{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T19:37:36Z","timestamp":1780601856595,"version":"3.54.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008908","name":"Universit\u00e0 degli Studi di Messina","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008908","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Zoledronic acid (Zol) is a widely used intravenous aminobisphosphonate to treat both benign and malignant skeletal diseases, and bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect whose pathophysiology remains poorly understood. Vascular Endothelial Growth Factor (VEGF) has been recognized to mediate BRONJ in cancer patients undergoing Zol treatment, however data on VEGF are lacking in patients with osteoporosis. Increasing evidences demonstrate that vitamin D influences VEGF levels. The aim of this study was to investigate the influence of Zol on VEGF levels and the possible role for vitamin D on the Zol mediated changes of VEGF concentration in women with postmenopausal osteoporosis. Twenty-eight postmenopausal women with osteoporosis were enrolled and randomized into two groups to receive Zol (5 mg) or placebo. At baseline, at day-3 and day-30 VEGF serum levels were measured; bone turnover markers, 25-hydroxyvitamin D [25(OH)D] and serum calcium were evaluated at baseline. In Zol-treated women, VEGF increased significantly on day-3, and then decreased on day-30. In the Zol-treated women, the percent change of VEGF levels between baseline and day-30 (\u221218% at day-30 vs. baseline, <jats:italic>p<\/jats:italic> = 0.01) was significantly associated with serum 25(OH)D values (<jats:italic>r<\/jats:italic> = 0.29, <jats:italic>p<\/jats:italic> = 0.028). At a stepwise multiple regression analysis, after correcting for age, BMI, time since menopause, femoral neck BMD, osteocalcin, C-terminal telopeptide of type 1 collagen, and baseline VEGF levels, 25(OH)D levels were independently associated with VEGF change (\u03b2 = 1.7, SE = 0.71, <jats:italic>p<\/jats:italic> = 0.03). For the first time, we detected early modifications of circulating VEGF in postmenopausal women receiving Zol for osteoporosis, identifying a vitamin D-dependent modulation of these changes.<\/jats:p>","DOI":"10.3389\/fmed.2021.748438","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T06:08:40Z","timestamp":1637215720000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Early Changes of VEGF Levels After Zoledronic Acid in Women With Postmenopausal Osteoporosis: A Potential Role of Vitamin D"],"prefix":"10.3389","volume":"8","author":[{"given":"Federica","family":"Bellone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Ruggero","family":"Sottile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Gaudio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Loddo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Corica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunziata","family":"Morabito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"115390","DOI":"10.1016\/j.bone.2020.115390","article-title":"Zoledronate","volume":"137","author":"Reid","year":"2020","journal-title":"Bone."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1056\/NEJMoa067312","article-title":"Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis","volume":"356","author":"Black","year":"2007","journal-title":"N Engl J Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1002\/jbmr.1494","article-title":"The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)","volume":"27","author":"Black","year":"2012","journal-title":"J Bone Miner Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1007\/BF02556671","article-title":"The acute-phase response after bisphosphonate administration","volume":"41","author":"Adami","year":"1987","journal-title":"Calcif Tissue Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.oooo.2020.03.051","article-title":"Which symptoms negatively affect the oral health-related quality of life in patients with osteonecrosis of the jaw?","volume":"130","author":"Sato","year":"2020","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol."},{"key":"B6","first-page":"37","article-title":"Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ)","volume":"4","author":"Ruggiero","year":"2007","journal-title":"Clin Cases Miner Bone Metab."},{"key":"B7","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.oooo.2012.08.439","article-title":"The relationship of denosumab pharmacology and osteonecrosis of the jaws","volume":"114","author":"Malan","year":"2012","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"135","DOI":"10.23736\/S0026-4970.17.04056-0","article-title":"Medication-related osteonecrosis of the jaw: risk factors in patients under biphosphonate versus patients under antiresorptive-antiangiogenic drugs","volume":"66","author":"Ghidini","year":"2017","journal-title":"Minerva Dent Oral Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1080\/14740338.2016.1177021","article-title":"Osteonecrosis of jaw beyond antiresorptive (Bone-Targeted) agents: new horizons in oncology","volume":"15","author":"Fusco","year":"2016","journal-title":"Expert Opin Drug Saf."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/4021952","article-title":"Could the combined administration of bone antiresorptive drug, taxanes, and corticosteroids worsen medication related osteonecrosis of the jaws in cancer patients?","volume":"2018","author":"Oteri","year":"2018","journal-title":"Biomed Res Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1359\/jbmr.0707onj","article-title":"Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research","volume":"22","author":"Khosla","year":"2007","journal-title":"J Bone Miner Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"8580","DOI":"10.1200\/JCO.2005.02.8670","article-title":"Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors","volume":"23","author":"Bamias","year":"2005","journal-title":"JCO."