Abstract：
We investigated whether the drug denosumab modulates the inflammatory response after total hip arthroplasty in a randomized controlled trial. Significantly increased expression of RANKL was found in patients treated with denosumab. This could provide an explanation for the rebound effect with rapid loss of BMD seen after discontinuation of denosumab treatment.
OBJECTIVE: To evaluate whether denosumab, a human monoclonal antibody directed against receptor activator of nuclear factor kappa-B ligand (RANKL), modulates the inflammatory response after cementless total hip arthroplasty (THA) in patients with osteoarthritis of the hip.
METHODS: Sixty-four patients operated with cementless THA were randomized to two doses of 60-mg denosumab or placebo 1-3 days and 6 months postoperatively. Serum samples were analyzed by a multiplex extension assay detecting 92 inflammation-related proteins. Bone turnover markers were assessed. Proteins were analyzed using linear mixed effect models. Validation of conspicuous findings was performed with ELISA.
RESULTS: Two proteins were significantly affected by denosumab treatment: RANKL and tumor necrosis factor receptor super family member 9 (TNFRSF9). Serum levels of RANKL were more than twice as high in the denosumab than in the placebo group 3 months after surgery (ratio 2.10, p<0.001). Six and 12 months after surgery, the expression of RANKL was still elevated in the denosumab-treated group (ratios 1.50, p < 0.001; 1.47, p =0.002). The expression of TNFRSF9 was lower in the denosumab group at 3 months (ratio 0.68, p<0.001). In the denosumab group, concentrations of bone turnover markers were substantially reduced after 3 months, remained suppressed after 6 and 12 months, but increased above baseline at 24 months after surgery.
CONCLUSIONS: Two subcutaneous denosumab injections 6 months apart increase RANKL and depress TNFRSF9 after THA. This provides a possible explanation for the rebound effect on bone turnover markers as well as bone mineral density (BMD) upon withdrawal of denosumab. None of the other measured markers of inflammation was influenced by denosumab treatment.
OBJECTIVE: To evaluate whether denosumab, a human monoclonal antibody directed against receptor activator of nuclear factor kappa-B ligand (RANKL), modulates the inflammatory response after cementless total hip arthroplasty (THA) in patients with osteoarthritis of the hip.
METHODS: Sixty-four patients operated with cementless THA were randomized to two doses of 60-mg denosumab or placebo 1-3 days and 6 months postoperatively. Serum samples were analyzed by a multiplex extension assay detecting 92 inflammation-related proteins. Bone turnover markers were assessed. Proteins were analyzed using linear mixed effect models. Validation of conspicuous findings was performed with ELISA.
RESULTS: Two proteins were significantly affected by denosumab treatment: RANKL and tumor necrosis factor receptor super family member 9 (TNFRSF9). Serum levels of RANKL were more than twice as high in the denosumab than in the placebo group 3 months after surgery (ratio 2.10, p<0.001). Six and 12 months after surgery, the expression of RANKL was still elevated in the denosumab-treated group (ratios 1.50, p < 0.001; 1.47, p =0.002). The expression of TNFRSF9 was lower in the denosumab group at 3 months (ratio 0.68, p<0.001). In the denosumab group, concentrations of bone turnover markers were substantially reduced after 3 months, remained suppressed after 6 and 12 months, but increased above baseline at 24 months after surgery.
CONCLUSIONS: Two subcutaneous denosumab injections 6 months apart increase RANKL and depress TNFRSF9 after THA. This provides a possible explanation for the rebound effect on bone turnover markers as well as bone mineral density (BMD) upon withdrawal of denosumab. None of the other measured markers of inflammation was influenced by denosumab treatment.
摘要：
我们在一项随机对照试验中研究了denosumab药物是否能调节全髋关节置换术后的炎症反应。在用denosumab治疗的患者中发现RANKL的表达显着增加。这可以解释在停止denosumab治疗后发现的BMD快速损失的反弹效应。
目的：评估地诺单抗是否，一种针对核因子κB受体活化因子配体（RANKL）的人单克隆抗体，调节髋关节骨关节炎患者非骨水泥全髋关节置换术（THA）后的炎症反应。
方法：64例接受无骨水泥THA手术的患者在术后1-3天和6个月随机接受两种剂量的60mg地诺塞马或安慰剂。通过检测92种炎症相关蛋白的多重延伸测定分析血清样品。评估骨转换标志物。使用线性混合效应模型分析蛋白质。用ELISA进行明显发现的验证。
结果：两种蛋白被denosumab治疗显着影响：RANKL和肿瘤坏死因子受体超家族成员9（TNFRSF9）。手术后3个月，denosumab的血清RANKL水平是安慰剂组的两倍多（比率2.10，p<0.001）。手术后6个月和12个月，在denosumab治疗组中,RANKL的表达仍然升高(比率1.50,p<0.001;1.47,p=0.002).Denosumab组在3个月时TNFRSF9的表达较低（比率0.68，p<0.001）。在denosumab组,骨转换标志物的浓度在3个月后显著降低，在6个月和12个月后仍然受到抑制，但在手术后24个月增加到基线以上。
结论：THA后，两次间隔6个月皮下注射地诺塞马可增加RANKL并降低TNFRSF9。这可能解释了denosumab戒断后对骨转换标志物和骨矿物质密度（BMD）的反弹作用。其他测量的炎症标志物均不受denosumab治疗的影响。
目的：评估地诺单抗是否，一种针对核因子κB受体活化因子配体（RANKL）的人单克隆抗体，调节髋关节骨关节炎患者非骨水泥全髋关节置换术（THA）后的炎症反应。
方法：64例接受无骨水泥THA手术的患者在术后1-3天和6个月随机接受两种剂量的60mg地诺塞马或安慰剂。通过检测92种炎症相关蛋白的多重延伸测定分析血清样品。评估骨转换标志物。使用线性混合效应模型分析蛋白质。用ELISA进行明显发现的验证。
结果：两种蛋白被denosumab治疗显着影响：RANKL和肿瘤坏死因子受体超家族成员9（TNFRSF9）。手术后3个月，denosumab的血清RANKL水平是安慰剂组的两倍多（比率2.10，p<0.001）。手术后6个月和12个月，在denosumab治疗组中,RANKL的表达仍然升高(比率1.50,p<0.001;1.47,p=0.002).Denosumab组在3个月时TNFRSF9的表达较低（比率0.68，p<0.001）。在denosumab组,骨转换标志物的浓度在3个月后显著降低，在6个月和12个月后仍然受到抑制，但在手术后24个月增加到基线以上。
结论：THA后，两次间隔6个月皮下注射地诺塞马可增加RANKL并降低TNFRSF9。这可能解释了denosumab戒断后对骨转换标志物和骨矿物质密度（BMD）的反弹作用。其他测量的炎症标志物均不受denosumab治疗的影响。
