Osteoporosis International

, Volume 28, Issue 11, pp 3261–3269 | Cite as

Impact of pioglitazone on bone mineral density and bone marrow fat content

  • L. M. Pop
  • I. Lingvay
  • Q. Yuan
  • X. Li
  • B. Adams-Huet
  • N. M. MaaloufEmail author
Original Article



Pioglitazone use is associated with an increased risk of fractures. In this randomized, placebo-controlled study, pioglitazone use for 12 months was associated with a significant increase in bone marrow fat content at the femoral neck, accompanied by a significant decrease in total hip bone mineral density. The change in bone marrow fat with pioglitazone use was predominantly observed in female vs. male participants.


Use of the insulin sensitizer pioglitazone is associated with greater fracture incidence, although the underlying mechanisms are incompletely understood. This study aimed to assess the effect of pioglitazone treatment on femoral neck bone marrow (BM) fat content and on bone mineral density (BMD), and to establish if any correlation exists between the changes in these parameters.


In this double-blind placebo-controlled clinical trial, 42 obese volunteers with metabolic syndrome were randomized to pioglitazone (45 mg/day) or matching placebo for 1 year. The following measurements were conducted at baseline and during the treatment: liver, pancreas, and femoral neck BM fat content (by magnetic resonance spectroscopy), BMD by DXA, abdominal subcutaneous and visceral fat, and beta-cell function and insulin sensitivity.


Results were available for 37 subjects who completed the baseline and 1-year evaluations. At 12 months, BM fat increased with pioglitazone (absolute change, +4.1%, p = 0.03), whereas BM fat content in the placebo group decreased non-significantly (−3.1%, p = 0.08) (p = 0.007 for the pioglitazone–placebo response difference). Total hip BMD declined in the pioglitazone group (−1.4%) and increased by 0.8% in the placebo group (p = 0.03 between groups). The change in total hip BMD was inversely and significantly correlated with the change in BM fat content (Spearman rho = −0.56, p = 0.01) in the pioglitazone group, but not within the placebo group (rho = −0.29, p = 0.24). Changes in BM fat with pioglitazone were predominantly observed in female vs. male subjects.


Pioglitazone use for 12 months compared with placebo is associated with significant increase in BM fat content at the femoral neck, accompanied by a small but significant decrease in total hip BMD.


Bone Marrow Fat Bone Mineral Density Fracture Pioglitazone 



The authors would like to thank Madhuri Poduri, MS (Department of Internal Medicine, UTSW) for her expert help in protocol implementation, patient care, and data collection. The authors would also like to express their gratitude to all the study volunteers and UTSW Hospital Staff.

Compliance with ethical standards

Funding sources

This work was supported by the National Institutes of Health grants: RR024476 and RR024982.

Conflicts of interest

Ildiko Lingvay received consultant/research grants from Novo Nordisk; consultant from AstraZeneca, Lilly, and Sanofi; and research grant from GI Dynamics and Pfizer/Merck and publication support from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. The remaining authors have nothing to disclose.

Ethical approval

All procedures performed in the present study involving human participants were approved by the University of Texas at Southwestern Medical Center at Dallas (TX) Institutional Review Board and have been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants in the study.

Supplementary material

198_2017_4164_MOESM1_ESM.docx (12 kb)
ESM 1 (DOCX 12 kb)


