Fracture incidence after denosumab discontinuation: Real-world data from a large healthcare provider

Tripto-Shkolnik, Liana; Fund, Naama; Rouach, Vanessa; Chodick, Gabriel; Shalev, Varda; Goldshtein, Inbal

doi:10.1016/j.bone.2019.115150

Cited by 54 publications

(55 citation statements)

References 28 publications

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“…Despite the small number of prospectively studied patients, this incidence is remarkably similar to that observed during 1 year observational follow‐up of 65 women treated with Dmab in a phase 2 study (7.7%) . These results together with those of the post hoc analysis of the FREEDOM trial and its Extension indicate that the frequency of this event is low, as also recently reported in a large retrospective study . Notably, in the study of Bone and colleagues no clinical vertebral fractures were reported in 128 osteopenic women following discontinuation of Dmab after treatment for 2 years.…”

Section: Discussionsupporting

confidence: 83%

“…(3) These results together with those of the post hoc analysis of the FREEDOM trial and its Extension (1,5) indicate that the frequency of this event is low, as also recently reported in a large retrospective study. (39) Notably, in the study of Bone and colleagues (2) no clinical vertebral fractures were reported in 128 osteopenic women following discontinuation of Dmab after treatment for 2 years. One clinical vertebral fracture was also observed in a patient treated with ZOL 12 months after the infusion (3.7%); in the study of McClung and colleagues (3) one of 17 patients (5.9%) patients who received other antiosteoporotic treatments following discontinuation of Dmab sustained multiple vertebral fractures on risedronate treatment.…”

Section: Discussionmentioning

confidence: 99%

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Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Anastasilakis

Papapoulos

Polyzos

et al. 2019

Journal of Bone and Mineral Research

113

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Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single 5‐mg infusion of zoledronate (ZOL) (n = 27) or two additional 60‐mg injections of denosumab (Dmab) (n = 30). Both groups were followed for a total period of 24 months. At 24 months lumbar spine–bone mineral density (LS‐BMD) was not different from baseline in the ZOL group, but decreased in the Dmab group by (mean ± SD) 4.82% ± 0.7% (p < 0.001) from the 12‐month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of femoral neck (FN)‐BMD changes were similar. ZOL infusion was followed by small but significant increases in serum procollagen type 1 N‐terminal propeptide (P1NP) and C‐terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the Dmab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12‐month bone turnover marker values were associated with BMD changes in either group of women. In the Dmab group, three patients sustained vertebral fractures (two patients multiple clinical, one patient morphometric) whereas one patient in the ZOL group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of ZOL given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow‐up is recommended, because in a few patients ZOL treatment might not have the expected effect at 2 years. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Anastasilakis

Papapoulos

Polyzos

et al. 2019

Journal of Bone and Mineral Research

113

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“…(31) In a large computerized survey, 7.3% of the patients who discontinued denosumab had VFs, but the follow-up did not include the first 3 months of the rebound period and was restricted to 1 year. (25) As in this study, these authors found that patients with VFs after denosumab discontinuation had a higher risk of nonvertebral fractures. (25) In this study, 2.2% of the women had VFs during the average 35 months of treatment with denosumab, whereas 10.4% experienced VFs during the 24 months after discontinuation, which corresponds to a sevenfold increase in the annualized risk, rising from 0.75% to 5.15%.…”

Section: Discussionsupporting

confidence: 63%

Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases

Burckhardt

Faouzi

Buclin³

et al. 2020

Journal of Bone and Mineral Research

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A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow-up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non-vertebral fractures. The pretreatment predictors of the post-treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs.

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“…Conventional thinking and the known retention of BPs in the skeleton support the notion of a possible protective effect against both bone loss and increased fracture risk from previous BP use as this could potentially blunt the rebound phenomenon. This, however, was not proved by a recent RCT, which included patients with an up to 3 years previous alendronate treatment or even longer treatment with any other BP [10], and a real-world observational study [11].…”

Section: Discussionmentioning

confidence: 95%

“…Both in a clinical trial and in a routine clinical setting Dmab discontinuation [5,11], or even delay by more than 4 months [12], could be associated by a 3 to 5-fold higher risk for vertebral, major osteoporotic, and hip fractures. However, in the placebo-controlled trials, the off-treatment fracture risk among patients who had received Dmab was not different than that of the placebo group [5,13], and one could argue that this is simply a relapse of the given fracture risk as the protective effect of treatment has been lost.…”

Section: Discussionmentioning

confidence: 99%

Questions and facts regarding denosumab discontinuation among postmenopausal women

Makras

Anastasilakis

2020

Expert Opinion on Drug Safety

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Fracture incidence after denosumab discontinuation: Real-world data from a large healthcare provider

Cited by 54 publications

References 28 publications

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases

Questions and facts regarding denosumab discontinuation among postmenopausal women

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