Skip to main content

Advertisement

Log in

Diabetes Drug Effects on the Skeleton

  • Review Paper
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone. The use of insulin has been associated with an increased risk of fragility fractures though it is not clear whether it is due to direct influence of insulin or whether it is mediated through hypoglycemia and increased falls risk. The overall effect of incretin mimetics appears to be beneficial; however, this has to be elucidated further. The bone effects of pramlintide, a synthetic analog of amylin, have not been explored fully. Finally, issues regarding bone safety of SGLT2 (sodium-dependent glucose transporter 2) inhibitors, the newest anti-diabetic medications on the market are of concern. The purpose of this review is to provide a comprehensive overview of the effect of these medications on bone metabolism and the studies exploring the risk or lack thereof of these medications on bone loss and fragility fractures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR et al (2006) Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 91(9):3349–3354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J 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(4):1305–1310

    Article  CAS  PubMed  Google Scholar 

  3. Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M 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(4):1519–1528

    Article  CAS  PubMed  Google Scholar 

  4. Borges JLC, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ et al (2011) A randomized, parallel 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 13(11):1036–1046

    Article  CAS  PubMed  Google Scholar 

  5. Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG 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(12):4691–4701

    Article  CAS  PubMed  Google Scholar 

  6. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355(23):2427–2443

    Article  CAS  PubMed  Google Scholar 

  7. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M 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(9681):2125–2135

    Article  CAS  PubMed  Google Scholar 

  8. Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180(1):32–39

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123

    Article  CAS  PubMed  Google Scholar 

  10. Colhoun HM, Livingstone SJ, Looker HC, Morris AD, Wild SH, Lindsay RS et al (2012) Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs. Diabetologia 55(11):2929–2937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR et al (2008) Use of thiazolidinediones and fracture risk. Arch Intern Med 168(8):820–825

    Article  CAS  PubMed  Google Scholar 

  12. Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK et al (2010) Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95(2):592–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dormandy J, Bhattacharya M, van Troostenburg de Bruyn AR (2009) PROactive investigators. Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive. Drug Saf 32(3):187–202

    Article  CAS  PubMed  Google Scholar 

  14. Gruntmanis U, Fordan S, Ghayee HK, Abdullah SM, See R, Ayers CR 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 Tissue Int 86(5):343–349

    Article  CAS  PubMed  Google Scholar 

  15. Harsløf T, Wamberg L, Møller L, Stødkilde-Jørgensen H, Ringgaard S, Pedersen SB et al (2011) Rosiglitazone decreases bone mass and bone marrow fat. J Clin Endocrinol Metab 96(5):1541–1548

    Article  PubMed  CAS  Google Scholar 

  16. Berberoglu Z, Gursoy A, Bayraktar N, Yazici AC, Bascil Tutuncu N, Guvener Demirag N et al (2007) Rosiglitazone decreases serum bone-specific alkaline phosphatase activity in postmenopausal diabetic women. J Clin Endocrinol Metab 92(9):3523–3530

    Article  CAS  PubMed  Google Scholar 

  17. Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG et al (2010) Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 95(1):134–142

    Article  CAS  PubMed  Google Scholar 

  18. Xiao WH, Wang YR, Hou WF, Xie C, Wang HN, Hong TP et al (2013) The effects of pioglitazone on biochemical markers of bone turnover in the patients with type 2 diabetes. Int J Endocrinol 2013:290734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S et al (2010) Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteoporos Int 21(12):2013–2018

    Article  CAS  PubMed  Google Scholar 

  20. Glintborg D, Andersen M, Hagen C, Heickendorff L, Hermann AP (2008) Association of pioglitazone treatment with decreased bone mineral density in obese premenopausal patients with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 93(5):1696–1701

    Article  CAS  PubMed  Google Scholar 

  21. van Lierop AH, Hamdy NAT, van der Meer RW, Jonker JT, Lamb HJ, Rijzewijk LJ et al (2012) Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus. Eur J Endocrinol 166(4):711–716

