FRI0469 CHANGES IN DKK-1, SCLEROSTIN, AND RANKL SERUM LEVELS FOLLOWING DISCONTINUATION OF LONG-TERM DENOSUMAB TREATMENT IN POSTMENOPAUSAL WOMEN
Authors: Giovanni Adami, Angelo Fassio, Camilla Benini, Elisabetta Vantaggiato, Kenneth Saag, Alessandro Giollo, Irma Lippolis, Luca Idolazzi, Giovanni Orsolini, Maurizio Rossini, Davide Gatti
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The positive effects of denosumab (DMAb) on bone mineral density (BMD) are quickly reversible after its discontinuation and concerns about the possible increase in vertebral fracture after stopping denosumab have been recently raised. Indeed, a rebound in bone turnover markers have been described after DMAb discontinuation. Dickkopf-1 (Dkk-1), and sclerostin, Wnt inhibitors, are considered master regulators of bone remodeling and directly influence the Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) serum levels. <h3>Objectives</h3> We sought to determine whether the rebound of bone turnover following DMAb discontinuation is associated with dysregulation of the Wnt canonical pathway and/or with the increase in the receptor-activator of nuclear factor-kappa B ligand (RANKL) serum levels in long-term DMAb postmenopausal users. <h3>Methods</h3> The present study included patients (n = 15) with postmenopausal osteoporosis to whom DMAb was administered for 78 months and then discontinued. We collected BMD data at DMAb administration month 60 (M60), M84 (6 months after last DMAb administration, coinciding when the next DMAb dose would typically be due), and after discontinuation, 3 and 12 months of follow-up (FU-M3 and FU-M12, respectively). Serum C-terminal telopeptide of type 1 collagen (CTX-I), Dkk-1, and sclerostin were measured at M60, M84, FU-M3, and FU-M12. Serum N-terminal propeptide of type 1 procollagen (PINP) and RANKL were dosed at M60, M84, FU-M3, and FU-12. <h3>Results</h3> We found a significant decrease in the T- score at all sites at FU-M12, when compared to M84 (-0.51 ± 0.91 at the lumbar spine; -0.72 ± 0.33 at the total hip; and -0.42 ± 0.27 at the femoral neck, p&lt;0.05). After DMAb discontinuation (M84 vs FU M12), RANKL, CTX-I and PINP significantly increased (+0.041 ± 0.062 ng/mL; +0.846 ± 0.590 and +124.6 ± 62.72, p&lt;0.05, respectively), while Dkk-1 and sclerostin significantly decreased (-10.90 ± 11.80 and -13.00 ± 10.52 pmol/L, respectively, p&lt;0.01) (Figure 1). No changes in BMD or any of the markers were found between M60 and M84. <h3>Conclusion</h3> RANKL serum levels progressively increased after discontinuation of long-term DMAb while Dkk-1 and sclerostin serum levels decreased. The increase in RANKL serum levels supports the hypothesis of a sudden loss of inhibition of the resting osteoclast line after DMAb clearance, with a hyperactivation of these cells. Our results suggest that the decrease in serum Wnt inhibitors after DMAb suspension might represent a mere feedback response to the increased bone turnover. <h3>Disclosure of Interests</h3> Giovanni Adami: None declared, Angelo Fassio Speakers bureau: Abiogen Pharma, Camilla Benini: None declared, Elisabetta Vantaggiato: None declared, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin, Alessandro Giollo: None declared, Irma Lippolis: None declared, Luca Idolazzi: None declared, Giovanni Orsolini Speakers bureau: Grunenthal, Maurizio Rossini: None declared, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer