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Risk of Thiazolidinedione-Associated Fracture Should Be Appropriately Assessed—Reply

Risk of Thiazolidinedione-Associated Fracture Should Be Appropriately Assessed—Reply In reply The position of van Troostenburg de Bruyn and Dormandy on the prospective/retrospective distinction of a study seems to be that timing of subject identification is the deciding factor for which label to use. We defined our study as prospective because exposure and covariates were recorded before fractures.1 This is a proper definition that is more relevant to the common concern with retrospective studies of potential bias caused by the outcome event influencing ascertainment of the exposure. Dormandy et al2 wrote in a recent review in Drug Safety that spinal fractures with pioglitazone use will be investigated further, but in their letter, he and van Troostenburg de Bruyn write that our statement of a potential association with spinal fractures is unwarranted. We wrote that a strong conclusion could not be drawn from that result.3 We wrote “potential association” to allow for the possibility that the true effect was different than what we observed. Just because a 95% confidence interval for the estimate includes 0% does not mean that 0% is the most credible hypothesis. In fact, there was less support for 0% more spinal fractures with pioglitazone use relative to rosiglitazone in our data than for 31% (the maximum likelihood estimate), if only minimally so. Given a choice between a statement of potential association and one of no association, therefore, the former was more warranted than the latter. Fracture data on pioglitazone use have not been adequately published. A meta-analysis on fractures and thiazolidinedione use stated that fracture data for the PROactive trial were drawn from the manufacturer's US product monograph.4 Not all information provided to the Food and Drug Administration is in the public domain, and there is no way of knowing what data are excluded from a product monograph. It is worth noting that the monograph would still be needed for a meta-analysis today because counts of fractures in men were not provided in either the safety review by Dormandy et al1 or in the article referenced in that review to support a statement of no increase of fractures in men.5 van Troostenburg de Bruyn and Dormandy claim that the benefits of pioglitazone treatment in terms of myocardial infarction as reported in the PROactive trial demonstrate reduced risk of all adverse cardiovascular events. A meta-analysis of 19 pioglitazone trials by Lincoff et al6 reported a nonsignificant difference on a subset of serious adverse events. Another meta-analysis of total serious adverse events in 22 trials by Richter et al7 found that patients randomized to pioglitazone treatment were more likely to develop edema and heart failure than were those randomized to placebo, including heart failure leading to hospitalization. Richter et al7 also concluded that diabetic patients gained no associated benefit to justify the cardiovascular risk. Correspondence: Dr Dormuth, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 1110 Government St, Ste 210, Victoria, BC V8W 1Y2, Canada (colin.dormuth@ti.ubc.ca). References 1. Rothman KJGreenland SLash TL Types of epidemiologic studies. Rothman KJGreenland SLash TL Modern Epidemiology. 3rd ed. Philadelphia, PA Lippincott Williams & Wilkins2008;95- 97Google Scholar 2. Dormandy JBhattacharya Mvan Troostenburg de Bruyn ARPROactive investigators, Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009;32 (3) 187- 202PubMedGoogle ScholarCrossref 3. Dormuth CRCarney GCarleton BBassett KWright JM Thiazolidinediones and fractures in men and women. Arch Intern Med 2009;169 (15) 1395- 1402PubMedGoogle ScholarCrossref 4. Loke YKSingh SFurberg CD Long-term use of thiazolidinediones and fractures in type diabetes: a meta-analysis. CMAJ 2009;180 (1) 32- 39PubMedGoogle ScholarCrossref 5. Short R Fracture risk is a class effect of glitazones. BMJ 2007;334 (7593) 551PubMedGoogle ScholarCrossref 6. Lincoff AMWolski KNicholls SJNissen SE Pioglitazone and risk of cardiovascular events inpatients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298 (10) 1180- 1188PubMedGoogle ScholarCrossref 7. Richter BBandeira-Echtler EBergerhoff KClar CEbrahim SH Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; (4) CD006060PubMedGoogle Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Risk of Thiazolidinedione-Associated Fracture Should Be Appropriately Assessed—Reply

