Endocrinol Metab.  2022 Feb;37(1):148-158. 10.3803/EnM.2021.1315.

Hip Fracture Risk According to Diabetic Kidney Disease Phenotype in a Korean Population

• Lee SE
• Yoo J
• Kim KA
• Han K
• Choi HS

• KMID: 2527145
• DOI: http://doi.org/10.3803/EnM.2021.1315

Abstract

Background
Diabetic kidney disease (DKD) is associated with an elevated risk of fractures. However, little is known about the association between proteinuric or non-proteinuric DKD and the risk of hip fracture. Thus, we investigated the incidence of hip fractures among Korean adults with type 2 diabetes mellitus (T2DM) stratified by DKD phenotype.
Methods
In this retrospective cohort study using the Korean National Health Insurance Service database, patients with T2DM who received at least one general health checkup between 2009 and 2012 were followed until the date of hip fracture, death, or December 31, 2018. We classified the DKD phenotype by proteinuria and estimated glomerular filtration rate (eGFR), as follows: no DKD (PU⁻GFR⁻), proteinuric DKD with normal eGFR (PU⁺GFR⁻), non-proteinuric DKD with reduced eGFR (PU⁻GFR⁺), and proteinuric DKD with reduced eGFR (PU⁺GFR⁺)
Results
The cumulative incidence of hip fractures was highest in the PU⁺GFR⁺ group, followed by the PU⁻GFR⁺ group and the PU⁺GFR⁻ group. After adjustment for confounding factors, the hazard ratio (HR) for hip fracture was still highest in the PU⁺GFR⁺ group. However, the PU⁺GFR⁻ group had a higher HR for hip fracture than the PU⁻GFR⁺ group (PU⁺GFR⁺ : HR, 1.69; 95% confidence interval [CI], 1.57 to 1.81; PU⁺GFR⁻ : HR, 1.37; 95% CI, 1.30 to 1.46; PU⁻GFR⁺ : HR, 1.20; 95% CI, 1.16 to 1.24 using the PU⁻GFR⁻ group as the reference category).
Conclusion
The present study demonstrated that DKD was significantly associated with a higher risk of hip fracture, with proteinuria as a major determinant.

Keyword

Diabetic nephropathies; Proteinuria; Azotemia; Hip fractures; Diabetes mellitus

Figure

• 

  Fig. 1 Flow chart of the study population. ESRD, end-stage renal disease; PU−GFR−, no diabetic kidney disease (DKD); PU+GFR−, proteinuric DKD with normal estimated glomerular filtration rate (eGFR); PU−GFR+, non-proteinuric DKD with reduced eGFR; PU+GFR+, proteinuric DKD with reduced eGFR.

• 

  Fig. 2 Cumulative incidence plot of hip fractures according to diabetic kidney disease (DKD) phenotype. PU−GFR−, no DKD; PU+GFR−, proteinuric DKD with normal estimated glomerular filtration rate (eGFR); PU−GFR+, non-proteinuric DKD with reduced eGFR; PU+GFR+, proteinuric DKD with reduced eGFR.

• 

  Fig. 3 Subgroup analyses according to age group, sex, and duration of diabetes. The analyses were adjusted with following covariates: age, sex, smoking, alcohol, exercise, income, hypertension, dyslipidemia, body mass index, stroke, proliferative diabetic retinopathy, insulin use, sulfonylurea use, thiazolidinedione use, renin-angiotensin system inhibitor use, and duration of diabetes (≥5 or <5 years). IR, incidence rate; PYs, person-years; HR, hazard ratio; CI, confidence interval; PU−GFR−, no diabetic kidney disease (DKD); PU+GFR−, proteinuric DKD with normal estimated glomerular filtration rate (eGFR); PU−GFR+, non-proteinuric DKD with reduced eGFR; PU+GFR+, proteinuric DKD with reduced eGFR.

Reference

1. Hygum K, Starup-Linde J, Langdahl BL. Diabetes and bone. Osteoporos Sarcopenia. 2019; 5:29–37.

2. Hong S, Han K. The incidence of hip fracture and mortality rate after hip fracture in Korea: a nationwide population-based cohort study. Osteoporos Sarcopenia. 2019; 5:38–43.

3. Gulcelik NE, Bayraktar M, Caglar O, Alpaslan M, Karakaya J. Mortality after hip fracture in diabetic patients. Exp Clin Endocrinol Diabetes. 2011; 119:414–8.