    Article  PubMed  CAS  Google Scholar 

  22. Wang L, Li L, Gao H, Li Y (2012) Effect of pioglitazone on transdifferentiation of preosteoblasts from rat bone mesenchymal stem cells into adipocytes. J Huazhong Univ Sci Technol Med Sci 32(4):530–533

    Article  CAS  PubMed  Google Scholar 

  23. Beck GR, Khazai NB, Bouloux GF, Camalier CE, Lin Y, Garneys LM et al (2013) The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl Res 161(3):145–155

    Article  CAS  PubMed  Google Scholar 

  24. Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL et al (2005) Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology 146(3):1226–1235

    Article  CAS  PubMed  Google Scholar 

  25. Cho ES, Kim MK, Son YO, Lee KS, Park SM, Lee JC et al (2012) The effects of rosiglitazone on osteoblastic differentiation, osteoclast formation and bone resorption. Mol Cells 33(2):173–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Broulík PD, Sefc L, Haluzík M (2011) Effect of PPAR-γ agonist rosiglitazone on bone mineral density and serum adipokines in C57BL/6 male mice. Folia Biol (Krakow) 57(4):133–138

    Google Scholar 

  27. Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR et al (2007) Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. Endocrinology 148(2):903–911

    Article  CAS  PubMed  Google Scholar 

  28. Mieczkowska A, Baslé MF, Chappard D, Mabilleau G (2012) Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism. J Biol Chem 287(28):23517–23526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gustafson B, Eliasson B, Smith U (2010) Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis. Diabetologia 53(3):536–540

    Article  CAS  PubMed  Google Scholar 

  30. Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B et al (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148(6):2669–2680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Seto-Young D, Avtanski D, Parikh G, Suwandhi P, Strizhevsky M, Araki T et al (2011) Rosiglitazone and pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase. Horm Metab Res 43(4):250–256

    Article  CAS  PubMed  Google Scholar 

  32. Mabilleau G, Mieczkowska A, Edmonds ME (2010) Thiazolidinediones induce osteocyte apoptosis and increase sclerostin expression. Diabet Med 27(8):925–932

    Article  CAS  PubMed  Google Scholar 

  33. Vestergaard P, Rejnmark L, Mosekilde L (2005) Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48(7):1292–1299

    Article  CAS  PubMed  Google Scholar 

  34. Melton LJ, Leibson CL, Achenbach SJ, Therneau TM, Khosla S (2008) Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 23(8):1334–1342

    Article  PubMed  PubMed Central  Google Scholar 

  35. Solomon DH, Cadarette SM, Choudhry NK, Canning C, Levin R, Stürmer T et al (2009) A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab 94(8):2792–2798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F et al (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 31(2):199–203

    Article  PubMed  Google Scholar 

  37. Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Sugimoto T (2008) Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. Biochem Biophys Res Commun 375(3):414–419

    Article  CAS  PubMed  Google Scholar 

  38. Napoli N, Strotmeyer ES, Ensrud KE, Sellmeyer DE, Bauer DC, Hoffman AR et al (2014) Fracture risk in diabetic elderly men: the MrOS study. Diabetologia 57(10):2057–2065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L (2006) Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 536(1–2):38–46

    Article  CAS  PubMed  Google Scholar 

  40. Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Yamamoto M, Sugimoto T et al (2007) Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells. BMC Cell Biol 8:51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Zhen D, Chen Y, Tang X (2010) Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complicat 24(5):334–344

    Article  PubMed  Google Scholar 

  42. Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV et al (2010) Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res 25(2):211–221

    Article  CAS  PubMed  Google Scholar 

  43. Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L et al (2008) Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Exp Clin Endocrinol Diabetes 116(6):333–340

    Article  CAS  PubMed  Google Scholar 

  44. Tolosa MJ, Chuguransky SR, Sedlinsky C, Schurman L, McCarthy AD, Molinuevo MS et al (2013) Insulin-deficient diabetes-induced bone microarchitecture alterations are associated with a decrease in the osteogenic potential of bone marrow progenitor cells: preventive effects of metformin. Diabetes Res Clin Pract 101(2):177–186

