Safety of Antidiabetic Therapies on Bone

Original Paper


Osteoporosis and diabetic disease have reached epidemic proportion and create significant public health concerns. The prevalence of these diseases is alarming and indicates that in the United States, 50% of elderly individuals are osteoporotic and almost 20% of population has either diabetic or prediabetic conditions (Centers for Disease Control and Prevention; Osteoporosis and diabetes share many features including genetic predispositions and molecular mechanisms. The linkage between these two chronic diseases, which stems from overlapping molecular controls involved in bone homeostasis and energy metabolism, creates a possibility that certain antidiabetic therapies may affect bone. This concurs with recent findings, indicating that bone status is closely linked to regulation of energy metabolism and insulin sensitivity. Indeed, bone and energy homeostasis is under the control of the same regulatory factors, including insulin, peroxisome proliferator-activated receptor gamma, gastrointestinal hormones such as glucose inhibitory protein and glucagon inhibitory peptide, and bone-derived hormone osteocalcin. These factors and related mechanisms control glucose homeostasis and fatty acid metabolism in fat tissue, pancreas, and intestine, which are pharmacological targets for antidiabetic therapies. The same factors contribute to the bone quality by their effect on bone cell differentiation and bone remodeling process. This implies that bone should be considered as a vital target for therapies that modulate energy metabolism. This review is summarizing available data on the skeletal effects of clinically approved antidiabetic therapies.


Bone BMD Fractures Antidiabetic therapy TZDs Metformin Insulin Glyburide Incretins DPP-4 inhibitors PPARγ 



This work was supported by grants from NIH/NIA AG028935 and American Diabetes Association’s Amaranth Diabetes Fund 1-09-RA-95.


  1. 1.
    Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55:273–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4:638–49.CrossRefPubMedGoogle Scholar
  3. 3.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418:41–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19:180–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Aubin JE. Regulation of osteoblast formation and function. Rev Endocr Metab Disord. 2001;2:81–94.CrossRefPubMedGoogle Scholar
  6. 6.
    Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation [see comments]. Cell. 1997;89:747–54.CrossRefPubMedGoogle Scholar
  7. 7.
    Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts [see comments]. Cell. 1997;89:755–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Karsenty G. Minireview: transcriptional control of osteoblast differentiation. Endocrinology. 2001;142:2731–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor [published erratum appears in Cell 1995 Mar 24;80(6):following 957]. Cell. 1994;79:1147–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Rosen ED, Spiegelman BM. PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem. 2001;276:37731–4.CrossRefPubMedGoogle Scholar
  11. 11.
    Lecka-Czernik B, Gubrij I, Moerman EA, Kajkenova O, Lipschitz DA, Manolagas SC, Jilka RL. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPAR-gamma 2. J Cell Biochem. 1999;74:357–71.CrossRefPubMedGoogle Scholar
  12. 12.
    Lian JB, Stein GS, Javed A, van Wijnen AJ, Stein JL, Montecino M, Hassan MQ, Gaur T, Lengner CJ, Young DW. Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endocr Metab Disord. 2006;7:1–16.CrossRefPubMedGoogle Scholar
  13. 13.
    Fulzele K, Riddle RC, Digirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Bruning JC, Clemens TL. Insulin Receptor Signaling in Osteoblasts Regulates Postnatal Bone Acquisition and Body Composition. Cell. 2010;142:309–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Ferron M, Wei J, Yoshizawa T, Del Fattore A, Depinho RA, Teti A, Ducy P, Karsenty G. Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism. Cell. 2010;142:296–308.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456–69.CrossRefPubMedGoogle Scholar
  16. 16.
    Clemens TL, Karsenty G. The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res. 2011;26:677–80.CrossRefPubMedGoogle Scholar
  17. 17.
    Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes. 1995;44:775–82.CrossRefPubMedGoogle Scholar
  18. 18.