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Publisher
American Medical Association
Copyright
Copyright © 2010 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2009.488
Publisher site
See Article on Publisher Site

Abstract

In reply The position of van Troostenburg de Bruyn and Dormandy on the prospective/retrospective distinction of a study seems to be that timing of subject identification is the deciding factor for which label to use. We defined our study as prospective because exposure and covariates were recorded before fractures.1 This is a proper definition that is more relevant to the common concern with retrospective studies of potential bias caused by the outcome event influencing ascertainment of the exposure. Dormandy et al2 wrote in a recent review in Drug Safety that spinal fractures with pioglitazone use will be investigated further, but in their letter, he and van Troostenburg de Bruyn write that our statement of a potential association with spinal fractures is unwarranted. We wrote that a strong conclusion could not be drawn from that result.3 We wrote “potential association” to allow for the possibility that the true effect was different than what we observed. Just because a 95% confidence interval for the estimate includes 0% does not mean that 0% is the most credible hypothesis. In fact, there was less support for 0% more spinal fractures with pioglitazone use relative to rosiglitazone in our data than for 31% (the maximum likelihood estimate), if only minimally so. Given a choice between a statement of potential association and one of no association, therefore, the former was more warranted than the latter. Fracture data on pioglitazone use have not been adequately published. A meta-analysis on fractures and thiazolidinedione use stated that fracture data for the PROactive trial were drawn from the manufacturer's US product monograph.4 Not all information provided to the Food and Drug Administration is in the public domain, and there is no way of knowing what data are excluded from a product monograph. It is worth noting that the monograph would still be needed for a meta-analysis today because counts of fractures in men were not provided in either the safety review by Dormandy et al1 or in the article referenced in that review to support a statement of no increase of fractures in men.5 van Troostenburg de Bruyn and Dormandy claim that the benefits of pioglitazone treatment in terms of myocardial infarction as reported in the PROactive trial demonstrate reduced risk of all adverse cardiovascular events. A meta-analysis of 19 pioglitazone trials by Lincoff et al6 reported a nonsignificant difference on a subset of serious adverse events. Another meta-analysis of total serious adverse events in 22 trials by Richter et al7 found that patients randomized to pioglitazone treatment were more likely to develop edema and heart failure than were those randomized to placebo, including heart failure leading to hospitalization. Richter et al7 also concluded that diabetic patients gained no associated benefit to justify the cardiovascular risk. Correspondence: Dr Dormuth, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 1110 Government St, Ste 210, Victoria, BC V8W 1Y2, Canada (colin.dormuth@ti.ubc.ca). References 1. Rothman KJGreenland SLash TL Types of epidemiologic studies. Rothman KJGreenland SLash TL Modern Epidemiology. 3rd ed. Philadelphia, PA Lippincott Williams & Wilkins2008;95- 97Google Scholar 2. Dormandy JBhattacharya Mvan Troostenburg de Bruyn ARPROactive investigators, Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 2009;32 (3) 187- 202PubMedGoogle ScholarCrossref 3. Dormuth CRCarney GCarleton BBassett KWright JM Thiazolidinediones and fractures in men and women. Arch Intern Med 2009;169 (15) 1395- 1402PubMedGoogle ScholarCrossref 4. Loke YKSingh SFurberg CD Long-term use of thiazolidinediones and fractures in type diabetes: a meta-analysis. CMAJ 2009;180 (1) 32- 39PubMedGoogle ScholarCrossref 5. Short R Fracture risk is a class effect of glitazones. BMJ 2007;334 (7593) 551PubMedGoogle ScholarCrossref 6. Lincoff AMWolski KNicholls SJNissen SE Pioglitazone and risk of cardiovascular events inpatients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298 (10) 1180- 1188PubMedGoogle ScholarCrossref 7. Richter BBandeira-Echtler EBergerhoff KClar CEbrahim SH Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; (4) CD006060PubMedGoogle Scholar

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jan 25, 2010

Keywords: fractures,thiazolidinedione

References