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Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health

  • Bone and Diabetes (A Schwartz and P Vestergaard, Section Editors)
  • Published:
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Abstract

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Schwartz AV, Vittinghoff E, Bauer DC, et al. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA. 2011;305(21):2184–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hamann C, Kirschner S, Gunther KP, Hofbauer LC. Bone, sweet bone—osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol. 2012;8(5):297–305.

    Article  CAS  PubMed  Google Scholar 

  3. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos Int. 2007;18(4):427–44.

    Article  CAS  PubMed  Google Scholar 

  4. Schwartz AV. Epidemiology of fractures in type 2 diabetes. Bone. 2015

  5. Koh WP, Wang R, Ang LW, Heng D, Yuan JM, Yu MC. Diabetes and risk of hip fracture in the Singapore Chinese health study. Diabetes Care. 2010;33(8):1766–70.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Li CI, Liu CS, Lin WY, et al. Glycated hemoglobin level and risk of Hip fracture in older people with type 2 diabetes: a competing risk analysis of Taiwan diabetes cohort study. J Bone Miner Res. 2015;30(7):1338–46.

    Article  CAS  PubMed  Google Scholar 

  7. 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(5):495–505.

    Article  PubMed  Google Scholar 

  8. Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton. Bone. 2016;82:93–100.

    Article  CAS  PubMed  Google Scholar 

  9. Leslie WD, Rubin MR, Schwartz AV, Kanis JA. Type 2 diabetes and bone. J Bone Miner Res. 2012;27(11):2231–7.

    Article  PubMed  Google Scholar 

  10. Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36(11-12):761–5.

    Article  CAS  PubMed  Google Scholar 

  11. Janssen P, Rotondo A, Mule F, Tack J. Review article: a comparison of glucagon-like peptides 1 and 2. Aliment Pharmacol Ther. 2013;37(1):18–36.

    Article  CAS  PubMed  Google Scholar 

  12. Drucker DJ, Yusta B. Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol. 2014;76:561–83.

    Article  CAS  PubMed  Google Scholar 

  13. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876–913.

    Article  CAS  PubMed  Google Scholar 

  14. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131–57.

    Article  CAS  PubMed  Google Scholar 

  15. Yamada C, Yamada Y, Tsukiyama K, et al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology. 2008;149(2):574–9.

    Article  CAS  PubMed  Google Scholar 

  16. Xie D, Zhong Q, Ding KH, et al. Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone. 2007;40(5):1352–60.

    Article  CAS  PubMed  Google Scholar 

  17. Zhong Q, Itokawa T, Sridhar S, et al. Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab. 2007;292(2):E543–548.

    Article  CAS  PubMed  Google Scholar 

  18. Henriksen DB, Alexandersen P, Hartmann B, et al. Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone. 2007;40(3):723–9.

    Article  CAS  PubMed  Google Scholar 

  19. Walsh JS, Henriksen DB. Feeding and bone. Arch Biochem Biophys. 2010;503(1):11–9.

    Article  CAS  PubMed  Google Scholar 

  20. Henriksen DB, Alexandersen P, Byrjalsen I, et al. Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone. 2004;34(1):140–7.

    Article  CAS  PubMed  Google Scholar 

  21. Henriksen DB, Alexandersen P, Hartmann B, et al. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone. 2009;45(5):833–42.

    Article  CAS  PubMed  Google Scholar 

  22. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9. Guidelines for the treatment of type 2 diabetes including the results of the latest studies.

    Article  PubMed  Google Scholar 

  23. Nielsen LL, Baron AD. Pharmacology of exenatide (synthetic exendin-4) for the treatment of type 2 diabetes. Curr Opin Investig Drugs. 2003;4(4):401–5.

    CAS  PubMed  Google Scholar 

  24. Ma X, Meng J, Jia M, et al. 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. 2013;28(7):1641–52.

    Article  CAS  PubMed  Google Scholar 

  25. Meng J, Ma X, Wang N, et al. Activation of GLP-1 receptor promotes bone marrow stromal cell osteogenic differentiation through beta-Catenin. Stem Cell Rep. 2016.

  26. Lu N, Sun H, Yu J, et al. Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes. PLoS One. 2015;10(7):e0132744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pereira M, Jeyabalan J, Jorgensen CS, et al. Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice. Bone. 2015;81:459–67.

    Article  CAS  PubMed  Google Scholar 

  28. Bunck MC, Eliasson B, Corner A, et al. Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):374–7.

    Article  CAS  PubMed  Google Scholar 

  29. Iepsen EW, Lundgren JR, Hartmann B, et al. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab. 2015;100(8):2909–17. A randomized controlled trial examining changes in bone mineral content and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. The study was of great interest and was discussed controversially through letters to the editor by two other research groups.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Su B, Sheng H, Zhang M, et al. Risk of bone fractures associated with glucagon-like peptide-1 receptor agonists’ treatment: a meta-analysis of randomized controlled trials. Endocrine. 2015;48(1):107–15.

