More Evidence of Increased Fractures With Thiazolidinediones 

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. 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 case-control study, the authors 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.

Odds ratio for fractures with eight or more thiazolidinedione prescriptions

Drug	OR for fractures (95% CI)
Any thiazolidinedione	2.43 (1.49 – 3.95)
Rosiglitazone	2.38 (1.39 – 4.09)
Pioglitazone	2.59 (0.96 – 7.01)

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.

Both diabetes mellitus and osteoporotic fractures are highly prevalent conditions. Thiazolidinediones, a class of orally administered hypoglycemic agents, may adversely affect the skeleton by decreasing osteoblastic bone formation and accelerating bone loss.
Practice Pearls:

• This analysis from a nested case-control study is further evidence of a possible association between long-term use of thiazolidinediones and fractures, particularly of the hip and wrist, in patients with type 2 diabetes.
• Current use of rosiglitazone and pioglitazone in women and men with type 2 diabetes may be associated with an approximately 2-fold to 3-fold increased risk for hip and nonvertebral osteoporotic fractures.

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).

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FACT:
Coffee Intake Not Linked to Increased Mortality in Men or Women: Coffee intake does not increase the risk for all-cause mortality in men or women and may decrease risk for cardiovascular mortality, according to the results of a new study. Both in men and in women, the relative risks for all-cause mortality across categories of coffee consumption decreased with increasing coffee intake, after adjustment for age, smoking, and other CVD and cancer risk factors. 
See this weeks’ Item # 5

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