Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women
Changes in Dkk-1, sclerostin, and RANKL serum levels following discontinuation of long-term denosumab treatment in postmenopausal women
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绝经后妇女停用长期地诺单抗治疗后血清Dkk-1、硬化蛋白和RANKL水平的变化
DOI：
10.1016/j.bone.2019.03.019
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发表时间：
2019-06-01
期刊：
影响因子：
4.1
通讯作者：
Gatti, D.
中科院分区：
文献类型：
--
作者：
Fassio, A.;Adami, G.;Gatti, D.
目的：地诺单抗（DMAb）对骨密度（BMD）的积极作用在停药后迅速可逆。我们研究了这种反弹是否与Wnt规范通路的失调和/或核因子- κ B配体受体激活剂（RANKL）血清水平的增加有关。方法：研究纳入绝经后骨质疏松症患者（n = 15），给予DMAb 78个月，然后停药。我们在基线/月0 (M0), M60, M84（最后一次DMAb给药后6个月，与下一次DMAb剂量通常到期的时间一致）以及随访3个月和12个月后（分别为FU-M3和FU-M12）收集BMD数据。在M0、M60、M84、FU-M3、FU-M12时测定血清1型胶原c -末端末端肽（CTX-I）、Dickkopf-1 （Dkk-1）、sclerostin。血清1型前胶原n端前肽（PINP）和RANKL分别在M60、M84、FU-M3和FU-12给药。结果：与M84相比，我们发现FU-M12所有部位的t评分均显著降低（腰椎- 0.51 +/- 0.91；全髋关节- 0.72 +/- 0.33；股骨颈- 0.42 +/- 0.27,p < 0.05）。停用DMAb后（M84 vs FU M12） CTX-I在FU- m3处PINP升高（分别为+ 0.921 +/- 0.482 ng/mL, + 126.60 +/- 30.36 ng/mL, p < 0.01）， RANKL升高（+ 0.041 +/- 0.062 ng/mL, p < 0.05）， Dkk-1和sclerostin降低（分别为-10.90 +/- 11.80和- 13.00 +/- 10.52 pmol/L, p < 0.01）。在M60和M84之间没有发现BMD或任何标记物的变化。结论：停用长期DMAb后，RANKL血清水平逐渐升高，而Dkk-1和sclerostin血清水平下降。RANKL血清水平的增加支持了静止破骨细胞系在DMAb清除后突然失去抑制的假设，这些细胞过度激活。我们的研究结果表明，DMAb悬浮液后血清Wnt抑制剂的变化可能仅仅代表了对骨转换增加的反馈反应。
Purpose: 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.Methods: 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.Results: 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.Conclusions: 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.