  1. 1.
    Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118. doi: 10.1056/NEJMra041001 CrossRefPubMedGoogle Scholar
  2. 2.
    Olefsky JM (2000) Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 106:467–472. doi: 10.1172/JCI10843 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bajaj M, Suraamornkul S, Hardies LJ et al (2004) Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disor 28:783–789. doi: 10.1038/sj.ijo.0802625 CrossRefGoogle Scholar
  4. 4.
    Tiikkainen M, Hakkinen AM, Korsheninnikova E et al (2004) Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 53:2169–2176. doi: 10.2337/diabetes.53.8.2169 CrossRefPubMedGoogle Scholar
  5. 5.
    McGavock JM, Lingvay I, Zib I et al (2007) Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116:1170–1175. doi: 10.1161/CIRCULATIONAHA.106.645614 CrossRefPubMedGoogle Scholar
  6. 6.
    Maalouf NM (2015) Impact of anti-hyperglycemic medications on bone health. Clinic Rev Bone Miner Metab 13:43–52CrossRefGoogle Scholar
  7. 7.
    Kahn SE, Zinman B, Lachin JM et al (2008) Rosiglitazone-associated fractures in type 2 diabetes: an analysis from a diabetes outcome progression trial (ADOPT). Diabetes Care 31:845–851. doi: 10.2337/dc07-2270 CrossRefPubMedGoogle Scholar
  8. 8.
    Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 23:2427–2443. doi: 10.1056/NEJMoa066224 CrossRefGoogle Scholar
  9. 9.
    FDA. Observation of an increased incidence of fractures in female patients who received long-term treatment with pioglitazone.
  10. 10.
    Home PD, Pocock SJ, Beck-Nielsen H et al (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135. doi: 10.1016/S0140-6736(09)60953-3 CrossRefPubMedGoogle Scholar
  11. 11.
    Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123. doi: 10.1016/j.bone.2014.08.010 CrossRefPubMedGoogle Scholar
  12. 12.
    Aubert RE, Herrera V, Chen W et al (2010) Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 12:716–721. doi: 10.1111/j.1463-1326.2010.01225.x CrossRefPubMedGoogle Scholar
  13. 13.
    Colhoun HM, Livingstone SJ, Looker HC et al (2012) Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 55:2929–2937. doi: 10.1007/s00125-012-2668-0 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rzonca SO, Suva LJ, Gaddy D et al (2004) Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 145:401–406. doi: 10.1210/en.2003-0746 CrossRefPubMedGoogle Scholar
  15. 15.
    Wan Y, Chong LW, Evans RM (2007) PPAR-gamma regulates osteoclastogenesis in mice. Nature Med 13:1496–1503. doi: 10.1038/nm1672 CrossRefPubMedGoogle Scholar
  16. 16.
    Grey A, Bolland M, Gamble G et al (2007) The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305–1310. doi: 10.1210/jc.2006-2646 CrossRefPubMedGoogle Scholar
  17. 17.
    Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285:2486–2497Google Scholar
  18. 18.
    Warshauer J, Lopez X, Gordillo R et al (2015) Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome. Diabetes Metab Res Rev 31:734–744. doi: 10.1002/dmrr.2662 CrossRefPubMedGoogle Scholar
  19. 19.
    Szczepaniak LS et al (1999) Measurement of intracellular triglyceride stores by 1H spectroscopy: validation in vivo. Am J Physiol Endocrinol Metab 276:977–989Google Scholar
  20. 20.
    Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468. doi: 10.1152/ajpendo.00064.2004 CrossRefPubMedGoogle Scholar
  21. 21.
    Lingvay I, Esser V, Legendre JL et al (2009) Noninvasive quantification of pancreatic fat in humans. J Clin Endocrinol Metab 94:4070–4076. doi: 10.1210/jc.2009-0584 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Griffith JF, Yeung DK, Chow SK et al (2009) Reproducibility of MR perfusion and 1H spectroscopy of bone marrow. J Magn Reson Imaging 29:1438–1342. doi: 10.1002/jmri.21765 CrossRefPubMedGoogle Scholar
  23. 23.
    Billington EO, Grey A, Bolland MJ (2015) The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. Diabetologia 58:2238–2246. doi: 10.1007/s00125-015-3660-2 CrossRefPubMedGoogle Scholar
  24. 24.
    Grey A, Beckley V, Doyle A et al (2012) Pioglitazone increases bone marrow fat in type 2 diabetes: results from a randomized controlled trial. Eur J Endocrinol 166:1087–1091. doi: 10.1530/EJE-11-1075 CrossRefPubMedGoogle Scholar
  25. 25.
    Harsløf T, Wamberg L, Møller L et al (2011) Rosiglitazone decreases bone mass and BM fat. J Clin Endocrinol Metab 96:1541–1548. doi: 10.1210/jc.2010-2077 CrossRefPubMedGoogle Scholar
  26. 26.
    Berberoglu Z, Gursoy A, Bayraktar N et al (2007) Rosiglitazone decreases serum bone-specific alkaline phosphatase activity in postmenopausal diabetic women. J Clin Endocrinol Metab 92:3523–3530. doi: 10.1210/jc.2007-0431 CrossRefPubMedGoogle Scholar
  27. 27.
