Skip to main content

Advertisement

SpringerLink
Log in

Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

We aimed to clarify the risks of initiating antidiabetic drugs for fractures using a nationwide health insurance claims database (NDBJ).

Materials and Methods

Patients aged ≥ 65 years initiating antidiabetic drugs at the outpatient department were enrolled after a 180-day period without prescribed antidiabetic drugs and followed with during 2012–2018 using NDBJ. The adjusted hazard risks (HRs) of each antidiabetic drug (thiazolidine, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, glinide, and insulin) for fractures compared with biguanide were obtained adjusting for age, gender, polypharmacy, dementia, and the other antidiabetic drugs.

Results

The DPP-4 inhibitor was the most often prescribed antidiabetic drug followed by biguanide with prescribed proportions of 71.7% and 12.9%. A total of 4,304 hip fractures and 9,388 vertebral fractures were identified among the 966,700 outpatient participants. Compared with biguanide, insulin, alpha-glucosidase inhibitor, and DPP-4 inhibitor were related to increased hip fracture risks. Vertebral fracture risk was higher in outpatients prescribed with insulin, thiazolidine, and DPP-4 inhibitor compared with biguanide. Patients prescribed insulin for hip and vertebral fractures’ adjusted HRs were 2.17 (95% CI 1.77–2.66) and 1.45 (95% CI 1.24–1.70), respectively. Those prescribed DPP-4 inhibitor for hip and vertebral fractures’ adjusted HRs were 1.27 (95% CI 1.15–1.40) and 1.20 (95% CI 1.12–1.28), respectively.

Conclusions

Initiating insulin increased the risk of not only hip fractures but also vertebral fractures. Patients initiating antidiabetic drugs had increased risks of hip and vertebral fractures compared with those initiating biguanide independently for age, gender, polypharmacy, and dementia in the Japanese elderly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. International Diabetes Federation. IDF Diabetes Atlas 10th edition 2021. https://diabetesatlas.org/idfawp/resourcefiles/2021/07/IDF_Atlas_10th_Edition_2021.pdf P35~41. Accessed on 22nd February, 2022

  2. Basu R, Breda E, Oberg AL et al (2003) Mechanisms of the age-associated deterioration in glucose tolerance: Contribution of alterations in insulin secretion, action, and clearance. Diabetes 52:1738–1748

    Article  CAS  Google Scholar 

  3. National Institutes of Biomedical Innovation, Health and Nutrition (2021) The National Health and Nutrition Survey Japan, 2019. P159–160. Daiichi Syuppan. 2021, Tokyo

  4. Amiel SA, Dixon T, Mann R et al (2008) Hypoglycemia in type 2 diabetes. Diabet Med 25:245–254

    Article  CAS  Google Scholar 

  5. Huang ES, Laiteerapong N, Liu JY et al (2014) Rates of complications and mortality in older patients with diabetes mellitus: the diabetes and aging study. JAMA Intern Med 174:251–258

    Article  Google Scholar 

  6. Johnston SS, Conner C, Aagren M et al (2012) Association between hypoglycemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 14:634–643

    Article  CAS  Google Scholar 

  7. Lee AK, Juraschek SP, Windham BG et al (2020) Severe hypoglycemia and risk of falls in type 2 diabetes: The Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 43:2060–2065

    Article  Google Scholar 

  8. Hung YC, Lin CC, Chen HJ et al (2017) Severe hypoglycemia and hip fracture in patients with type 2 diabetes: a nationwide population-based cohort study. Osteoporos Int 28:2053–2060

    Article  CAS  Google Scholar 

  9. Flory J, Lipska K (2019) Metformin in 2019. JAMA 321:1926–1927

    Article  Google Scholar 

  10. Buse JB, Wexler DJ, Tsapas A et al (2020) 2019 Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 43:487–493

    Article  CAS  Google Scholar 

  11. American Diabetes Association (2021) 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care 2 (Suppl 1):S111-S124

  12. Hidayat K, Du X, Wu MJ et al (2019) The use of metformin, insulin, sulfonylureas, and thiazolidinediones and the risk of fracture: Systematic review and meta-analysis of observational studies. Obes Rev 20:1494–1503

    Article  Google Scholar 

  13. Salari-Moghaddam A, Sadeghi O, Keshteli AH et al (2019) Metformin use and risk of fracture: a systematic review and meta-analysis of observational studies. Osteoporos Int 30:1167–1173

    Article  CAS  Google Scholar 

  14. Fukushima M, Suzuki H, Seino Y (2004) Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract 66:S37-43

    Article  CAS  Google Scholar 

  15. The Japan Diabetes Society, the Japan Geriatrics Society (2017) Practice Guideline for the Treatment of Elderly Diabetes in Japan. P61–64. Nankodo, Tokyo

