Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women

• Published in: Bone (New York, N.Y.) Vol. 123; pp. 191 - 195
• Main Authors: Fassio, A., Adami, G., Benini, C., Vantaggiato, E., Saag, K.G., Giollo, A., Lippolis, I., Viapiana, O., Idolazzi, L., Orsolini, G., Rossini, M., Gatti, D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2019
• Subjects: Denosumab; Dkk-1; Osteoporosis; RANKL; Sclerostin; Dkk-1; Osteoporosis; Sclerostin; RANKL; Denosumab
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2019.03.019

The positive effects of denosumab (DMAb) on bone mineral density (BMD) are quickly reversible after its discontinuation. We investigated whether this rebound was associated with dysregulation of the Wnt canonical pathway and/or by the increase in the receptor-activator of nuclear factor-kappa B ligand (RANKL) serum levels. The study included patients (n = 15) with postmenopausal osteoporosis to whom DMAb was administered for 78 months and then discontinued. We collected BMD data at baseline/month 0 (M0), M60, M84 (6 months after last DMAb administration, coinciding when the next DMAb dose would typically be due), and after 3 and 12 months of follow-up (FU-M3 and FU-M12, respectively). Serum C-terminal telopeptide of type 1 collagen (CTX-I), Dickkopf-1 (Dkk-1), and sclerostin were measured at M0, 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. 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 < 0.05). After DMAb discontinuation (M84 vs FU M12) CTX-I, PINP increased already at FU-M3 (+0.921 ± 0.482 ng/mL, +126.60 ± 30.36 ng/mL, respectively, p < 0.01), RANKL increased at FU-M12 (+0.041 ± 0.062 ng/mL, p < 0.05), while Dkk-1 and sclerostin decreased at FU-M12 (−10.90 ± 11.80 and − 13.00 ± 10.52 pmol/L, respectively, p < 0.01). No changes in BMD or any of the markers were found between M60 and M84. 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 changes in serum Wnt inhibitors after DMAb suspension might represent a mere feedback response to the increased bone turnover. •The increases in BMD have been shown to be lost after discontinuation.•We found a slow increase in RANKL which was associated with the early increase in CTX-I.•The increase in lumbar spine BMD during treatment with denosumab are a strong predictor of the increase in RANKL after denosumab discontinuation.•The dysregulation of Wnt inhibitors (Dkk-1 and sclerostin) initially seemed to be a promising mechanism for the BMD impairment after denosumab discontinuation; nevertheless, our results suggest that this pathway might be only marginally involved, and the changes in Dkk-1 and sclerostin might simply be a compensatory response to the abrupt increase in bone resorption.