Title: Acute Phase Reaction and Fracture Risk Reduction: Are Gamma-Delta T Cells and Hypovitaminosis D the Missing Link?
Abstract: Journal of Bone and Mineral ResearchEarly View Letter to the EditorOpen Access Acute Phase Reaction and Fracture Risk Reduction: Are Gamma-Delta T Cells and Hypovitaminosis D the Missing Link? Giovanni Adami, Corresponding Author Giovanni Adami [email protected] orcid.org/0000-0002-8915-0755 Rheumatology Unit, University of Verona, Verona, Italy Address correspondence to: Giovanni Adami, Rheumatology Unit, University of Verona, Pz Scuro 10, 37134 Verona, Italy. E-mail: [email protected] for more papers by this authorAngelo Fassio, Angelo Fassio orcid.org/0000-0001-9187-232X Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorDavide Gatti, Davide Gatti orcid.org/0000-0002-7471-3076 Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorOmbretta Viapiana, Ombretta Viapiana Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorMaurizio Rossini, Maurizio Rossini orcid.org/0000-0001-9692-2293 Rheumatology Unit, University of Verona, Verona, Italy Contribution: Conceptualization, Supervision, Validation, Writing - original draft, Writing - review & editingSearch for more papers by this author Giovanni Adami, Corresponding Author Giovanni Adami [email protected] orcid.org/0000-0002-8915-0755 Rheumatology Unit, University of Verona, Verona, Italy Address correspondence to: Giovanni Adami, Rheumatology Unit, University of Verona, Pz Scuro 10, 37134 Verona, Italy. E-mail: [email protected] for more papers by this authorAngelo Fassio, Angelo Fassio orcid.org/0000-0001-9187-232X Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorDavide Gatti, Davide Gatti orcid.org/0000-0002-7471-3076 Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorOmbretta Viapiana, Ombretta Viapiana Rheumatology Unit, University of Verona, Verona, Italy Contribution: Writing - review & editingSearch for more papers by this authorMaurizio Rossini, Maurizio Rossini orcid.org/0000-0001-9692-2293 Rheumatology Unit, University of Verona, Verona, Italy Contribution: Conceptualization, Supervision, Validation, Writing - original draft, Writing - review & editingSearch for more papers by this author First published: 01 March 2022 https://doi.org/10.1002/jbmr.4534AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor: We read with great interest the paper by Black and colleagues(1) on the interaction between acute-phase reaction (APR) and efficacy for osteoporosis after zoledronic acid. In this post hoc analysis of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, women that experienced an APR had a greater fracture risk reduction compared to women that did not experience an APR. However, there is no clear mechanistic explanation to this phenomenon, as pointed out by the authors in the Discussion. One intriguing hypothesis, raised by the authors, regards the well-known immunological effects of the aminobisphosphonates mediated by the activation of γδ T-cells. We previously noted that APR after aminobisphosphonate administration was associated with a long-term decrease in circulating γδ T-cells and, remarkably, the higher the drop in γδ T-cells the lower risk of additional APRs after the second zoledronic acid infusion.(2, 3) In this scenario, aminobisphosphonates might chronically reduce proinflammatory circulating T-cells; a hypothesis that is supported by several clinical experiences. As a matter of fact, aminobisphosphonate use has been associated with lower risk of severe pulmonary infections(4) and higher chance of discontinuation in polymyalgia rheumatica.(5) Therefore, because the subjects with prominent inflammation have been shown to have higher fracture incidence,(6) zoledronic acid might be beneficial in terms of fracture risk reduction through long-term anti-inflammatory action, which is pronounced in patients with APR after infusion. Nonetheless, there is at least another hypothesis possibly explaining the intriguing result by Black and colleagues.(1) Indeed, vitamin D baseline status, which is negatively associated with both APR(7) and fracture risk, was not considered as a potential confounder in the multivariable analysis. In this case, women with vitamin D deficiency at baseline were at higher risk of experiencing an APR and might had benefited more in terms of fracture risk reduction. Disclosures All authors state that they have no potential conflict of interest related to the present paper. Conflict of Interest GA, AF, DG, OV, and MR declare that they have no conflict of interest related to the present work. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no conflicts of interest. Author Contributions Angelo Fassio: Writing – review and editing. Davide Gatti: Writing – review and editing. Ombretta Viapiana: Writing – review and editing. Maurizio Rossini: Conceptualization; supervision; validation; writing – original draft; writing – review and editing. References 1Black DM, Reid IR, Napoli N, et al. The interaction of acute-phase reaction and efficacy for osteoporosis after zoledronic acid: HORIZON pivotal fracture trial. J Bone Miner Res. 2021; 37(1): 21- 28. Wiley Online LibraryPubMedWeb of Science®Google Scholar 2Rossini M, Adami S, Viapiana O, et al. Circulating γδ T cells and the risk of acute-phase response after zoledronic acid administration. J Bone Miner Res. 2012; 27(1): 227- 230. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3Rossini M, Adami S, Viapiana O, et al. Long-term effects of amino-bisphosphonates on circulating γδ T cells. Calcif Tissue Int. 2012; 91(6): 395- 399. CrossrefCASPubMedWeb of Science®Google Scholar 4Sing C-W, Kiel DP, Hubbard RB, et al. Nitrogen-containing bisphosphonates are associated with reduced risk of pneumonia in patients with hip fracture. J Bone Miner Res. 2020; 35(9): 1676- 1684. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 5Giollo A, Rossini M, Bettili F, et al. Permanent discontinuation of glucocorticoids in polymyalgia rheumatica is uncommon but may be enhanced by amino bisphosphonates. J Rheumatol. 2019; 46(3): 318- 322. CrossrefCASPubMedWeb of Science®Google Scholar 6Barbour KE, Lui L-Y, Ensrud KE, et al. Study of osteoporotic fractures (SOF) research group. Inflammatory markers and risk of hip fracture in older white women: the Study of Osteoporotic Fractures. J Bone Miner Res. 2014; 29(9): 2057- 2064. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 7Bertoldo F, Pancheri S, Zenari S, et al. Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion. J Bone Miner Res. 2010; 25(3): 447- 454. 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