Risk of Fracture with Thiazolidinediones: Disease or Drugs?

Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Calcified Tissue International (Impact Factor: 3.27). 04/2012; 90(6):450-7. DOI: 10.1007/s00223-012-9591-8
Source: PubMed


The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996-2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06-1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20-1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13-1.18) and second (HR = 1.00, 95 % CI 0.96-1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account.

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    • "All participants were followed from the index date to the end of data collection, the patient’s transfer out of the registry, emigration, or the patient’s death, whichever came first. The study populations from PHARMO and Denmark have been described before (Bazelier et al., 2012a,b). "
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    ABSTRACT: Background: The use of thiazolidinediones (TZDs) has been associated with increased fracture risks. Our aim was to estimate the risk of fracture with TZDs in three different healthcare registries, using exactly the same study design, and to perform an individual patient data meta-analysis of these three studies. Methods: Population-based cohort studies were performed utilizing the British General Practice Research Database (GPRD), the Dutch PHARMO Record Linkage System (RLS), and the Danish National Health Registers. In all three databases, the exposed cohort consisted of all patients (aged 18+) with at least one prescription of antidiabetic (AD) medication. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. The total period of follow-up for each patient was divided into periods of current exposure and past exposure, with patients moving between current and past use. Results: In all three registries, the risk of fracture was increased for women who were exposed to TZDs: HR 1.48 (1.37-1.60) in GPRD, HR 1.35 (1.15-1.58) in PHARMO, and HR 1.22 (1.03-1.44) in Denmark. Combining the data in an individual patient data meta-analysis resulted, for women, in a 1.4-fold increased risk of any fracture for current TZD users versus other AD drug users [adj. HR 1.44 (1.35-1.53)]. For men, there was no increased fracture risk [adj. HR 1.05 (0.96-1.14)]. Risks were increased for fractures of the radius/ulna, humerus, tibia/fibula, ankle, and foot, but not for hip/femur or vertebral fractures. Current TZD users with more than 25 TZD prescriptions ever before had a 1.6-fold increased risk of fracture compared with other AD drug users [HR 1.59 (1.46-1.74)]. Conclusion: In this study, we consistently found a 1.2- to 1.5-fold increased risk of fractures for women using TZDs, but not for men, across three different healthcare registries. TZD users had an increased risk for fractures of the extremities, and risks further increased for prolonged users of TZDs.
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    ABSTRACT: Since their approval, thiazolidinediones (TZDs) have been used extensively as insulin-sensitizers for the management of type 2 diabetes mellitus (T2DM). Activation of peroxisomal proliferator-activated receptor gamma (PPARγ) nuclear receptors by TZDs leads to a vast spectrum of metabolic and antiinflammatory effects. In the past decade, clinicians and scientists across the fields of metabolism, diabetes, liver disease (NAFLD), atherosclerosis, inflammation, infertility, and even cancer have had high hopes about the potential for TZDs to treat many of these diseases. However, an increasing awareness about undesirable "off-target" effects of TZDs have made us rethink their role and be more cautious about the long-term benefits and risks related to their use. This review examines the most relevant work on the benefits and risks associated with TZD treatment, with a focus on the only PPARγ agonist currently available (pioglitazone), aiming to offer the reader a balanced overview about the current and future role of TZDs in the management of insulin-resistant states and T2DM.
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    ABSTRACT: Context:Meta-analyses of clinical studies have suggested an increased incidence of peripheral fractures in postmenopausal women with type 2 diabetes mellitus taking pioglitazone. The mechanism behind this apparent increase is unknown.Objective:The objective of the study was to examine the effects of pioglitazone on bone mineral density (BMD) and turnover.Design and Setting:Twenty-five sites (in the United States) enrolled participants in this randomized, double-blind, placebo-controlled study.Participants:Postmenopausal women (n = 156) with impaired fasting glucose or impaired glucose tolerance participated in the study.Interventions:The intervention consisted of pioglitazone 30 mg/d (n = 78) or placebo (n = 78), increased to 45 mg/d after 1 month, for 12 months of treatment total, followed by 6 months of washout/follow-up.Main Outcome Measures:Percentage changes from baseline to month 12 and from month 12 to month18 in BMD in total proximal femur (primary end point), total body, femoral neck, lumbar spine, and radius were measured.Results:Least squares mean changes from baseline to month 12 in total proximal femur BMD were -0.69% for pioglitazone and -0.14% for placebo (P = .170). No statistically significant between-group differences were observed for any BMD or bone remodeling marker end point. We observed improved glycemic control and insulin sensitivity with pioglitazone treatment. In addition, pioglitazone appeared to increase body fat, which may affect bone density measurements, especially in the lumbar spine. One pioglitazone-treated and three placebo-treated women experienced confirmed fractures. Over 18 months, one pioglitazone-treated (1.3%) and eight placebo-treated women (10.3%) developed overt type 2 diabetes mellitus. The pattern and incidence of adverse events with pioglitazone were consistent with clinical experience with thiazolidinediones.Conclusions:Maximal-dose pioglitazone had no effects on BMD or bone turnover, while improving glycemic control as expected, in postmenopausal women with impaired fasting glucose or impaired glucose tolerance.
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