    Grey A (2009) Thiazolidinedione-induced skeletal fragility–mechanisms and implications. Diab Obes Metab 11:275–284. doi: 10.1111/j.1463-1326.2008.00931.x CrossRefGoogle Scholar
  28. 28.
    Gruntmanis U, Fordan S, Ghayee HK et al (2010) The peroxisome proliferator-activated receptor gamma agonist rosiglitazone increases bone resorption in women with type 2 diabetes: a randomized, controlled trial. Calcif Tis Int 86:343–349. doi: 10.1007/s00223-010-9352-5 CrossRefGoogle Scholar
  29. 29.
    Bilezikian JP, Josse RG, Eastell R et al (2013) Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab 98:1519–1528. doi: 10.1210/jc.2012-4018 CrossRefPubMedGoogle Scholar
  30. 30.
    Bone HG, Lindsay R, McClung MR et al (2013) 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 Endocrinol Metab 98:4691–4701. doi: 10.1210/jc.2012-4096 CrossRefPubMedGoogle Scholar
  31. 31.
    Grey A, Bolland M, Fenwick S et al (2014) The skeletal effects of pioglitazone in type 2 diabetes or impaired glucose tolerance: a randomized controlled trial. Eur J Endocrinol 170:255–262. doi: 10.1530/EJE-13-0793 CrossRefPubMedGoogle Scholar
  32. 32.
    Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR (2009) Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 32:187–202. doi: 10.2165/00002018-200932030-00002 CrossRefPubMedGoogle Scholar
  33. 33.
    Fazeli PK, Horowitz MC, MacDougald OA et al (2013) Marrow fat and bone--new perspectives. J Clin Endocrinol Metab 98:935–945. doi: 10.1210/jc.2012-3634 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Benvenuti S, Cellai I, Luciani P et al (2012) Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells. J Endocrinol Investig 35:365–371. doi: 10.3275/7739 Google Scholar
  35. 35.
    Seto-Young D, Avtanski D, Parikh G et al (2011) Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. Horm Metab Res 43:250–256. doi: 10.1055/s-0030-1270525 CrossRefPubMedGoogle Scholar
  36. 36.
    Sahi J, Black C, Hamilton G et al (2003) Comparative effects of thiazolidinediones on in vitro p450 enzyme induction and inhibition. Drug Metab Dispos 31:439–446. doi: 10.1124/dmd.31.4.439 CrossRefPubMedGoogle Scholar
  37. 37.
    Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124. doi: 10.1016/j.canlet.2004.10.007 CrossRefPubMedGoogle Scholar
  38. 38.
    Hirose JH, Kawai T, Yamamoto Y et al (2002) Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51:314–317. doi: 10.1053/meta.2002.30506 CrossRefPubMedGoogle Scholar
  39. 39.
    Kudoh A, Satoh H, Hirai H et al (2011) Pioglitazone upregulates adiponectin receptor 2 in 3T3-L1 adipocytes. Life Sci 88:1055–1062. doi: 10.1016/j.lfs.2011.04.001 CrossRefPubMedGoogle Scholar
  40. 40.
    Berner HS, Lyngstadaas SP, Spahr A et al (2004) Adiponectin and its receptors are expressed in bone-forming cells. Bone 35:842–849. doi: 10.1016/j.bone.2004.06.008 CrossRefPubMedGoogle Scholar
  41. 41.
    Liu Y, Song CY, Wu SS et al (2013) Novel adipokines and bone metabolism. Int J Endocrinol. doi: 10.1155/2013/895045
  42. 42.
    Takano T, Li YJ, Kukita A et al (2014) Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis. Lab Investig 94:286–296. doi: 10.1038/labinvest.2013.152 CrossRefPubMedGoogle Scholar
  43. 43.
    Park JS, Cho MH, Nam JS et al (2011) Effect of pioglitazone on serum concentrations of osteoprotegerin in patients with type 2 diabetes mellitus. Eur J Endocrinol 164:69–74. doi: 10.1530/EJE-10-0875 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Thommesen L, Stunes AK, Monjo M et al (2006) Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem 99:824–834. doi: 10.1002/jcb.20915 CrossRefPubMedGoogle Scholar
  45. 45.
    Patsch JM, Xiaojuan L, Baum T et al (2013) Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures. J Bone Miner Res 28:1721–1728. doi: 10.1002/jbmr.1950 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yu EW, Thomas BJ, Brown JK et al (2012) Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT. J Bone Miner Res 27:119–124. doi: 10.1002/jbmr.506 CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Authors and Affiliations

  • L. M. Pop
    • 1
  • I. Lingvay
    • 1
    • 2
  • Q. Yuan
    • 3
  • X. Li
    • 2
  • B. Adams-Huet
    • 2
    • 4
    • 5
  • N. M. Maalouf
    • 4
    • 5
    Email author
  1. 1.Department of Internal Medicine, Division of EndocrinologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Clinical SciencesUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Department of RadiologyUniversity of Texas Southwestern Medical CenterDallasUSA
  4. 4.Center for Mineral Metabolism and Clinical ResearchUniversity of Texas Southwestern Medical CenterDallasUSA
  5. 5.Department of Internal Medicine, Division of Mineral MetabolismUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations