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1.  Risk of Fracture with Thiazolidinediones: An Individual Patient Data Meta-Analysis 
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.
PMCID: PMC3582108  PMID: 23549934
thiazolidinediones; fracture; individual patient data; meta-analysis; epidemiology
2.  Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis 
Current Osteoporosis Reports  2010;8(4):178-184.
Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy.
PMCID: PMC2947013  PMID: 20809203
Diabetes; Thiazolidinediones; Bone; Osteoporosis; Fracture
3.  Association Between Longer Therapy With Thiazolidinediones and Risk of Bladder Cancer: A Cohort Study 
The use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer in patients with type 2 diabetes. In this study, we assessed the risk of bladder cancer associated with the use of TZDs and between pioglitazone and rosiglitazone, an alternative TZD.
We conducted a retrospective cohort study of patients with type 2 diabetes mellitus who initiated treatment with a TZD (n = 18 459 patients) or a sulfonylurea (SU) (n = 41 396 patients) between July 1, 2000, and August 31, 2010, using The Health Improvement Network database in the United Kingdom. Incident cancers were identified for 196 708 person-years of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of bladder cancer in the TZD cohort compared with the SU cohort (referent), adjusted for potential confounders. Risk associated with increasing duration of drug exposure was also examined. All statistical tests were two-sided.
We identified 60 incident bladder cancers in the TZD cohort and 137 cancers in the SU cohort. No difference in bladder cancer risk was found between the two cohorts (TZD vs SU, HR = 0.93, 95% CI = 0.68 to 1.29) in analyses that did not account for duration of exposure. However, the risk of bladder cancer was increased among patients with the longest duration of TZD vs SU therapy (≥5 years of use, HR = 3.25, 95% CI = 1.08 to 9.71) and among those with the longest time since initiation of therapy (≥5 years since first use, HR = 2.53, 95% CI = 1.12 to 5.77). Risk of bladder cancer also increased with increasing time since initiation of pioglitazone (P trend < .001) and rosiglitazone (P trend = .006). Comparison of pioglitazone to rosiglitazone use did not demonstrate difference in cancer risk (P = .49).
Long-term TZD therapy (≥5 years) in patients with type 2 diabetes may be associated with an increased risk of bladder cancer, which may be common to all TZDs.
PMCID: PMC3529598  PMID: 22878886
4.  Thiazolidinediones, Cardiovascular Disease and Cardiovascular Mortality: Translating Research Into Action For Diabetes (TRIAD) 
Studies have associated thiazolidinedione (TZD) treatment with cardiovascular disease (CVD) and questioned whether the two available TZDs, rosiglitazone and pioglitazone, have different CVD risks. We compared CVD incidence, cardiovascular (CV) and all-cause mortality in type 2 diabetic patients treated with rosiglitazone or pioglitazone as their only TZD.
We analyzed survey, medical record, administrative, and National Death Index (NDI) data from 1999 through 2003 from Translating Research Into Action for Diabetes (TRIAD), a prospective observational study of diabetes care in managed care. Medications, CV procedures, and CVD were determined from health plan (HP) administrative data, and mortality was from NDI. Adjusted hazard rates (AHR) were derived from Cox proportional hazard models adjusted for age, sex, race/ethnicity, income, history of diabetic nephropathy, history of CVD, insulin use, and HP.
Across TRIAD’s ten HPs, 1,815 patients (24%) filled prescriptions for a TZD, 773 (10%) for only rosiglitazone, 711 (10%) for only pioglitazone, and 331 (4%) for multiple TZDs. In the seven HPs using both TZDs, 1,159 patients (33%) filled a prescription for a TZD, 564 (16%) for only rosiglitazone, 334 (10%) for only pioglitazone, and 261 (7%) for multiple TZDs. For all CV events, CV and all-cause mortality, we found no significant difference between rosiglitazone and pioglitazone.
In this relatively small, prospective, observational study, we found no statistically significant differences in CV outcomes for rosiglitazone- compared to pioglitazone-treated patients. There does not appear to be a pattern of clinically meaningful differences in CV outcomes for rosiglitazone- versus pioglitazone-treated patients.
PMCID: PMC3548906  PMID: 20583206
Thiazolidinediones; rosiglitazone; pioglitazone; diabetes
5.  Thiazolidinediones and Cardiovascular Events In High-Risk Patients with Type-2 Diabetes Mellitus 
Pharmacy and Therapeutics  2009;34(9):490-501.
The use of thiazolidinediones (TZDs) in patients with type-2 diabetes mellitus appears to be associated with an increased risk of myocardial infarction (MI) compared with placebo or other oral antidiabetic drug regimens.
