Type 2 diabetes is associated with an increased risk of fractures,with the risk increasing with longer duration of disease. Thiazolidinediones are relatively a new class of anti-diabetic agents who predominantly increase endogenous insulin’s sensitivity. Precautions have been taken towards the risk of cardiac events and oedema in patients using these drugs. Newer data have emerged concerning a different and serious side-effect; that is of bone fractures. Increased loss of bone mass and a higher incidence of fractures have been associated with the use of this class of drugs in post-menopausal women. In this review of press, we will highlight on recent studies that have discussed this subject.
In animal models using rodents, the activation of peroxisome proliferator–activatedreceptor-
promotes adipocyte rather than osteoblast differentiationfrom mesenchymal progenitor cells and may reduceIGF-1 levels in bone and thereby also decrease osteoblast formation1. In experimental models using human cells, Benvuti et al 2 showed that there was a rosiglitazone-dependent shift from osteoblastogenesis toward adipogenesis using a human cell model. They found out that the exposure to rosiglitazone potentiated adipogenic differentiation and shifted the differentiation toward an osteogenic phenotype into an adipogenic phenotype, as assessed by the appearance of lipid droplets. Accordingly, rosiglitazone markedly increased the expression of the typical marker of adipogenesis fatty-acid binding protein 4, whereas it reduced the expression of Runx2, a marker of osteoblastogenesis.
What do epidemiological studies show?
“A Diabetes Outcome Progression Trial” (ADOPT) was a randomized,controlled clinical trial comparing the effect of the thiazolidinedionerosiglitazone, the biguanide metformin, and the sulfonylureaglyburide on glucose control in drug-naive patients recentlydiagnosed (<3 years) with type 2 diabetes 3. Additional analysis showed important and rather dangerous side effects: In women there wasan increased occurrence of bone fractures in the upper and lowerlimbs.
In a recent publication, the authors reported in detail theADOPT findings related to fractures 4. In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified.
Although in this above-mentioned study men were spared from fractures, Yuturu et al 5 reported that thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men. They retrieved data of 354 subjects withdiabetes. Among them, they hadfollow-up of bone mineral density data for 32 men with type 2 diabetes receivingrosiglitazone (considered the study group) and 128 men withtype 2 diabetes not receiving any thiazolidinedione (consideredthe control group). Their analysis showed asignificant increase in bone loss both at total hip and femoralneck areas in type 2 diabetic men on rosiglitazone treatment
Is it the case of all thiazolidinediones or just rosiglitazone?
In a recent study, Meier et al 6 examined the association between the use of thiazolidinediones or other oral antidiabetic drugs and the risk of fracture. They build a case-control study using the UK General Practice Research Database and including case patients with fracture aged 30 to 89 years with an incident fracture diagnosis between January 1994 and December 2005 and control subjects who were matched to case patients on age, sex, disease duration, and general practice attended. There were 1020 case patients with an incident low-trauma fracture and 3728 matched controls. After adjustment for age, body mass index, other antidiabetic drugs, co-medication and co-morbidities, the Odds Ratios for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy) compared with non-use was 2.43 (95% [CI], 1.49-3.95). Rosiglitazone (OR, 2.38; 95% CI, 1.39-4.09) and pioglitazone (OR, 2.59; 95% CI, 0.96-7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. 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.
