Bone Mineral Density After Transitioning From Denosumab to Alendronate

David Kendler; Arkadi Chines; Patricia Clark; Peter R. Ebeling; Michael McClung; Yumie Rhee; Shuang Huang; Robert Kees Stad

Disclosures

J Clin Endocrinol Metab. 2020;105(3) 

In This Article

Materials and Methods

Study Design

The DAPS study (NCT00518531) was a 24-month, multicenter, randomized, open-label, crossover study conducted at 20 centers in the US and 5 centers in Canada, from October 2007 to July 2010. Study details have been previously described.[15,16] Briefly, participants were randomized 1:1 to receive 1 of 2 treatment sequences: denosumab followed by alendronate or alendronate followed by denosumab. The current analysis focused on the denosumab/alendronate sequence, in which subjects received subcutaneous denosumab, 60 mg every 6 months, in the first year and then crossed over to oral alendronate, 70 mg once weekly, in the second year. All participants received daily supplementation of calcium (1000 mg) and vitamin D (at least 400 IU). Women who withdrew from treatment during the first year but wished to remain in the study were allowed to crossover early to the second year of treatment.

Eligibility Criteria

Enrolled participants were ambulatory postmenopausal women aged 55 years or older with baseline BMD T-scores from −4.0 to −2.0 at the lumbar spine (LS), total hip (TH), or femoral neck (FN), as measured using dual-energy x-ray absorptiometry (DXA). Patients were excluded if they had received prior bisphosphonate or denosumab treatment or bone-acting drugs, including glucocorticoids. Additional exclusion criteria included hyper/hypocalcemia, vitamin D deficiency (< 20 ng/mL [49.9 nmol/L]), or contraindications to alendronate treatment. Written informed consent was obtained from each participant, and this study was conducted in accordance with the principles set out in the Declaration of Helsinki and was formally approved by the appropriate institutional review board, ethical review committee, or equivalent at each study site.

Outcome Measures

BMD at the LS, TH, and FN was measured by DXA at baseline (day 1 visit) and at months 12 and 24 of the treatment period. DXA scans were performed at the local study sites, and the same DXA machine was used for all study procedures for a particular participant. Bone turnover markers (BTMs), including fasting serum C-telopeptide (CTX-1) and N-terminal propeptide type I procollagen (P1NP), were assessed at baseline and months 12, 18, and 24 of treatment. Adherence to oral alendronate was defined as a composite endpoint of A) taking ≥ 80% of weekly alendronate tablets (overall treatment compliance) and at least 2 tablets in the last month (treatment persistence), as monitored using Medication Event Monitoring System (MEMS) technology, and B) completing the relevant treatment period. We evaluated participant characteristics including baseline age, history of fracture, baseline BMD, change in BMD at months 12 and 24, change in BTM at months 12 and 24, and adherence to alendronate.

Statistical Analyses

BMD and BTM values were summarized using descriptive statistics and plotted as the mean with 95% confidence interval (CI) and median with interquartile range (IQR), respectively. BMD change during the study period was also plotted at the level of individual participants. Descriptive analysis was performed to evaluate baseline and month 12 and 24 characteristics in groups of participants that lost, maintained, or gained BMD after transitioning from denosumab to alendronate in year 2, defined using a 3% BMD least significant change threshold. The 3% threshold was selected according to DXA scanner precision of approximately 1% corresponding to an approximate least significant change in BMD of 3%, as applied previously in responder analyses of drugs used to treat osteoporosis or increase BMD.[17–21] For LS BMD assessment, participants were excluded if there were fewer than 4 evaluable vertebrae. A change in BMD ≤ −3% indicated lost BMD, change from > −3% to < 3% indicated maintained BMD, and change ≥ 3% indicated gained BMD. This grouping was applied separately for each skeletal site. All analyses were descriptive in nature. A summary of incidence of adverse events was generated for each treatment year.

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