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Risk of fractures and diabetes medications: a nationwide cohort study

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Abstract

Summary

The effects of diabetes medications on risk of fracture were investigated using the South Korea nationwide claims database. We demonstrated that the use of dipeptidyl peptidase-4 inhibitor could be associated with decreased risk of fracture. Thiazolidinedione use was associated with about 60 % increased risk of fracture in real clinical practice.

Introduction

The effects of diabetes medication on fracture have important clinical health consequences, since most diabetes patients are at high risk of fracture. We aimed to investigate the effect of diabetes medication on fracture risk.

Methods

The nationwide medical claim database in South Korea was investigated. Among 2,886,555 subjects with antidiabetes prescriptions, 207,558 subjects aged 50 years and older, who initiated diabetes medication from 2008 to 2011, were analyzed. The subjects were classified based on diabetes medication classes: non-user (insufficient exposure), metformin (MET), sulfonylurea (SU), alpha-glucosidase inhibitor (AGI), MET + SU, MET + thiazolidinedione (TZD), MET + dipeptidyl peptidase-4 inhibitor (DPP4-I), and SU + TZD.

Results

A total of 5996 fractures were observed. The fracture rate varied significantly across type of diabetes medications, with MET + DPP4-I combination group having the lowest rate and SU + TZD combination group having the highest rate. Compared to non-users, MET + DPP4-I inhibitor combination group had significantly reduced composite fracture risk (hazard ratio (HR) = 0.83, P = 0.025) and significantly reduced vertebral fracture risk (HR = 0.73, P = 0.013) in the unadjusted analysis. Compared to MET + SU users, MET + DPP4-I users showed a trend of lower non-vertebral fracture risk (HR = 0.82, P = 0.086) after adjusting for all confounding variables. Patients using TZD had significantly increased risk of fracture (HR = 1.59, P < 0.001) compared with patients not using TZDs adjusting for all confounding variables.

Conclusions

The results of this nationwide study showed a trend that DPP4 inhibitor might have a protective effect on bone metabolism compared with SU, when added to MET. Clinicians should take these results into consideration when prescribing diabetes medication, especially in elderly patients or those at high risk or fracture.

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References

  1. Zhang L, Choi HJ, Estrada K et al (2014) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet 23:1923–1933

    Article  CAS  PubMed  Google Scholar 

  2. Schwartz AV, Sellmeyer DE, Vittinghoff E et al (2006) Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 91:3349–3354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR (2007) The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305–1310

    Article  CAS  PubMed  Google Scholar 

  4. Yaturu S, Bryant B, Jain SK (2007) Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men. Diabetes Care 30:1574–1576

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz AV, Vittinghoff E, Margolis KL, Scibora LM, Palermo L, Ambrosius WT, Hue TF, Ensrud KE (2013) Intensive glycemic control and thiazolidinedione use: effects on cortical and trabecular bone at the radius and tibia. Calcif Tissue Int 92:477–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kahn SE, Zinman B, Lachin JM et al (2008) Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31:845–851

    Article  CAS  PubMed  Google Scholar 

  7. Cortizo AM, Sedlinsky C, McCarthy AD, Blanco A, Schurman L (2006) Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. Eur J Pharmacol 536:38–46

    Article  CAS  PubMed  Google Scholar 

  8. 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 48:1292–1299

    Article  CAS  PubMed  Google Scholar 

  9. Melton LJ 3rd, Leibson CL, Achenbach SJ, Therneau TM, Khosla S (2008) Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 23:1334–1342

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kahn SE, Haffner SM, Heise MA et al (2006) Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443

    Article  CAS  PubMed  Google Scholar 

  11. 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 28:554–560

    Article  CAS  PubMed  Google Scholar 

  12. 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 34:2474–2476

    Article  PubMed  PubMed Central  Google Scholar 

  13. Driessen JH, van Onzenoort HA, Henry RM, Lalmohamed A, van den Bergh JP, Neef C, Leufkens HG, de Vries F (2014) Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture. Bone 68C:124–130

    Article  Google Scholar 

  14. Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326

    Article  CAS  PubMed  Google Scholar 

  15. Driessen JH, van Onzenoort HA, Starup-Linde J, Henry R, Neef C, van den Bergh J, Vestergaard P, de Vries F, Burden AM (2015) Use of dipeptidyl peptidase 4 inhibitors and fracture risk compared to use of other anti-hyperglycemic drugs. Pharmacoepidemiol Drug Saf 24:1017–1025

    Article  CAS  PubMed  Google Scholar 

  16. Kwon S (2003) Payment system reform for health care providers in Korea. Health Policy Plan 18:84–92

    Article  PubMed  Google Scholar 

  17. Lee YK, Ha YC, Choi HJ, Jang S, Park C, Lim YT, Shin CS (2013) Bisphosphonate use and subsequent hip fracture in South Korea. Osteoporos Int 24:2887–2892