We conducted a study to investigate whether there was a difference in the risk of acute MI and hemorrhagic and non-hemorrhagic stroke between specific TZDs, namely rosiglitazone maleate (Avandia) and pioglitazone (Actos), and other oral antidiabetic agents in a high-risk, largely underrepresented and largely minority Medicaid population.
Study Design, Setting, and Patients.
We analyzed patient encounter data using propensity-scoring methods and logistic regression to compare the risk of cardiovascular (CV) events in patients with type-2 diabetes in a high-risk population.
Main Outcome Measures.
Outcomes were identified through International Classification of Disease (ICD-9) codes 410–411 for acute MI; 430–438 for stroke; and revenue (emergency department) codes 450–459 in the case of MI.
Using retrospective medical encounter and prescription data analyses, we found that rosiglitazone, compared with other oral antidiabetic agents, was associated with an increased rate of CV events by 20% in a high-risk cohort of diabetic patients. Neither pioglitazone nor the TZD drug class as a whole was associated with an increased CV risk.
Rosiglitazone was associated with a significant increase in CV events (MI and stroke) among high-risk patients with type-2 diabetes, whereas pioglitazone was not. We recommend further research to capture risk factors that were not observed in our encounter data.
PMCID: PMC2799132  PMID: 20140111
6.  Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs 
Diabetologia  2012;55(11):2929-2937.
Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.
Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.
There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10−5), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).
Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.
PMCID: PMC3464390  PMID: 22945303
Fractures; Hip fracture; Pharmacoepidemiology; Thiazolidinedione; Type 2 diabetes
7.  The Risk of Fracture in Patients With Multiple Sclerosis: The UK General Practice Research Database 
Journal of Bone and Mineral Research  2011;26(9):2271-2279.
Patients with multiple sclerosis (MS) may be at an increased risk of fracture owing to a greater risk of falling and decreased bone mineral density when compared with the general population. This study was designed to estimate the relative and absolute risk of fracture in patients with MS. We conducted a population-based cohort study using data from the UK General Practice Research Database linked to the National Hospital Registry (1997–2008). Incident MS patients (n = 5565) were matched 1:6 by year of birth, sex, and practice with patients without MS (controls). Cox proportional-hazards models were used to derive adjusted hazard ratios (HRs) for fracture associated with MS. Time-dependent adjustments were made for age, comorbidity, and drug use. Absolute 5- and 10-year risks of fracture were estimated for MS patients as a function of age. Compared with controls, MS patients had an almost threefold increased risk of hip fracture [HR = 2.79, 95% confidence interval (CI) 1.83–4.26] and a risk of osteoporotic fracture that was increased 1.4-fold (HR = 1.35, 95% CI 1.13–1.62). Risk was greater in patients who had been prescribed oral/intravenous glucocorticoids (GCs; HR = 1.85, 95% CI 1.14–2.98) or antidepressants (HR = 1.79, 95% CI 1.37–2.35) in the previous 6 months. Absolute fracture risks were low in younger MS patients but became substantial when patients were older than 60 years of age. It is concluded that MS is associated with an increased risk of fracture. Fracture risk assessment may be indicated in patients with MS, especially those prescribed GCs or antidepressants. © 2011 American Society for Bone and Mineral Research
PMCID: PMC3193376  PMID: 21557309
8.  Diffusion patterns of new anti-diabetic drugs into hospitals in Taiwan: the case of Thiazolidinediones for diabetes 
Diffusion of new drugs in the health care market affects patients' access to new treatment options and health care expenditures. We examined how a new drug class for diabetes mellitus, thiazolidinediones (TZDs), diffused in the health care market in Taiwan.
Assuming that monthly hospital prescriptions of TZDs could serve as a micro-market to perform drug penetration studies, we retrieved monthly TZD prescription data for 580 hospitals in Taiwan from Taiwan's National Health Insurance Research Database for the period between March 1, 2001 and December 31, 2005. Three diffusion parameters, time to adoption, speed of penetration (monthly growth on prescriptions), and peak penetration (maximum monthly prescription) were evaluated. Cox proportional hazards model and quantile regressions were estimated for analyses on the diffusion parameters.
Prior hospital-level pharmaceutical prescription concentration significantly deterred the adoption of the new drug class (HR: 0.02, 95%CI = 0.01 to 0.04). Adoption of TZDs was slower in district hospitals (HR = 0.43, 95%CI = 0.24 to 0.75) than medical centers and faster in non-profit hospitals than public hospitals (HR = 1.79, 95%CI = 1.23 to 2.61). Quantile regression showed that penetration speed was associated with a hospital's prior anti-diabetic prescriptions (25%Q: 18.29; 50%Q: 25.57; 75%Q: 30.97). Higher peaks were found in hospitals that had adopted TZD early (25%Q: -40.33; 50%Q: -38.65; 75%Q: -32.29) and in hospitals in which the drugs penetrated more quickly (25%Q: 16.53; 50%Q: 24.91; 75%Q: 31.50).
