Acta Diabetologica

, Volume 55, Issue 10, pp 1043–1050 | Cite as

FRAX tool in type 2 diabetic subjects: the use of HbA1c in estimating fracture risk

  • Alessia Valentini
  • Maria Assunta Cianfarani
  • Livia De Meo
  • Pasquale Morabito
  • Daniele Romanello
  • Umberto Tarantino
  • Massimo Federici
  • Aldo BertoliEmail author
Original Article



Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures, despite having greater bone mineral density (BMD) than non-diabetic subjects. This has led to the hypothesis that the presence of impaired bone quality among diabetics reduces bone strength. The Fracture Risk Assessment Score (FRAX) algorithm, introduced to facilitate the evaluation of fracture risk, underestimates the risk of fracture in diabetic patients. The purpose of this study is to confirm the relationship between the degree of metabolic compensation and the 10-year probability of a major fracture or a hip osteoporotic fracture observed in our previous study and to ascertain whether glycosylated hemoglobin (HbA1c) can improve the predictive value of FRAX in patients with T2DM.


Our data derive from a retrospective clinical study conducted at the “Tor Vergata” Polyclinic in Rome on 6355 subjects over 50 years of age evaluated for osteoporosis. All available clinical records were examined. HbA1c was available for 242 of these subjects and all had had a Dual-energy X-ray Absorption (DXA) scan of the lumbar spine and femoral neck. The risk of fracture was estimated using the Italian version of the FRAX algorithm.


Patients with T2DM had BMD and T-scores higher than those of non-diabetic subjects, while FRAX average values were higher in the non-diabetic group. HbA1c and FRAX are inversely correlated with each other: for each incremental percentage point of HbA1c growth, the FRAX major osteoporotic fracture probability is reduced by 0.915 points and the FRAX hip osteoporotic fracture probability by 1.438 points. The introduction of a correction factor derived from HbA1c, resulted in mean FRAX values of diabetic patients equivalent to those of non-diabetic subjects.


We propose a correction factor derived from HbA1c that could enhance the predictive ability of fracture risk estimated by the FRAX algorithm in subjects with T2DM.


Type 2 diabetes mellitus HbA1c FRAX Osteoporosis BMD T-score Fracture risk Elderly 



Bone mineral density


Dual-energy X-ray absorptiometry


Fracture Risk Assessment Score


Glycosylated hemoglobin


Rheumatoid arthritis


Type 2 diabetes mellitus


Type 1 diabetes mellitus


Author contribution

AB, AV and MAC participated in the study concept and design, selection of subjects and data, analysis and interpretation of data, and manuscript preparation. UT and MF participated in the study concept and design, as well as in the selection of participants. LDM, PM and DR participated in the selection of subjects and data. All authors contributed toward drafting and critically revising the paper and agree to be accountable for all aspects of the work.


