Advertisement

Aging Clinical and Experimental Research

, Volume 27, Issue 2, pp 115–124 | Cite as

The prevention of fragility fractures in diabetic patients

  • Stefano GonnelliEmail author
  • Carla Caffarelli
  • Nicola Giordano
  • Ranuccio Nuti
Review

Abstract

Patients with diabetes mellitus (DM) are at greater risk of fractures mostly due to not only extraskeletal factors, such as propensity to falls, but also to bone quality alteration, which reduces bone strength. In people with DM, insulin deficit and hyperglycemia seem to play a role in determining bone formation alteration by AGE accumulation which directly influences osteoblast activity. Although there are conflicting data in the literature, adequate glycemic control with hypoglycemic treatment may be an important element in preventing bone tissue alterations in both type 1 and type 2 DM. Diabetes status is a predictive of future hip and major osteoporosis fractures independently of BMD and FRAX probability. Attention should be paid to the use of thiazolidinediones, especially in older women, because the direct negative effect on bone could exceed the positive effect of glycemic control. Systematic screening for complications and fall prevention efforts, along with calcium and vitamin D repletion and adequate physical activity, represents the mainstay of fracture prevention in DM patients. All anticatabolic drugs (raloxifene, bisphosphonates, denosumab) seem to be effective in DM patients. On the basis of pathophysiological evidence that suggests low bone formation in DM patients, osteoanabolic therapies such as teriparatide might represent an important therapeutic option for DM patients with severe osteoporosis and/or multiple fractures. The search for better methods for the identification of fragility fracture risk in the growing population of adult and elderly subjects with DM might be considered a clinical priority which could improve the prevention of fracture in DM patients.

Keywords

Osteoporosis Diabetes mellitus Fragility fractures Prevention 

Notes

Conflict of interest

On behalf of all authors, I declare no conflict of interest.