Medical centers began to prescribe TZDs earlier, and they prescribed more TZDs at a faster pace. The TZD diffusion patterns varied among hospitals depending accreditation level, ownership type, and prescription volume of Anti-diabetic drugs.
PMCID: PMC3042909  PMID: 21281475
9.  Rosiglitazone Inhibits Bone Regeneration and Causes Significant Accumulation of Fat at Sites of New Bone Formation 
Calcified tissue international  2012;91(2):139-148.
Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma activators, and insulin sensitizers represent drugs used to treat hyperglycemia in diabetic patients. Type 2 diabetes mellitus (T2DM) is associated with a twofold increase in fracture risk, and TZDs use increases this risk by an additional twofold. In this study, we analyzed the effect of systemic administration of the TZD rosiglitazone on new bone formation in two in vivo models of bone repair, a model of drilled bone defect regeneration (BDR) and distraction osteogenesis (DO) and a model of extended bone formation. Rosiglitazone significantly inhibited new endosteal bone formation in both models. This effect was correlated with a significant accumulation of fat cells, specifically at sites of bone regeneration. The diminished bone regeneration in the DO model in rosiglitazone-treated animals was associated with a significant decrease in cell proliferation measured by the number of cells expressing proliferating cell nuclear antigen and neovascularization measured by both the number of vascular sinusoids and the number of cells producing proangiogenic vascular endothelial growth factor at the DO site. In summary, rosiglitazone decreased new bone formation in both BDR and DO models of bone repair by mechanisms which include both intrinsic changes in mesenchymal stem cell proliferation and differentiation and changes in the local environment supporting angiogenesis and new bone formation. These studies suggest that bone regeneration may be significantly compromised in T2DM patients on TZD therapy.
PMCID: PMC3630993  PMID: 22752619
Rosiglitazone; Diabetes; Bone healing; Osteoblast; Angiogenesis; Adipocyte
10.  Thiazolidinediones on PPARγ: The Roles in Bone Remodeling 
PPAR Research  2011;2011:867180.
Thiazolidinediones (TZDs) are synthetic PPARγ (peroxisome proliferator-activated receptor gamma) agonists and a class of drugs for diabetes mellitus type 2 that can decrease blood sugar efficiently by enhancing insulin sensitivity. However, increased bone fracture risk in diabetic individuals treated with TZDs is one of the reported side effects. Recent studies show that TZDs such as rosiglitazone simultaneously inhibit osteoblast differentiation and activate osteoclast differentiation, leading to bone loss due to decreased bone formation and increased bone resorption. Furthermore, TZDs may activate PPARγ in tissues other than bone, such as the hypothalamus-pituitary-gonad (HPG) axis to indirectly regulate bone mass. This paper will focus on current new developments that implicate potential mechanisms for how PPARγ modulates skeletal homeostasis and how TZDs exert bone-loss side effects.
PMCID: PMC3205770  PMID: 22135675
11.  Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database 
Thiazolidinediones (TZDs), rosiglitazone (RGZ) and pioglitazone (PGZ) are widely used as hypoglycemic drugs in patients with type 2 diabetes mellitus. The aim of our study was to investigate the profile of adverse drug reactions (ADRs) related to TZDs and to investigate potential risk factors of these ADRs.
Type 2 diabetic patients were identified from the French Database of PharmacoVigilance (FPVD) between 2002 and 2006. We investigated ADR related to TZD, focusing on 4 ADR: edema, heart failure, myocardial infarction and hepatitis corresponding to specific WHO-ART terms.
Among a total of 99,284 adult patients in the FPVD, 2295 reports concerned type 2 diabetic patients (2.3% of the whole database), with 161 (7%) exposed to TZDs. The frequency of edema and cardiac failure was significantly higher with TZDs than in other patients (18% and 7.4% versus 0.8% and 0.1% respectively, p < 0.001) whereas the frequency of hepatitis was similar (5.9% versus 4%, NS). A multiple logistic regression model taking into account potential confounding factors (age, gender, drug exposure and co-morbidities) found that TZD exposure remained associated with heart failure and edema, but not with hepatitis or myocardial infarction.
Thiazolidinediones exposure is associated with an increased risk of edema and heart failure in patients with type 2 diabetes even when recommendations for use are respected. In contrast, the risk of hepatic reactions and myocardial infarction with this class of drugs seems to be similar to other hypoglycemic agents.
PMCID: PMC3119167  PMID: 21609444
12.  Cancer Risk for Patients Using Thiazolidinediones for Type 2 Diabetes: A Meta-Analysis 
The Oncologist  2013;18(2):148-156.
