Antidiabetic drugs and their effect on bone

Czech version

Authors: Peter Jackuliak; Martin Kužma; Juraj Payer
Authors‘ workplace: V. interná klinika LF UK a UNB, Nemocnica Ružinov, Bratislava, Slovenská republika
Published in: Vnitř Lék 2017; 63(9): 609-616
Category: Reviews

Overview

It is well established that osteoporosis and diabetes are prevalent diseases with significant associated morbidity and mortality. Patients with diabetes mellitus are at an increased risk of bone fractures. Today we have several groups of effective and save antidiabetic drugs, which are very given often in combination. Although diabetes-related complications are important in the etiology, the effects of medications on bone metabolism and fracture risk should not be neglected, because the diabetes medication may affect also bone health and fracture risk. Increased risk of fracture has been identified with use of thiazolidinediones, most definitively in women. Also treatment with sulfonylureas can have negative adverse effect on bone. One consequence of these findings has been greater attention to fracture outcomes in trails of new diabetes medication (incretins and SGLT2 inhibitors). The aim of the review is to summarize effects of antidiabetic treatment on bone – bone mineral density, fractures and bone turnover markers. The authors also try to recommend a strategy how to treat a diabetic patient regarding the risk of osteoporotic fractures.

Key words:
antidiabetic drugs – diabetes mellitus – fracture risk – osteoporosis

Sources

1. Kurra S, Siris E. Diabetes and bone health: the relationship between diabetes and osteoporosis-associated fractures. Diabetes Metab Res Rev 2011; 27(5): 430–435. Dostupné z DOI: <http://dx.doi.org/10.1002/dmrr.1197>.

2. Jackuliak P, Payer J. Osteoporosis, Fractures, and Diabetes. Int J Endocrinol 2014; 2014: 820615. Dostupné z DOI: <http://dx.doi.org/10.1155/2014/820615>.

3. Nazrun AS, Tzar MN, Mokhtar SA et al. A systematic review of the outcomes of osteoporotic fracture patients after hospital discharge: morbidity, subsequent fractures, and mortality. Ther Clin Risk Manag 2014; 10: 937–948. Dostupné z DOI: <http://dx.doi.org/10.2147/TCRM.S72456>.

4. Ferrari S. Diabetes and Bone. Calcif Tissue Int 2017; 100(2): 107–108. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–017–0234-y>.

5. 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(1): 45–55. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–008–9195–5>.

6. 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): 427–444.

7. Hough FS, Pierroz DD, Cooper C et al. Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol 2016; 174(4): R127-R138. Dostupné z DOI: <http://dx.doi.org/10.1530/EJE-15–0820>.

8. Hayakawa N, Suzuki A. Diabetes mellitus and osteoporosis. Effect of antidiabetic medicine on osteoporotic fracture. Clin Calcium 2012; 22(9): 1383–1390. Dostupné z DOI: <http://dx.doi.org/CliCa120913831390>.

9. Paul T, Thomas N. Impact of oral antidiabetic agents on bone metabolism. Indian J Med Res 2015; 141(4): 385–388. Dostupné z DOI: <http://dx.doi.org/10.4103/0971–5916.159244>.

10. McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes 2016; 7(6): 122–133. <http://dx.doi.org/10.4239/wjd.v7.i6.122>.

11. Gilbert MP, Pratley RE. The Impact of Diabetes and Diabetes Medications on Bone Health. Endocr Rev 2015; 36(2): 194–213. Dostupné z DOI: <http://dx.doi.org/10.1210/er.2012–1042>.

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

13. Majumdar SR, Leslie WD, Lix LM et al. Longer Duration of Diabetes Strongly Impacts Fracture Risk Assessment: The Manitoba BMD Cohort. J Clin Endocrinol Metab 2016; 101(11): 4489–4496.

14. Yavropoulou M, Mousiolis A, Kolokouri V et al. Anti-diabetic treatment as an additional factor in a FRAX based evaluation of osteoporotic fracture risk. Endocrine Abstracts 2015; 37: EP300. Dostupné z DOI: <http://dx.doi.org/10.1530/endoabs.37.EP300>.

15. Schwartz AV. Diabetes and Metabolism of Bone. In: Leahy J, Danoff A (ed.) ENDO 2017: Meet-The-Professor Endocrine Case Management. Washington DC 2017: 63–65. ISBN 978–1–943550–02–9. Dostupné z DOI: <http://dx.doi.org/10.1210/MTP5.9781943550043>.