    Reyes-Garcia R, Rozas-Moreno P, Lopez-Gallardo G, Garcia-Martin A, Varsavsky M, Aviles-Perez MD, Munoz-Torres M. Serum levels of bone resorption markers are decreased in patients with type 2 diabetes. Acta Diabetol. 2011.Google Scholar
  19. 19.
    Garcia-Martin A, Rozas-Moreno P, Reyes-Garcia R, Morales-Santana S, Garcia-Fontana B, Garcia-Salcedo JA, Munoz-Torres M. Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2011;97:234–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Lecka-Czernik B. Bone as a target of type 2 diabetes treatment. Curr Opin Investig Drugs. 2009;10:1085–90.PubMedGoogle Scholar
  21. 21.
    Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166:495–505.CrossRefPubMedGoogle Scholar
  22. 22.
    Yamamoto M, Yamaguchi T, Yamauchi M. Kaji H. Sugimoto T: Diabetic Patients Have an Increased Risk of Vertebral Fractures Independent of Bone Mineral Density or Diabetic Complications. J Bone Miner Res; 2008.Google Scholar
  23. 23.
    Vestergaard P, Rejnmark L, Mosekilde L. Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int. 2009;84:45–55.CrossRefPubMedGoogle Scholar
  24. 24.
    Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, Schreiner PJ, Margolis KL, Cauley JA, Nevitt MC, Black DM, Cummings SR. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care. 2002;25:1749–54.CrossRefPubMedGoogle Scholar
  25. 25.
    Melton LJ, Leibson CL, Achenbach SJ, Therneau TM, Khosla S. Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res. 2008;23:1334–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Huang S, Kaw M, Harris MT, Ebraheim N, McInerney MF, Najjar SM, Lecka-Czernik B. Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1. Bone. 2010;46:1138–45.CrossRefPubMedGoogle Scholar
  27. 27.
    Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2008;93:1013–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Vashishth D. Collagen glycation and its role in fracture properties of bone. J Musculoskelet Neuronal Interact. 2005;5:316.PubMedGoogle Scholar
  29. 29.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.CrossRefPubMedGoogle Scholar
  31. 31.
    Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Jama. 2007;298:1180–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106–18.CrossRefPubMedGoogle Scholar
  33. 33.
    Lecka-Czernik B. Bone loss in diabetes: use of anti-diabetic thiazolidinediones and secondary osteoporosis. Current Osteoporosis Reports. 2010;8:178–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Won Park S, Lane NE, Harris TB, Cummings SR. Thiazolidinedione (TZD) use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91:3349–54.CrossRefPubMedGoogle Scholar
  35. 35.
    Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. 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. 2007;92:1305–10.CrossRefPubMedGoogle Scholar
  36. 36.
    Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP, Viberti G. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care. 2008;31:845–51.CrossRefPubMedGoogle Scholar
  37. 37.
    Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S, Sugimoto T. Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteoporos Int. 2010.Google Scholar
  38. 38.
    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 syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2008;93:1696–701.CrossRefPubMedGoogle Scholar
  39. 39.
    Gruntmanis U, Fordan S, Ghayee HK, Abdullah SM, See R, Ayers CR, McGuire DK. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increases bone resorption in women with type 2 diabetes: a randomized, controlled trial. Calcif Tissue Int. 2010;86:343–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Zinman B, Haffner SM, Herman WH, Holman RR, Lachin JM, Kravitz BG, Paul G, Jones NP, Aftring RP, Viberti G, Kahn SE. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab. 2010;95:134–42.CrossRefPubMedGoogle Scholar
  41. 41.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Cmaj. 2009;180:32–9.PubMedGoogle Scholar
  42. 42.
    Jones SG, Momin SR, Good MW, Shea TK, Patric K. Distal upper and lower limb fractures associated with thiazolidinedione use. Am J Manag Care. 2009;15:491–6.PubMedGoogle Scholar
  43. 43.
    Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95:592–600.CrossRefPubMedGoogle Scholar
  44. 44.
    Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009;169:1395–402.CrossRefPubMedGoogle Scholar
  45. 45.
    Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008;168:820–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Solomon DH, Cadarette SM, Choudhry NK, Canning C, Levin R, Sturmer T. A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab. 2009;94:2792–8.CrossRefPubMedGoogle Scholar
  47. 47.
    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:e1000154.CrossRefPubMedGoogle Scholar
  48. 48.
    Wan Y, Chong LW, Evans RM. PPAR-gamma regulates osteoclastogenesis in mice. Nat Med. 2007;13:1496–503.CrossRefPubMedGoogle Scholar
  49. 49.
    Ren D, Collingwood TN, Rebar EJ, Wolffe AP, Camp HS. PPARgamma knockdown by engineered transcription factors: exogenous PPARgamma2 but not PPARgamma1 reactivates adipogenesis. Genes Dev. 2002;16:27–32.CrossRefPubMedGoogle Scholar
  50. 50.
    Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology. 2002;143:2376–84.CrossRefPubMedGoogle Scholar
  51. 51.
    Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B. Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology. 2004;145:401–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Sottile V, Seuwen K, Kneissel M. Enhanced marrow adipogenesis and bone resorption in estrogen-deprived rats treated with the PPARgamma agonist BRL49653 (rosiglitazone). Calcif Tissue Int. 2004;75:329–37.CrossRefPubMedGoogle Scholar
  53. 53.
    Soroceanu MA, Miao D, Bai XY, Su H, Goltzman D, Karaplis AC. Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. J Endocrinol. 2004;183:203–16.CrossRefPubMedGoogle Scholar
  54. 54.
    Cock TA, Back J, Elefteriou F, Karsenty G, Kastner P, Chan S, Auwerx J. Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen. EMBO Rep. 2004;5:1007–12.CrossRefPubMedGoogle Scholar
  55. 55.
    Ali AA, Weinstein RS, Stewart SA, Parfitt AM, Manolagas SC, Jilka RL. Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation. Endocrinology. 2005;146:1226–35.CrossRefPubMedGoogle Scholar
  56. 56.
    Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004;113:846–55.PubMedGoogle Scholar
  57. 57.
    Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B. Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology. 2007;148:2669–80.CrossRefPubMedGoogle Scholar
  58. 58.
    Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. PPARg2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem. 2009;106:232–46.CrossRefPubMedGoogle Scholar
  59. 59.
    Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR, Reid IR, Grey A, Rosen CJ. 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. 2007;148:903–11.CrossRefPubMedGoogle Scholar
  60. 60.
    Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell. 2004;3:379–89.CrossRefPubMedGoogle Scholar
  61. 61.
    Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.CrossRefPubMedGoogle Scholar
  62. 62.
    Higgins LS, Depaoli AM. Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr. 2010;91:267S–72S.CrossRefPubMedGoogle Scholar
  63. 63.
    Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–76.CrossRefPubMedGoogle Scholar
  64. 64.
    Lazarenko OP, Rzonca SO, Suva LJ, Lecka-Czernik B. Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat. Bone. 2006;38:74–85.CrossRefPubMedGoogle Scholar
  65. 65.
    Grether U, Benardeau A, Benz J, Binggeli A, Blum D, Hilpert H, Kuhn B, Marki HP, Meyer M, Mohr P, Puntener K, Raab S, Ruf A, Schlatter D. Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists. ChemMedChem. 2009;4:951–6.CrossRefPubMedGoogle Scholar
  66. 66.
    Lecka-Czernik B. Aleglitazar, a dual PPARalpha and PPARgamma agonist for the potential oral treatment of type 2 diabetes mellitus. IDrugs. 2010;13:793–801.PubMedGoogle Scholar
  67. 67.
    Sanwald-Ducray P, Lioger D’ardhuy X, Jamois C, Banken L. Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from randomized, placebo-controlled clinical study. Clin Pharmacol Ther. 2010;88:197–203.CrossRefPubMedGoogle Scholar
  68. 68.