References

  1. 1.
    Janghorbani M, van Dam R, Willett W, Hu F (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166:495–505CrossRefPubMedGoogle Scholar
  2. 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 18:427–444CrossRefPubMedGoogle Scholar
  3. 3.
    Vestergaard P, Rejnmark L, Mosekilde L (2009) Diabetes and its complications and their relationship with risk of fractures in type 1 and 2 diabetes. Calcif Tissue Int 84:45–55CrossRefPubMedGoogle Scholar
  4. 4.
    Hamann C, Kirschner S, Günther KP, Hofbauer LC (2012) Bone, sweet bone—osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol 8:297–305CrossRefPubMedGoogle Scholar
  5. 5.
    Montagnani A, Gonnelli S, Alessandri M, Nuti R (2011) Osteoporosis and risk fracture in patients with diabetes: an update. Aging Clin Exp Res 23:84–90CrossRefPubMedGoogle Scholar
  6. 6.
    Munoz-Torres M, Jodar E, Escobar-Jimenez F, López-Ibarra PJ, Luna JD (1996) Bone mineral density measured by dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcif Tissue Int 58:316–319CrossRefPubMedGoogle Scholar
  7. 7.
    Räkel A, Sheehy O, Rahme E, LeLorier J (2008) Osteoporosis among patients with type 1 and type 2 diabetes. Diabetes Metab 34:193–205CrossRefPubMedGoogle Scholar
  8. 8.
    Jehle PM, Jehle DR, Mohan S, Böhm BO (1998) Serum levels of insulin-like growth factor system components and relationship to bone metabolism in type 1 and type 2 diabetes mellitus patients. J Endocrinol 159:297–306CrossRefPubMedGoogle Scholar
  9. 9.
    Van Daele PLA, Stolk RP, Burger H, Algra D, Grobbee DE, Hofman A, Birkenhäger JC, Pols HA (1995) Bone density in non-insulin-dependent diabetes mellitus. Ann Intern Med 122:409–414CrossRefPubMedGoogle Scholar
  10. 10.
    Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR, Study of Osteoporotic Features Research Group (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86:32–38CrossRefPubMedGoogle Scholar
  11. 11.
    Lipscombe LL, Jamal SA, Booth GL, Hawaker GA (2007) The risk of hip fractures in older individuals with diabetes: a population-based study. Diabetes Care 30:835–841CrossRefPubMedGoogle Scholar
  12. 12.
    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 48:1292–1299CrossRefPubMedGoogle Scholar
  13. 13.
    Montagnani A, Gonnelli S (2013) Antidiabetic therapy effects on bone metabolism and fracture risk. Diabetes Obes Metab 15:784–9112CrossRefPubMedGoogle Scholar
  14. 14.
    Wang X, Shen X, Li X, Agrawal CM (2002) Age-related changes in the collagen network and toughness of bone. Bone 31:1–7CrossRefPubMedGoogle Scholar
  15. 15.
    Katayama Y, Akatsu T, Yamamoto M, Kugai N, Nagata N (1996) Role of nonenzymatic glycosylation of type 1 collagen in diabetic osteopenia. J Bone Miner Res 11:931–937CrossRefPubMedGoogle Scholar
  16. 16.
    Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214CrossRefPubMedGoogle Scholar
  17. 17.
    Schwartz AV, Garnero P, Hillier TA, Sellmeyer DE, Strotmeyer ES, Feingold KR, Resnick HE, Tylavsky FA, Black DM, Cummings SR, Harris TB, Bauer DC (2009) Health, aging, and body composition study. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab 94:2380–2386CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T (2008) Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 93:1013–1019CrossRefPubMedGoogle Scholar
  19. 19.
    Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278–1282CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Gennari L, Merlotti D, Valenti R, Ceccarelli E, Ruvio M, Pietrini MG, Capodarca C, Franci MB, Campagna MS, Calabrò A, Cataldo D, Stolakis K, Dotta F, Nuti R (2012) Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. J Clin Endocrinol Metab 97:1737–1744CrossRefPubMedGoogle Scholar
  21. 21.
    Gaudio A, Privitera F, Battaglia K, Torrisi V, Sidoti MH, Pulvirenti I, Canzonieri E, Tringali G, Fiore CE (2012) Sclerostin levels associated with inhibition of the Wnt/β-catenin signaling and reduced bone turnover in type 2 diabetes mellitus. J Clin Endocrinol Metab 97:3744–3750CrossRefPubMedGoogle Scholar
  22. 22.
    Karsenty G (2001) Minireview: transcriptional control of osteoblast differentiation. Endocrinology 142:2731–2733CrossRefPubMedGoogle Scholar
  23. 23.
    Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL (2002) Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 143:2376–2384PubMedGoogle Scholar
  24. 24.
    Follak N, Klting I, Wolf E, Merk H (2004) Improving metabolic control reverses the histomorphometric and biomechanical abnormalities of an experimentally induced bone deficit in spontaneously diabetic rats. Calcif Tissue Int 74:551–560CrossRefPubMedGoogle Scholar
  25. 25.
    Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM (1995) Bone loss and bone turnover in diabetes. Diabetes 44:775–782CrossRefPubMedGoogle Scholar
  26. 26.
    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 11:455–459CrossRefPubMedGoogle Scholar
  27. 27.