  16. The Japan Diabetes Society (2019) Practice Guideline for the Treatment of Diabetes in Japan. P70. Nankodo, Tokyo

  17. Matsuda S, Fujimori K (2012) The claim database in Japan. APJDM (Asian Pacific journal of disease management. 3: 55–59

  18. Fujimori K (2012) Practical use of E-claim data for regional healthcare planning. Nihon Eiseigaku Zasshi 67:56–61(in Japanese)

  19. Japanese Ministry of Health, Labour and Welfare, Proportion of electronic claims in the Japanese health insurance system, 2016. https://www.mhlw.go.jp/file/06-Seisakujouhou-12400000-Hokenkyoku/0000099002.pdf. Accessed on 14th May, 2022

  20. Nakatoh S, Fujimori K, Ishii S et al (2021) Insufficient increase in bone mineral density testing rates and pharmacotherapy after hip and vertebral fracture: analysis of the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Arch Osteoporos 16:130. https://doi.org/10.1007/s11657-021-00992-9 (PMID: 34510296)

    Article  Google Scholar 

  21. Iki M, Fujimori K, Nakatoh S, et al (2022) Guideline adherence by physicians for management of glucocorticoid-induced osteoporosis in Japan: a nationwide health insurance claims database study.　Osteoporos Int doi: https://doi.org/10.1007/s00198-021-06265-y. Online ahead of print. PMID: 35022812

  22. Japanese Ministry of Health Labour and Welfare. (2020 Guideline for secondary use of the National Database of Health Insurance Claims and Specific Health Check-ups of Japan. October, 2020 (Amended in March, 2022). P33

  23. https://www.mhlw.go.jp/content/12400000/000904655.pdf. Accessed on 11th March, 2022

  24. Morita Y, Murayama H, Odawara M et al (2019) (2019) Treatment patterns of drug-naive patients with type 2 diabetes mellitus: a retrospective cohort study using a Japanese hospital database. Diabetol Metab Syndr 11:90. https://doi.org/10.1186/s13098-019-0486-y.eCollection (PMID: 31695754)

    Article  Google Scholar 

  25. Al-Mashhadi Z, Viggers R, Fuglsang-Nielsen R et al (2020) Glucose-lowering drugs and fracture risk-a systematic review. Curr Osteoporos Rep 18:737–758

    Article  CAS  Google Scholar 

  26. Hippisley-Cox J, Coupland C (2012) Derivation and validation of updated QFracture algorithm to predict risk of osteoporotic fracture in primary care in the United Kingdom: prospective open cohort study. BMJ 22:e3427. https://doi.org/10.1136/bmj.e3427

    Article  Google Scholar 

  27. Zhang YS, Zheng YD, Yuan Y et al (2021) Effects of anti-diabetic drugs on fracture risk: a systematic review and network meta-analysis. Front Endocrinol (Lausanne) 12:2021. https://doi.org/10.3389/fendo.2021.735824.eCollection (PMID: 34721294)

    Article  Google Scholar 

  28. Kalaitzoglou E, Fowlkes JL, Popescu I et al (2019) Diabetes pharmacotherapy and effects on the musculoskeletal system. Diabetes Metab Res Rev 35:e3100. https://doi.org/10.1002/dmrr.3100

    Article  Google Scholar 

  29. American Diabetes Association (2018) 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care 41:S73–S85

    Article  Google Scholar 

  30. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group (2020) KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 98:S1–S115

    Article  Google Scholar 

  31. Kadowaki T, Sarai N, Hirakawa T et al (2018) Persistence of oral antidiabetic treatment for type 2 diabetes characterized by drug class, patient characteristics and severity of renal impairment: A Japanese database analysis. Diabetes Obes Metab 20:2830–2839

    Article  CAS  Google Scholar 

  32. Zhang Y, Chen Q, Liang Y et al (2019) Insulin use and fracture risk in patients with type 2 diabetes: A meta-analysis of 138,690 patients. Exp Ther Med 17:3957–3964

    CAS  Google Scholar 

  33. Kanazawa I, Yamaguchi T, Yamamoto M et al (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  Google Scholar 

  34. Kim JH, Choi HJ, Ku EJ et al (2015) Trabecular bone score as an indicator for skeletal deterioration in diabetes. J Clin Endocrinol Metab 100:475–482

    Article  CAS  Google Scholar 

  35. Koromani F, Oei L, Shevroja E et al (2020) Vertebral fractures in individuals with type 2 diabetes: More than skeletal complications alone. Diabetes Care 43:137–144

    Article  Google Scholar 

  36. Zhang Z, Cao Y, Tao Y et al (2020) Sulfonylurea and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Res Clin Pract 159:107990

    Article  CAS  Google Scholar 

  37. doi: https://doi.org/10.1016/j.diabres.2019.107990.

