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We hypothesized that treatments to reduce reactive oxygen species formation and reduce parathyroid hormone (PTH) levels would have additive beneficial effects to prevent cardiovascular calcification and deleterious bone architecture and mechanics before end\u2010stage kidney disease. To test this hypothesis, we treated a naturally progressive model of CKD\u2010MBD, the Cy\/+ rat, beginning early in CKD with the NADPH oxidase (NOX1\/4) inhibitor GKT\u2010137831 (GKT), the preclinical analogue of the calcimimetic etelcalcetide, KP\u20102326 (KP), and their combination. The results demonstrated that CKD animals had elevated blood urea nitrogen, PTH, fibroblast growth factor 23 (FGF23), and phosphorus. Treatment with KP reduced PTH levels compared with CKD animals, whereas GKT treatment increased C\u2010terminal FGF23 levels without altering intact FGF23. GKT treatment alone reduced aortic calcification and NOX4 expression but did not alter the oxidative stress marker 8\u2010OHdG in the serum or aorta. KP treatment reduced aortic 8\u2010OHdG and inhibited the ability for GKT to reduce aortic calcification. Treatments did not alter heart calcification or left ventricular mass. In the skeleton, CKD animals had reduced trabecular bone volume fraction and trabecular number with increased trabecular spacing that were not improved with either treatment. The cortical bone was not altered by CKD or by treatments at this early stage of CKD. These results suggest that GKT reduces aortic calcification while KP reduces aortic oxidative stress and reduces PTH, but the combination was not additive. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10600","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T02:05:03Z","timestamp":1642039503000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>Non\u2010Additive<\/scp>\n                    Effects of Combined\n                    <scp>NOX1<\/scp>\n                    \/4 Inhibition and Calcimimetic Treatment on a Rat Model of Chronic Kidney Disease\u2010Mineral and Bone Disorder (\n                    <scp>CKD\u2010MBD<\/scp>\n                    )"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7374-0187","authenticated-orcid":false,"given":"John G","family":"Damrath","sequence":"first","affiliation":[{"name":"Weldon School of Biomedical Engineering Purdue University  West Lafayette IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal X","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne E","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruthi","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalisha","family":"O'Neill","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Biruete","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith G","family":"Avin","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Department of Physical Therapy Indiana University School of Health and Rehabilitation Sciences  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-8058","authenticated-orcid":false,"given":"Joseph M","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Indiana University\u2010Purdue University at Indianapolis  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-9004","authenticated-orcid":false,"given":"Matthew R","family":"Allen","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Department of Anatomy and Cell Biology Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3562-9725","authenticated-orcid":false,"given":"Sharon M","family":"Moe","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Department of Anatomy and Cell Biology Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Department of Medicine Roudebush Veterans Administration Medical Center  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Centers for Disease Control and Prevention Chronic kidney disease in the United States 2021 [Internet]. 2021. 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