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Effect of exenatide, insulin and pioglitazone on bone metabolism in patients with newly diagnosed type 2 diabetes

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Abstract

Aim

Preclinical studies suggested that insulin, incretin and thiazolidinediones had effect on regulation of bone metabolism. But clinical evidence is limited. We assessed the effects of these antihyperglycemic agents on bone metabolism in patients with newly diagnosed type 2 diabetes.

Methods

The present study was a two-center, randomized, parallel-group clinical trial. Sixty-two newly diagnosed and drug-naïve patients with type 2 diabetes were randomized to exenatide (EXE, n = 20), mixed protamine zinc recombinant human insulin lispro injection (25R; INS, n = 21) or pioglitazone (PIO, n = 21) group for a 24-week treatment. Glycosylated hemoglobin A1c (HbA1c), body weight, body mineral density (BMD) and fasting serum concentration of bone turnover markers including osteocalcin (OC), C-telopeptide of type I collagen (CTX) and tartrate-resistant alkaline phosphatase 5b (TRAcP5b) were assessed at baseline and week 24.

Results

Baseline characteristics were similar among groups. At week 24, HbA1c improved in all patients (EXE:−2.4 ± 0.3 %, INS:−2.4 ± 0.3 %, PIO:−2.0 ± 0.2 %; p > 0.05 among groups). Patients treated with exenatide lost body weight remarkably (−4.7 ± 0.8 kg). In spite of the amelioration of glucose control, no significant improvement of OC, CTX or TRAcP5b was observed at week 24 (EXE: OC −0.619 ± 0.728 ng/ml, CTX 0.147 ± 0.046 ng/ml, TRAcP5b 0.302 ± 0.149 U/L;INS: OC 0.637 ± 0.787 ng/ml, CTX −0.012 ± 0.074 ng/ml, TRAcP5b 0.124 ± 0.395 U/L; PIO: OC −0.150 ± 0.691 ng/ml, CTX 0.073 ± 0.094 ng/ml, TRAcP5b 0.586 ± 0.183 U/L; p > 0.05), as well as BMD measurement, regardless of the treatments.

Conclusions

Twenty-four-week treatment with exenatide, insulin and pioglitazone improved glucose control in patients with newly diagnosed type 2 diabetes, but had no impact on bone turnover markers or BMD.

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References

  1. de Liefde II, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA (2005) Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam study. Osteoporos Int 16:1713–1720

    Article  PubMed  Google Scholar 

  2. Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int 18:427–444

    Article  CAS  PubMed  Google Scholar 

  3. Hamilton EJ, Rakic V, Davis WA, Paul Chubb SA, Kamber N, Prince RL, Davis TME (2012) A five-year prospective study of bone mineral density in men and women with diabetes: the fremantle diabetes study. Acta Diabetol 49:153–158

    Article  CAS  PubMed  Google Scholar 

  4. Saller A, Maggi S, Romanato G, Tonin P, Crepaldi G (2008) Diabetes and osteoporosis. Aging Clin Exp Res 20:280–289

    Article  PubMed  Google Scholar 

  5. Maggi S, Siviero P, Brocco E, Albertin M, Romanato G, Crepaldi G (2014) Vitamin D deficiency, serum leptin and osteoprotegerin levels in older diabetic patients: an input to new research avenues. Acta Diabetol 51:461–469

    Article  CAS  PubMed  Google Scholar 

  6. Khazai NB, Beck GR Jr, Umpierrez GE (2009) Diabetes and fractures: an overshadowed association. Curr Opin Endocrinol Diabetes Obes 16:435–445

    Article  PubMed Central  PubMed  Google Scholar 

  7. Clowes JA, Allen HC, Prentis DM, Eastell R, Blumsohn A (2003) Octreotide abolishes the acute decrease in bone turnover in response to oral glucose. J Clin Endocrinol Metab 88:4867–4873

    Article  CAS  PubMed  Google Scholar 

  8. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G (2010) Insulin signaling in o Guillermo E. Umpierrez, osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Asmar M, Holst JJ (2010) Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances. Curr Opin Endocrinol Diabetes Obes 17:57–62

    CAS  PubMed  Google Scholar 

  10. Wei W, Wan Y (2011) Thiazolidinediones on PPARgamma: the roles in bone remodeling. PPAR Res 2011:867180

    Article  PubMed Central  PubMed  Google Scholar 

  11. Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, Wu G, Shi L, Feng Z, Qiu L, Li Q, Guo X, Luo Z, Lu J, Shan Z, Yang W, Ji Q, Yan L, Li H, Yu X, Li S, Zhou Z, Lv X, Liang Z, Lin S, Zeng L, Yan J, Ji L, Weng J (2015) Comparison of the effects on glycaemic control and b-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: a multicenter randomized parallel-group trial (the confidence study). J Intern Med 277:137–150