    Article  CAS  PubMed  Google Scholar 

  45. Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L et al (2011) Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 112(10):2902–2909

    Article  CAS  PubMed  Google Scholar 

  46. Liu L, Zhang C, Hu Y, Peng B (2012) Protective effect of metformin on periapical lesions in rats by decreasing the ratio of receptor activator of nuclear factor kappa B ligand/osteoprotegerin. J Endod 38(7):943–947

    Article  PubMed  Google Scholar 

  47. Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML et al (2011) Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 668(3):477–485

    Article  CAS  PubMed  Google Scholar 

  48. Gao Y, Li Y, Xue J, Jia Y, Hu J (2010) Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats. Eur J Pharmacol 635(1–3):231–236

    Article  CAS  PubMed  Google Scholar 

  49. Wang C, Li H, Chen SG, He JW, Sheng CJ, Cheng XY et al (2012) The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice. J Bone Miner Metab 30(6):630–637

    Article  CAS  PubMed  Google Scholar 

  50. Wu W, Ye Z, Zhou Y, Tan WS (2011) AICAR, a small chemical molecule, primes osteogenic differentiation of adult mesenchymal stem cells. Int J Artif Organs 34(12):1128–1136

    Article  CAS  PubMed  Google Scholar 

  51. Patel JJ, Butters OR, Arnett TR (2014) PPAR agonists stimulate adipogenesis at the expense of osteoblast differentiation while inhibiting osteoclast formation and activity. Cell Biochem Funct 32(4):368–377

    Article  CAS  PubMed  Google Scholar 

  52. Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C et al (2013) The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int 24(10):2659–2670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kasai T, Bandow K, Suzuki H, Chiba N, Kakimoto K, Ohnishi T et al (2009) Osteoblast differentiation is functionally associated with decreased AMP kinase activity. J Cell Physiol 221(3):740–749

    Article  CAS  PubMed  Google Scholar 

  54. Salai M, Somjen D, Gigi R, Yakobson O, Katzburg S, Dolkart O et al (2013) Effects of commonly used medications on bone tissue mineralisation in SaOS-2 human bone cell line: an in vitro study. Bone Joint J 95(11):1575–1580

    Article  PubMed  Google Scholar 

  55. Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM (2009) Thiazolidinediones and fractures in men and women. Arch Intern Med 169(15):1395–1402

    Article  CAS  PubMed  Google Scholar 

  56. Kanazawa I, Yamaguchi T, Yamamoto M, Sugimoto T (2010) Relationship between treatments with insulin and oral hypoglycemic agents versus the presence of vertebral fractures in type 2 diabetes mellitus. J Bone Miner Metab 28(5):554–560

    Article  CAS  PubMed  Google Scholar 

  57. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet 352(9131):837–853

    Article  Google Scholar 

  58. Lapane KL, Yang S, Brown MJ, Jawahar R, Pagliasotti C, Rajpathak S et al (2013) Sulfonylureas and risk of falls and fractures: a systematic review. Drugs Aging 30(7):527–547

    Article  CAS  PubMed  Google Scholar 

  59. Ma P, Gu B, Ma J, Lingling E, Wu X, Cao J et al (2010) Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 59(3):359–366

    Article  CAS  PubMed  Google Scholar 

  60. Ma P, Xiong W, Liu H, Ma J, Gu B, Wu X et al (2011) Extrapancreatic roles of glimepiride on osteoblasts from rat manibular bone in vitro: regulation of cytodifferentiation through PI3-kinases/Akt signalling pathway. Arch Oral Biol 56(4):307–316

    Article  CAS  PubMed  Google Scholar 

  61. Fronczek-Sokół J, Pytlik M (2014) Effect of glimepiride on the skeletal system of ovariectomized and non-ovariectomized rats. Pharmacol Rep 66(3):412–417