    Article  CAS  PubMed  Google Scholar 

  32. Driessen JH, van Onzenoort HA, Starup-Linde J, et al. Use of glucagon-like-peptide 1 receptor agonists and risk of fracture as compared to use of other anti-hyperglycemic drugs. Calcif Tissue Int. 2015;97(5):506–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Glorie L, Behets GJ, Baerts L, De Meester I, D’Haese PC, Verhulst A. DPP4 inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats. Am J Physiol Endocrinol Metab. 2014.

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

    Article  CAS  PubMed  Google Scholar 

  35. 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(11):2474–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Driessen JH, van Onzenoort HA, Henry RM, et al. Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture. Bone. 2014;68:124–30.

    Article  CAS  PubMed  Google Scholar 

  37. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.

    Article  PubMed  Google Scholar 

  38. Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551–9.

    Article  CAS  PubMed  Google Scholar 

  39. Gorboulev V, Schurmann A, Vallon V, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61(1):187–96.

    Article  CAS  PubMed  Google Scholar 

  40. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005;20(6):452–77.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. Randomized controlled trial including over 7000 type 2 diabetics with increased risk for cardiovascular disease. The addition of empagliflozin to standard care leads to a lower rate of the primary composite cardiovascular outcome and of death. The article seems to be a milestone paper, promoting the application of SGLT-2 inhibitors.

    Article  CAS  PubMed  Google Scholar 

  43. Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabet Endocrinol. 2016.

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

    Article  CAS  PubMed  Google Scholar 

  45. Quarles LD. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol. 2012;8(5):276–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nauck MA, Del Prato S, Meier JJ, et al. 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. 2011;34(9):2015–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32(4):650–7.

    Article  CAS  PubMed  Google Scholar 

  48. Ljunggren O, Bolinder J, Johansson L, et al. 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. 2012;14(11):990–9.

    Article  CAS  PubMed  Google Scholar 

  49. Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016;101(1):44–51. A randomized controlled multicenter study including 700 patients. It showed a possible negative effect of the use of SGLT-2 inhibitors on BMD and therefore puts the advantages of the new drugs into perspective.

    Article  CAS  PubMed  Google Scholar 

  50. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring). 2014;22(4):1042–9.

    Article  CAS  Google Scholar 

  52. Hyldstrup L, Andersen T, McNair P, Breum L, Transbol I. Bone metabolism in obesity: changes related to severe overweight and dietary weight reduction. Acta Endocrinol (Copenh). 1993;129(5):393–8.

    CAS  Google Scholar 

  53. Bleicher K, Cumming RG, Naganathan V, et al. The role of fat and lean mass in bone loss in older men: findings from the CHAMP study. Bone. 2011;49(6):1299–305.

    Article  PubMed  Google Scholar 

  54. Schwartz AV, Johnson KC, Kahn SE, et al. Effect of 1 year of an intentional weight loss intervention on bone mineral density in type 2 diabetes: results from the Look AHEAD randomized trial. J Bone Miner Res. 2012;27(3):619–27.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Schafer AL. Decline in bone mass during weight loss: a cause for concern? J Bone Miner Res. 2016;31(1):36–9.

    Article  PubMed  Google Scholar 

  56. Zibellini J, Seimon RV, Lee CM, et al. Does diet-induced weight loss lead to bone loss in overweight or obese adults? a systematic review and meta-analysis of clinical trials. J Bone Miner Res. 2015;30(12):2168–78.

    Article  CAS  PubMed  Google Scholar 

  57. Villareal DT, Fontana L, Das SK, et al. Effect of two-year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: a randomized clinical trial. J Bone Miner Res. 2016;31(1):40–51.

    Article  CAS  PubMed  Google Scholar 

  58. Kohan DE, Fioretto P, Tang W, List JF. 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. 2014;85(4):962–71.

    Article  CAS  PubMed  Google Scholar 

  59. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157–66.

    Article  CAS  PubMed  Google Scholar 

  60. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–23. e211.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Christian Meier.

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Andrea Egger, Marius E. Kraenzlin, and Christian Meier declare that they have no conflict of interest.

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This article is part of the Topical Collection on Bone and Diabetes

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Egger, A., Kraenzlin, M.E. & Meier, C. Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health. Curr Osteoporos Rep 14, 345–350 (2016). https://doi.org/10.1007/s11914-016-0337-9

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