Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
The prevalence of osteoporosis and diabetes mellitus is alarming. In the United States, 50% of elderly individuals are osteoporotic and 20% of population have either diabetes or prediabetic condition. It was found that both diseases had similar features including molecular mechanisms and genetic predispositions (1). Bone and energy homeostasis are under the control of the same regulatory factors, including insulin, bone derived hormone – osteocalcin, peroxisome proliferator-activated receptor-γ (PPAR-γ), as well as gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP).
Insulin exerts an anabolic effect on bone tissue due to its structural homology to insulin-like growth factor-I (IGF-I), interacting with the IGF-I receptor present on osteoblasts (2). It was shown that lower serum IGF-I concentrations are associated with a higher number of vertebral fractures in postmenopausal women with type 2 diabetes (3, 4). On the other hand insulin increases bone resorption by reducing an expression of osteoprotegerin (OPG) – a decoy receptor for receptor activator of nuclear factor kB ligand (RANKL) and stimulates bone turnover (5-8).
A complex and heterogenous molecular pathophysiology seems to underlie osteoporosis and fracture risk in diabetes-related bone disease. Diabetes mellitus (DM) was found to induce the overexpression of many cytokines and hormones, such as sclerostin, gremlin, angiotensin II (Ang-II), parathyroid hormone (PTH), interleukin-6 (IL-6) and tumor necrosis factors (TNFs) but it also sequesters the over expression of vitamin D and neurotransmitters required for growth of osteoblasts (1). DM is responsible for the upregulation of PPAR-γ, fatty acid binding protein, tumor necrosis factor-α (TNF-α) and for increased availability of mesenchymal stem cells for adipocyte formation at the cost of osteoblast formation (9-12). For this reason DM is considered responsible for the deposition of lipids in the bone marrow, expansion of marrow cavity, diminishing of bone microcirculation, and the reduction of osteoblast number available for bone formation (13-15).
Serum osteocalcin concentration has been reported to be negatively correlated with hemoglobin A1c (HbA1c) level (16). In patients with DM osteocalcin, both in bone and serum, has been found to be incompletely carboxylated, and undercarboxylated osteocalcin has been negatively implicated in energy metabolism and glucose control (17, 18). Higher levels of undercarboxylated osteocalcin were suggested to be linked to increased risk of hip fractures (19).
Recent human cross-sectional studies confirm that bone turnover is attenuated in type 2 diabetes mellitus (T2DM). Sclerostin, an inhibitor of bone formation, was shown to be increased in patients with T2DM, independent of gender and age. Positive correlation was documented between sclerostin level and both duration of T2DM and HbA1c, and negative correlations between sclerostin and bone turnover markers (13).
Decreased bone quality in patients with T2DM is partly combined with advanced glycation end products (AGEs) – highly reactive glucose metabolites, which are implicated in forming additional cross-links between collagen fibres in bone. It results in excessive stiffness and in fragility of bone tissue (20, 21). AGEs accumulate in various tissues including bone, interfere with normal tissue function, as well as increase inflammation and cellular damage. AGEs have been identified as a biomarkers of increased fracture risk. Accumulation of pentosidine, one of the AGEs, in cortical and trabecular bone tissues was reported to exert negative impact on bone strength (22-24), while higher levels of the endogenous secretory receptor for AGEs (esRAGE) – a decoy AGE receptor – have protective effects on fracture risk in diabetes (25).
1. Lecka-Czernik B: Safety of anti-diabetic therapies on bone. Clin Rev Bone Miner Metab 2013; 11: 49-58.
2. Pun KK, Lau P, Ho PW: The characterization, regulation, and function of insulin receptors on osteoblast-like clonal osteosarcoma cell line. J Bone Miner Res 1989; 4: 853-862.
3. Kanazawa I, Yamaguchi T, Sugimoto T: Serum insulin-like growth factor-I is a marker for assessing the severity of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporos Int 2011; 22: 1191-1198.
4. Kanazawa I, Yamaguchi T, Yamamoto M et al.: Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporos Int 2007; 18: 1675-1681.
5. Fulzele K, Riddle RC, Digirolamo DJ et al.: Insulin Receptor Signaling in Osteoblasts Regulates Postnatal Bone Acquisition and Body Composition. Cell 2010; 142: 309-319.
6. Ferron M, Wei J, Yoshizawa T et al.: Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism. Cell 2010; 142: 296-308.
7. Lee NK, Sowa H, Hinoi E et al.: Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130: 456-469.
8. Clemens TL, Karsenty G: The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 2011; 26: 677-680.
9. Masoud G, Ghorbani P, Ardestani MS: Treatment with CL316, 243 Improves Insulin Resistance by Down Regulation of Tumor Necrosis Factor-α (TNF-α) Expression. Insight Biomedical Science 2012; 2: 6-9.
10. Gonzalez Y, Herrera MT, Soldevila G et al.: High glucose concentrations induce TNF-a production through the down-regulation of CD33 in primary human monocytes. BMC Immunology 2012; 13: 19.
11. Yang N, Wang G, Hu C et al.: Tumor necrosis factor α suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res 2013; 28: 559-573.
12. Bojin FM, Gruia AT, Cristea MI et al.: Adipocytes differentiated in vitro from rat mesenchymal stem cells lack essential free fatty acids compared to adult adipocytes. Stem Cells Dev 2012; 21: 507-512.