4. Schwartz AV, Hillier TA, Sellmeyer DE, Resnick HE, Gregg E, Ensrud KE, et al. Older women with diabetes have a higher risk of falls: a prospective study. Diabetes Care. 2002; 25:1749–54.

5. Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J. Association between hypoglycaemic events and fall-related fractures in medicare-covered patients with type 2 diabetes. Diabetes Obes Metab. 2012; 14:634–43.

6. Murray CE, Coleman CM. Impact of diabetes mellitus on bone health. Int J Mol Sci. 2019; 20:4873.

7. Persson F, Rossing P. Diagnosis of diabetic kidney disease: state of the art and future perspective. Kidney Int Suppl (2011). 2018; 8:2–7.

8. Yamanouchi M, Furuichi K, Hoshino J, Ubara Y, Wada T. Nonproteinuric diabetic kidney disease. Clin Exp Nephrol. 2020; 24:573–81.

9. 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; 84:45–55.

10. Lee YH, Han K, Ko SH, Ko KS, Lee KU; Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Data analytic process of a nationwide population-based study using national health information database established by National Health Insurance Service. Diabetes Metab J. 2016; 40:79–82.

11. Song SO, Jung CH, Song YD, Park CY, Kwon HS, Cha BS, et al. Background and data configuration process of a nationwide population-based study using the Korean National Health Insurance System. Diabetes Metab J. 2014; 38:395–403.

12. Korean National Health Insurance Service. Health insurance guide. Wonju: NHIS;2022.

13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461–70.

14. Kim SH, Yi SW, Yi JJ, Kim YM, Won YJ. Chronic kidney disease increases the risk of hip fracture: a prospective cohort study in Korean adults. J Bone Miner Res. 2020; 35:1313–21.

15. 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; 18:427–44.

16. Jia P, Bao L, Chen H, Yuan J, Liu W, Feng F, et al. Risk of low-energy fracture in type 2 diabetes patients: a meta-analysis of observational studies. Osteoporos Int. 2017; 28:3113–21.

17. Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, et al. Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab. 2006; 91:3404–10.

18. Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007; 166:495–505.

19. Wang H, Ba Y, Xing Q, Du JL. Diabetes mellitus and the risk of fractures at specific sites: a meta-analysis. BMJ Open. 2019; 9:e024067.

20. Dytfeld J, Michalak M. Type 2 diabetes and risk of low-energy fractures in postmenopausal women: meta-analysis of observational studies. Aging Clin Exp Res. 2017; 29:301–9.

21. Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, et al. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010; 95:5045–55.

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

23. Farr JN, Drake MT, Amin S, Melton LJ 3rd, McCready LK, Khosla S. In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. J Bone Miner Res. 2014; 29:787–95.

24. Moreira CA, Dempster DW. Bone histomorphometry in diabetes mellitus. Osteoporos Int. 2015; 26:2559–60.

25. Schwartz AV, Vittinghoff E, Sellmeyer DE, Feingold KR, de Rekeneire N, Strotmeyer ES, et al. Diabetes-related complications, glycemic control, and falls in older adults. Diabetes Care. 2008; 31:391–6.

26. Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013; 24:302–8.

27. Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017; 12:2032–45.

28. Vistisen D, Andersen GS, Hulman A, Persson F, Rossing P, Jorgensen ME. Progressive decline in estimated glomerular filtration rate in patients with diabetes after moderate loss in kidney function-even without albuminuria. Diabetes Care. 2019; 42:1886–94.

29. Yamanouchi M, Furuichi K, Hoshino J, Toyama T, Hara A, Shimizu M, et al. Nonproteinuric versus proteinuric phenotypes in diabetic kidney disease: a propensity score-matched analysis of a nationwide, biopsy-based cohort study. Diabetes Care. 2019; 42:891–902.

30. Buyadaa O, Magliano DJ, Salim A, Koye DN, Shaw JE. Risk of rapid kidney function decline, all-cause mortality, and major cardiovascular events in nonalbuminuric chronic kidney disease in type 2 diabetes. Diabetes Care. 2020; 43:122–9.

31. Penno G, Solini A, Zoppini G, Orsi E, Zerbini G, Trevisan R, et al. Rate and determinants of association between advanced retinopathy and chronic kidney disease in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care. 2012; 35:2317–23.

32. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020; 383:2219–29.

33. Kim CS, Bae EH, Ma SK, Han SH, Lee KB, Lee J, et al. Chronic kidney disease-mineral bone disorder in korean patients: a report from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). J Korean Med Sci. 2017; 32:240–8.

34. Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg. 2010; 126:2234–42.