PO:20:007 | Mind the rebound: ctx dynamics after denosumab discontinuation and zoledronate rescue in patients with postmenopausal osteoporosis or with cancer treatment-induced bone loss

Federico Aldegheri¹, Francesca Ruzzon¹, Matteo Appoloni¹, Giovanni Adami¹, Davide Gatti¹, Maurizio Rossini¹, Angelo Fassio¹, Ombretta Viapiana¹ | ¹Università di Verona, Italy

Introduction. Denosumab (Dmab) discontinuation is associated with a rebound in bone turnover and an increased risk of vertebral fractures. To mitigate this, intravenous (i.v.) Zoledronate is usually administered six months after the last Dmab injection. However, the precise kinetics of bone turnover markers following Zoledronate for the mitigation of the Dmab discontinuation-associated rebound are still unclear. Moreover, it is unclear whether they differ between subjects treated for postmenopausal osteoporosis (PMO) and those receiving treatment to prevent cancer treatment-induced bone loss (CTBIL).

Materials and Methods. We analyzed longitudinally collected serum samples assayed for Collagen Type I C-Telopeptide (s-CTx-I) from women who discontinued Dmab and who received a single Zoledronate infusion (“day 0”) administered exactly six months after their last Dmab dose. Subjects who received Dmab either as treatment of PMO or CTBIL were included. The reasons for Dmab discontinuation were: achievement of a low fracture risk (as measured by the DEFRA algorithm) for PMO, and discontinuation of endocrine adjuvant therapy (ET) for CTBIL plus low fracture risk. To model s-CTX-I trajectories over time, we initially fitted a linear mixed-effects model, subsequently added polynomial terms (quadratic and cubic), and ultimately employed a natural cubic spline mixed-effects regression to achieve the best fit, using two internal knots (the first at day -30—approximately one month before zoledronate administration—and the second at day 180). An interaction term between time and subgroup (PMO or CTBIL) was added to assess potential between-group differences. Models were adjusted for age and duration of prior Dmab exposure. To determine the best fit, models were compared through Akaike information criterion (AIC), Bayesian information criterion (BIC), and Bayes factor.

Results. Thirty women with PMO and thirty-six with CTIBL were enrolled. CTIBL patients were younger and had a shorter duration of Dmab compared to PMO patients, while baseline bone mineral density and s-CTX-I levels were comparable (table 1). Among the models tested, the spline model provided the best fit compared to linear and polynomial models to describe s-CTX-I trends. Specifically, s-CTX-I trajectories exhibited a significant non-linear rise during the first six to nine months post-zoledronate, followed by a plateau (figure 1A). No significant treatment by subgroup interaction was observed (interaction p = ns; figure 1B), even after adjustment for age or Dmab duration.

Conclusions. Following denosumab discontinuation, and despite subsequent zoledronate administration, s-CTX-I levels rise rapidly and nonlinearly, peaking within six to nine months, with a comparable pattern observed between the PMO and CTBIL subgroups. Furthermore, ET discontinuation does not appear to offer substantial protection against the rebound associated with denosumab withdrawal. Close monitoring of s-CTX-I levels in the early phase after denosumab discontinuation seems crucial to detect early increases in bone turnover and to appropriately adjust sequential therapies.