The study was in part supported by PRIN 2015.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ethical Committee of the Polyclinic “Tor Vergata” and was carried out according to the last version of Declaration of Helsinki.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Sambrook P, Cooper C (2006) Osteoporosis. Lancet 367:2010–2018CrossRefGoogle Scholar
  2. 2.
    Rachner TD, Khosla S, Hofbauer LC (2011) Osteoporosis: now and the future. Lancet 377:1276–1287CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cummings SR, Bates D, Black DM (2002) Clinical use of bone densitometry: scientific review. JAMA 288:1889–1897CrossRefPubMedGoogle Scholar
  4. 4.
    Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N et al (2011) Interpretation and use of FRAX in clinical practice. Osteoporos Int 22:2395–2411CrossRefPubMedGoogle Scholar
  5. 5.
    Hamann C, Kirschner S, Gunter KP, Hofbauer LC (2012) Bone, sweet bone—osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol 8(5):297–305CrossRefPubMedGoogle Scholar
  6. 6.
    Napoli N, Chandran M, Pierroz DD et al (2017) Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol 13(4):208–219CrossRefPubMedGoogle Scholar
  7. 7.
    Rubin MR (2015) Bone cells and bone turnover in diabetes mellitus. Curr Osteoporos Rep 13:186–191CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Oei L, Zillikens MC, Dehghan A, Buitendijk GHS, Castano-Betancourt MC, Estrada K et al (2013) High bone mineral density and fracture risk in type 2 diabetes as skeletal complication of inadequate glucose control. Diabetes Care 36:1619–1628CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Conte C, Epstein S, Napoli N (2018) Insulin resistance and bone: a biological partnership. Acta Diabetol 55(4):305–314CrossRefPubMedGoogle Scholar
  11. 11.
    Leslie WD, Rubin MR, Schwartz AV, Kanis JA (2012) Type 2 diabetes and bone. J Bone Miner Res 27(11):2231–2237CrossRefPubMedGoogle Scholar
  12. 12.
    Viguet-Carrin S et al (2006) The role of collagen in bone strenght. Osteoporos Int 17(3):319–336CrossRefPubMedGoogle Scholar
  13. 13.
    Melton LJ et al (2008) A bone structural basis for fracture risk in diabetes. J Clin Endocrinol Metab 93(12):4804–4809CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Giangregorio LM, Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E et al (2012) FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res 27(2):301–308CrossRefPubMedGoogle Scholar
  15. 15.
    Leslie W, Hough S (2016) Fracture risk assessment in diabetes. In: Lecka-Czernik B, Fowlkes J (eds) Diabetic bone disease: basic and translational research and clinical applications. Springer International Publishing, Basel, pp 45–69CrossRefGoogle Scholar
  16. 16.
    Schacter GI, Leslie WD (2017) DXA-based measurements in diabetes: can they predict fracture risk? Calcif Tissue Int 100:150–164CrossRefPubMedGoogle Scholar
  17. 17.
    Conway BN, Long DM, Figaro MK, May ME (2016) Glycemic control and fracture risk in elderly patients with diabetes. Diabetes Res Clin Pract 115:47–53CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Li CI, Liu CS, Lin WY 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):1338–1346CrossRefPubMedGoogle Scholar
  19. 19.
    Bertoli A, Valentini A, Cianfarani MA, Gasbarra E, Tarantino U, Federici M (2017) Low FT3: a possible marker of frailty in the elderly. Clin Interv Aging 12:335–341CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
  21. 21.
    ADA (2017) Standards of medical care in diabetes-2017. Diabetes Care 40(Suppl 1):S1–S135Google Scholar
  22. 22.
    Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB et al (2012) Diabetes in older adults. Diabetes Care 35(12):2650–2664CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hendickx G, Boudin E, Hul WV (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11(8):462–474CrossRefGoogle Scholar
  24. 24.
    de Liefde II, van der Klift M, de Laet CEDH, van Daele PLA, Hofman A, Pols HAP (2005) Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int 16:1713–1720CrossRefPubMedGoogle Scholar
  25. 25.
    Schwartz AV (2016) Epidemiology of fractures in type 2 diabetes. Bone 82: 2–8CrossRefPubMedGoogle Scholar
  26. 26.
    Kanis JA, McCloskey EV, Johansson H, Oden A, Strom O, Borgstrom F (2010) Development and use of FRAX in osteoporosis. Osteoporos Int 21(Suppl 2):407–413Google Scholar
  27. 27.
    Kanis JA, on behalf of the World Health Organization Scientific Group (2007) Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UKGoogle Scholar
  28. 28.
    Carnevale V, Morano S, Fontana A, Annese MA, Fallarino M, Filardi T et al (2014) Assessment of fracture risk by the FRAX algorithm in men and women with and without type 2 diabetes mellitus: a cross-sectional study. Diabetes Metab Res Rev 30:313–322CrossRefPubMedGoogle Scholar
  29. 29.
    Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE et al (2011) Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 305(21):2184–2192CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T (2009) Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications. J Bone Miner Res 24(4):702–709CrossRefPubMedGoogle Scholar
  31. 31.
    Napoli N, Schwartz AV, Schafer AL et al (2018) Vertebral fracture risk in diabetic elderly men: the MrOS Study. J Bone Miner Res 33(1):63–69CrossRefPubMedGoogle Scholar
  32. 32.
    Leslie WD, Lix LM, Prior HJ, Derksen S, Metge C, O’Neil J (2007) Biphasic fracture risk in diabetes: a population-based study. Bone 40:1595–1601CrossRefPubMedGoogle Scholar
  33. 33.
    Janghorbani M, Feskanich D, Willet WC, Hu F (2006) Prospective study of diabetes and risk of hip fracture. Diabetes Care 29:1573–1578CrossRefPubMedGoogle Scholar
  34. 34.
    Skyler JS (1996) Diabetic complications. The importance of glucose control. Endocrinol Metab Clin N Am 25(2):243–254CrossRefGoogle Scholar
  35. 35.
    Ivers RQ, Cumming RG, Mitchell P, Peduto AJ, Blue Mountains Eye Study (2001) Diabetes and risk of fracture: the blue mountains eye study. Diabetes Care 24(7):1198–1203CrossRefPubMedGoogle Scholar
  36. 36.
    Majumdar SR, Leslie WD, Lix LM et al (2016) Longer duration of diabetes strongly impacts fracture risk assessment: the Manitoba BMD cohort. J Clin Endocrinol Metab 101(11):4489–4496CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schwartz AV, Vittinghoff E, Sellmeyer DE et al (2008) Diabetes-related complications, glycemic control, and falls in older adults. Diabetes Care 31 (3): 391–396CrossRefPubMedGoogle Scholar
  38. 38.
    Monami M, Cresci B, Colombini A et al (2008) Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care 31(2):199–203CrossRefPubMedGoogle Scholar
  39. 39.
    Schwartz AV (2017) Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia 60(7):1170–1179CrossRefPubMedGoogle Scholar
  40. 40.
    Gilbert MP, Pratley RE (2015) The impact of diabetes and diabetes medications on bone health. Endocr Rev 36(2):194–213CrossRefPubMedGoogle Scholar
  41. 41.
    Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J (2012) Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 14(7):634–643CrossRefPubMedGoogle Scholar
  42. 42.
    Zhao Y, Kachroo S, Kawabata H et al (2016) Association between hypoglycemia and fall-related fractures and health care utilization in older veterans with type 2 diabetes. Endocr Pract 22(2):196–204CrossRefPubMedGoogle Scholar
  43. 43.
    Goh SY, Cooper ME (2008) The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab 93:1143–1152CrossRefPubMedGoogle Scholar
  44. 44.
    Yamamoto M, Sugimoto T (2016) Advanced glycation end products, diabetes, and bone strength. Curr Osteoporos Rep 14:320–326CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ahmed N (2005) Advanced glycation end products-role in pathology of diabetic complications. Diabetes Res Clin Pract 67:3–21CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Alessia Valentini
    • 1
  • Maria Assunta Cianfarani
    • 1
  • Livia De Meo
    • 1
  • Pasquale Morabito
    • 1
  • Daniele Romanello
    • 1
  • Umberto Tarantino
    • 2
  • Massimo Federici
    • 1
  • Aldo Bertoli
    • 1
    Email author
  1. 1.Department of Systems’ MedicineUniversity of Roma “Tor Vergata”RomeItaly
  2. 2.Department of Orthopaedics and TraumatologyUniversity of Roma “Tor Vergata”RomeItaly

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