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

Fu, Shau-Huai; Wang, Chen Yu; Hung, Chih Chien; Lee, Chia-Che; Yang, Rong‐Sen; Huang, Chuan Ching; Farn, Chui Jia; Lin, Wei-Hsin; Chen, Ho Min; Hsiao, Fei‐Yuan; Lin, Jou‐Wei; Li, Chung‐Yi

doi:10.1111/joim.13354

Cited by 21 publications

(10 citation statements)

References 35 publications

(46 reference statements)

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“…An additional analysis undertaken to assess the potential for residual confounding associated with BMD and BMI found that both variables were balanced between the two study arms at baseline, therefore mitigating the concern of residual confounding due to inability to include these parameters as part of the PS matching in the primary analysis. Another residual confounder could be an increased fracture risk in the off-treatment cohort due to rebound bone resorption after denosumab discontinuation [ 32 ]. However, this potential confounder is unlikely as it has been shown that rebound of bone turnover is absent in subjects receiving a single injection of denosumab [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study

et al. 2022

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To determine denosumab's effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. Introduction After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among realworld postmenopausal women. Methods This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. Results In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52-0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. Conclusion The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial. Registration: EnCePP registration number: EUPAS26372; registration date: 12/11/2018.

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Section: Discussionmentioning

confidence: 99%

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study

et al. 2022

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“…Our nationwide population-based cohort study also showed discontinuation of Dmab resulted in an increased risk of major osteoporotic and vertebral fractures. The increased risk tended to reveal within 1 year after discontinuation and the risk was greater among the patients with longer duration of Dmab treatment (11). In addition to vertebral fractures, higher incidences of major osteoporotic fractures and hip fractures were also observed in the following years of Dmab withdrawal (12).…”

Section: Introductionmentioning

confidence: 95%

A Multi-Institutional Randomized Controlled Trial to Investigate Whether Zoledronate Prevents Bone Loss After Discontinuation of Denosumab: The Study Protocol of Denosumab Sequential Therapy (DST) Trial

et al. 2021

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Background: Though denosumab is an effective treatment for osteoporosis, the rebound effect after discontinuation has drawn investigators' attention. It includes a dramatic loss of gained bone mineral density (BMD) and an increased risk of vertebral fractures. This prospective multi-institutional randomized controlled trial aims to investigate whether zoledronate prevents loss of BMD after discontinuation of denosumab. The trial was registered as Denosumab Sequential Therapy (DST) trial in March 2019 at clinicaltrials.gov, with the identifier NCT03868033.Methods: The study is conducted at National Taiwan University Hospital and its branches. Patients who have continuously received denosumab treatment for two or more years are surveyed for eligibility. Baseline characteristics and questionnaires of life quality are recorded after recruitment. BMD, circulating levels of bone turnover markers (BTMs), including serum N-terminal propeptide of type 1 collagen (P1NP) and C-terminal telopeptide (CTX), are checked before the stratified randomization to 4 groups. Biological sex and the T-scores are used to create 4 strata. The participants in group 1 adhere to regular denosumab therapy for another 2 years. All the other patients receive on-time zoledronate treatment in the first year. The participants in group 2, 3, and 4 have on-time denosumab, on-time zoledronate and drug holiday in the second year, respectively. BMDs are checked annually. Pre-scheduled checkpoints of BTMs are also arranged. For patient safety, rescue treatment with another injection of zoledronate will be applied to the patients on drug holiday if the CTX levels raise above the pre-specified threshold, 0.573 ng/mL for women and 0.584 ng/mL for men. The primary outcomes are the percentage changes of BMDs in lumbar spine, total hip and femoral neck. The secondary outcomes include the changes of serum level of the BTMs, new osteoporotic fractures, extra zoledronate injections needed in group 4 and the differences of quality of life.Discussion: We aim to provide evidence whether zoledronate prevents bone loss after denosumab cessation. To our knowledge, the study has the largest sample size. No other randomized controlled study included all the three different treatment strategies and a positive control. It is also the first associated randomized controlled trial outside Europe.

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We have carefully read the cohort study by Fu et al on anti-osteoporosis medication (AOM) [1]. The authors reported that persistent anti-osteoporosis drug users have a lower risk of major fractures compared with patients who discontinued the treatment.

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confidence: 99%

“…A better understanding of the relation between the discontinuation of AOM and fracture risk can help improve clinical medication usage. The authors took into account several variables to minimize the bias such as hospital accreditation level, duration between index admissions, and selected comorbidities [1]. Nevertheless, we still identified a few potential confounders.…”

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confidence: 99%

Regarding: Increased fracture risk after discontinuation of anti‐osteoporosis medications among hip fracture patients

Chen

et al. 2021

J Intern Med

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We have carefully read the cohort study by Fu et al. on anti-osteoporosis medication (AOM) [1]. The authors reported that persistent anti-osteoporosis drug users have a lower risk of major fractures compared with patients who discontinued the treatment. The strengths of the study are its size and follow-up period from analyzing Taiwan's nationwide database (National Health Insurance Research Database [NHIRD]), which includes 99% of Taiwan's population.

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

Abstract: R et al. Increased fracture risk after discontinuation of anti-osteoporosis medications among hip fracture patients: A population-based cohort study.

Cited by 21 publications

References 35 publications

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study

Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study

A Multi-Institutional Randomized Controlled Trial to Investigate Whether Zoledronate Prevents Bone Loss After Discontinuation of Denosumab: The Study Protocol of Denosumab Sequential Therapy (DST) Trial

Regarding: Increased fracture risk after discontinuation of anti‐osteoporosis medications among hip fracture patients

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