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

Results

Participant Characteristics

The DAPS study enrolled 250 participants. Of 126 women randomized to the denosumab/alendronate sequence, 114 (90.5%) completed denosumab treatment in year 1 and 115 (91%) transitioned to alendronate at month 12, including 3 who crossed over early. Alendronate treatment in year 2 was completed by 95 participants (82.6%). Most common reasons for discontinuation before completion of treatment included withdrawn consent (6 participants [4.8%] in year 1; 8 [7.0%] in year 2), lost to follow-up (3 [2.4%] in year 1; 0 [0.0%] in year 2), and adverse events (0 [0.0%] in year 1; 7 [6.1%] in year 2) (Table 1). Characteristics of the 126 participants initiating denosumab treatment in year 1 and the 115 participants initiating alendronate treatment in year 2 are shown in Table 2. At baseline, participants had a mean age of 65 years and mean BMD T-scores of −2.0, −1.6, and −2.0 at the LS, TH, and FN, respectively. Prior osteoporotic fracture was reported for 37.3% of participants at baseline. Similar characteristics were observed for the participants who transitioned to alendronate at month 12.

Change in BMD and BTM With Denosumab in Year 1 and Alendronate in Year 2

With denosumab treatment in year 1, the mean percent change in BMD from baseline to month 12 was 5.4%, 3.1%, and 2.7% for the LS, TH, and FN, respectively. After transitioning to alendronate in year 2, the mean percent change in BMD from month 12 to month 24 was 0.5%, 0.5%, and −0.2% at the LS, TH, and FN, respectively. Evaluating the entire study period, participants showed an average gain in BMD above baseline of 5.9%, 3.6%, and 2.5% at the LS, TH, and FN, respectively (Figure 1). The median percent change in CTX-1 from baseline to month 12, month 18, and month 24 was −69.1%, −64.7%, and −54.8%, respectively. The median percent change in P1NP from baseline to month 12, month 18, and month 24 was −67.7%, −57.0%, and −53.1%, respectively (Figure 2).

Figure 1.

BMD percentage change from baseline with denosumab in year 1 and alendronate in year 2. Data show mean and 95% confidence interval. n = number of participants with measurements at baseline and month 12 (DMAb) or month 24 (ALN). Abbreviations: ALN, alendronate; BMD, bone mineral density; DMAb, denosumab.

Figure 2.

BTM percentage change from baseline with denosumab in year 1 and alendronate in year 2. Data show mean and interquartile range. n = number of participants with measurements at baseline and month 12 (DMAb) or month 24 (ALN). Abbreviations: ALN, alendronate; BTM, bone turnover marker; CTX-1, serum C-telopeptide; DMAb, denosumab; P1NP, N-terminal propeptide type I procollagen. aAt month 18, n = 60.

Participants Grouped Into Those who Lost, Maintained, or Gained BMD in Year 2

Figure 3 shows BMD responses for individual participants throughout the study for the groups that lost, maintained, and gained BMD during year 2 on alendronate. Of the 82 participants with BMD measurements available at the LS, 13 (15.9%) lost BMD, 52 (63.4%) maintained BMD, and 17 (20.7%) gained BMD at this site. Of the 92 participants with BMD measurements available at the TH and FN, 7 (7.6%) lost BMD, 75 (81.5%) maintained BMD, and 10 (10.9%) gained BMD at the TH, and 20 (21.7%) lost BMD, 56 (60.9%) maintained BMD, and 16 (17.4%) gained BMD at the FN (Table 3). Of the 82 participants with BMD measurements available at the LS, TH, and FN, only 1 participant (1.2%) lost BMD at all 3 sites.

Figure 3.

Individual participant BMD changes for groups that lost, maintained, or gained BMD in year 2 on alendronate. Abbreviation: BMD, bone mineral density.

Participant Characteristics and BMD Change in Year 2

The BMD change in year 2 was similar regardless of baseline characteristics such as age, BMD T-score, baseline levels of BTMs, and history of fracture (Table 3). For all skeletal sites, subjects who lost BMD with alendronate in year 2 had shown a greater percent change in BMD with denosumab in year 1 (Figure 3, Table 3). At the LS, participants who lost BMD in year 2 had gained an average of 7.1% BMD in year 1, while those who gained BMD in year 2 had gained an average of 3.1% BMD in year 1, and a similar difference was observed at the TH (6.2% vs 2.8%). At the FN, participants who lost BMD in year 2 had gained an average of 7.0% BMD in year 1, while those who gained BMD in year 2 had gained an average of 0.6% BMD in year 1. BMD did not fall below pretreatment baseline in the majority of participants and was observed most often in participants who lost BMD with alendronate. Among participants who lost BMD in year 2 at a given skeletal site, 23.1% fell below their baseline BMD value at the LS, 28.6% fell below their baseline value at the TH, and 50.0% fell below their baseline value at the FN.

While adherence to oral alendronate in year 2 was lower than adherence to denosumab in year 1,[16] there was no numeric trend between alendronate adherence and the BMD response in year 2 (Table 3). Compliance, defined as the percentage of provided alendronate tablets taken, was also investigated in terms of the BMD change in year 2 using quartiles of compliance, and there were no differences in the percent change in BMD in year 2 among the 4 compliance subgroups (data not shown).

Adverse Event Summary

Safety analysis was performed for 125 participants who received at least 1 dose of denosumab in year 1 and 110 participants who received at least 1 dose of alendronate in year 2 (Table 4). The adverse event profiles were similar between treatment periods, with 74.4% and 61.8% of participants experiencing adverse events during denosumab and alendronate treatment, respectively. The most frequent adverse events (denosumab year 1, alendronate year 2) included arthralgia (8.8%, 6.4%), pain in extremity (7.2%, 3.6%), back pain (4.0%, 2.7%), and cough (4.0%, 4.5%). Adverse events of fracture were experienced by 1 participant during year 1 and 1 participant during year 2; both fracture events were classified as osteoporotic and nonvertebral. No deaths, osteonecrosis of the jaw, or atypical femoral fractures were reported.

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