This systematic review and meta-analysis examined the effect of thiazolidinediones on overall cancer risk, as well as bladder and other site-specific tumors, in patients with type 2 diabetes. Overall, there was no association between TZD and cancer risk. A modestly increased risk of bladder cancer was found, particularly with use of pioglitazone.
Learning Objectives
Evaluate the risk of cancer as well as cardiovascular and renal disease in the use of oral antidiabetics.Define and adequately quantify the effect of TZD on the risk of bladder cancer, other selected cancers, and all neoplasms.
To clarify and quantify the effect of thiazolidinediones (TZDs; e.g., pioglitazone, rosiglitazone) on the risk of bladder cancer, other selected cancers, and overall cancer in patients with type 2 diabetes, we performed a systematic review and meta-analysis of observational studies.
A PubMed/MEDLINE search was conducted for studies published in English up to June 30, 2012. Random-effect models were fitted to estimate summary relative risks (RR).
Seventeen studies satisfying inclusion criteria (3 case-control studies and 14 cohort studies) were considered. Use of TZDs was not associated to the risk of cancer overall (summary RR: 0.96; 95% confidence interval [CI]: 0.91–1.01). A modest excess risk of bladder cancer was reported in pioglitazone (RR: 1.20; 95% CI: 1.07–1.34 from six studies) but not in rosiglitazone (RR: 1.08; 95% CI: 0.95–1.23 from three studies) users. The RRs of bladder cancer were higher for longer duration (RR: 1.42 for >2 years) and higher cumulative dose of pioglitazone (RR: 1.64 for >28,000 mg). Inverse relations were observed with colorectal cancer (RR: 0.93; 95% CI: 0.90–0.97 from six cohort studies) and liver cancer (RR: 0.65; 95% CI: 0.48–0.89 from four studies), whereas there was no association with pancreatic, lung, breast, and prostate cancers.
Adequate evidence excludes an overall excess cancer risk in TZD users within a few years after starting treatment. However, there is a modest excess risk of bladder cancer, particularly with reference to pioglitazone. Assuming that this association is real, the potential implications on the risk-benefit analysis of TZD use should be evaluated.
PMCID: PMC3579598  PMID: 23345544
Cancer; Diabetes; Meta-analysis; Oral antidiabetic therapy; Pioglitazone; Thiazolidinedione
13.  Diabetes, TZDs, and Bone: A Review of the Clinical Evidence 
PPAR Research  2006;2006:24502.
Evidence from rodent and in vitro models suggests that activation of PPAR-γ by thiazolidinediones (TZDs) causes increased bone marrow adiposity and decreased osteoblastogenesis, resulting in bone loss. TZDs are prescribed for the treatment of diabetes, providing an opportunity to determine whether PPAR-γ activation also impacts bone in humans. In addition, since type 2 diabetes is associated with higher fracture risk, an understanding of the clinical impact of TZDs on bone is needed to guide fracture prevention efforts in this population. This review summarizes current findings regarding type 2 diabetes and increased fracture risk and then considers the available evidence regarding TZD use and bone metabolism in humans.
PMCID: PMC1779575  PMID: 17259663
14.  The Risk of Fractures Associated with Thiazolidinediones: A Self-controlled Case-Series Study 
PLoS Medicine  2009;6(9):e1000154.
Ian Douglas and colleagues analyze records from the UK General Practice Research Database, and find that among individuals prescribed thiazolidinediones who develop a fracture, fractures are more common during periods of thiazolidinedione exposure than unexposed periods.
The results of clinical trials have suggested that the thiazolidinedione antidiabetic agents rosiglitazone and pioglitazone are associated with an increased risk of fractures, but such studies had limited power. The increased risk in these trials appeared to be limited to women and mainly involved fractures of the arm, wrist, hand, or foot: risk patterns that could not be readily explained. Our objective was to further investigate the risk of fracture associated with thiazolidinedione use.
Methods and Findings
The self-controlled case-series design was used to compare rates of fracture during thiazolidinedione exposed and unexposed periods and thus estimate within-person rate ratios. We used anonymised primary care data from the United Kingdom General Practice Research Database (GPRD). All patients aged 40 y or older with a recorded fracture and at least one prescription for a thiazolidinedione were included (n = 1,819). We found a within-person rate ratio of 1.43 (95% confidence interval [CI] 1.25–1.62) for fracture at any site comparing exposed with unexposed periods among patients prescribed any thiazolidinedione. This association was similar in men and women and in patients treated with either rosiglitazone or pioglitazone. The increased risk was also evident at a range of fracture sites, including hip, spine, arm, foot, wrist, or hand. The risk increased with increasing duration of thiazolidinedione exposure: rate ratio 2.00 (95% CI 1.48–2.70) for 4 y or more of exposure.
