, and, potentially, antidiabetic medication use.

Noting that the insulin-sensitizing thiazolidinediones are a relatively new class of oral antidiabetic agents that have gained wide use, with pioglitazone and rosiglitazone accounting for 21% of the oral antidiabetic drugs prescribed in the US, Meier et al cite studies suggesting that these drugs may exert unfavorable effects on bone, resulting in reduced osteoblastic bone formation and accelerated bone loss. They report that both rosiglitazone and pioglitazone have been associated with an increased fracture risk, but it remains unclear whether their use is associated with peripheral fracture sites only and whether this effect is sex specific. They thus conducted a large population-based study to explore the association between thiazolidinedione use and use of other oral antidiabetic drugs and the risk of fractures in women and men aged 30 to 89 years.

For their nested case-control study, the authors used the UK General Practice Research Database. They identified 1020 patients aged 30 to 89 years with an incident fracture diagnosis between January 1994 and December 2005 (cases) and 3728 control subjects matched for age, sex, calendar time, and general practice attended. They then calculated the odds ratios (ORs) of having a fracture associated with the use of rosiglitazone, pioglitazone, other oral antidiabetic agents, or insulin.

Results showed that after adjustment for age, body-mass index, other antidiabetic drugs, comedication, and comorbidities, patients who had eight or more thiazolidinedione prescriptions (corresponding to approximately 12 to 18 months of therapy) had a two- to threefold increased risk of hip and nonvertebral osteoporotic fractures compared with subjects who had never used these drugs.

The association was independent of patient age and sex and tended to increase with thiazolidinedione dose. No materially altered relative fracture risk was found in association with the use of other oral antidiabetic drugs.

Meier et al say this study provides further evidence that current use of rosiglitazone and pioglitazone in women and men with type 2 diabetes may be associated with increased risk of hip and nonvertebral osteoporotic fractures. The numbers of vertebral and rib fractures were too low for a meaningful assessment of fracture risk in relation to thiazolidinedione use.

They note that previous trials have suggested that a deleterious effect of thiazolidinediones on bones may be restricted to women, but in this study an increased fracture risk was also seen in men, a finding that correlates with the observation that accelerated bone loss has been observed in postmenopausal women and older men treated with these agents.

But they add that their findings are based on relatively few thiazolidinedione-exposed patients and need to be confirmed by additional observational studies and by controlled clinical trials.

In an accompanying editorial [2], Drs Jane Cauley and Kristine Ensrud (University of Pittsburgh, PA) say that the increase in fracture risk with thiazolidinedione use in this study seemed to be strong, consistent with other studies, and biologically plausible. "This evidence should be viewed in the context of the following: other data that indicate thiazolidinedione use (specifically, rosiglitazone) may increase the risk of cardiovascular disease, adverse effects of thiazolidinedione use (weight gain, hepatotoxicity, fluid retention, and congestive heart failure), higher cost of thiazolidinediones, and inconsistent evidence that thiazolidinedione is more effective in lowering glycemia than older oral hypoglycemic agents. Thus, in the absence of long-term trials demonstrating the benefit of thiazolidinedione therapy in reducing clinical outcomes, older oral hypoglycemic agents (second-generation sulfonylureas and metformin) should be preferentially prescribed to patients with type 2 diabetes," they conclude.