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Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial
SUMMARY: 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 wi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer London
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463208/ https://www.ncbi.nlm.nih.gov/pubmed/35608639 http://dx.doi.org/10.1007/s00198-022-06423-w |
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author | Sköld, C. Kultima, K. Freyhult, E. Larsson, A. Gordh, T. Hailer, N.P. Mallmin, H. |
author_facet | Sköld, C. Kultima, K. Freyhult, E. Larsson, A. Gordh, T. Hailer, N.P. Mallmin, H. |
author_sort | Sköld, C. |
collection | PubMed |
description | SUMMARY: 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. PURPOSE: 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. CONCLUSION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00198-022-06423-w. |
format | Online Article Text |
id | pubmed-9463208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer London |
record_format | MEDLINE/PubMed |
spelling | pubmed-94632082022-09-11 Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial Sköld, C. Kultima, K. Freyhult, E. Larsson, A. Gordh, T. Hailer, N.P. Mallmin, H. Osteoporos Int Original Article SUMMARY: 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. PURPOSE: 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. CONCLUSION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00198-022-06423-w. Springer London 2022-05-24 2022 /pmc/articles/PMC9463208/ /pubmed/35608639 http://dx.doi.org/10.1007/s00198-022-06423-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Original Article Sköld, C. Kultima, K. Freyhult, E. Larsson, A. Gordh, T. Hailer, N.P. Mallmin, H. Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title | Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title_full | Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title_fullStr | Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title_full_unstemmed | Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title_short | Effects of denosumab treatment on the expression of receptor activator of nuclear kappa-B ligand (RANKL) and TNF-receptor TNFRSF9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
title_sort | effects of denosumab treatment on the expression of receptor activator of nuclear kappa-b ligand (rankl) and tnf-receptor tnfrsf9 after total hip arthroplasty—results from a randomized placebo-controlled clinical trial |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463208/ https://www.ncbi.nlm.nih.gov/pubmed/35608639 http://dx.doi.org/10.1007/s00198-022-06423-w |
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