16. Palermo A, D‘Onofrio L, Eastell R et al. Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int 2015; 26(8): 2073–2089. Dostupné z DOI: <http://dx.doi.org/10.1007/s00198–015–3123–0>.

17. Lecka-Czernik B. Safety of Anti-Diabetic Therapies on Bone. Clinical Rev Bone Miner Metab 2013; 11(1): 49–58.

18. Molinuevo MS, Schurman L, McCarthy AD et al. Effect of metformin on bone marrow progenitor cell differentiation: In vivo and in vitro studies. J Bone Miner Res 2010; 25(2): 211–221. Dostupné z DOI: <http://dx.doi.org/10.1359/jbmr.090732>.

19. Sundararaghavan V, Mazur MM, Evans B et al. Diabetes and bone health: latest evidence and clinical implications. Ther Adv Musculoskelet Dis 2017; 9(3): 67–74. Dostupné z DOI: <http://dx.doi.org/10.1177/1759720X16687480>.

20. Hegazy SK. Evaluation of the anti-osteoporotic effects of metformin and sitagliptin in postmenopausal diabetic women. J Bone Miner Metab 2015; 33(2): 207–212. Dostupné z DOI: <http://dx.doi.org/10.1007/s00774–014–0581-y>.

21. Sedlinsky C, Molinuevo MS, Cortizo AM et al. Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats. Eur J Pharmacol 2011; 668(3): 477–485. Dostupné z DOI: <http://dx.doi.org/10.1016/j.ejphar.2011.07.033>.

22. Gu Q, Gu Y, Yang H et al. Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells. Tohoku J Exp Med 2017; 241(1): 13–19. Dostupné z DOI: <http://dx.doi.org/10.1620/tjem.241.13>.

23. Schurman L, McCarthy AD, Sedlinsky C et al. Metformin Reverts Deleterious Effects of Advanced Glycation End-Products (AGEs) on Osteoblastic Cells. Exp Clin Endocrinol Diabetes 2008; 116(6): 333–340. Dostupné z DOI: <http://dx.doi.org/10.1055/s-2007–992786>.

24. Melton LJ, Leibson CL, Achenbach SJ et al. Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 2008; 23(8): 1334–1342. Dostupné z DOI: <http://dx.doi.org/10.1359/jbmr.080323>.

25. Russo GT, Giandalia A, Romeo EL et al. Fracture Risk in Type 2 Diabetes: Current Perspectives and Gender Differences. Int J Endocrinol 2016; 2016: 1615735. Dostupné z DOI: <http://dx.doi.org/10.1155/2016/1615735>.

26. Kahn SE, Zinman B, Lachin JM et al. Rosiglitazone-Associated Fractures in Type 2 Diabetes. An analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008; 31(5): 845–851. Dostupné z DOI: <http://dx.doi.org/10.2337/dc07–2270>.

27. Zinman B, Haffner SM, Herman WH et al. Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes. J Clin Endocrinol Metab 2010; 95(1): 134–142. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2009–0572>.

28. Monami M, Cresci B, Colombini A et al. Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 2008; 31(2): 199–203.

29. Lapane KL, Yang S, Brown MJ et al. Sulfonylureas and risk of falls and fractures: a systematic review. Drugs Aging 2013; 30(7): 527-S47. Dostupné z DOI: <http://dx.doi.org/10.1007/s40266–013–0081–0>.

30. Mehta S. Comparative Safety of Oral Antidiabetic Therapy on Risk of Fracture in Patients with Diabetes. American Diabetes Association 2014 Scientific Sessions 2014, 165-OR. Dostupné z DOI: <https://professional.diabetes.org/meeting/scientific-sessions/74th-scientific-sessions-2014>.

31. Tucker ME. Sulfonylureas May Up Fracture Risk in Diabetes along with TZDs. American Diabetes Association 2014 Scientific Sessions 2014. Dostupné z WWW: http://www.medscape.com/viewarticle/826774.

32. Berberoglu Z, Yazici AC, Demirag NG. Effects of rosiglitazone on bone mineral density and remodelling parameters in Postmenopausal diabetic women: a 2-year follow-up study. Clin Endocrinol (Oxf) 2010; 73(3): 305–312. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1365–2265.2010.03784.x>.