    Article  CAS  PubMed  Google Scholar 

  12. Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall DM, Taskinen MR, Smith U, Yki-Järvinen H, Heine RJ (2009) One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 32:762–768

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Meloni AR, DeYoung MB, Han J, Best JH, Grimm M (2013) Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals. Cardiovasc Diabetol 12:48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, González JG, Chan M, Wolka AM, Boardman MK, DURATION-4 Study Group (2012) Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 35:252–258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Reyes-García R, Rozas-Moreno P, López-Gallardo G, García-Martín A, Varsavsky M, Avilés-Perez MD, Muñoz-Torres M (2013) Serum levels of bone resorption markers are decreased in patients with type 2 diabetes. Acta Diabetol 50:47–52

    Article  PubMed  Google Scholar 

  16. Gerdhem P, Isaksson A, Akesson K, Obrant KJ (2005) Increased bone density and decreased bone turnover, but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus. Osteoporos Int 16:1506–1512

    Article  CAS  PubMed  Google Scholar 

  17. Rosato MT, Schneider SH, Shapses SA (1998) Bone turnover and insulin-like growth factor I levels increase after improved glycemic control in noninsulin-dependent diabetes mellitus. Calcif Tissue Int 63:107–111

    Article  CAS  PubMed  Google Scholar 

  18. Okazaki R, Totsuka Y, Hamano K, Ajima M, Miura M, Hirota Y, Hata K, Fukumoto S, Matsumoto T (1997) Metabolic improvement of poorly controlled noninsulin-dependent diabetes mellitus decreases bone turnover. J Clin Endocrinol Metab 82:2915–2920

    CAS  PubMed  Google Scholar 

  19. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2009) Adiponectin is associated with changes in bone markers during glycemic control in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:3031–3037

    Article  CAS  PubMed  Google Scholar 

  20. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791

    Article  CAS  PubMed  Google Scholar 

  21. Im JA, Yu BP, Jeon JY, Kim SH (2008) Relationship between osteocalcin and glucose metabolism in postmenopausal women. Clin Chim Acta 396:66–69

    Article  CAS  PubMed  Google Scholar 

  22. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T (2009) Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab 94:45–49

    Article  CAS  PubMed  Google Scholar 

  23. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2010) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int 22:187–194

    Article  PubMed  Google Scholar 

  24. Sayinalp S, Gedik O, Koray Z (1995) Increasing serum osteocalcin after glycemic control in diabetic men. Calcif Tissue Int 57:422–425

    Article  CAS  PubMed  Google Scholar 

  25. Gregorio F, Cristallini S, Santeusanio F, Filipponi P, Fumelli P (1994) Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes? Diabetes Res Clin Pract 23:43–54

    Article  CAS  PubMed  Google Scholar 

  26. Hong SH, Koo JW, Hwang JK, Hwang YC, Jeong IK, Ahn KJ, Chung HY, Kim DY (2013) Changes in serum osteocalcin are not associated with changes in glucose or insulin for osteoporotic patients treated with bisphosphonate. J Bone Metab 20:37–41

    Article  PubMed Central  PubMed  Google Scholar 

  27. Poomthavorn P, Nantarakchaikul P, Mahachoklertwattana P, Chailurkit LO, Khlairit P (2014) Effects of correction of vitamin D insufficiency on serum osteocalcin and glucose metabolism in obese children. Clin Endocrinol (Oxf) 80:516–523

    Article  CAS  Google Scholar 

  28. Finkelstein JS, Sowers M, Greendale GA, Lee ML, Neer RM, Cauley JA, Ettinger B (2003) Ethnic variation in bone turnover in pre- and early perimenopausal women: effects of anthropometric and lifestyle factors. J Clin Endocrinol Metab 87:3051–3056

    Article  Google Scholar 

  29. Nuche-Berenguer B, Portal-Núñez S, Moreno P, González N, Acitores A, López-Herradón A, Esbrit P, Valverde I, Villanueva-Peñacarrillo ML (2010) Presence of a functional receotpr for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J Cell Physiol 225:585–592

    Article  CAS  PubMed  Google Scholar 

  30. Ng KW (2011) Regulation of glucose metabolism and the skeleton. Clin Endocrinol (Oxford) 75:147–155

    Article  CAS  Google Scholar 

  31. Nuche-Berenguer B, Moreno P, Esbrit P, Dapía S, Caeiro JR, Cancelas J, Haro-Mora JJ, Villanueva-Peñacarrillo ML (2009) Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. Calcif Tissue Int 84:453–461

