The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis
Open accessAbstract
Aims/hypothesis Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. Methods PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. Results In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n = 3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference -1.1% [95% CI -1.6, -0.7]; p < 0.0001), total hip (-1.0% [-1.4, -0.6]; p < 0.0001) and forearm (-0.9% [-1.6, -0.3]; p = 0.007). There were statistically non-significant decreases in BMD at the femoral neck (-0.7% [-1.4, 0.0]; p = 0.06) and total body (-0.3% [-0.5, 0.0]; p = 0.08). Five trials (n = 450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. Conclusions/interpretation Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment.
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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 [114]
The Results (Study characteristics; page not provided) report reduced bone mineral density with thiazolidinediones, and the subgroup analysis says findings for pioglitazone were similar. The Discussion advises caution in older patients and those at high risk of fracture. The paper does not substantiate the sentence’s other cautions about heart failure, fluid retention, weight gain, falls, macular edema, or insulin therapy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPioglitazone 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 [119]
The Study characteristics section reports that thiazolidinediones reduced bone mineral density and that analyses restricted to pioglitazone trials were similar; the Discussion advises caution in patients at high fracture risk. This supports a skeletal-risk concern, though the paper does not establish osteoporosis as a diagnosed outcome. Our copy does not support the claims about low hypoglycemia risk, heart failure, fluid retention, weight gain, or macular edema. (LLM, conf=0.88)
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Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy
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Rosiglitazone-Associated Fractures in Type 2 Diabetes
Kahn, S. E., Zinman, B., Lachin, J. M., Haffner, S. M., Herman, W. H., Holman, R. R., Kravitz, B. G., Yu, D., Heise, M. A., Aftring, R. P., et al. (2008) · Diabetes Care · doi:10.2337/dc07-2270 · Cited by 537 · see citing works
Risk of fracture with thiazolidinediones: An updated meta-analysis of randomized clinical trials
Zhu, Z.-N., Jiang, Y.-F., & Ding, T. (2014) · Bone · doi:10.1016/j.bone.2014.08.010 · Cited by 253 · see citing works
The DREAM trial – Authors' reply
Gerstein, H. C., Yusuf, S., & Bosch, J. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69829-2 · Cited by 253 · see citing works
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Tahrani, A. A., Barnett, A. H., & Bailey, C. J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.86 · Cited by 398 · see citing works
13. Older Adults: <i>Standards of Medical Care in Diabetes—2022</i>
American Diabetes Association Professional Practice Committee (2022) · Diabetes Care · doi:10.2337/dc22-s013 · Cited by 381 · see citing works
13. Older Adults: Standards of Care in Diabetes—2025
American Diabetes Association Professional Practice Committee, ElSayed, N. A., McCoy, R. G., Aleppo, G., Balapattabi, K., Beverly, E. A., Briggs Early, K., Bruemmer, D., Echouffo-Tcheugui, J. B., Ekhlaspour, L., et al. (2025) · Diabetes Care · doi:10.2337/dc25-s013 · Cited by 209 · see citing works
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American Diabetes Association Professional Practice Committee, ElSayed, N. A., Aleppo, G., Bannuru, R. R., Bruemmer, D., Collins, B. S., Ekhlaspour, L., Hilliard, M. E., Johnson, E. L., Khunti, K., et al. (2024) · Diabetes Care · doi:10.2337/dc24-s013 · Cited by 161 · see citing works
PFAS and Potential Adverse Effects on Bone and Adipose Tissue through Interactions with PPARγ
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American Diabetes Association Professional Practice Committee for Diabetes*, Bajaj, M., McCoy, R. G., Balapattabi, K., Bannuru, R. R., Bellini, N. J., Bennett, A. K., Beverly, E. A., Briggs Early, K., ChallaSivaKanaka, S., et al. (2026) · Diabetes Care · doi:10.2337/dc26-s013 · Cited by 87 · see citing works
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- Authors
- Billington, E. O., Grey, A., & Bolland, M. J.
- Affiliations
- University of Auckland (NZ)
- Corresponding author
- Billington, Emma O.
- Venue
- Diabetologia
- Published
- 2015-06-25
- Volume
- 58
- Issue
- 10
- Pages
- 2238-2246
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2109434372
- Cited by
- 133
- References
- 4
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 15 · 2023: 9 · 2022: 9 · 2021: 14 · 2020: 12 · 2019: 18 · 2018: 14 · 2017: 19 · 2016: 9
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- Louisiana State University
- Universität Wien
- Medizinische Universität Wien
- University of California, San Francisco
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- thiazolidinediones, bone mineral density, bone turnover markers, bone loss, fracture risk, type 2 diabetes, metformin, sulfonylureas, lumbar spine, hip bone density
- MeSH terms
- Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Bone Density, Bone Remodeling, Thiazolidinediones, Fractures, Bone
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