33. Mieczkowska A, Basle MF, Chappard D et al. Thiazolidinediones induce osteocyte apoptosis by a G protein-coupled receptor 40-dependent mechanism. J Biol Chem 2012; 287(28): 23517–23526. Dostupné z DOI: <http://dx.doi.org/10.1074/jbc.M111.324814>.

34. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009 ; 180(1): 32–39. Dostupné z DOI: <http://dx.doi.org/10.1503/cmaj.080486>.

35. Fukunaga T, Zou W, Rohatgi N et al. An Insulin-Sensitizing Thiazolidinedione, Which Minimally Activates PPARγ, Does Not Cause Bone Loss. J Bone Miner Res 2015; 30(3): 481–488. Dostupné z DOI: <http://dx.doi.org/10.1002/jbmr.2364>.

36. Marchetti P, Lupi R, Bugliani M et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia 2012; 55(12): 3262–3272. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–012–2716–9>.

37. Whalley NM, Pritchard LE, Smith DM et al. Processing of proglucagon to GLP-1 in pancreatic alpha-cells: is this a paracrine mechanism enabling GLP-1 to act on beta-cells? J Endocrinol 2011; 211(1): 99–106. Dostupné z DOI: <http://dx.doi.org/10.1530/JOE-11–0094>.

38. Ceccarelli E, Guarino E, Merlotti D et al. Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism. Front Endocrinol (Lausanne) 2013;4: 73. Dostupné z DOI: <http://dx.doi.org/10.3389/fendo.2013.00073>.

39. 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): 574–579.

40. Meng J, Ma X, Wang N et al. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin. Stem Cell Reports 2016; 6(4): 579–591. Dostupné z DOI: <http://dx.doi.org/10.1016/j.stemcr.2016.02.002>.

41. 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): 1641–1652. Dostupné z DOI: <http://dx.doi.org/10.1002/jbmr.1898>.

42. 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): 833–842. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2009.07.008>.

43. Holst JJ, Windeløv JA, Boer GA et al. Searching for the physiological role of glucose‐dependent insulinotropic polypeptide. J Diabetes Investig 2016; 7(Suppl 1): 8–12. Dostupné z DOI: <http://dx.doi.org/10.1111/jdi.12488>.

44. Bunck MC, Eliasson B, Cornér 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): 374–377. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1463–1326.2010.01355.x>.

45. Mabilleau G, Mieczkowska A, Irwin N et al. Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor. J Endocrinol 2013; 219(1): 59–68. Dostupné z DOI: <http://dx.doi.org/10.1530/JOE-13–0146>.

46. 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): 107–115. Dostupné z DOI: <http://dx.doi.org/10.1007/s12020–014–0361–4>.

47. 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): 506–515. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–015–0037-y>.

48. Monami M, Dicembrini I, Antenore A et al. Dipeptidyl peptidase-4 inhibitors and bone fractures: a meta-analysis of randomized clinical trials. Diabetes Care 2011; 34(11): 2474–2476. Dostupné z DOI: <http://dx.doi.org/10.2337/dc11–1099>. Erratum in Diabetes Care 2014; 37(1): 312.

49. Josse RG, Majumdar SR, Zheng Y et al. Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial. Diabetes Obes Metab 2017; 19(1): 78–86. Dostupné z DOI: <http://dx.doi.org/10.1111/dom.12786>.

50. 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): 2015–2022. Dostupné z DOI: <http://dx.doi.org/10.2337/dc11–0606>.

51. List JF, Woo V, Morales E et al. Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes. Diabetes Care 2009; 32(4): 650–657. Dostupné z DOI: <http://dx.doi.org/10.2337/dc08–1863>.

52. Ljunggren Ö, 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): 990–999. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1463–1326.2012.01630.x>.

53. Kohan DE, Fioretto P, Tang W et al. 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): 962–971. Dostupné z DOI: <http://dx.doi.org/10.1038/ki.2013.356>.

54. 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): 157–166. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2015–3167>.

55. 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. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2015–1860>.

56. 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): 1232–1238. Dostupné z DOI: <http://dx.doi.org/10.2337/dc11–1926>.

57. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015; 3(1): 8–10. <http://dx.doi.org/10.1016/S2213–8587(14)70227-X>.

58. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol 2013; 1(2): 140–151. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(13)70050–0>.

59. Martin RB. The importance of mechanical loading in bone biology and medicine. J Musculoskelet Neuronal Interact 2007; 7(1): 48–53.

