CoChat
Sign Up
Cited by 85Bone health and osteoporosis researchDiabetes Treatment and ManagementHIV-related health complications and treatments

Effects of TZD use and discontinuation on fracture rates in ACCORD bone study

Open access
Schwartz, Ann V., Chen, Haiying, Ambrosius, Walter T., Sood, Ajay, Josse, Robert G., Bonds, Denise E., Schnall, Adrian M., Vittinghoff, Eric +10 more·2015·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2015-1215PMC PMC4702444
Open this paper in CoChat — free accountOpen PDF

Abstract

CONTEXT: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown. OBJECTIVE: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men. DESIGN: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2-4 months at clinic visits, were modeled as time-varying covariates in proportional hazards models for occurrence of first non-spine fracture. PARTICIPANTS: We studied a total of 6865 participants in ACCORD BONE. MAIN OUTCOME MEASURES: Main outcome measures were centrally adjudicated non-spine fracture. RESULTS: Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1-2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or >2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1-2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men. CONCLUSIONS: TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/jc.2015-1215

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Pioglitazone is associated with heart failure, fluid retention, weight gain, osteoporosis, falls or fractures, and/or macular edema.

    “Pioglitazone, if used at all, should be used very cautiously in older adults on insulin therapy as well as in those with or at risk for heart failure, fluid retention, weight gain, osteoporosis, falls or fractures, and/or macular edema (113,114).”

    From 13. Older Adults: Standards of Care in Diabetes—2025 (2025) · cites this paper as [113]

    The Discussion reports prior evidence of increased fracture risk with pioglitazone and bone loss in some populations, while noting that ACCORD could not assess pioglitazone separately from rosiglitazone. The paper does not establish the other attributed concerns—heart failure, fluid retention, weight gain, falls, or macular edema—or a specific risk from use with insulin. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Pioglitazone has low risk for hypoglycemia but carries risks for heart failure, fluid retention, weight gain, osteoporosis, and/or macular edema.

    “Pioglitazone has low risk for hypoglycemia but should be used cautiously and in select individuals due to risks for heart failure, fluid retention, weight gain, osteoporosis, and/or macular edema”

    From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [118]

    The Discussion (page not provided) reports increased bone loss with pioglitazone in some groups and cites increased fracture risk with pioglitazone, supporting the skeletal-risk portion of the claim. The paper does not establish low hypoglycemia risk or address heart failure, fluid retention, weight gain, or macular edema as pioglitazone risks. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 24

  1. Cauley JA. Public health impact of osteoporosis. J Gerontol A Biol Sci Med Sci. 2013;68(10):1243-1251.
  2. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta-analysis. Osteoporos Int. 2007;18(4):427-444.
  3. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009; 180(1):32-39.
  4. Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008; 168(8):820 -825.
  5. Douglas IJ, Evans SJ, Pocock S, Smeeth L. The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med. 2009;6(9):e1000154.
  6. Kumar S, Hoffman SJ, Samadfam R, et al. The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate. J Bone Miner Res. 2013;28(7):1653-1665.
  7. Bilezikian JP, Josse RG, Eastell R, et al. Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98(4):1519 -1528.
  8. Schwartz AV, Margolis KL, Sellmeyer DE, et al. Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial. Diabetes Care. 2012;35(7):1525-1531.
  9. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
  10. Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone-osteoporotic fractures in diabetes mellitus. Nat Rev Endocri- nol. 2012;8(5):297-305.
  11. Vittinghoff E, Glidden DV, Shiboski SC, McCulloch CE. Regression methods in biostatistics: linear, logistic, survival, and repeated mea- sures models. 2nd ed. San Francisco, CA: Springer; 2012.
  12. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125-2135.
  13. Rubin GL, Zhao Y, Kalus AM, Simpson ER. Peroxisome prolifera- tor-activated receptor ␥ ligands inhibit estrogen biosynthesis in hu- man breast adipose tissue: possible implications for breast cancer therapy. Cancer Res. 2000;60(6):1604 -1608.
  14. Seto-Young D, Avtanski D, Parikh G, et al. Rosiglitazone and pi- oglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. Horm Metab Res. 2011;43(4):250 -256.
  15. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000; 15(6):993-1000.
  16. Grey A, Bolland M, Gamble G, et al. The peroxisome proliferator- activated receptor-␥ agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a ran- domized, controlled trial. J Clin Endocrinol Metab. 2007;92(4): 1305-1310.
  17. Berberoglu Z, Yazici AC, Demirag NG. Effects of rosiglitazone on bone mineral density and remodelling parameters in postmeno- pausal diabetic women: a 2-year follow-up study. Clin Endocrinol (Oxf). 2010;73(3):305-312.
  18. Borges JL, Bilezikian JP, Jones-Leone AR, et al. A randomized, par- allel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011;13(11):1036 -1046.
  19. Glintborg D, Andersen M, Hagen C, Heickendorff L, Hermann AP. Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syn- drome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2008;93(5):1696 -1701.
  20. Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Span- heimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin En- docrinol Metab. 2013;98(12):4691-4701.
  21. Grey A, Bolland M, Fenwick S, et al. The skeletal effects of piogli- tazone in type 2 diabetes or impaired glucose tolerance: a random- ized controlled trial. Eur J Endocrinol. 2014;170(2):255-262.
  22. Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf. 2009; 32(3):187-202.
  23. Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299(13):1561-1573.
  24. White E. The effect of misclassification of disease status in follow-up studies: implications for selecting disease classification criteria. Am J Epidemiol. 1986;124(5):816 -825.

Cited by

Sorted by citations

Authors
Schwartz, A. V., Chen, H., Ambrosius, W. T., Sood, A., Josse, R. G., Bonds, D. E., Schnall, A. M., Vittinghoff, E., Bauer, D. C., Banerji, M. A., Cohen, R. M., Hamilton, B. P., Isakova, T., Sellmeyer, D. E., Simmons, D. L., Shibli-Rahhal, A., Williamson, J. D., & Margolis, K. L.
Affiliations
  • St. Michael's Hospital (CA)
  • University of Iowa (US)
Corresponding author
Schwartz, Ann V.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2015-11
Volume
100
Issue
11
Pages
4059-4066
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2015-1215
PMC
PMC4702444
OpenAlex
W2124007477
Cited by
85
References
2
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 16 · 2018: 9 · 2017: 12 · 2016: 6 · 2015: 1
FWCI
9.63
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (n01hc95183-23-0-0, n01hc95180-24-0-1, n01hc95184-24-0-1, n01hc95181-23-0-1, n01hc95182-23-0-1, n01hc95178-28-0-1, n01hc95179-25-0-0)
  • National Heart, Lung, and Blood Institute (N01- HC-95181, N01 HC095184, N01-HC- 95180, N01-HC-95178, N01 HC095182, N01 HC095181, Y01 HC001010, N01-HC-095183, N01 HC095178, N01-HC-95184, IAAY1-HC-1010, IAA #Y1-HC-9035, N01 HC095180, Y01 HC009035, N01‐HC‐95183, N01-HC-95182, N01 HC095179)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK069514)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24AR051895)
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 › Emergency Medicine › HIV-related health complications and treatments
Keywords
thiazolidinediones, fracture risk, rosiglitazone, pioglitazone, type 2 diabetes, sex differences, drug discontinuation, ACCORD trial, bone health
MeSH terms
Rosiglitazone, Pioglitazone, Aged, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Longitudinal Studies, Male, Middle Aged, Cohort Studies, Incidence, Thiazolidinediones, Fractures, Bone

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review