    Article  CAS  PubMed  Google Scholar 

  32. Nuche-Berenguer B, Moreno P, Portal-Nuñez S, Dapía S, Esbrit P, Villanueva-Peñacarrillo ML (2010) Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states. Regul Pept 159:61–66

    Article  CAS  PubMed  Google Scholar 

  33. Bunck MC, Eliasson B, Cornér A, Heine RJ, Shaginian RM, Taskinen MR, Yki-Järvinen H, Smith U, Diamant M (2011) Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab 13:374–377

    Article  CAS  PubMed  Google Scholar 

  34. Bunck MC, Poelma M, Eekhoff EM, Schweizer A, Heine RJ, Nijpels G, Foley JE, Diamant M (2012) Effects of Vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled, type 2 diabetes patients. J Diabetes 4:181–185

    Article  CAS  PubMed  Google Scholar 

  35. Garnero P (2008) Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther 12:157–170

    Article  CAS  PubMed  Google Scholar 

  36. Jensen LB, Kollerup G, Quaade F, Sørensen OH (2001) Bone mineral changes in obese women during a moderate weight loss with and without calcium supplementation. J Bone Miner Res 16:141–147

    Article  CAS  PubMed  Google Scholar 

  37. Riedt CS, Cifuentes M, Stahl T, Chowdhury HA, Schlussel Y, Shapses SA (2005) Overweight postmenopausal women lose bone with moderate weight eduction and 1 g/day calcium intake. J Bone Miner Res 20:455–463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Carrasco F, Ruz M, Rojas P, Csendes A, Rebolledo A, Codoceo J, Inostroza J, Basfi-Fer K, Papapietro K, Rojas J, Pizarro F, Olivares M (2009) Changes in bone mineral density, body composition and adiponectin levels in morbidly obese patients after bariatric surgery. Obes Surg 19:41–46

    Article  PubMed  Google Scholar 

  39. Holecki M, Zahorska-Markiewicz B, Chudek J, Wiecek A (2010) Changes in bone mineral density and bone turnover markers in obese women after short-term weight loss therapy during a 5-year follow-up. Pol Arch Med Wewn 120:248–254

    CAS  PubMed  Google Scholar 

  40. Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N, Tanaka K, Drucker DJ, Seino Y, Inagaki N (2008) The murine glucagonlike peptide-1 receptor is essential for control of bone resorption. Endocrinology 149:574–579

    Article  CAS  PubMed  Google Scholar 

  41. Antonopoulou M, Bahtiyar G, Banerji MA, Sacerdote AS (2013) Diabetes and bone health. Maturitas 76:253–259

    Article  CAS  PubMed  Google Scholar 

  42. Waser B, Beetschen K, Pellegata NS, Reubi JC (2011) Incretin receptors in non-neoplastic and neoplastic thyroid C cells in rodents and humans: relevance for incretin-based diabetes therapy. Neuroendocrinology 94:291–301

    Article  CAS  PubMed  Google Scholar 

  43. Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh MW (2012) Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab 97:121–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Lecka-Czernik B (2010) Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep 8:178–184

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Motyl KJ, McCabe LR, Schwartz AV (2010) Bone and glucose metabolism: a two-way street. Arch Biochem Bioph 503:2–10

    Article  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank all the participating patients in the study. This study was supported by the Key Clinical Project from the Ministry of Health of China and investigator-initiated trial research funds from Eli Lilly and Co. and Amylin Pharmaceuticals, Inc. The sponsors had no role in the study design, collection, analysis and interpretation of data, or writing the report.

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    Authors and Affiliations

    1. Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

      Renyuan Li, Wen Xu, Sihui Luo, Haixia Xu, Longyi Zeng & Jianping Weng

    2. Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China

      Guoyu Tong & Dalong Zhu

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    1. Renyuan Li
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    2. Wen Xu
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    Correspondence to Jianping Weng.

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    Ethical standard

    The study protocol has been reviewed by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University and Drum Tower Hospital Affiliated to Nanjing University Medical School, and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki.

    Human and animal rights

    All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

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    Informed consent was obtained from all patients for being included in the study.

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    Managed by Antonio Secchi.

    Renyuan Li, Wen Xu and Sihui Luo have contributed equally to this work.

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    Li, R., Xu, W., Luo, S. et al. Effect of exenatide, insulin and pioglitazone on bone metabolism in patients with newly diagnosed type 2 diabetes. Acta Diabetol 52, 1083–1091 (2015). https://doi.org/10.1007/s00592-015-0792-2

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