Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study

doi:10.1111/joim.13354

. 2021 Dec;290(6):1194-1205.

doi: 10.1111/joim.13354. Epub 2021 Aug 2.

Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study

Shau-Huai Fu^{1

2

3}, Chen-Yu Wang^{4

5

6}, Chih-Chien Hung¹, Chia-Che Lee³, Rong-Sen Yang³, Chuan-Ching Huang³, Chui-Jia Farn³, Wei-Hsin Lin³, Ho-Min Chen⁷, Fei-Yuan Hsiao^{4

5

8}, Jou-Wei Lin⁹, Chung-Yi Li^{2

10

11}

Affiliations

¹ Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
² Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Department of Orthopedics, National Taiwan University Hospital, Taipei, Taiwan.
⁴ School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁶ Department of Pharmacy, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
⁷ Health Data Research Center, National Taiwan University, Taipei, Taiwan.
⁸ Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
⁹ Cardiovascular Center, National Taiwan University Hospital YunlinBranch, Douliu, Taiwan.
¹⁰ Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.
¹¹ Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.

PMID: 34237171
DOI: 10.1111/joim.13354

Free article

Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study

Shau-Huai Fu et al. J Intern Med. 2021 Dec.

Free article

. 2021 Dec;290(6):1194-1205.

doi: 10.1111/joim.13354. Epub 2021 Aug 2.

Authors

Affiliations

¹ Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
² Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Department of Orthopedics, National Taiwan University Hospital, Taipei, Taiwan.
⁴ School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁶ Department of Pharmacy, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan.
⁷ Health Data Research Center, National Taiwan University, Taipei, Taiwan.
⁸ Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
⁹ Cardiovascular Center, National Taiwan University Hospital YunlinBranch, Douliu, Taiwan.
¹⁰ Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.
¹¹ Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.

PMID: 34237171
DOI: 10.1111/joim.13354

Abstract

Background: To compare the risks of major osteoporotic, vertebral, and non-vertebral fractures between patients who discontinued anti-osteoporosis medications.

Methods: We conducted a comparative effectiveness study with a nationwide population-based cohort study design. Patients aged ≥50 years admitted between 2012 and 2015 for incident hip fractures and receiving denosumab or bisphosphonates with sufficient compliance for at least 1 year were included. Patients were categorized into persistent or non-persistent denosumab or bisphosphonates users based on their subsequent use pattern. The main outcomes were subsequent hospitalizations for a major osteoporotic, vertebral or non-vertebral fracture. Multivariate, time-varying Cox proportional hazards model was used to evaluate the risk of major outcomes.

Results: Compared with persistent denosumab users, non-persistent denosumab users had a significantly higher risk of major osteoporotic fractures (hazard ratio [HR] = 1.60; 95% confidence interval [CI], 1.20-2.14), vertebral fractures (HR = 2.18; 95% CI, 1.46-3.24) and death (HR = 3.57; 95%CI, 2.63-4.84). However, the increased risk of fracture was not found in both persistent and non-persistent bisphosphonates users. Noteworthy, the increased risk of vertebral fractures in non-persistent denosumab users was more pronounced within 1 year post-discontinuation (HR = 2.90; 95% CI, 1.77-4.74) and among patients who discontinued from 2-year denosumab therapy (HR = 3.58; 95% CI, 1.74-7.40).

Discussion: Discontinuation of denosumab resulted in an increased risk of major osteoporotic fractures, especially vertebral fractures. The increased risk tends to reveal within 1 year post-discontinuation and be greater after a longer treatment duration. Notably, only fracture with hospitalization was identified as our research outcome, the real risk of osteoporotic fracture post discontinuation is believed to be higher, especially for vertebral fracture.

Keywords: bisphosphonate; denosumab; discontinuation; fractures; osteoporosis.

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Comment in

Stopping osteoporosis medications.
Reid IR. Reid IR. J Intern Med. 2021 Dec;290(6):1102-1104. doi: 10.1111/joim.13369. Epub 2021 Sep 28. J Intern Med. 2021. PMID: 34582593 No abstract available.
Regarding: Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients.
Wu YC, Chen S, Wu PL, Tsou HK, Wei JC. Wu YC, et al. J Intern Med. 2022 Mar;291(3):384-385. doi: 10.1111/joim.13400. Epub 2021 Nov 14. J Intern Med. 2022. PMID: 34779048 No abstract available.
Authors' reply: Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients.
Fu SH, Wang CY, Li CY. Fu SH, et al. J Intern Med. 2022 Mar;291(3):386-387. doi: 10.1111/joim.13401. Epub 2021 Nov 14. J Intern Med. 2022. PMID: 34779060 No abstract available.

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References

1. Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65. https://doi.org/10.1056/NEJMoa0809493
1. Orwoll E, Teglbjaerg CS, Langdahl BL, Chapurlat R, Czerwinski E, Kendler DL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-9. https://doi.org/10.1210/jc.2012-1569
1. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab. 2014;99(7):2599-607. https://doi.org/10.1210/jc.2013-4175
1. Karlsson L, Lundkvist J, Psachoulia E, Intorcia M, Ström O. Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis: a retrospective, observational study, and a meta-analysis. Osteoporos Int. 2015;26(10):2401-11. https://doi.org/10.1007/s00198-015-3253-4
1. Reyes C, Tebe C, Martinez-Laguna D, Ali MS, Soria-Castro A, Carbonell C, et al. One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int. 2017;28(10):2997-3004. https://doi.org/10.1007/s00198-017-4144-7

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[1] Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65. https://doi.org/10.1056/NEJMoa0809493

[2] Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-65. https://doi.org/10.1056/NEJMoa0809493

[3] Orwoll E, Teglbjaerg CS, Langdahl BL, Chapurlat R, Czerwinski E, Kendler DL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-9. https://doi.org/10.1210/jc.2012-1569

[4] Orwoll E, Teglbjaerg CS, Langdahl BL, Chapurlat R, Czerwinski E, Kendler DL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-9. https://doi.org/10.1210/jc.2012-1569

[5] Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab. 2014;99(7):2599-607. https://doi.org/10.1210/jc.2013-4175

[6] Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab. 2014;99(7):2599-607. https://doi.org/10.1210/jc.2013-4175

[7] Karlsson L, Lundkvist J, Psachoulia E, Intorcia M, Ström O. Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis: a retrospective, observational study, and a meta-analysis. Osteoporos Int. 2015;26(10):2401-11. https://doi.org/10.1007/s00198-015-3253-4

[8] Karlsson L, Lundkvist J, Psachoulia E, Intorcia M, Ström O. Persistence with denosumab and persistence with oral bisphosphonates for the treatment of postmenopausal osteoporosis: a retrospective, observational study, and a meta-analysis. Osteoporos Int. 2015;26(10):2401-11. https://doi.org/10.1007/s00198-015-3253-4

[9] Reyes C, Tebe C, Martinez-Laguna D, Ali MS, Soria-Castro A, Carbonell C, et al. One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int. 2017;28(10):2997-3004. https://doi.org/10.1007/s00198-017-4144-7

[10] Reyes C, Tebe C, Martinez-Laguna D, Ali MS, Soria-Castro A, Carbonell C, et al. One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int. 2017;28(10):2997-3004. https://doi.org/10.1007/s00198-017-4144-7

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Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study

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Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study

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