},{"key":"B13","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s00223-011-9499-8","article-title":"Adverse reactions and drug\u2013drug interactions in the management of women with postmenopausal osteoporosis","volume":"89","author":"Rizzoli","year":"2011","journal-title":"Calcif Tissue Int."},{"key":"B14","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nrrheum.2011.181","article-title":"Epidemiology and pathogenesis of osteonecrosis of the jaw","volume":"8","author":"Reid","year":"2012","journal-title":"Nat Rev Rheumatol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4037","DOI":"10.1200\/JCO.2007.15.5424","article-title":"Osteonecrosis of the jaw related to bevacizumab","volume":"26","author":"Estilo","year":"2008","journal-title":"JCO."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1124\/jpet.102.035295","article-title":"Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid","volume":"302","author":"Wood","year":"2002","journal-title":"J Pharmacol Exp Ther."},{"key":"B17","first-page":"2893","article-title":"Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients","volume":"9","author":"Santini","year":"2003","journal-title":"Clin Cancer Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1756-8722-5-56","article-title":"Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw","volume":"5","author":"Vincenzi","year":"2012","journal-title":"J Hematol Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.maturitas.2009.02.009","article-title":"The menopause and oral health","volume":"63","author":"Meurman","year":"2009","journal-title":"Maturitas."},{"key":"B20","doi-asserted-by":"publisher","first-page":"E1045","DOI":"10.1111\/j.1741-2358.2011.00608.x","article-title":"Oral microcirculation in post-menopause: a possible correlation with periodontitis: oral microcirculation in post-menopause","volume":"29","author":"Scardina","year":"2012","journal-title":"Gerodontology."},{"key":"B21","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.cyto.2014.10.025","article-title":"The effect of nitrogen containing bisphosphonates, zoledronate and alendronate, on the production of pro-angiogenic factors by osteoblastic cells","volume":"71","author":"Ishtiaq","year":"2015","journal-title":"Cytokine."},{"key":"B22","doi-asserted-by":"publisher","first-page":"110656","DOI":"10.1016\/j.nut.2019.110656","article-title":"Effects of cholecalciferol supplementation on serum angiogenic biomarkers in breast cancer patients treated with tamoxifen: a controlled randomized clinical trial","volume":"72","author":"Shahvegharasl","year":"2020","journal-title":"Nutrition."},{"key":"B23","doi-asserted-by":"publisher","first-page":"108444","DOI":"10.1016\/j.clim.2020.108444","article-title":"Vitamin D suppress the production of vascular endothelial growth factor in mast cell by inhibiting PI3K\/Akt\/p38 MAPK\/HIF-1\u03b1 pathway in chronic spontaneous urticaria","volume":"215","author":"Zhao","year":"2020","journal-title":"Clin Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.3390\/nu13061878","article-title":"Vitamin D boosts alendronate tail effect on bone mineral density in postmenopausal women with osteoporosis","volume":"13","author":"Catalano","year":"2021","journal-title":"Nutrients."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1093\/annonc\/mdl045","article-title":"Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?","volume":"17","author":"Ardine","year":"2006","journal-title":"Ann Oncol."},{"key":"B26","first-page":"191","article-title":"Fracture risk assessment in postmenopausal women referred to an italian center for osteoporosis: a single day experience in Messina","volume":"10","author":"Catalano","year":"2013","journal-title":"Clin Cases Miner Bone Metab."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1002\/jbmr.5650080915","article-title":"Vertebral fracture assessment using a semiquantitative technique","volume":"8","author":"Genant","year":"2009","journal-title":"J Bone Miner Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/jbmr.521","article-title":"Circulating \u03b3\u03b4 T cells and the risk of acute-phase response after zoledronic acid administration","volume":"27","author":"Rossini","year":"2012","journal-title":"J Bone Miner Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00223-012-9577-6","article-title":"Vitamin D reduces musculoskeletal pain after infusion of zoledronic acid for postmenopausal osteoporosis","volume":"90","author":"Catalano","year":"2012","journal-title":"Calcif Tissue Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4380","DOI":"10.1210\/jc.2010-0597","article-title":"Characterization of and risk factors for the acute-phase response after zoledronic acid","volume":"95","author":"Reid","year":"2010","journal-title":"J Clin Endocrinol Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2008\/707864","article-title":"Circulating VEGF as a biological marker in patients with rheumatoid arthritis? Preanalytical and biological variability in healthy persons and in patients","volume":"24","author":"Hetland","year":"2008","journal-title":"Dis Markers."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.4161\/cbt.22274","article-title":"Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid","volume":"13","author":"Misso","year":"2012","journal-title":"Cancer Biol Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.bbrc.2005.07.145","article-title":"Vascular endothelial growth factor receptors in osteoclast differentiation and function","volume":"335","author":"Aldridge","year":"2005","journal-title":"Biochem Biophys Res Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1111\/j.1582-4934.2005.tb00379.x","article-title":"Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF)","volume":"9","author":"Byrne","year":"2005","journal-title":"J Cellular Mol Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1007\/s40618-017-0636-8","article-title":"The effect of parathyroid hormone (1\u201384) treatment on serum bone morphogenetic protein 4 and vascular endothelial growth factor in postmenopausal women with established osteoporosis","volume":"40","author":"Pepe","year":"2017","journal-title":"J Endocrinol Invest."