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One-Year Mean A1c of > 7% is Associated with Poor Bone Microarchitecture and Strength in Men with Type 2 Diabetes Mellitus

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Abstract

Introduction

Type 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM.

Methods

This was a secondary analysis of baseline data from 169 male participants, aged 35–65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography.

Results

At the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively).

Conclusion

Poor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality.

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References

  1. Saeedi P et al (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843

    PubMed  Google Scholar 

  2. Hanley DA et al (2003) Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian multicentre osteoporosis study. J Bone Miner Res 18(4):784–790

    CAS  PubMed  Google Scholar 

  3. Melton LJ 3rd et al (2008) A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab 93(12):4804–4809

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Strotmeyer ES et al (2004) Diabetes is associated independently of body composition with BMD and bone volume in older white and black men and women: the health, aging, and body composition study. J Bone Miner Res 19(7):1084–1091

    PubMed  Google Scholar 

  5. Moayeri A et al (2017) Fracture risk in patients with type 2 diabetes mellitus and possible risk factors: a systematic review and meta-analysis. Ther Clin Risk Manag 13:455–468

    PubMed  PubMed Central  Google Scholar 

  6. Wallander M et al (2017) Type 2 diabetes and risk of hip fractures and non-skeletal fall injuries in the elderly: a study from the fractures and fall injuries in the elderly cohort (FRAILCO). J Bone Miner Res 32(3):449–460

    CAS  PubMed  Google Scholar 

  7. Janghorbani M et al (2006) Prospective study of diabetes and risk of hip fracture: the nurses’ health study. Diabetes Care 29(7):1573–1578

    PubMed  Google Scholar 

  8. Forsén L et al (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag health survey. Diabetologia 42(8):920–925

    PubMed  Google Scholar 

  9. 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(4):427–444

    CAS  PubMed  Google Scholar 

  10. Magaziner J et al (1989) Survival experience of aged hip fracture patients. Am J Public Health 79(3):274–278

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Cooper C et al (1993) Population-based study of survival after osteoporotic fractures. Am J Epidemiol 137(9):1001–1005

    CAS  PubMed  Google Scholar 

  12. Colleluori G et al (2017) Hypogonadal men with type 2 diabetes mellitus have smaller bone size and lower bone turnover. Bone 99:14–19

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Napoli N et al (2017) Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13(4):208–219

    CAS  PubMed  Google Scholar 

  14. Farr JN, Khosla S (2016) Determinants of bone strength and quality in diabetes mellitus in humans. Bone 82:28–34

    CAS  PubMed  Google Scholar 

  15. Compston J (2018) Type 2 diabetes mellitus and bone. J Intern Med 283(2):140–153

    CAS  PubMed  Google Scholar 

  16. Gerdhem P et al (2005) Increased bone density and decreased bone turnover, but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus. Osteoporos Int 16(12):1506–1512

    CAS  PubMed  Google Scholar 

  17. Adami S (2009) Bone health in diabetes: considerations for clinical management. Curr Med Res Opin 25(5):1057–1072

    PubMed  Google Scholar 

  18. Burghardt AJ et al (2010) High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95(11):5045–5055

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Farr JN et al (2014) In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res 29(4):787–795

    PubMed  Google Scholar 

  20. Bala Y et al (2015) Trabecular and cortical microstructure and fragility of the distal radius in women. J Bone Miner Res 30(4):621–629

    PubMed  Google Scholar 

  21. Samelson EJ et al (2018) Diabetes and deficits in cortical bone density, microarchitecture, and bone size: Framingham HR-pQCT study. J Bone Miner Res 33(1):54–62

    PubMed  Google Scholar 

  22. Karim L, Vashishth D (2012) Heterogeneous glycation of cancellous bone and its association with bone quality and fragility. PLoS ONE 7(4):e35047

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Vashishth D et al (2001) Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28(2):195–201

    CAS  PubMed  Google Scholar 

  24. Hernandez CJ et al (2005) Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links. Bone 37(6):825–832

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sanches CP, Vianna AGD, Barreto FC (2017) The impact of type 2 diabetes on bone metabolism. Diabetol Metab Syndr 9:85

