{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:09:26Z","timestamp":1768565366750,"version":"3.49.0"},"posted":{"date-parts":[[2023,5,11]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":46,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Context.<\/jats:italic>\n                  Canagliflozin has been reported to increase the risk of bone fracture \u2013 possibly mediated by decreasing 1,25-dihydroxyvitamin D [1,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D] and increasing PTH.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Objective.<\/jats:italic>\n                  To investigate whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Design.<\/jats:italic>\n                  This study had a paired design comparing individual participants before and after VitD3 supplementation.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Setting.<\/jats:italic>\n                  Community-based outpatient.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Patients.<\/jats:italic>\n                  11 VitD deficient (25-hydroxyvitamin D [25(OH)D] \u2264 20 ng\/mL) individuals recruited from the Amish population in Lancaster PA.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Interventions.<\/jats:italic>\n                  Participants underwent two canagliflozin challenge protocols (300 mg daily for five days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4-6 weeks) to achieve 25(OH)D \u2265 30 ng\/mL.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Main Outcome Measures.<\/jats:italic>\n                  Two co-primary endpoints were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D and PTH. Secondary endpoints included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH.\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Results.<\/jats:italic>\n                  VitD3 supplementation increased mean 25(OH)D from 16.5\u00b11.6 to 44.3\u00b15.5 ng\/mL (p=0.0006) and 24,25-dihydroxyvitamin D [24,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D] from 1.0\u00b10.1 to 4.3\u00b10.6 ng\/mL (p=0.0002). Mean 1,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D (from \u221231.3%\u00b14.7% to \u22129.3%\u00b18.3%; p=0.04) and PTH (from +36.2%\u00b16.2% to +9.7%\u00b13.7%; p=0.005).\n                <\/jats:p>\n                <jats:p>\n                  <jats:italic>Conclusions.<\/jats:italic>\n                  VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin\u2019s short-term adverse effects on 1,25(OH)\n                  <jats:sub>2<\/jats:sub>\n                  D and PTH.\n                <\/jats:p>","DOI":"10.1101\/2023.05.11.23289854","type":"posted-content","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T18:10:12Z","timestamp":1683828612000},"source":"Crossref","is-referenced-by-count":1,"title":["Vitamin D deficiency increases vulnerability to canagliflozin-induced adverse effects on 1,25-dihydroxyvitamin D and PTH"],"prefix":"10.64898","author":[{"given":"Zhinous","family":"Shahidzadeh Yazdi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth A.","family":"Streeten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary B.","family":"Whitlatch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"May E.","family":"Montasser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amber L.","family":"Beitelshees","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-7854","authenticated-orcid":false,"given":"Simeon I.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023083013101048000_2023.05.11.23289854v2.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1811744"},{"key":"2023083013101048000_2023.05.11.23289854v2.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1812389"},{"key":"2023083013101048000_2023.05.11.23289854v2.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"2023083013101048000_2023.05.11.23289854v2.4","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3167"},{"issue":"14","key":"2023083013101048000_2023.05.11.23289854v2.5","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1001\/jama.2020.1906","article-title":"Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes","volume":"323","year":"2020","journal-title":"JAMA"},{"key":"2023083013101048000_2023.05.11.23289854v2.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2022190"},{"issue":"9","key":"2023083013101048000_2023.05.11.23289854v2.7","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1161\/CIRCULATIONAHA.122.059785","article-title":"Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes","volume":"146","year":"2022","journal-title":"Circulation"},{"key":"2023083013101048000_2023.05.11.23289854v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.356"},{"key":"2023083013101048000_2023.05.11.23289854v2.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1600827"},{"key":"2023083013101048000_2023.05.11.23289854v2.10","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1860"},{"key":"2023083013101048000_2023.05.11.23289854v2.11","doi-asserted-by":"crossref","unstructured":"Blau JE , Bauman V , Conway EM , Piaggi P , Walter MF , Wright EC , et al. 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