  38. Tao Y, Meng E, Shi J et al (2021) Sulfonylureas use and fractures risk in elderly patients with type 2 diabetes mellitus: a meta-analysis study. Aging Clin Exp Res 33:2133–2139

    Article  Google Scholar 

  39. Zhu ZN, Jiang YF, Ding T (2014) Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 68:115–123

    Article  CAS  Google Scholar 

  40. Vilaca T, Schini M, Harnan S et al (2020) The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update. Bone 137:115457. https://doi.org/10.1016/j.bone.2020.115457 (Epub 2020 May 29PMID: 32480023)

    Article  Google Scholar 

  41. Ministry of Health, Labour and Welfare. Patient Survey 2017. https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/index.html. Accessed on 1st March, 2022

  42. Cooper C, Atkinson EJ, O’Fallon WM et al (1992) Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989. J Bone Miner Res 7:221–227

    Article  CAS  Google Scholar 

  43. Kanazawa I, Notsu M, Takeno A et al (2019) Overweight and underweight are risk factors for vertebral fractures in patients with type 2 diabetes mellitus. J Bone Miner Metab 37:703–710

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the personnel of the Osteoporosis Foundation to support the present study. Sources of funding for the present article were as follows: a 52nd Taiju Life Social Welfare Foundation Medical Research Grant 2019, a Japan Osteoporosis Foundation Grant for Bone Research 2019, and a 28th Pfizer Health Research Grant 2019. The funding bodies had no role in either designing the study, collecting and analyzing the, or interpreting the findings, writing the manuscript, or choosing the journal to submit the manuscript.

Funding

Taiju Life Social Welfare Foundation,a 52nd Taiju Life Social Welfare Foundation Medical Research Grant 2019,Junko Tamaki,Japan Osteoporosis Foundation,a Japan Osteoporosis Foundation Grant for Bone Research 2019,Junko Tamaki,Pfizer Japan,a 28th Pfizer Health Research Grant 2019,Junko Tamaki

Author information

Authors and Affiliations

  1. Department of Hygiene and Public Health, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan

    Junko Tamaki & Kuniyasu Kamiya

  2. Department of Geriatric Medicine, GraduateSchoolofMedicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8511, Japan

    Sumito Ogawa

  3. Department of Health Administration and Policy, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Kenji Fujimori

  4. Department of Regulatory Science, SchoolofPharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi, Hachiouji, Tokyo, Japan

    Shigeyuki Ishii

  5. Department of Orthopedic Surgery, Asahi General Hospital, 477 TomariShimo-Nikawa-gun, Asahimachi, 939-0798, Japan

    Shinichi Nakatoh

  6. Okimoto Clinic, 185-4 Kubi, Yutaka-machi, Kure, Hiroshima, 734-0304, Japan

    Nobukazu Okimoto

  7. Faculty of Medicine, Kindai University, 377-2 Oono-higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Masayuki Iki

  8. Faculty of Medicine, National Database Japan-Osteoporosis Management (NDBJ-OS) Study Group, KindaiUniversity, 377-2 Oono-higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Junko Tamaki, Sumito Ogawa, Kenji Fujimori, Shigeyuki Ishii, Shinichi Nakatoh, Nobukazu Okimoto & Masayuki Iki

Authors
  1. Junko Tamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumito Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenji Fujimori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shigeyuki Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinichi Nakatoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobukazu Okimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kuniyasu Kamiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masayuki Iki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JT got funding, designed a research question, analyzed the data, and made the original draft of the manuscript. SO conceptualized the study, and reviewed the manuscript. KF conceptualized and supervised the study, made the dataset, and reviewed the manuscript. SI administered the study project, and reviewed the manuscript. SN and NO conceptualized the study and reviewed the manuscript. KK reviewed the manuscript. MI planned the study project, conceptualized and supervised the study, and reviewed the manuscript.

Corresponding author

Correspondence to Junko Tamaki.

Ethics declarations

Conflict of interest

Shigeyuki Ishii has received written manuscripts fees for Asahi Kasei Pharma Ltd. and honorarium from Teijin Pharma Ltd.. Shinichi Nakatoh has received payments for lectures, speakers’ bureau fees from Asahi-Kasei Pharmaceutical Co. Ltd., Amgen K. K. and Astellas Pharma Inc.. Nobukazu Okimoto has received honoraria for lectures from Asahi-Kasei Pharmaceutical Co. Ltd., Amgen Astellas Biopharma K.K., Astellas Pharma Inc., Chugai Pharmaceutical Co., Daiichi-Sankyo Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan, and Teijin Pharma Ltd.. Junko Tamaki, Sumito Ogawa, Kenji Fujimori, Kuniyasu Kamiya and Masayuki Iki declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 89 KB)

Supplementary file2 (PDF 90 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tamaki, J., Ogawa, S., Fujimori, K. et al. Hip and vertebral fracture risk after initiating antidiabetic drugs in Japanese elderly: a nationwide study. J Bone Miner Metab 41, 29–40 (2023). https://doi.org/10.1007/s00774-022-01372-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-022-01372-0

Keywords

Search

Navigation