    Schwartz AV, Margolis KL, Sellmeyer DE, Sellmeyer DE, Vittinghoff E, Ambrosius WT, Bonds DE, Josse RG, Schnall AM, Simmons DL, Hue TF, Palermo L, Hamilton BP, Green JB, Atkinson HH, O’Connor PJ, Force RW, Bauer DC (2012) Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial. Diabetes Care 35:1525–1531CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F, Chiasserini V, Marchionni N, Rotella CM, Mannucci E (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case–control study. Diabetes Care 31:199–203CrossRefPubMedGoogle Scholar
  29. 29.
    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 28:554–560CrossRefPubMedGoogle Scholar
  30. 30.
    Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM, Poh CB, Ng JM (2012) Association between glycemic control and hip fracture. J Am Geriatr Soc 60:1493–1497CrossRefPubMedGoogle Scholar
  31. 31.
    Oei L, Zillikens MC, Dehghan A, Buitendijk GH, Castaño-Betancourt MC, Estrada K, Stolk L, Oei EH, van Meurs JB, Janssen JA, Hofman A, van Leeuwen JP, Witteman JC, Pols HA, Uitterlinden AG, Klaver CC, Franco OH, Rivadeneira F (2013) High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam study. Diabetes Care 36:1619–1628CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Schneider AL, Williams EK, Brancati FL, Blecker S, Coresh J, Selvin E (2013) Diabetes and risk of fracture-related hospitalization: the Atherosclerosis Risk in Communities study. Diabetes Care 36:1153–1158CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180:32–39CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G, ADOPT Study Group (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443CrossRefPubMedGoogle Scholar
  35. 35.
    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 34:2474–2476CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    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 6:260–266CrossRefPubMedGoogle Scholar
  37. 37.
    Shapses SA, Riedt CS (2006) Bone, body weight, and weight reduction: what are the concerns? J Nutr 136:1453–1456PubMedCentralPubMedGoogle Scholar
  38. 38.
    Schwartz AV, Johnson KC, Kahn SE, Shepherd JA, Nevitt MC, Peters AL, Walkup MP, Hodges A, Williams CC, Bray GA, Look AHEAD Research Group (2012) 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 27(3):619–627CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Daly RM, Dunstan DW, Owen N, Jolley D, Shaw JE, Zimmet PZ (2005) Does high-intensity resistance training maintain bone mass during moderate weight loss in older overweight adults with type 2 diabetes? Osteoporos Int 16:1703–1712CrossRefPubMedGoogle Scholar
  40. 40.
    Mayne D, Stout NR, Aspray TJ (2010) Diabetes, falls and fractures. Age Ageing 39:522–525CrossRefPubMedGoogle Scholar
  41. 41.
    Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, Schreiner PJ, Margolis KL, Cauley JA, Nevitt MC, Black DM, Cummings SR (2002) Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care 25:1749–1754CrossRefPubMedGoogle Scholar
  42. 42.
    Saller A, Maggi S, Romanato G, Tonin P, Crepaldi G (2008) Diabetes and osteoporosis. Aging Clin Exp Res 20:280–289CrossRefPubMedGoogle Scholar
  43. 43.
    Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, Lamb SE (2012) Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 9:CD007146. doi: 10.1002/14651858.CD007146 PubMedGoogle Scholar
  44. 44.
    Gordon BA, Benson AC, Bird SR, Fraser SF (2009) Resistance training improves metabolic health in type 2 diabetes: a systematic review. Diabetes Res Clin Pract 83:157–175CrossRefPubMedGoogle Scholar
  45. 45.
    American Diabetes Association (2011) Standards of medical care in diabetes. Diabetes Care 34(Suppl 1):S11–S61CrossRefPubMedCentralGoogle Scholar
  46. 46.
    Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR (2008) Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 336:262–266CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 29:341–369Google Scholar
  48. 48.
    Lewis JR, Zhu K, Thompson PL, Prince RL (2013) The effects of 3 years of calcium supplementation on common carotid artery intimal medial thickness and carotid atherosclerosis in older women: an ancillary study of the CAIFOS randomized controlled trial. Bone Miner Res. doi: 10.1002/jbmr.2117 Google Scholar
  49. 49.
    Radford LT, Bolland MJ, Mason B, Horne A, Gamble GD, Grey A, Reid IR (2014) The Auckland calcium study: 5-year post-trial follow-up. Osteoporos Int 25:297–304CrossRefPubMedGoogle Scholar
  50. 50.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281CrossRefPubMedGoogle Scholar
  51. 51.
    Bacon CJ, Gamble GD, Horne AM, Scott MA, Reid IR (2009) High-dose oral vitamin D3 supplementation in the elderly. Osteoporos Int 20:1407–1415CrossRefPubMedGoogle Scholar
  52. 52.
    Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822CrossRefPubMedGoogle Scholar
  53. 53.
