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Average daily glucocorticoid dose, number of prescription days, and cumulative dose in the initial 90 days of glucocorticoid therapy are associated with subsequent hip and clinical vertebral fracture risk: a retrospective cohort study using a nationwide health insurance claims database in Japan

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Abstract

Purpose

Fracture risk assessment is recommended at three months after glucocorticoid (GC) therapy initiation. This study aimed to assess whether GC exposure in the initial 90 days of GC therapy is associated with subsequent hip and clinical vertebral fracture risk using the nationwide health insurance claims database of Japan (NDBJ).

Methods

Patients aged \(\ge\) 50 years who were prescribed GC (≥ 70 mg prednisolone or equivalent; PSL) in the initial 90 days of GC therapy and were followed for hip and clinical vertebral fracture incidences for the subsequent 1080 days were selected from NDBJ. Associations of GC exposure with hip or clinical vertebral fracture risk were evaluated by Cox regression analysis adjusted for potential confounders.

Results

We selected 316,396 women and 299,871 men for the GC-exposed group and 43,164 women and 33,702 men for the reference group. Higher GC doses and longer prescription days in the initial 90 days of GC therapy were significantly and dose-dependently associated with increased fracture risk relative to the reference group. Patients receiving GC \(\ge\) 5 mg PSL/day had a significantly increased fracture risk in the stratum of 30–59 days of GC prescription. In addition, female patients who received GC (≥ 1 and < 2.5 mg PSL/day) for 90 days in the initial 90 days of GC therapy had a significantly increased fracture risk.

Conclusions

GC exposure in the initial 90 days of GC therapy was dose-dependently associated with hip and clinical vertebral fracture risk. GC may increase fracture risk with lower doses for shorter durations than previously reported.

Summary

Fracture risk assessment three months after glucocorticoid (GC) therapy initiation is recommended. We found that GC exposure in the initial 90 days of GC therapy at lower daily doses for shorter durations than previously reported were significantly and dose-dependently associated with fracture risk using a nationwide health insurance claims database.

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Data availability

Data cannot be shared with researchers who are not approved to access them by the Ministry of Health, Labour and Welfare of Japan.

Code availability

Codes for data analysis will be made available on request.

References

  1. LoCascio V, Bonucci E, Imbimbo B, Ballanti P, Adami S, Milani S, Tartarotti D, DellaRocca C (1990) Bone loss in response to long-term glucocorticoid therapy. Bone Miner 8(1):39–51. https://doi.org/10.1016/0169-6009(91)90139-q

    Article  CAS  PubMed  Google Scholar 

  2. Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van’t Hof MA, Lemmens JA, (1993) Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. A randomized, controlled study. Ann Int Med 119(10):963–968. https://doi.org/10.7326/0003-4819-119-10-199311150-00001

    Article  CAS  PubMed  Google Scholar 

  3. Steinbuch M, Youket TE, Cohen S (2004) Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int 15(4):323–328. https://doi.org/10.1007/s00198-003-1548-3

    Article  CAS  PubMed  Google Scholar 

  4. Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton IL, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA, McCloskey EV, Mellstrom D (2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 19(6):893–899. https://doi.org/10.1359/jbmr.040134

    Article  PubMed  Google Scholar 

  5. van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13(10):777–787. https://doi.org/10.1007/s001980200108

    Article  PubMed  Google Scholar 

  6. Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D (2000) Risk of mortality following clinical fractures. Osteoporos Int 11(7):556–561. https://doi.org/10.1007/s001980070075

    Article  CAS  PubMed  Google Scholar 

  7. Peeters CM, Visser E, Van de Ree CL, Gosens T, Den Oudsten BL, De Vries J (2016) Quality of life after hip fracture in the elderly: A systematic literature review. Injury 47(7):1369–1382. https://doi.org/10.1016/j.injury.2016.04.018

    Article  PubMed  Google Scholar 

  8. Buckley L, Humphrey MB (2018) Glucocorticoid-Induced Osteoporosis. N Engl J Med 379(26):2547–2556. https://doi.org/10.1056/NEJMcp1800214

    Article  PubMed  Google Scholar 

  9. Chotiyarnwong P, McCloskey EV (2020) Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol 16(8):437–447. https://doi.org/10.1038/s41574-020-0341-0

    Article  PubMed  Google Scholar 

  10. Lee TH, Song YJ, Kim H, Sung YK, Cho SK (2020) Intervention Thresholds for Treatment in Patients with Glucocorticoid-Induced Osteoporosis: Systematic Review of Guidelines. J Bone Metab 27(4):247–259. https://doi.org/10.11005/jbm.2020.27.4.247