    PubMed  PubMed Central  Google Scholar 

  26. Purnamasari D et al (2017) Low bone turnover in premenopausal women with type 2 diabetes mellitus as an early process of diabetes-associated bone alterations: a cross-sectional study. BMC Endocr Disord 17(1):72

    PubMed  PubMed Central  Google Scholar 

  27. Rubin MR, Patsch JM (2016) Assessment of bone turnover and bone quality in type 2 diabetic bone disease: current concepts and future directions. Bone Res 4(1):16001

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Manavalan JS et al (2012) Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab 97(9):3240–3250

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Oei L et al (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(6):1619–1628

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Li CI et al (2015) 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 30(7):1338–1346

    PubMed  Google Scholar 

  31. Schneider ALC et al (2013) Diabetes and risk of fracture-related hospitalization. Atheroscler Risk Communities Study 36(5):1153–1158

    CAS  Google Scholar 

  32. Joad SS et al (2021) Hemoglobin A1c of 7% is the threshold for bone impairment in men with type 2 diabetes mellitus. J Endocr Soc 5(Supplement_1):A276–A276

    PubMed Central  Google Scholar 

  33. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352(9131):837–53

    Google Scholar 

  34. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352(9131):854–65

    Google Scholar 

  35. Association AD (2021) 6 Glycemic targets: standards of medical care in diabetes—2021. Diabetes Care 44(1):73–84

    Google Scholar 

  36. Colleluori G et al (2020) Aromatase inhibitors plus weight loss improves the hormonal profile of obese hypogonadal men without causing major side effects. Front Endocrinol (Lausanne) 11:277

    Google Scholar 

  37. Vigevano F et al (2021) In men with obesity, T2DM is associated with poor trabecular microarchitecture and bone strength and low bone turnover. J Clin Endocrinol Metab 106(5):1362–1376

    PubMed  PubMed Central  Google Scholar 

  38. Colleluori G et al (2019) MON-094 aromatase inhibitors and weight loss in severely obese male veterans with hypogonadism: a randomized clinical trial. J Endocr Soc. https://doi.org/10.1210/js.2019-MON-094

    Article  PubMed Central  Google Scholar 

  39. Russo V et al (2021) Testosterone therapy and bone quality in men with diabetes and hypogonadism: study design and protocol. Contemp Clin Trials Commun 21:100723

    PubMed  PubMed Central  Google Scholar 

  40. Mohamed O et al (2010) The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism. Int J Impot Res 22(1):20–24

    CAS  PubMed  Google Scholar 

  41. Quattrocchi E, Goldberg T, Marzella N (2020) Management of type 2 diabetes: consensus of diabetes organizations. Drugs Context 9:212607

    PubMed  PubMed Central  Google Scholar 

  42. Aguirre LE et al (2015) High aromatase activity in hypogonadal men is associated with higher spine bone mineral density, increased truncal fat and reduced lean mass. Eur J Endocrinol 173(2):167–174

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Silva BC et al (2014) Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res 29(3):518–530

    PubMed  Google Scholar 

  44. Vilayphiou N et al (2011) Finite element analysis performed on radius and tibia HR-pQCT images and fragility fractures at all sites in men. J Bone Miner Res 26(5):965–973

    PubMed  Google Scholar 

  45. Pistoia W et al (2002) Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone 30(6):842–848

    CAS  PubMed  Google Scholar 

  46. Falchetti A, Masi L, Brandia ML (2007) Thiazolidinediones and bone. Clin Cases Miner Bone Metab 4(2):103–107

    PubMed  PubMed Central  Google Scholar 

  47. Bhasin S et al (2018) Testosterone therapy in men with hypogonadism: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab 103(5):1715–1744

    PubMed  Google Scholar 

  48. Das SK, Elbein SC (2006) The genetic basis of type 2 diabetes. Cellscience 2(4):100–131

    PubMed  PubMed Central  Google Scholar 

  49. Gastaldelli A et al (2007) Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133(2):496–506

    CAS  PubMed  Google Scholar 

  50. Basat O et al (2006) Visceral adipose tissue as an indicator of insulin resistance in nonobese patients with new onset type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 114(2):58–62