60. Gonnelli S, Caffarelli C, Tanzilli L et al. The association of body composition and sex hormones with quantitative ultrasound parameters at the calcaneus and phalanxes in elderly women. Calcif Tissue Int 2011; 89(6): 456–463. <http://dx.doi.org/10.1007/s00223–011–9534–9>.

61. Liu M, Goss PE, Ingle JN et al. Aromatase Inhibitor-Associated Bone Fractures: A Case-Cohort GWAS and Functional Genomics. Mol Endocrinol 2014; 28(10): 1740–1751. Dostupné z DOI: <http://dx.doi.org/10.1210/me.2014–1147>.

62. Hofbauer LC, Brueck CC, Singh SK et al. Osteoporosis in Patients with Diabetes Mellitus. J Bone Miner Res 2007; 22(9): 1317–1328.

63. Moayeri A, Mohamadpour M, Mousavi SF et al. Fracture risk in patients with type 2 diabetes mellitus and possible risk factors: a systematic review and meta-analysis. Ther Clin Risk Manag 2017; 13: 455–468. Dostupné z DOI: <http://dx.doi.org/10.2147/TCRM.S131945>.

64. Klein GL. Insulin and bone: Recent developments. World J Diabetes 2014; 5(1):14–16. Dostupné z DOI: <http://dx.doi.org/10.4239/wjd.v5.i1.14>.

65. Thrailkill KM, Lumpkin CK, Bunn RC et al. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am J Physiol Endocrinol Metab 2005; 289(5): E735–745.

66. Campos Pastor MM, Lopez-Ibarra PJ, Escobar-Jimenez F et al. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporos Int 2000; 11(5): 455–459.

67. Fowlkes JL, Bunn RC, Thrailkill KM. Contributions of the Insulin/Insulin-Like Growth Factor-1 Axis to Diabetic Osteopathy. J Diabetes Metab 2011; 1(3). pii: S1–003. Dostupné z DOI: <http://dx.doi.org/10.4172/2155–6156.S1–003>.

68. Zhukouskaya VV, Shepelkevich AP, Chiodini I. Bone Health in Type 1 Diabetes: Where We Are Now and How We Should Proceed. ADV ENDOCRINOL 2014; 2014: Article ID 982129. Dostupné z DOI: <http://dx.doi.org/10.1155/2014/982129>.

69. Leidig-Bruckner G, Grobholz S, Bruckner T et al. Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus. BMC Endocr Disord 2014; 14: 33. Dostupné z DOI: <http://dx.doi.org/10.1186/1472–6823–14–33>.

70. Kanazawa I, Yamaguchi T, Yamamoto M et al. Relationships between serum adiponectin levels versus bone mineral density, bone metabolic markers, and vertebral fractures in type 2 diabetes mellitus. Eur J Endocrinol 2009; 160(2): 265–273. Dostupné z DOI: <http://dx.doi.org/10.1530/EJE-08–0642>.

71. Chandran M. Diabetes Drug Effects on the Skeleton. Calcif Tissue Int 2017; 100(2): 133–149. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–016–0203-x>.

72. Quandt SA, Stafford JM, Bell RA et al. Predictors of Falls in a Multiethnic Population of Older Rural Adults with Diabetes. J Gerontol A Biol Sci Med Sci 2006; 61(4): 394–398.

73. Starup-Linde J, Vestergaard P. Biochemical bone turnover markers in diabetes mellitus – A systematic review. Bone 2016; 82: 69–78. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2015.02.019>.

74. Keegan THM, Schwartz AV, Bauer DC et al. Effect of Alendronate on Bone Mineral Density and Biochemical Markers of Bone Turnover in Type 2 Diabetic Women. The Fracture Intervention Trial 2004. Diabetes Care 2004; 27(7): 1547–1553.

75. Ensrud KE, Stock JL, Barrett-Connor E et al. Effects of Raloxifene on Fracture Risk in Postmenopausal Women: The Raloxifene Use fortThe Heart Trial. J Bone Miner Res 2008; 23(1): 112–120.

76. Vestergaard P, Rejnmark L, Mosekilde L. Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int 2011; 88(3): 209–214. Dostupné z DOI: <http://dx.doi.org/10.1007/s00223–010–9450–4>.

77. Schwartz AV, Pavo I, Alam J et al. Teriparatide in patients with osteoporosis and type 2 diabetes. Bone 2016; 91: 152–158. Dostupné z DOI: <http://dx.doi.org/10.1016/j.bone.2016.06.017>.