    Article  CAS  PubMed  Google Scholar 

  18. Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK (2010) Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95:592–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yoon HK, Park C, Jang S, Jang S, Lee YK, Ha YC (2011) Incidence and mortality following hip fracture in Korea. J Korean Med Sci 26:1087–1092

    Article  PubMed  PubMed Central  Google Scholar 

  20. Park C, Ha YC, Jang S, Jang S, Yoon HK, Lee YK (2011) The incidence and residual lifetime risk of osteoporosis-related fractures in Korea. J Bone Miner Metab 29:744–751

    Article  PubMed  Google Scholar 

  21. Deyo RA, Cherkin DC, Ciol MA (1992) Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 45:613–619

    Article  CAS  PubMed  Google Scholar 

  22. Clowes JA, Khosla S, Eastell R (2005) Potential role of pancreatic and enteric hormones in regulating bone turnover. J Bone Miner Res 20:1497–1506

    Article  CAS  PubMed  Google Scholar 

  23. Bollag RJ, Zhong Q, Phillips P et al (2000) Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 141:1228–1235

    Article  CAS  PubMed  Google Scholar 

  24. Zhong Q, Itokawa T, Sridhar S et al (2007) Effects of glucose-dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab 292:E543–548

    Article  CAS  PubMed  Google Scholar 

  25. Xie D, Cheng H, Hamrick M et al (2005) Glucose-dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone 37:759–769

    Article  CAS  PubMed  Google Scholar 

  26. Xie D, Zhong Q, Ding KH et al (2007) Glucose-dependent insulinotropic peptide-overexpressing transgenic mice have increased bone mass. Bone 40:1352–1360

    Article  CAS  PubMed  Google Scholar 

  27. Yamada C, Yamada Y, Tsukiyama K, Yamada K, Udagawa N, Takahashi N, Tanaka K, Drucker DJ, Seino Y, Inagaki N (2008) The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149:574–579

    Article  CAS  PubMed  Google Scholar 

  28. Nuche-Berenguer B, Moreno P, Esbrit P, Dapia S, Caeiro JR, Cancelas J, Haro-Mora JJ, Villanueva-Penacarrillo ML (2009) Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states. Calcif Tissue Int 84:453–461

    Article  CAS  PubMed  Google Scholar 

  29. Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG, Holst JJ, Christiansen C (2007) Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women. Bone 40:723–729

    Article  CAS  PubMed  Google Scholar 

  30. Zheng T, Yang L, Liu Y, Liu H, Yu J, Zhang X, Qin S (2015) Plasma DPP4 activities are associated with osteoporosis in postmenopausal women with normal glucose tolerance. J Clin Endocrinol Metab 100:3862–3870

    Article  CAS  PubMed  Google Scholar 

  31. Choi HJ, Park C, Lee YK, Ha YC, Jang S, Shin CS (2015) Risk of fractures in subjects with antihypertensive medications: a nationwide claim study. Int J Cardiol 184:62–67

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Hwa-Young Kim of Korean Society for Bone and Mineral Research for data collection and analysis. This study was a part of the Korean Nationwide-Databased Osteoporosis Study (KNOS) that was performed by the policy and information analysis department of the Health Insurance Review and Assessment Service and Korean Society for Bone and Mineral Research.

Funding

This work was supported by a 2011 grant from the Korea Academy of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea

    H. J. Choi

  2. Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, South Korea

    C. Park

  3. Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea

    Y.-K. Lee

  4. Department of Orthopaedic Surgery, Chung-Ang University Hospital, Seoul, South Korea

    Y.-C. Ha

  5. College of Pharmacy Gachon University, Incheon, South Korea

    S. Jang

  6. Department of Internal Medicine, Seoul National University College of Medicine, 28 Yungun-Dong, Chongno-Gu, Seoul, 110-744, South Korea

    C. S. Shin

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  1. H. J. Choi
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Corresponding author

Correspondence to C. S. Shin.

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The study protocol was approved by the HIRA institutional review boards.

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None.

Written permission has been obtained from all authors.

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ESM 1

Supplemental Figure 1 Fracture Rates by Diabetes Medication Groups (per 10,000 Person-Years). SU, sulfonylurea; MET, metformin; AGI, alpha-glucosidase inhibitor; TZD, thiazolidinedione; DPP4-I, dipeptidyl peptidase-4 inhibitors. (DOCX 82 kb)

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Choi, H.J., Park, C., Lee, YK. et al. Risk of fractures and diabetes medications: a nationwide cohort study. Osteoporos Int 27, 2709–2715 (2016). https://doi.org/10.1007/s00198-016-3595-6

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  • DOI: https://doi.org/10.1007/s00198-016-3595-6

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