    Rossini M, Adami S, Viapiana O, Fracassi E, Idolazzi L, Povino MR, Gatti D (2012) Dose-dependent short-term effects of single high doses of oral vitamin D(3) on bone turnover markers. Calcif Tissue Int 91:365–369CrossRefPubMedGoogle Scholar
  54. 54.
    Bischoff HA, Stähelin HB, Dick W, Akos R, Knecht M, Salis C, Nebiker M, Theiler R, Pfeifer M, Begerow B, Lew RA, Conzelmann M (2003) Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 18:343–351CrossRefPubMedGoogle Scholar
  55. 55.
    Saito O, Saito T, Asakura S, Akimoto T, Inoue M, Ando Y, Muto S, Kusano E (2012) Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes. Int J Endocrinol Metab 10:464–469CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Johnell O, Kanis JA, Black DM, Balogh A, Poor G, Sarkar S, Zhou C, Pavo I (2004) Associations between baseline risk factors and vertebral fracture risk in the multiple outcomes of raloxifene evaluation (MORE) study. J Bone Miner Res 19:764–772CrossRefPubMedGoogle Scholar
  57. 57.
    Keegan TH, Schwartz AV, Bauer DC, Sellmeyer DE, Kelsey JL, Fracture Intervention Trial (2004) Effect of alendronate on bone mineral density and biochemical markers of bone turnover in type 2 diabetic women: the fracture intervention trial. Diabetes Care 27:1547–1553CrossRefPubMedGoogle Scholar
  58. 58.
    Iwamoto J, Sato Y, Uzawa M, Takeda T, Matsumoto H (2011) Three-year experience with alendronate treatment in postmenopausal osteoporotic Japanese women with or without type 2 diabetes. Diabetes Res Clin Pract 93:166–173CrossRefPubMedGoogle Scholar
  59. 59.
    Dagdelen S, Sener D, Bayraktar M (2007) Influence of type 2 diabetes mellitus on bone mineral density response to bisphosphonates in late postmenopausal osteoporosis. Adv Ther 24:1314–1320CrossRefPubMedGoogle Scholar
  60. 60.
    Vestergaard P, Rejnmark L, Mosekilde L (2011) Are antiresorptive drugs effective against fractures in patients with diabetes? Calcif Tissue Int 88:209–214CrossRefPubMedGoogle Scholar
  61. 61.
    Favus MJ (2010) Bisphosphonates for osteoporosis. N Engl J Med 363:2027–2035CrossRefPubMedGoogle Scholar
  62. 62.
    Khamaisi M, Regev E, Yarom N, Avni B, Leitersdorf E, Raz I, Elad S (2007) Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 92:1172–1175CrossRefPubMedGoogle Scholar
  63. 63.
    Schwartz AV, Schafer AL, Grey A, Vittinghoff E, Palermo L, Lui LY, Wallace RB, Cummings SR, Black DM, Bauer DC, Reid IR (2013) Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Miner Res 28:1348–1354CrossRefPubMedGoogle Scholar
  64. 64.
    Motyl KJ, McCauley LK, McCabe LR (2012) Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol 227:1326–1334CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Anastasilakis A, Goulis DG, Koukoulis G, Kita M, Slavakis A, Avramidis A (2007) Acute and chronic effect of teriparatide on glucose metabolism in women with established osteoporosis. Exp Clin Endocrinol Diabetes 115:108–111CrossRefPubMedGoogle Scholar
  66. 66.
    Hamann C, Rauner M, Höhna Y, Bernhardt R, Mettelsiefen J, Goettsch C, Günther KP, Stolina M, Han CY, Asuncion FJ, Ominsky MS, Hofbauer LC (2013) Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res 28:627–638CrossRefPubMedGoogle Scholar
  67. 67.
    Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, Donaldson MG, Cauley JA, Harris TB, Koster A, Womack CR, Palermo L, Black DM, Study of Osteoporotic Fractures (SOF) Research Group, Osteoporotic Fractures in Men (MrOS) Research Group, Health, Aging, and Body Composition (Health ABC) Research Group (2011) Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 305:2184–2192CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    Giangregorio LM, Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis JA (2012) FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res 27:301–318CrossRefPubMedGoogle Scholar
  69. 69.
    Leslie WD, Rubin MR, Schwartz AV, Kanis JA (2012) Type 2 diabetes and bone. J Bone Miner Res 27:2231–2237CrossRefPubMedGoogle Scholar
  70. 70.
    Kanis JA, Johansson H, Oden A, McCloskey EV (2011) Guidance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos Int 22:809–816CrossRefPubMedGoogle Scholar
  71. 71.
    Gonnelli S, Cepollaro C, Gennari L, Montagnani A, Caffarelli C, Merlotti D, Rossi S, Cadirni A, Nuti R (2005) Quantitative ultrasound and dual-energy X-ray absorptiometry in the prediction of fragility fracture in men. Osteoporos Int 16:963–968CrossRefPubMedGoogle Scholar
  72. 72.
    Krieg MA, Barkmann R, Gonnelli S, Stewart A, Bauer DC, Del Rio Barquero L, Kaufman JJ, Lorenc R, Miller PD, Olszynski WP, Poiana C, Schott AM, Lewiecki EM, Hans D (2008) Quantitative ultrasound in the management of osteoporosis: the 2007 ISCD Official Positions. J Clin Densitom 11:163–187CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Stefano Gonnelli
    • 1
    Email author
  • Carla Caffarelli
    • 1
  • Nicola Giordano
    • 1
  • Ranuccio Nuti
    • 1
  1. 1.Department of Medicine, Surgery and NeuroscienceUniversity of SienaSienaItaly

Personalised recommendations