    CAS  PubMed  Google Scholar 

  51. Javeed N, Matveyenko AV (2018) Circadian etiology of type 2 diabetes mellitus. Physiology (Bethesda) 33(2):138–150

    CAS  Google Scholar 

  52. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98

    PubMed  Google Scholar 

  53. Ding EL et al (2006) Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295(11):1288–1299

    CAS  PubMed  Google Scholar 

  54. van de Peppel J, van Leeuwen JPTM (2014) Vitamin D and gene networks in human osteoblasts. Front Physiol. https://doi.org/10.3389/fphys.2014.00137

    Article  PubMed  PubMed Central  Google Scholar 

  55. Viereck V et al (2002) Differential regulation of Cbfa1/Runx2 and osteocalcin gene expression by vitamin-D3, dexamethasone, and local growth factors in primary human osteoblasts. J Cell Biochem 86(2):348–356

    CAS  PubMed  Google Scholar 

  56. Jesudason D et al (2002) Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency. Bone 31(5):626–630

    CAS  PubMed  Google Scholar 

  57. Nilsson AG et al (2017) Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res 32(5):1062–1071

    PubMed  Google Scholar 

  58. Hunt HB et al (2019) Altered tissue composition, microarchitecture, and mechanical performance in cancellous bone from men with type 2 diabetes mellitus. J Bone Miner Res 34(7):1191–1206

    CAS  PubMed  Google Scholar 

  59. de Waard EAC et al (2017) The association between insulin use and volumetric bone mineral density, bone micro-architecture and bone strength of the distal radius in patients with type 2 diabetes—the Maastricht study. Bone 101:156–161

    PubMed  Google Scholar 

  60. Mittra E et al (2008) Evaluation of trabecular mechanical and microstructural properties in human calcaneal bone of advanced age using mechanical testing, μCT, and DXA. J Biomech 41(2):368–375

    PubMed  Google Scholar 

  61. Patton DM et al (2019) The relationship between whole bone stiffness and strength is age and sex dependent. J Biomech 83:125–133

    PubMed  Google Scholar 

  62. Conway BN et al (2016) Glycemic control and fracture risk in elderly patients with diabetes. Diabetes Res Clin Pract 115:47–53

    PubMed  PubMed Central  Google Scholar 

  63. Puar TH et al (2012) Association between glycemic control and hip fracture. J Am Geriatr Soc 60(8):1493–1497

    PubMed  Google Scholar 

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Acknowledgements

This work was conducted using the facilities at the Michael E. DeBakey VA Medical Center, Houston, TX, USA and the Center for Translational Research in Inflammatory Diseases at the Michael E. DeBakey VA Medical Center, Houston, TX, Alkek Foundation. Additional support was provided by staff at Baylor College of Medicine.

Funding

This work was supported by the National Institutes of Health (Grant No. 5R01HD093047-02) and the VA Merit Review (1I01CX001665-01A2).

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Elliot Ballato, F. N. U. Deepika, Vittoria Russo, Alcibiades Fleires-Gutiérrez, Georgia Colleluori, Virginia Fuenmayor, Rui Chen, Dennis T. Villareal & Reina Armamento-Villareal

  2. Center for Translational Research on Inflammatory Disease, Michael E DeBakey VA Medical Center, Houston, TX, USA

    Elliot Ballato, F. N. U. Deepika, Alcibiades Fleires-Gutiérrez, Georgia Colleluori, Virginia Fuenmayor, Rui Chen, Dennis T. Villareal & Reina Armamento-Villareal

  3. Biomedical Research Institute of New Mexico, Albuquerque, NM, USA

    Clifford Qualls

  4. New Mexico VA Health Care System, Albuquerque, NM, USA

    Clifford Qualls

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  1. Elliot Ballato
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  2. F. N. U. Deepika
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Correspondence to Reina Armamento-Villareal.

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Elliot Ballato, F. N. U. Deepika, Vittoria Russo, Alcibiades Leonardo Fleires Gutierrez, Georgia Colleluori, Virginia Fuenmayor, Rui Chen, Dennis T. Villareal, Clifford Qualls, and Reina Armamento-Villareal of this work have no conflicts of interest to declare.

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Ballato, E., Deepika, F.N.U., Russo, V. et al. One-Year Mean A1c of > 7% is Associated with Poor Bone Microarchitecture and Strength in Men with Type 2 Diabetes Mellitus. Calcif Tissue Int 111, 267–278 (2022). https://doi.org/10.1007/s00223-022-00993-x

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