    Hansen BC, Tigno XT, Benardeau A, Meyer M, Sebokova E, Mizrahi J. Aleglitazar, a balanced peroxisome proliferator-activated receptor (PPAR)a/g agonist, exerts potent lipid-modifying effects in a primate model of metabolic syndrome in Type 2 diabetes. Circulation. 2009;120:S469–70.Google Scholar
  69. 69.
    Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7:1028–34.CrossRefPubMedGoogle Scholar
  70. 70.
    Jang WG, Kim EJ, Bae IH, Lee KN, Kim YD, Kim DK, Kim SH, Lee CH, Franceschi RT, Choi HS, Koh JT. Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone. 2011;48:885–93.CrossRefPubMedGoogle Scholar
  71. 71.
    Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem. 2011;112:2902–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Sedlinsky C, Molinuevo MS, Cortizo AM, Tolosa MJ, Felice JI, Sbaraglini ML, Schurman L, McCarthy AD. Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol. 2011;668:477–85.CrossRefPubMedGoogle Scholar
  73. 73.
    Borges JL, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ, Grosse M, Fitzpatrick LA, Cobitz AR. 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-naive type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011;13:1036–46.CrossRefPubMedGoogle Scholar
  74. 74.
    Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR. Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab. 2001;86:32–8.CrossRefPubMedGoogle Scholar
  75. 75.
    Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007;117:24–32.CrossRefPubMedGoogle Scholar
  76. 76.
    Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36:761–5.CrossRefPubMedGoogle Scholar
  77. 77.
    Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005;65:1325–34.CrossRefPubMedGoogle Scholar
  78. 78.
    McGuinness C, Wesley UV. Dipeptidyl peptidase IV (DPPIV), a candidate tumor suppressor gene in melanomas is silenced by promoter methylation. Front Biosci. 2008;13:2435–43.CrossRefPubMedGoogle Scholar
  79. 79.
    Arscott WT, LaBauve AE, May V, Wesley UV. Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation. Oncogene. 2009;28:479–91.CrossRefPubMedGoogle Scholar
  80. 80.
    Clowes JA, Khosla S, Eastell R. Potential role of pancreatic and enteric hormones in regulating bone turnover. J Bone Miner Res. 2005;20:1497–506.CrossRefPubMedGoogle Scholar
  81. 81.
    Reid IR, Cornish J, Baldock PA. Nutrition-related peptides and bone homeostasis. J Bone Miner Res. 2006;21:495–500.CrossRefPubMedGoogle Scholar
  82. 82.
    Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG, Holst JJ, Christiansen C. Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone. 2007;40:723–9.CrossRefPubMedGoogle Scholar
  83. 83.
    Xie D, Zhong Q, Ding KH, Cheng H, Williams S, Correa D, Bollag WB, Bollag RJ, Insogna K, Troiano N, Coady C, Hamrick M, Isales CM. Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone. 2007;40:1352–60.CrossRefPubMedGoogle Scholar
  84. 84.
    Zhong Q, Itokawa T, Sridhar S, Ding KH, Xie D, Kang B, Bollag WB, Bollag RJ, Hamrick M, Insogna K, Isales CM. Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab. 2007;292:E543–8.CrossRefPubMedGoogle Scholar
  85. 85.
    Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N, Tanaka K, Drucker DJ, Seino Y, Inagaki N. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology. 2008;149:574–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Bunck MC, Eliasson B, Corner A, Heine RJ, Shaginian RM, Taskinen MR, Yki-Jarvinen H, Smith U, Diamant M. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:374–7.CrossRefPubMedGoogle Scholar
  87. 87.
    Monami M, Dicembrini I, Antenore A, Mannucci E. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care. 2011;34:2474–6.CrossRefPubMedGoogle Scholar
  88. 88.
    Kyle KA, Willett TL, Baggio LL, Drucker DJ, Grynpas MD. Differential effects of PPAR-{gamma} activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice. Endocrinology. 2011;152:457–67.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Orthopaedic Surgery, Department of Physiology and Pharmacology, Center for Diabetes and Endocrine ResearchUniversity of Toledo College of MedicineToledoUSA

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