Background/Purpose: Prompt anti-resorptive treatment with bisphosphonates after denosumab discontinuation is generally recommended. Glucocorticoid users may not require longer term denosumab and are at greater fracture risk, yet the timing and route of bisphosphonate (BP) administration after denosumab (DMAB) discontinuation in glucocorticoid users has not been studied. A strategy of delayed administration of a pulse (IV) BP could be of greater benefit than other strategies.Objective: To test different exit strategies in patients on chronic glucocorticoids who discontinued denosumab

Methods: We conducted an open-label, randomized, parallel group, multicenter, clinical trial in which participants with ≥2 doses of DMAB 60 mg were assigned 1:1:1 to weekly oral alendronate for 6 months (70 mg; started 6 months after last DMAB dose, ALN group) OR 1 dose of IV zoledronic acid (5 mg; 6 months after last DMAB dose, EARLY ZA) OR 1 dose of IV zoledronic acid (5 mg; 9 months after last DMAB dose, LATE ZA). Participants were recruited at 2 sites. Inclusion criteria: post-menopausal women and men ≥50 years; on prednisone ≥7.5 mg /day; baseline BMD T-score of ≤ -1.0 at the lumbar spine, total hip, or femoral neck. Exclusion criteria: no past BPs, > 24 months ( > 4 injections) of prior DMAB treatment. Primary outcome was difference in CTX between randomization (baseline) and 6 months post randomization (+6M) between groups. Secondary outcomes were markers changes at follow-up times and bone mineral density (BMD) changes. We used repeated measures models with random intercepts by participant, time, and time x treatment as independent variables with an unstructured correlation matrix.

Results: A total of 45 patients were randomized (N&#3f15 to ALN, N&#3f14 to EARLY ZA, N&#3f16 to LATE ZA). Baseline characteristics are reported in Table 1. Median glucocorticoid dose at baseline (DMAB discontinuation) was 5.0 mg/day (IQR 5.0-10.0). Groups were well balanced except for BMD at femoral neck and total hip. Figure 1 shows the bone turnover markers (Figure 1) data by group at baseline, +3M and +6M. Figure 2 shows the BMD data for groups at +6M. At 6 months, we found a non-significant trend for change in CTX in the LATE ZA compared to ALN (p=0.07), but there was no difference in CTX between the LATE ZA and EARLY ZA groups (p=0.12). However, at 3 month there was a significant difference in change in CTX between LATE ZA vs ALN (p=0.0182) but not between LATE ZA and EARLY ZA (p=0.757). For lumbar spine BMD, at 6 months, we observed a non-significant trend between LATE ZA and EARLY ZA (p=0.059), but there was no statistically significant difference in the BMD between LATE ZA and ALN (p=0.28). At 12 months, there was a statistically significant difference in BMD between LATE ZA and ALN (p=0.04), but not between LATE ZA and EARLY ZA (p=0.11).

Conclusion: Among those receiving delayed ZA, an escape in bone turnover at 3 months could create a window for fractures. However, it could be offset by greater BMD gain at 6 months, which, however, was not sustained at12 months, albeit not significantly greater than the other two groups. Larger studies are needed to assess relative safety and benefit of different post-DMAB strategies among this higher risk population.

Table 1. Baseline characteristics of participants by randomization assignment

Figure 1. CTX changes over the study periodchanges over the study period

Figure 2. Bone mineral density (BMD) in gm/cm2 at lumbar spine at baseline, 3-, 6- and 12 months

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/denosumab-discontinuation-and-switching-in-glucocorticoid-induced-osteoporosis-a-multi-site-randomized-clinical-trial/