Pioglitazone and Risk for Bone Fracture: Safety Data from a Randomized Clinical Trial
Open accessAbstract
Context: Pioglitazone reduces cardiovascular risk in nondiabetic patients after an ischemic stroke or transient ischemic attack (TIA) but is associated with increased risk for bone fracture. Objective: To characterize fractures associated with pioglitazone by location, mechanism, severity, timing, and sex. Design, Setting, and Patients: Patients were 3876 nondiabetic participants in the Insulin Resistance Intervention after Stroke trial randomized to pioglitazone or placebo and followed for a median of 4.8 years. Fractures were identified through quarterly interviews. Results: At 5 years, the increment in fracture risk between pioglitazone and placebo groups was 4.9% [13.6% vs 8.8%; hazard ratio (HR), 1.53; 95% confidence interval (CI), 1.24 to 1.89). In each group, ∼80% of fractures were low energy (i.e., resulted from fall) and 45% were serious (i.e., required surgery or hospitalization). For serious fractures most likely to be related to pioglitazone (low energy, nonpathological), the risk increment was 1.6% (4.7% vs 3.1%; HR, 1.47; 95% CI, 1.03 to 2.09). Increased risk for any fracture was observed in men (9.4% vs 5.2%; HR, 1.83; 95% CI, 1.36 to 2.48) and women (14.9% vs 11.6%; HR, 1.32; 95% CI, 0.98 to 1.78; interaction P = 0.13). Conclusions: Fractures affected 8.8% of placebo-treated patients within 5 years after an ischemic stroke or TIA. Pioglitazone increased the absolute fracture risk by 1.6% to 4.9% and the relative risk by 47% to 60%, depending on fracture classification. Our analysis suggests that treatments to improve bone health and prevent falls may help optimize the risk/benefit ratio for pioglitazone.
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TZDs are associated with possible side effects of fluid retention and congestive heart failure, weight gain, and bone fracture.
“However, these bene fi ts must be balanced against possible side effects of fl uid retention and congestive HF (196,197,202), weight gain (196 -198,202,203), and bone fracture (204,205).”
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- Authors
- Viscoli, C. M., Inzucchi, S. E., Young, L. H., Insogna, K. L., Conwit, R., Furie, K. L., Gorman, M., Kelly, M. A., Lovejoy, A. M., Kernan, W. N., & for the IRIS Trial Investigators
- Affiliations
- Yale University (US)
- National Institute of Neurological Disorders and Stroke (US)
- Brown University (US)
- Maine Medical Center (US)
- Cook County Health and Hospitals System (US)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-12-09
- Volume
- 102
- Issue
- 3
- Pages
- jc.2016-3237
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5460686
- OpenAlex
- W2560143854
- Cited by
- 124
- References
- 30
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 16 · 2023: 11 · 2022: 12 · 2021: 17 · 2020: 15 · 2019: 16 · 2018: 11 · 2017: 6 · 2016: 1
- FWCI
- 13.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (U01NS044876)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- pioglitazone, bone fracture risk, insulin resistance, ischemic stroke, transient ischemic attack, non-diabetic patients, sex differences, fragility fractures, fall-related fractures, drug safety
- MeSH terms
- Accidental Falls, Pioglitazone, Aged, Ischemic Attack, Transient, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Risk Factors, Sex Factors, Proportional Hazards Models, Stroke, Thiazolidinediones, Fractures, Bone, Kaplan-Meier Estimate
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