Observations following discontinuation of long-term denosumab therapy

M R McClung, R B Wagman, P D Miller, A Wang, E M Lewiecki, M R McClung, R B Wagman, P D Miller, A Wang, E M Lewiecki

Abstract

Stopping denosumab after 8 years of continued treatment was associated with bone loss during a 1-year observation study in patients who were not prescribed osteoporosis treatment. Bone loss was attenuated in patients who began another osteoporosis therapy. Treatment to prevent bone loss upon stopping denosumab should be considered.

Introduction: This study aimed to understand osteoporosis management strategies during a 1-year observational follow-up after up to 8 years of denosumab treatment in a phase 2 study.

Methods: During the observational year, patients received osteoporosis management at the discretion of their physician and returned to the clinic for BMD assessment and completion of an osteoporosis management questionnaire. Incidence of serious adverse events and fractures was collected. Analyses were descriptive.

Results: Of 138 eligible patients, 82 enrolled in and completed the observation study. Most (65 [79%]) did not receive prescription osteoporosis medication, with "my doctor felt I no longer needed a medication" being the most common reason (23 [35%]). Of the 17 patients who took osteoporosis medications, 8 discontinued therapy during the observation study. In patients treated with denosumab for 8 years (N = 52), BMD decreased during the 1-year observation study (6.7% [lumbar spine], 6.6% [total hip]). Those who took osteoporosis medication during the observation study showed a smaller decline in BMD than those who did not. No new safety concerns were identified. Eight patients (9.8%), all of whom had at least one predisposing risk factor, experienced 17 fractures. This included seven patients who experienced one or more vertebral fractures.

Conclusions: Consistent with denosumab's mechanism of action, treatment cessation led to reversal of the drug's effect on BMD and perhaps fracture risk. For patients who took osteoporosis therapy, bone loss was attenuated. For patients at high fracture risk, switching to another osteoporosis therapy if denosumab is discontinued seems appropriate.

Keywords: Denosumab; Discontinuation; Osteoporosis; Treatment cessation.

Conflict of interest statement

Conflicts of interest

MRM is a consultant for Amgen Inc., Merck, and Radius Health and receives honoraria from Amgen Inc. and Merck. RBW and AW are employees of and holders of stock and/or stock options in Amgen Inc. PDM receives research grants from Alexion, Eli Lilly, Amgen Inc., Novartis, National Bone Health Alliance, Pfizer, University of Alabama, Boehringer Ingelheim, Merck, Merck Serono, and Radius Health and is a consultant for Grunenthal, Shionogi, Radius Health, Amgen Inc., and Eli Lilly. EML receives research grants from Amgen Inc., Eli Lilly, and Merck and is a consultant for Amgen Inc., Eli Lilly, Merck, and Radius Health.

Financial support

This study was sponsored by Amgen Inc., Thousand Oaks, CA, USA.

Figures

Fig. 1
Fig. 1
Design of the parent study, its extension, and the observation study. DMAb denosumab, Q3M once every 3 months, Q6M once every 6 months, QW once weekly
Fig. 2
Fig. 2
Percentage change from phase 2 dose-ranging trial baseline for a lumbar spine and b total hip bone mineral density (BMD). Includes patients who enrolled into the observation study with 8 years of denosumab (DMAb) treatment (N = 52) or those with 4 years of placebo followed by 4 years of DMAb treatment (N = 10). n = number of subjects with observed BMD at baseline and year 9. CI confidence interval, LSM least squares mean
Fig. 3
Fig. 3
Percentage change from observation study baseline in bone mineral density (BMD) during the 1-year observation study stratified by postmenopausal osteoporosis (PMO) medication (med) status. Data are from 52 patients who enrolled into the observation study after 8 years of continued denosumab treatment. n = number of subjects with observed BMD at year 8 and year 9. In each box-and-whisker plot, the box represents the 25th and 75th percentiles, the middle line represents the median, and the diamond represents the mean

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