13. Wongdee K, Charoenphandhu N: Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World J Diabetes 2011; 2: 41-48.
14. Abdulameer SA, Sulaiman SA, Hassali MA et al.: Osteoporosis and type 2 diabetes mellitus: what do we know, and what we can do? Patient Prefer Adherence 2012; 6: 435-448.
15. Sheng HH, Zhang GG, Cheung WH et al.: Elevated adipogenesis of marrow mesenchymal stem cells during early steroid associated osteonecrosis development. J Orthop Surg Res 2007; 2: 15.
16. Kanazawa I, Yamaguchi T, Yamamoto M et al.: Combination of obesity with hyperglycemia is a risk factor for the presence of vertebral fractures in type 2 diabetic men. Calcif Tissue Int 2008; 83(5): 324-331.
17. Ferron M, Wei J, Yoshizawa T et al.: Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 2010; 142(2): 296-308.
18. Rached MT, Kode A, Silva BC et al.: Expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 2010; 120(1): 357-368.
19. Vergnaud P, Garnero P, Meunier PJ et al.: Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab 1997; 82(3): 719-724.
20. Huang S, Kaw M, Harris MT et al.: Decreased osteoclastogenesis and high bone mass in mice with impaired insulin clearance due to liver-specific inactivation to CEACAM1. Bone 2010; 46: 1138-1145.
21. Vashishth D: Collagen glycation and its role in fracture properties of bone. J Musculoskelet Neuronal Interact 2005; 5: 316.
22. Hernandez CJ, Tang SY, Baumbach BM et al.: Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen crosslinks. Bone 2005; 37(6): 825-832.
23. Wang X, Shen X, Li X et al.: Age-related changes in the collagen network and toughness of bone. Bone 2002; 31(1): 1-7.
24. Bipradas R: Biomolecular basis of the role of diabetes mellitus in osteoporosis and bone fractures. World J Diabetes 2013; 4(4): 101-113.
25. Yamamoto M, Yamaguchi T, Yamauchi M et al.: Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes Care 2009; 32(12): 2263-2268.
26. Lecka-Czernik B: Bone as a target of type 2 diabetes treatment. Curr Opin Investig Drugs 2009; 10: 1085-1090.
27. Teitelbaum SL, Ross FP: Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4: 638-649.
28. Yamamoto M, Yamaguchi T, Yamauchi M et al.: Diabetic Patients Have an Increased Risk of Vertebral Fractures Independent of Bone Mineral Density or Diabetic Complications. J Bone Miner Res 2009; 24(4): 702-709.
29. de Liefde II, van der Klift M, de Laet CE et al.: Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int 2005; 16(12): 1713-1720.
30. Oei L, Zillikens MC, Dehghan A et al.: High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam Study. Diabetes Care 2013; 36(6): 1619-1628.
31. Krakauer JC, McKenna MJ, Buderer NF et al.: Bone loss and bone turnover in diabetes. Diabetes 1995; 44: 775-782.
32. Spinasanta S: Analysis of Increased Risk of Fracture in Diabetes. The Endocrine Society’s 97th Annual Meeting & Expo.
33. Khazai NB, Beck GR, Umpierrez GE: Diabetes and Fractures – An overshadowed association. Curr Opin Endocrinol Diabetes Obes 2009 Dec; 16(6): 435-445.
34. Oei L, Rivadeneira F, Zillikens MC, Oei EH: Diabetes, diabetic complications, andfracture risk. Curr Osteoporos Rep 2015; 13: 106-115.
35. Kahn SE, Haffner SM, Heise MA et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-2443.
36. Schwartz AV, Sellmeyer DE, Vittinghoff E et al.: Thiazolidinedione (TZD) Use and Bone Loss in Older Diabetic Adults. J Clin Endocrinol Metab 2006; 91: 3349-3354.
37. 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: 845-851.
38. Dormuth CR, Carney G, Carleton B et al.: Thiazolidinediones and fractures in men and women. Arch Intern Med 2009; 169: 1395-1402.
39. Solomon DH, Cadarette SM, Choudhry NK et al.: A cohort study of thiazolidinediones and fractures in older adults with diabetes. J Clin Endocrinol Metab 2009; 94: 2792-2798.
40. Douglas IJ, Evans SJ, Pocock S et al.: The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med 2009; 6: e1000154.
41. Panday K, Gona A, Humphrey MB: Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis 2014; 6(5): 185-202.
42. Drucker DJ: The role of gut hormones in glucose homeostasis. J Clin Invest 2007; 117: 24-32.
43. 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: 723-729.
44. Xie D, Zhong Q, Ding KH et al.: Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone 2007; 40: 1352-1360.
45. Zhong Q, Itokawa T, Sridhar S et al.: Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab 2007; 292: E543-548.
46. 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: 574-579.
47. 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: 374-377.
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: 2474-2476.
49. Schwartz AV, Sellmeyer DE, Ensrud KE et al.: Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 2001; 86: 32-38.
50. 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: 1334-1342.
51. 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: 134-142.
52. Zhou S, Schuetz JD, Bunting KD et al.: 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: 1028-1034.
53. Jang WG, Kim EJ, Bae IH et al.: Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. Bone 2011; 48: 885-893.
54. Mai QG, Zhang ZM, Xu S et al.: Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem 2011; 112: 2902-2909.