    Article  PubMed  CAS  Google Scholar 

  62. Campos Pastor MM, López-Ibarra PJ, Escobar-Jiménez F, Serrano Pardo MD, García-Cervigón AG (2000) Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int 11(5):455–459

    Article  CAS  PubMed  Google Scholar 

  63. Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ et al (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86(1):32–38

    Article  CAS  PubMed  Google Scholar 

  64. Ivers RQ, Cumming RG, Mitchell P, Peduto AJ (2001) Diabetes and risk of fracture: the Blue Mountains eye study. Diabetes Care 24(7):1198–1203

    Article  CAS  PubMed  Google Scholar 

  65. Nicodemus KK, Folsom AR (2001) Iowa Women’s Health Study. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24(7):1192–1197

    Article  CAS  PubMed  Google Scholar 

  66. Klein GL (2014) Insulin and bone: recent developments. World J Diabetes 5(1):14–16

    Article  PubMed  PubMed Central  Google Scholar 

  67. Maor G, Karnieli E (1999) The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. Endocrinology 140(4):1841–1851

    CAS  PubMed  Google Scholar 

  68. Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y et al (2000) Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 105(7):935–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K et al (2002) Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol 159(1):147–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shimoaka T, Kamekura S, Chikuda H, Hoshi K, Chung UI, Akune T et al (2004) Impairment of bone healing by insulin receptor substrate-1 deficiency. J Biol Chem 279(15):15314–15322

    Article  CAS  PubMed  Google Scholar 

  71. Abd El Aziz GS, Ramadan WS, El-Fark MO, Saleh HAM (2015) The beneficial roles of insulin and parathyroid hormones in the treatment of experimentally induced diabetic osteoporosis in female rats: bone mineral density, morphometric and histological studies. Folia Morphol

  72. Bollag RJ, Zhong Q, Phillips P, Min L, Zhong L, Cameron R et al (2000) Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 141(3):1228–1235

    CAS  PubMed  Google Scholar 

  73. Pacheco-Pantoja EL, Ranganath LR, Gallagher JA, Wilson PJM, Fraser WD (2011) Receptors and effects of gut hormones in three osteoblastic cell lines. BMC Physiol 11:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lecka-Czernik B (2013) Safety of anti-diabetic therapies on bone. Clin Rev Bone Miner Metab 11(1):49–58

    Article  CAS  PubMed  Google Scholar 

  75. Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG et al (2009) Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone 45(5):833–842

    Article  CAS  PubMed  Google Scholar 

  76. Bunck MC, Eliasson B, Cornér A, Heine RJ, Shaginian RM, Taskinen MR et al (2011) Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 13(4):374–377

    Article  CAS  PubMed  Google Scholar 

  77. Gilbert MP, Marre M, Holst JJ, Garber A, Baeres FMM, Thomsen H et al (2015) Comparison of the long-term effects of liraglutide and glimepiride monotherapy on bone mineral density in patients with type 2 diabetes. Endocr Pract 22(4):406–411

    Article  PubMed  Google Scholar 

  78. Mabilleau G, Mieczkowska A, Chappard D (2014) Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials. J Diabetes 6(3):260–266

    Article  CAS  PubMed  Google Scholar 

  79. Su B, Sheng H, Zhang M, Bu L, Yang P, Li L et al (2015) Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: a meta-analysis of randomized controlled trials. Endocrine 48(1):107–115

    Article  CAS  PubMed  Google Scholar 

  80. Monami M, Dicembrini I, Antenore A, Mannucci E (2011) Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 34(11):2474–2476

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hirshberg B, Parker A, Edelberg H, Donovan M, Iqbal N (2014) Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 30(7):556–569

    Article  CAS  PubMed  Google Scholar 

  82. Mosenzon O, Wei C, Davidson J, Scirica BM, Yanuv I, Rozenberg A et al (2015) Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 trial. Diabetes Care 38(11):2142–2150