},{"key":"B36","doi-asserted-by":"publisher","first-page":"709","DOI":"10.5114\/aoms.2013.36896","article-title":"Circulating vascular endothelial growth factor concentrations in patients with postmenopausal osteoporosis","volume":"4","author":"Senel","year":"2013","journal-title":"Aoms."},{"key":"B37","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s11914-020-00564-9","article-title":"Osteocyte-mediated translation of mechanical stimuli to cellular signaling and its role in bone and non-bone-related clinical complications","volume":"18","author":"Yan","year":"2020","journal-title":"Curr Osteoporos Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"S19","DOI":"10.1016\/j.ctrv.2008.03.006","article-title":"Antitumor effects of bisphosphonates: promising preclinical evidence","volume":"34","author":"Guise","year":"2008","journal-title":"Cancer Treat Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"S25","DOI":"10.1016\/j.ctrv.2008.03.008","article-title":"Emerging role of bisphosphonates in the clinic\u2014antitumor activity and prevention of metastasis to bone","volume":"34","author":"Lipton","year":"2008","journal-title":"Cancer Treat Rev."},{"key":"B40","doi-asserted-by":"publisher","first-page":"4482","DOI":"10.1158\/1078-0432.CCR-07-0551","article-title":"Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients","volume":"13","author":"Santini","year":"2007","journal-title":"Clin Cancer Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1002\/jbmr.23","article-title":"Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats","volume":"25","author":"Hokugo","year":"2010","journal-title":"J Bone Miner Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1634\/theoncologist.2012-0141","article-title":"Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?","volume":"17","author":"Bedogni","year":"2012","journal-title":"Oncologist."},{"key":"B43","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1096\/fba.2018-00067","article-title":"1,25(OH) [[sb]]2[[\/s]] D [[sb]]3[[\/s]] regulates the proangiogenic activity of pericyte through VDR-mediated modulation of VEGF production and signaling of VEGF and PDGF receptors","volume":"1","author":"Jamali","year":"2019","journal-title":"FASEB BioAdvances."},{"key":"B44","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.atherosclerosis.2008.08.020","article-title":"1,25-Dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter","volume":"204","author":"Cardus","year":"2009","journal-title":"Atherosclerosis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1007\/s40618-019-01057-y","article-title":"Vitamin D status and cardiovascular outcome","volume":"42","author":"Saponaro","year":"2019","journal-title":"J Endocrinol Invest."},{"key":"B46","doi-asserted-by":"publisher","first-page":"655739","DOI":"10.3389\/fimmu.2021.655739","article-title":"Vitamin D resistance as a possible cause of autoimmune diseases: a hypothesis confirmed by a therapeutic high-dose vitamin D protocol","volume":"12","author":"Lemke","year":"2021","journal-title":"Front Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"10413","DOI":"10.1039\/D0FO01782E","article-title":"Prenatal vitamin D supplementation reduces blood pressure and improves placental angiogenesis in an animal model of preeclampsia","volume":"11","author":"Nema","year":"2020","journal-title":"Food Funct."},{"key":"B48","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1186\/s12884-017-1408-3","article-title":"The role of vitamin D in pre-eclampsia: a systematic review","volume":"17","author":"Purswani","year":"2017","journal-title":"BMC Pregnancy Childbirth."},{"key":"B49","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1080\/10641955.2019.1647231","article-title":"Role of vitamin D in influencing angiogenesis in preeclampsia","volume":"38","author":"Nema","year":"2019","journal-title":"Hypertens Pregnancy."},{"key":"B50","doi-asserted-by":"publisher","first-page":"C954","DOI":"10.1152\/ajpcell.00030.2012","article-title":"Vitamin D improves the angiogenic properties of endothelial progenitor cells","volume":"303","author":"Grundmann","year":"2012","journal-title":"Am J Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jsbmb.2013.11.017","article-title":"Activation of vitamin D receptor promotes VEGF and CuZn-SOD expression in endothelial cells","volume":"140","author":"Zhong","year":"2014","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1093\/carcin\/bgi049","article-title":"22-Oxa-1\u03b1,25-Dihydroxyvitamin D 3 inhibits metastasis and angiogenesis in lung cancer","volume":"26","author":"Nakagawa","year":"2005","journal-title":"Carcinogenesis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"101086","DOI":"10.1016\/j.ctcp.2020.101086","article-title":"Vitamin D suppresses proangiogenic factors in patients with ulcerative colitis: a randomized double blind placebo controlled clinical trial","volume":"39","author":"Emami","year":"2020","journal-title":"Complement Ther Clin Pract."},{"key":"B54","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.apsb.2018.09.002","article-title":"Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment","volume":"9","author":"Wu","year":"2019","journal-title":"Acta Pharmaceutica Sinica B."},{"key":"B55","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1161\/01.RES.87.3.214","article-title":"1\u03b1,25-Dihydroxyvitamin D [[sb]]3[[\/s]] inhibits angiogenesis in vitro and in vivo","volume":"87","author":"Mantell","year":"2000","journal-title":"Circ Res."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.748438\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T06:08:50Z","timestamp":1637215730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.748438\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":55,"alternative-id":["10.3389\/fmed.2021.748438"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.748438","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"article-number":"748438"}}