    Article  PubMed  PubMed Central  Google Scholar 

  11. Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, Humphrey MB, Lane NE, Magrey M, Miller M, Morrison L, Rao M, Robinson AB, Saha S, Wolver S, Bannuru RR, Vaysbrot E, Osani M, Turgunbaev M, Miller AS, McAlindon T (2017) 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol 69(8):1521–1537. https://doi.org/10.1002/art.40137

    Article  PubMed  Google Scholar 

  12. Suzuki Y, Nawata H, Soen S, Fujiwara S, Nakayama H, Tanaka I, Ozono K, Sagawa A, Takayanagi R, Tanaka H, Miki T, Masunari N, Tanaka Y (2014) Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update. J Bone Miner Metab 32(4):337–350. https://doi.org/10.1007/s00774-014-0586-6

    Article  PubMed  Google Scholar 

  13. Compston J, Cooper A, Cooper C, Gittoes N, Gregson C, Harvey N, Hope S, Kanis JA, McCloskey EV, Poole KES, Reid DM, Selby P, Thompson F, Thurston A, Vine N (2017) UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 12(1):43. https://doi.org/10.1007/s11657-017-0324-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoes JN, Jacobs JW, Boers M, Boumpas D, Buttgereit F, Caeyers N, Choy EH, Cutolo M, Da Silva JA, Esselens G, Guillevin L, Hafstrom I, Kirwan JR, Rovensky J, Russell A, Saag KG, Svensson B, Westhovens R, Zeidler H, Bijlsma JW (2007) EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 66(12):1560–1567. https://doi.org/10.1136/ard.2007.072157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgström F, Cooper C, Diez Perez A, Eastell R, Hofbauer LC, Kanis JA, Langdahl BL, Lesnyak O, Lorenc R, McCloskey E, Messina OD, Napoli N, Obermayer-Pietsch B, Ralston SH, Sambrook PN, Silverman S, Sosa M, Stepan J, Suppan G, Wahl DA, Compston JE (2012) A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 23(9):2257–2276. https://doi.org/10.1007/s00198-012-1958-1

    Article  CAS  PubMed  Google Scholar 

  16. Amiche MA, Abtahi S, Driessen JHM, Vestergaard P, de Vries F, Cadarette SM, Burden AM (2018) Impact of cumulative exposure to high-dose oral glucocorticoids on fracture risk in Denmark: a population-based case-control study. Arch Osteoporos 13(1):30. https://doi.org/10.1007/s11657-018-0424-x

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bours S, de Vries F, van den Bergh JPW, Lalmohamed A, van Staa TP, Leufkens HGM, Geusens PPP, Drent M, Harvey NC (2016) Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort. Osteoporos Int 27(4):1603–1610. https://doi.org/10.1007/s00198-015-3426-1

    Article  CAS  PubMed  Google Scholar 

  18. Kim D, Cho SK, Park B, Jang EJ, Bae SC, Sung YK (2018) Glucocorticoids Are Associated with an Increased Risk for Vertebral Fracture in Patients with Rheumatoid Arthritis. J Rheumatol 45(5):612–620. https://doi.org/10.3899/jrheum.170054

    Article  CAS  PubMed  Google Scholar 

  19. Lee E, Lee MJ, Park B, Park I (2020) Risk of fracture according to glucocorticoid use after renal biopsy: a nationwide population-based study. Sci Rep 10(1):13846. https://doi.org/10.1038/s41598-020-70935-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robinson DE, van Staa TP, Dennison EM, Cooper C, Dixon WG (2018) The limitations of using simple definitions of glucocorticoid exposure to predict fracture risk: A cohort study. Bone 117:83–90. https://doi.org/10.1016/j.bone.2018.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. van Staa TP (2006) The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 79(3):129–137. https://doi.org/10.1007/s00223-006-0019-1

    Article  CAS  PubMed  Google Scholar 

  22. van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HG (2001) Public health impact of adverse bone effects of oral corticosteroids. Br J Clin Pharmacol 51(6):601–607. https://doi.org/10.1046/j.0306-5251.2001.1385.x

    Article  PubMed  PubMed Central  Google Scholar 

  23. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15(6):993–1000. https://doi.org/10.1359/jbmr.2000.15.6.993

    Article  PubMed  Google Scholar 

  24. van Staa TPLH, Abenhaim L, Zhang B, Cooper C (2000) Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology 39:1383–1389

    Article  PubMed  Google Scholar 

  25. Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257(4):374–384. https://doi.org/10.1111/j.1365-2796.2005.01467.x

    Article  CAS  PubMed  Google Scholar 

  26. Balasubramanian A, Wade SW, Adler RA, Lin CJF, Maricic M, O’Malley CD, Saag K, Curtis JR (2016) Glucocorticoid exposure and fracture risk in patients with new-onset rheumatoid arthritis. Osteoporos Int 27(11):3239–3249. https://doi.org/10.1007/s00198-016-3646-z

