Therapeutic Strategies of Denosumab Sequential Therapy: A Four‐Armed Randomized Controlled Trial

After denosumab discontinuation, the rebound effect can lead to rapid bone loss and increased fracture risk. Identifying effective sequential therapies after denosumab discontinuation is crucial to mitigate these risks. We conducted the Denosumab Sequential Therapy (DST) trial, a two‐year, multicenter, open‐label, randomized controlled trial, conducted at a referral center and two affiliated hospitals in Taiwan. The DST trial enrolled 101 patients aged 50 years or older who received denosumab for at least 2 years (median: 2 years) and stratified the patients into four intervention groups to evaluate the effectiveness of three therapeutic strategies compared to continuous denosumab treatment. The four arms were as follows: (1) continued denosumab for 2 years (denosumab group); (2) two consecutive annual zoledronate infusions (annual‐zoledronate group); (3) one zoledronate infusion followed by a supervised medication‐free year (biennial‐zoledronate group); and (4) one zoledronate infusion followed by resumed denosumab (double‐switching group). The primary outcome was the percent change in the lumbar spine (LS) bone mineral density (BMD), total hip BMD (TH‐BMD), and femoral neck BMD (FN‐BMD). Secondary outcomes included changes in BTMs, the incidence of clinical fractures, and the need for rescue zoledronate in the biennial‐zoledronate group. LS‐BMD increased by 1.77% in the denosumab group, by 2.25% in the double‐switching group, while decreasing by 0.71% in the annual‐zoledronate group and by 2.76% in the biennial‐zoledronate group. One‐third of patients in the biennial‐zoledronate group showed LS‐BMD loss exceeding the least significant change (LSC), and 22% required rescue zoledronate infusions. Given the significant bone loss observed, a single zoledronate infusion followed by a medication‐free year is not recommended. Two consecutive zoledronate infusions and the double‐switching regimen with resumed denosumab showed promising BMD preservation, making them advisable clinical alternatives after denosumab discontinuation.