    Article  PubMed  Google Scholar 

  83. Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS et al (2016) Risk of fractures and diabetes medications: a nationwide cohort study. Osteoporos Int 27(9):2709–2715

    Article  CAS  PubMed  Google Scholar 

  84. Henriksen DB, Alexandersen P, Bjarnason NH, Vilsbøll T, Hartmann B, Henriksen EEG et al (2003) Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 18(12):2180–2189

    Article  CAS  PubMed  Google Scholar 

  85. Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG et al (2007) Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone 40(3):723–729

    Article  CAS  PubMed  Google Scholar 

  86. Henriksen DB, Alexandersen P, Byrjalsen I, Hartmann B, Bone HG, Christiansen C et al (2004) Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone 34(1):140–147

    Article  CAS  PubMed  Google Scholar 

  87. Tsukiyama K, Yamada Y, Yamada C, Harada N, Kawasaki Y, Ogura M et al (2006) Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol 20(7):1644–1651

    Article  CAS  PubMed  Google Scholar 

  88. Xie D, Cheng H, Hamrick M, Zhong Q, Ding KH, Correa D et al (2005) Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone 37(6):759–769

    Article  CAS  PubMed  Google Scholar 

  89. Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N et al (2008) The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149(2):574–579

    Article  CAS  PubMed  Google Scholar 

  90. Nuche-Berenguer B, Moreno P, Esbrit P, Dapía S, Caeiro JR, Cancelas J et al (2009) Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. Calcif Tissue Int 84(6):453–461

    Article  CAS  PubMed  Google Scholar 

  91. Ma X, Meng J, Jia M, Bi L, Zhou Y, Wang Y et al (2013) Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. J Bone Miner Res 28(7):1641–1652

    Article  CAS  PubMed  Google Scholar 

  92. Nuche-Berenguer B, Portal-Núñez S, Moreno P, González N, Acitores A, López-Herradón A et al (2010) Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 225(2):585–592

    Article  CAS  PubMed  Google Scholar 

  93. Sanz C, Vázquez P, Blázquez C, Barrio PA, Alvarez MDM, Blázquez E et al (2010) Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow. Am J Physiol Endocrinol Metab 298(3):E634–E643

    Article  CAS  PubMed  Google Scholar 

  94. Mabilleau G, Mieczkowska A, Irwin N, Flatt PR, Chappard D (2013) Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol 219(1):59–68

    Article  CAS  PubMed  Google Scholar 

  95. Kim JY, Lee SK, Jo KJ, Song DY, Lim DM, Park KY et al (2013) Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life Sci 92(10):533–540

    Article  PubMed  CAS  Google Scholar 

  96. Sbaraglini ML, Molinuevo MS, Sedlinsky C, Schurman L, McCarthy AD (2014) Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells. Eur J Pharmacol 727:8–14

    Article  CAS  PubMed  Google Scholar 

  97. Gallagher EJ, Sun H, Kornhauser C, Tobin-Hess A, Epstein S, Yakar S et al (2014) The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 30(3):191–200

    Article  CAS  PubMed  Google Scholar 

  98. Glorie L, Behets GJ, Baerts L, De Meester I, D’Haese PC, Verhulst A et al (2014) DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab 307(5):E447–E455

    Article  CAS  PubMed  Google Scholar 

  99. Cusick T, Mu J, Pennypacker BL, Li Z, Scott KR, Shen X et al (2013) Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione. Diabetes Obes Metab 15(10):954–957

    Article  CAS  PubMed  Google Scholar 

  100. Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD (2011) Differential effects of PPAR-γ activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology 152(2):457–467

    Article  CAS  PubMed  Google Scholar 

  101. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D et al (2016) Evaluation of bone mineral density and bone biomarkers in patients with type 2 Diabetes treated with canagliflozin. J Clin Endocrinol Metab 101(1):44–51

    Article  CAS  PubMed  Google Scholar 

  102. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD et al (2014) Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16(2):159–169

    Article  CAS  PubMed  Google Scholar 

  103. Kohan DE, Fioretto P, Tang W, List JF (2014) Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85(4):962–971

    Article  CAS  PubMed  Google Scholar 

  104. Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TWA, Apanovitch AM, List JF et al (2014) Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf 37(10):815–829

    Article  CAS  PubMed  Google Scholar 

  105. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G et al (2016) Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 101(1):157–166

    Article  CAS  PubMed  Google Scholar 

  106. Harada N, Inagaki N (2012) Role of sodium-glucose transporters in glucose uptake of the intestine and kidney. J Diabetes Investig 3(4):352–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Taylor SI, Blau JE, Rother KI (2015) Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 3(1):8–10

    Article  CAS  PubMed  Google Scholar 

  108. Hinton PS, Rector RS, Linden MA, Warner SO, Dellsperger KC, Chockalingam A et al (2012) Weight-loss-associated changes in bone mineral density and bone turnover after partial weight regain with or without aerobic exercise in obese women. Eur J Clin Nutr 66(5):606–612

    Article  CAS  PubMed  Google Scholar 

  109. List JF, Woo V, Morales E, Tang W, Fiedorek FT (2009) Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32(4):650–657

    Article  CAS  PubMed  Google Scholar 

  110. Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder K, Elze M et al (2011) Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34(9):2015–2022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ljunggren Ö, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjöström CD et al (2012) Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 14(11):990–999

    Article  CAS  PubMed  Google Scholar 

  112. Bays HE, Weinstein R, Law G, Canovatchel W (2014) Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring) 22(4):1042–1049

    Article  CAS  Google Scholar 

  113. Ways K, Johnson MD, Mamidi RNVS, Proctor J, De Jonghe S, Louden C et al (2015) Successful integration of nonclinical and clinical findings in interpreting the clinical relevance of rodent neoplasia with a new chemical entity. Toxicol Pathol 43(1):48–56

    Article  PubMed  CAS  Google Scholar 

  114. Mamidi RNVS, Proctor J, De Jonghe S, Feyen B, Moesen E, Vinken P et al (2014) Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin. Chem Biol Interact 221:109–118

    Article  CAS  PubMed  Google Scholar 

  115. Bronský J, Průsa R (2004) Amylin fasting plasma levels are decreased in patients with osteoporosis. Osteoporos Int 15(3):243–247

    Article  PubMed  Google Scholar 

  116. Borm AK, Klevesath MS, Borcea V, Kasperk C, Seibel MJ, Wahl P et al (1999) The effect of pramlintide (amylin analogue) treatment on bone metabolism and bone density in patients with type 1 diabetes mellitus. Horm Metab Res 31(8):472–475

    Article  CAS  PubMed  Google Scholar 

  117. Cornish J, Callon KE, Cooper GJ, Reid IR (1995) Amylin stimulates osteoblast proliferation and increases mineralized bone volume in adult mice. Biochem Biophys Res Commun 207(1):133–139

    Article  CAS  PubMed  Google Scholar 

  118. Naot D, Cornish J (2008) The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism. Bone 43(5):813–818

    Article  CAS  PubMed  Google Scholar 

  119. Cornish J, Callon KE, Bava U, Kamona SA, Cooper GJ, Reid IR et al (2001) Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development. Bone 29(2):162–168

    Article  CAS  PubMed  Google Scholar 

  120. Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR et al (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164(4):509–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Horcajada-Molteni MN, Chanteranne B, Lebecque P, Davicco MJ, Coxam V, Young A et al (2001) Amylin and bone metabolism in streptozotocin-induced diabetic rats. J Bone Miner Res 16(5):958–965

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

Manju Chandran does not have any conflict of interests to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Manju Chandran.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chandran, M. Diabetes Drug Effects on the Skeleton. Calcif Tissue Int 100, 133–149 (2017). https://doi.org/10.1007/s00223-016-0203-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-016-0203-x

Keywords

Navigation