Within individuals who experience a fracture, fracture risk is increased during periods of exposure to thiazolidinediones (both rosiglitazone and pioglitazone) compared with unexposed periods. The increased risk is observed in both men and women and at a range of fracture sites. The risk also increases with longer duration of use.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, nearly 250 million people have diabetes and this number is increasing rapidly, particularly in developing countries. Diabetes is a chronic disease characterized by dangerous amounts of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after eating (the digestion of food produces glucose). Blood-sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or because the fat cells and muscle cells that usually respond to insulin by removing sugar from the blood have become insulin insensitive (type 2 diabetes). Type 1 diabetes is treated with insulin injections; type 2 diabetes—the most common type of diabetes—is controlled with diet, exercise, and antidiabetic pills, drugs that help the pancreas make more insulin (for example, sulfonylureas) or that make cells more sensitive to insulin (for example, thiazolidinediones). Long-term complications of diabetes include kidney failure, blindness, and nerve damage, and an increased risk of developing cardiovascular problems, including heart disease and strokes.
Why Was This Study Done?
Thiazolidinediones are widely used to treat type 2 diabetes but, worryingly, these drugs seem to increase people's risk of developing cardiovascular problems. In addition, they may increase the risk of bone fractures although the evidence for this particular association is limited. Given the large number of people with diabetes, it is important to understand the benefits and risks of thiazolidinedione treatment of diabetes as fully as possible. In this self-controlled case-series study, therefore, the researchers investigate the risk of fracture associated with the use of rosiglitazone and pioglitazone (two thiazolidinedione antidiabetic agents). A “self-controlled case-series study” compares how often an event (in this case, a fracture) occurs (the event's “rate”) in a population of individuals during a period of time when the individuals are not exposed to a medical intervention (in this case, treatment with thiazolidinediones) to its rate during a period when they are exposed to the intervention. Because each person acts as their own control, this study design helps to eliminate the possibility that unrecognized characteristics that vary between people (“confounders”) are responsible for differences in the event rate rather than the intervention itself.
What Did the Researchers Do and Find?
The researchers identified 1,819 people aged 40 years or older with a recorded fracture and at least one prescription for a thiazolidinedione by searching the UK General Practice Research Database, which contains personal and health data for more than 6 million UK residents. They compared these people's fracture rate during periods when they were taking a thiazolidinedione to their fracture rate when they weren't taking one of these drugs. After adjusting for age (age is a potential confounder because the risk of fractures increases with age and all the patients were older during their exposed period than during their unexposed period), the rate ratio for fracture at any site in patients during thiazolidinedione-exposed periods compared with thiazolidinedione-unexposed periods was 1.43. That is, nearly one and half times as many fractures occurred when people were taking thiazolidinediones than when they were not taking these drugs. The association between taking thiazolidinediones and the risk of fracture was similar in men and women and at several fracture sites but increased with the length of thiazolidinedione exposure.
What Do These Findings Mean?
These findings suggest that taking thiazolidinediones is associated with an increased risk of fracture at a wide range of sites in both men and women. They also suggest that the risk of fracture increases with treatment duration. These findings do not prove that thiazolidinediones cause fractures because, despite the self-controlled case-series design of this study, it remains possible that the people who have fractures share some unknown characteristic that affects their chances of breaking a bone. The accuracy of the findings is also dependent on the quality of the data in the General Practice Research Database. Nonetheless, these results are in keeping with the findings of clinical trials and other observational studies, suggesting they represent a real effect of treatment with thiazolidinediones. Although it is not clear yet how thiazolidinediones weaken bones, these findings need to be included in the ongoing debate about the risks and benefits of the treatment of type 2 diabetes with thiazolidinediones.
Additional Information
Please access these Web sites via the online version of this summary at
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information ClearingHouse provides detailed information about diabetes (including information on medicines for diabetes) for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service also provides information for patients and carers about type 2 diabetes (in several languages)
MedlinePlus provides links to further resources and advice about diabetes and diabetes medicines (in English and Spanish)
Information about the UK General Practice Research Database and about the self-controlled case-series method is available
More information is available where the research was done at The London School of Hygiene & Tropical Medicine
PMCID: PMC2741577  PMID: 19787025
15.  Management of type 2 diabetes mellitus 
Canadian Family Physician  2005;51(5):683-687.
To review evidence supporting use of thiazolidinediones (TZDs) in management of type 2 diabetes mellitus (DM2).
A MEDLINE search found several randomized controlled trials (level I evidence). No systematic reviews of these trials were found in the Cochrane Library.
Thiazolidinediones lower hemoglobin AIc levels by as much as 1.0% to 1.5%. Effects can be seen in as little as 4 weeks, but full lowering takes 6 to 12 weeks. When used in combination with other diabetic agents, such as sulfonylureas and biguanides, TZDs’ hypoglycemic effects appear to be complementary. Thiazolidinediones directly improve insulin sensitivity and recovery of pancreatic beta cell function. Nevertheless, there is no evidence indicating that TZDs are superior to other antidiabetic agents currently available or that TZDs reduce the long-term complications of DM2.
Ongoing trials will further define the role of TZDs in management of diabetic patients. In current practice, cost is often a factor in the decision to prescribe TZDs.
PMCID: PMC1472920  PMID: 15934272
16.  Rosiglitazone disrupts endosteal bone formation during distraction osteogenesis by local adipocytic infiltration 
Bone  2012;52(1):247-258.
Rosiglitazone (Rosi) is a drug in the thiazolidinedione class for treatment of Type 2 diabetes mellitus (T2DM), which binds and activates PPARγ nuclear receptor in fat cells, sensitizing them to insulin. Despite proven antidiabetic efficacy, Rosi therapy may be associated with trabecular bone loss and an increased risk of fractures. To examine the potential side effects of Rosi treatment on bone formation, we delivered Rosi to mice using a combined model of distraction osteogenesis (DO) and Type 2 Diabetes Mellitus (T2DM). DO provides a unique method to isolate the sequence of intramembranous bone formation, an important component of both fracture healing and bone homeostasis. Four groups of n=6 mice were used to compare the effects of Rosi on bone formation and cellular composition in both diabetic (Avy/a strain) and non-diabetic mice (a/a strain). New bone formation was examined by high resolution radiographs, micro-computed tomography, and histology. Precursor cells in the distraction gap were quantitated using immunohistochemical stains for proliferating cell nuclear antigen. Committed osteoblasts and adipocytes in the gap were identified and quantitated by immunostaining for osteocalcin and FABP4/aP2, respectively. The diabetic model developed obesity, hyperglycemia, hyperinsulinemia and insulin resistance while the control littermates remained lean, normoglycemic and insulin sensitive. Rosi treatment decreased levels of nonfasted glucose and insulin and improved insulin sensitivity in the Avy/a mice, but had no effect in a/a mice, indicating antidiabetic efficacy of Rosi at the tested dose. Despite the diabetic, obese mice having twice the number of fat cells in their marrow than the non-diabetic mice, bone formation using DO was not adversely affected by the diabetes itself. However, Rosi treatment significantly diminished intramembranous endosteal bone formation, while increasing adipogenesis in and adjacent to the distraction gap up to 3.5–3.8 fold in both diabetic and non-diabetic models. This effect was independent of the anti-diabetic therapeutic response. These results raise the question of whether osteoblast precursors are inhibited in their development or actually converted to adipocytic phenotypes, possibly via marrow fat PPARγ nuclear receptor.
PMCID: PMC3513662  PMID: 23069375
Rosiglitazone; Adipogenesis; Distraction Osteogenesis; Diabetes
17.  Relationship between thiazolidinedione use and cardiovascular outcomes and all-cause mortality among patients with diabetes: A time-updated propensity analysis 
To investigate the association of the thiazolidinediones (TZDs), rosiglitazone and pioglitazone, together and individually on the risk of cardiovascular outcomes and all-cause mortality, using time-updated propensity score adjusted analysis
We conducted a retrospective cohort study in a large vertically integrated health system in southeast Michigan. Cohort inclusion criteria included adult patients with diabetes treated with oral medications and followed longitudinally within the health system between January 1, 2000 and December 1, 2006. The primary outcome was fatal and non-fatal acute myocardial infarction. Secondary outcomes included hospitalizations for congestive heart failure, fatal and non-fatal cerebrovascular accidents and transient ischemic attacks, combined coronary heart disease events, and all-cause mortality.
19,171 patients were included in this study. Use of TZDs (adjusted hazard ratio [aHR] with propensity adjustment [PA], 0.92; 95% confidence interval [CI] 0.73–1.17), rosiglitazone (aHR with PA, 1.06; 95% CI 0.66–1.70), and pioglitazone (aHR with PA, 0.91; 95% CI 0.69–1.21) was not associated with a higher risk of acute myocardial infarction. However, pioglitazone use was associated with a reduction in all-cause mortality (aHR with PA, 0.60; 95% CI 0.42–0.96). Compared with rosiglitazone, pioglitazone use was associated with a lower risk of all outcomes assessed, particularly congestive heart failure (P = 0.013) and combined coronary heart disease events (P = 0.048).
Our findings suggest that pioglitazone may have a more favorable risk profile when compared to rosiglitazone, arguing against a singular effect for TZDs on cardiovascular outcomes.
PMCID: PMC2919167  PMID: 19235778
Thiazolidinediones; Coronary Heart Disease; Congestive Heart Failure; Cerebrovascular Accident; Mortality
18.  Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study 
Background: Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance.
Objectives: The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change.
Methods: This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase).
Results: Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m2) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal.
Conclusions: Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.
PMCID: PMC3969936
insulin resistance; metformin; pioglitazone; Japanese
19.  PPARγ: a circadian transcription factor in adipogenesis and osteogenesis 
Nature reviews. Endocrinology  2010;6(11):629-636.
Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones (TZDs), have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose. However, the use of TZDs has been associated with bone loss and fractures. TZD-induced alterations in the bone marrow milieu—that is, increased marrow adiposity with suppression of osteogenesis—could partially explain the pathogenesis of TZD-induced bone loss Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One of the circadian-regulated genes expressed in peripheral tissues, nocturnin (Noc), has been shown to enhance PPARγ activity. Importantly Noc-deficient mice are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
PMCID: PMC3132113  PMID: 20820194
20.  Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARγ independent mechanisms 
Gut  2004;53(11):1688-1697.
Background/Aims: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of some epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferators activated receptor γ (PPARγ) the mechanism by which TZD exert their anticancer effect is currently unclear. Furthermore, the effect of TZD on local motility and metastatic potential of cancer cells is unknown. The authors analysed the effects of two TZD, rosiglitazone and pioglitazone, on invasiveness of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.
Methods: Expression of PPARγ in human pancreatic adenocarcinomas and pancreatic carcinoma cell lines was measured by reverse transcription polymerase chain reaction and confirmed by western blot analysis. PPARγ activity was evaluated by transient reporter gene assay. Invasion assay was performed in modified Boyden chambers. Gelatinolytic and fibrinolytic activity were evaluated by gel zymography.
Results: TZD inhibited pancreatic cancer cells’ invasiveness, affecting gelatinolytic and fibrinolytic activity with a mechanism independent of PPARγ activation and involving MMP-2 and PAI-1 expression.
Conclusion: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth and invasiveness suggesting that these drugs may have application for prevention and treatment of pancreatic cancer in humans.
PMCID: PMC1774261  PMID: 15479693
thiazolidinediones; pancreatic cancer; PPARγ; cancer invasiveness
21.  The effects of thiazolidinediones (TZD) on human bone marrow stromal cell differentiation in vitro and in TZD-treated patients with type 2 diabetes 
Thiazolidinedione (TZD) therapy has been associated with increased risk of bone fractures. Studies in rodents have led to a model in which decreased bone quality in response to TZDs is due to a competition of lineage commitment between osteoblasts and adipocytes for a common precursor cell resulting in decreased osteoblast numbers. Our goal was to investigate the effects of TZD exposure on osteoblast-adipocyte lineage determination from primary human bone marrow stromal cells (hBMSCs) both in vitro and in vivo from non-diabetic subjects and patients with type 2 diabetics. Our experimental design included two phases. Phase 1: An in vitro study of TZDs effects on hBMSCs differentiation into osteoblasts and adipocytes in non-diabetic subjects. Phase 2: a randomized placebo controlled trial to determine the effects of six month pioglitazone treatment in vivo on hBMSC differentiation using adipocyte/osteoblast colony forming unit assays in patients with type 2 diabetes. In vitro, TZDs (pioglitazone and rosiglitazone) enhanced adipogenesis of hBMSCs while neither altered osteoblast differentiation and/or function as measured by alkaline phosphatase activity, gene expression, and mineralization. The ability of TZDs to enhance adipogenesis occurred at a specific time/stage of the differentiation process and pre-treating with TZDs did not further enhance adipogenesis. In vivo, six month TZD treatment decreased osteoblast precursors, increased adipocyte precursors, and increased total colony number in patients with type 2 diabetes. Our results indicate that TZD exposure in vitro potently stimulates adipogenesis but does not directly alter osteoblast differentiation/mineralization or lineage commitment from hBMSCs. TZD-treatment in type 2 diabetic patients however results in decreased osteoblastogenesis from hBMSCs compared to placebo indicating an indirect negative effect on osteoblasts suggesting an alternative model by which TZDs might negatively regulate bone quality.
PMCID: PMC3546231  PMID: 23022285
osteoblast; adipocyte; human bone marrow; osteoporosis; drug-induced osteopenia
22.  PPAR-γ Agonists and Their Effects on IGF-I Receptor Signaling: Implications for Cancer 
PPAR Research  2009;2009:830501.
It is now well established that the development and progression of a variety of human malignancies are associated with dysregulated activity of the insulin-like growth factor (IGF) system. In this regard, promising drugs have been developed to target the IGF-I receptor or its ligands. These therapies are limited by the development of insulin resistance and compensatory hyperinsulinemia, which in turn, may stimulate cancer growth. Novel therapeutic approaches are, therefore, required. Synthetic PPAR-γ agonists, such as thiazolidinediones (TZDs), are drugs universally used as antidiabetic agents in patients with type 2 diabetes. In addition of acting as insulin sensitizers, PPAR-γ agonists mediate in vitro and in vivo pleiotropic anticancer effects. At least some of these effects appear to be linked with the downregulation of the IGF system, which is induced by the cross-talk of PPAR-γ agonists with multiple components of the IGF system signaling. As hyperinsulinemia is an emerging cancer risk factor, the insulin lowering action of PPAR-γ agonists may be expected to be also beneficial to reduce cancer development and/or progression. In light of these evidences, TZDs or other PPAR-γ agonists may be exploited in those tumors “addicted” to the IGF signaling and/or in tumors occurring in hyperinsulinemic patients.
PMCID: PMC2709717  PMID: 19609453
23.  Pioglitazone Initiation and Subsequent Hospitalisation for Congestive Heart Failure 
Thiazolidinediones (TZD) have been associated with an expansion in plasma volume and the development of peripheral oedema. A recent study reported an association between the use of TZDs and development of congestive heart failure (CHF). The objective of this study was to determine if short-term use of pioglitazone, a TZD, is associated with increased risk of CHF hospitalisation in a well-characterised, community-based cohort of type 2 diabetic patients without prevalent CHF.
A cohort study of all patients in the Kaiser Permanente Medical Care Program with type 2 diabetes (Kaiser Permanente Northern California Diabetes Registry) who initiated any diabetes pharmacotherapy (n=23,440) between October, 1999 and November, 2001. Only patients initiating single new therapies (“new users”) were included to reduce confounding and create mutually-exclusive exposure groups. We constructed Cox proportional hazards models (with sulfonylureas initiators specified as the reference group) to evaluate the impact of initiating new diabetes therapies on time to incident CHF hospitalisation, defined by primary hospital discharge diagnosis.
Patients initiated pioglitazone (15.2%), sulfonylureas (25.3%), metformin (50.9%), and insulin (8.6%) alone or as additions to pre-existing or maintained therapies. Three hundred and twenty CHF hospitalisations were observed during the follow-up (10.2 months on average) after initiation. Relative to sulfonylurea initiators, there were no significant increases in the incidence of CHF hospitalisation among those initiating pioglitazone (hazard ratio (HR) = 1.28; 95% confidence interval (CI): 0.85 – 1.92) after adjusting for demographic, behavioural, and clinical factors. There was a significantly higher incidence among those initiating insulin (HR = 1.56; 95% CI: 1.00 – 2.45) and lower incidence among those initiating metformin, (HR = 0.70; 95% CI: 0.49 – 0.99).
This study of patients with type 2 diabetes failed to find evidence that short-term pioglitazone use was associated with an elevated risk of CHF hospitalisation relative to the standard, first line diabetes therapy.
PMCID: PMC3557913  PMID: 16026362
diabetes mellitus; congestive heart failure; thiazolidinediones; pioglitazone; hypoglycaemic agents; pharmacoepidemiology; new user design
24.  Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis 
Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically.
To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH.
Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters.
Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33–3.36), 2.58 (95% CI, 1.68–3.97) and 3.39 (95% CI, 2.19–5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03–14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02–2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment.
Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis.
PMCID: PMC3488596  PMID: 22050199
25.  Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study 
Gut  2004;53(2):251-255.
Background: Inflammatory bowel disease (IBD) is known to be associated with reduced bone density but the extent to which this results in an increased risk of fracture and the contribution of corticosteroid therapy are unclear. We have conducted a large cohort study to address these issues.
Methods: We selected subjects within the General Practice Research Database (GPRD) with a diagnosis of IBD and up to five matched controls for each patient. We derived dates of recorded hip fractures and also information on smoking, use of corticosteroids, and a number of other drugs. We calculated the absolute risk of fracture and the relative risk as a hazard ratio corrected for available confounders by Cox regression.
Results: Seventy two hip fractures were recorded in 16 550 IBD cases and 223 in 82 917 controls. Cox modelling gave an unadjusted relative risk of hip fracture of 1.62 (95% confidence interval (CI) 1.24–2.11) for all IBD, 1.49 (1.04–2.15) for ulcerative colitis (UC) and 2.08 (1.36–3.18) for Crohn’s disease (CD). Multivariate modelling showed that both current and cumulative use of corticosteroids and use of opioid analgesics confounded this relationship. After adjusting for confounding, the relative risk was 1.41 (0.94–2.11) for UC and 1.68 (1.01–2.78) for CD.
Conclusion: The risk of hip fracture is increased approximately 60% in IBD patients. Corticosteroid use is a contributor to this, both in the long term as previously recognised and also in an acute reversible manner. The majority of hip fracture risk in IBD patients however cannot be attributed to steroid use.
PMCID: PMC1774916  PMID: 14724159
corticosteroids; fracture; inflammatory bowel disease

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