    Article  CAS  PubMed  Google Scholar 

  27. Ozen G, Pedro S, Wolfe F, Michaud K (2019) Medications associated with fracture risk in patients with rheumatoid arthritis. Ann Rheum Dis 78(8):1041–1047. https://doi.org/10.1136/annrheumdis-2019-215328

    Article  CAS  PubMed  Google Scholar 

  28. Koh JW, Kim J, Cho H, Ha YC, Kim TY, Lee YK, Kim HY, Jang S (2020) Effects of Systemic Glucocorticoid Use on Fracture Risk: A Population-Based Study. Endocrinol Metab 35(3):562–570. https://doi.org/10.3803/EnM.2020.659

    Article  CAS  Google Scholar 

  29. Matsuda S, Fujimori K (2012) The claim database in Japan. Asian Pac J Dis Manag 6(3–4):55–59

    Google Scholar 

  30. Ministry of Health Labour, and Welfare (2016) Proportion of electronic claims in the Japanese health insurance system. Ministry of Health, Labour, and Welfare. https://www.mhlw.go.jp/file/06-Seisakujouhou-12400000-Hokenkyoku/0000099002.pdf. Accessed 16 November, 2023

  31. Ministry of Health Labour, and Welfare (2017) NDB open data. Ministry of Health, Labour, and Welfare. https://www.mhlw.go.jp/file/06-Seisakujouhou-12400000-Hokenkyoku/0000193322.pdf. Accessed 16 November, 2023

  32. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H (2013) A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin 9(1):30. https://doi.org/10.1186/1710-1492-9-30

    Article  Google Scholar 

  33. Hudson M, Avina-Zubieta A, Lacaille D, Bernatsky S, Lix L, Jean S (2013) The validity of administrative data to identify hip fractures is high–a systematic review. J Clin Epidemiol 66(3):278–285. https://doi.org/10.1016/j.jclinepi.2012.10.004

    Article  PubMed  Google Scholar 

  34. Kyriacou DN, Lewis RJ (2016) Confounding by Indication in Clinical Research. JAMA 316(17):1818–1819. https://doi.org/10.1001/jama.2016.16435

    Article  PubMed  Google Scholar 

  35. The Japanese Orthopaedic Association (2019) Results of national survey of hip fracture in 2019. https://www.joa.or.jp/member/committee/osteoporosis/pdf/femur19.pdf. Accessed 16 November, 2023

  36. Cooper C, Atkinson EJ, O’Fallon WM, Melton LJ 3rd (1992) Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989. J Bone Miner Res 7(2):221–227. https://doi.org/10.1002/jbmr.5650070214

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the personnel of the Osteoporosis Foundation who supported the present study.

Funding

Financial support for the present study was provided by 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 designing the study, collecting, analyzing, or interpreting the data, writing the manuscript, or deciding where to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Public Health, Kindai University Faculty of Medicine, 377-2 Oono-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Masayuki Iki & Hironori Imano

  2. National Database Japan-Osteoporosis Management (NDBJ-OS) Study Group, Department of Public Health, Kindai University Faculty of Medicine, 377-2 Oono-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan

    Masayuki Iki, Kenji Fujimori, Shinichi Nakatoh, Junko Tamaki, Shigeyuki Ishii, Nobukazu Okimoto & 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 Orthopedic Surgery, Asahi General Hospital, 477 Tomari, Asahimachi, Shimo-Nikawa-Gun, Toyama, 939-0798, Japan

    Shinichi Nakatoh

  5. Department of Hygiene and Public Health, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan

    Junko Tamaki

  6. Department of Regulatory Science, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachiouji, Tokyo, 193-0392, Japan

    Shigeyuki Ishii

  7. Okimoto Clinic, 185-4 Kubi, Yutaka-Machi, Kure, Hiroshima, 734-0304, Japan

    Nobukazu Okimoto

  8. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan

    Sumito Ogawa

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  1. Masayuki Iki
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Corresponding author

Correspondence to Masayuki Iki.

Ethics declarations

Ethics approval

The study protocol was approved by the Ethics Committee of Kindai University Faculty of Medicine (Approval Number: 31–065).

Consent to participate

We analyzed data provided by the Ministry of Health, Labour and Welfare which were completely anonymous. Therefore, informed consent from each patient was not required.

Consent for publication

Publication of the present manuscript was approved by the Ministry of Health, Labour and Welfare and all authors.

Conflicts of interest

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

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Iki, M., Fujimori, K., Nakatoh, S. et al. Average daily glucocorticoid dose, number of prescription days, and cumulative dose in the initial 90 days of glucocorticoid therapy are associated with subsequent hip and clinical vertebral fracture risk: a retrospective cohort study using a nationwide health insurance claims database in Japan. Osteoporos Int 35, 805–818 (2024). https://doi.org/10.1007/s00198-024-07023-6

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