{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T22:51:05Z","timestamp":1780440665502,"version":"3.54.1"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,13]],"date-time":"2018-09-13T00:00:00Z","timestamp":1536796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Hrvatska Zaklada za Znanost","doi-asserted-by":"publisher","award":["IP-2014-09-9730"],"award-info":[{"award-number":["IP-2014-09-9730"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nutrition is an important factor that influences bone metabolism, the endocrine and\/or paracrine system, and bone-active mineral elements homeostasis. We studied antiosteoporotic effects of grape seed proanthocyanidins extract, icariin or alendronate (ALN) in retinoic acid-induced (13cRA) bone loss in rats. Proanthocyanidins and icariin have beneficial effects on bone health; they have improved the bone weight reduction, the length and the diameter of the bone, calcium, and phosphorus content in bone ash, bone mineral density (BMD), the biochemical markers of bone turnover and uterus atrophy induced by 13cRA. All results suggest that proanthocyanidins and icariin reverse osteoporosis in 13cRA rats by stimulating bone formation or regulating bone resorption by their antioxidative and estrogenic-like activity without toxic side-effects observed in ALN treatment.<\/jats:p>","DOI":"10.3390\/ijms19092746","type":"journal-article","created":{"date-parts":[[2018,9,13]],"date-time":"2018-09-13T11:46:04Z","timestamp":1536839164000},"page":"2746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Beneficial Effect of Proanthocyanidins and Icariin on Biochemical Markers of Bone Turnover in Rats"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5102-3606","authenticated-orcid":false,"given":"Nada","family":"Or\u0161oli\u0107","sequence":"first","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Nemrava","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-0197","authenticated-orcid":false,"given":"\u017deljko","family":"Jele\u010d","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Specialty Hospital St. Catherine, 49210 Zabok, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kukolj","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-755X","authenticated-orcid":false,"given":"Dyana","family":"Odeh","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svjetlana","family":"Terzi\u0107","sequence":"additional","affiliation":[{"name":"Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajko","family":"Fure\u0161","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, General Hospital Zabok, 49210 Zabok, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomica","family":"Bagatin","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinko","family":"Bagatin","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1007\/s00394-013-0622-7","article-title":"Role of flavonoids on oxidative stress and mineral contents in the retinoic acid-induced bone loss model of rat","volume":"53","author":"Lazarus","year":"2014","journal-title":"Eur. J. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.phrs.2017.03.002","article-title":"Berberine bioisostere Q8 compound stimulates osteoblast differentiation and function in vitro","volume":"119","author":"Han","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.phrs.2011.03.012","article-title":"Green tea and bone health: Evidence from laboratory studies","volume":"64","author":"Shen","year":"2011","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.phrs.2016.06.013","article-title":"Emblica officinalis (Amla): A review for its phytochemistry, ethnomedicinal uses and medicinal potentials with respect to molecular mechanisms","volume":"111","author":"Variya","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4062\/biomolther.2015.122","article-title":"Quercetin Directly Interacts with Vitamin D Receptor (VDR): Structural Implication of VDR Activation by Quercetin","volume":"24","author":"Lee","year":"2016","journal-title":"Biomol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.3748\/wjg.v23.i16.2841","article-title":"Oxidative stress, antioxidants and intestinal calcium absorption","volume":"23","author":"Guizzardi","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3896\/IBRA.4.02.1.01","article-title":"A review of propolis antitumor action in vivo and in vitro","volume":"2","year":"2010","journal-title":"J. ApiProd. ApiMed. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lephart, E.D. (2015). Modulation of Aromatase by Phytoestrogens. Enzyme Res., 2015.","DOI":"10.1155\/2015\/594656"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1007\/s13197-017-2692-7","article-title":"Bioactivity-based antioxidative components screening and evaluation in grape seed proanthocyanidin extract","volume":"54","author":"Gao","year":"2017","journal-title":"J. Food Sci. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xiong, W., Zhang, W., Yuan, W., Du, H., Ming, K., Yao, F., Bai, J., Chen, Y., Liu, J., and Wang, D. (2017). Phosphorylation of Icariin Can Alleviate the Oxidative Stress Caused by the Duck Hepatitis Virus A through Mitogen-Activated Protein Kinases Signaling Pathways. Front Microbiol.","DOI":"10.3389\/fmicb.2017.01850"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev.arplant.55.031903.141729","article-title":"Phytoestrogens","volume":"55","author":"Dixon","year":"2004","journal-title":"Annu. Rev. Plant Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0378-4274(01)00503-3","article-title":"Tissue-specific estrogenic response and molecular mechanisms","volume":"127","author":"Diel","year":"2002","journal-title":"Toxicol. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1002\/jbmr.1645","article-title":"Oral alendronate use and risk of cancer in postmenopausal women with osteoporosis: A. nationwide study","volume":"27","author":"Chiang","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1056\/NEJMoa0807684","article-title":"WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women","volume":"360","author":"Chlebowski","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1001\/jama.288.3.321","article-title":"Writing Group for the Women\u2019s Health Initiative Investigators. Writing group for the Women\u2019s Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women\u2019s Health Initiative randomized controlled trial","volume":"288","author":"Rossouw","year":"2002","journal-title":"JAMA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1634\/theoncologist.9-90004-28","article-title":"Safety of intravenous and oral bisphosphonates and compliance with dosing regimens","volume":"9","author":"Conte","year":"2004","journal-title":"Oncologist"},{"key":"ref_17","first-page":"106","article-title":"Alendronate-associated osteonecrosis of the jaws: A review of the main topic","volume":"19","author":"Vargas","year":"2014","journal-title":"Med. Oral Patol. Oral. Cir. Bucal"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"338","DOI":"10.4065\/mcp.2010.0636","article-title":"Update on medications with adverse skeletal effects","volume":"86","author":"Pitts","year":"2011","journal-title":"Mayo Clin. Proc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1359\/jbmr.2001.16.10.1899","article-title":"Vitamin A antagonizes calcium response to vitamin D in man","volume":"16","author":"Johansson","year":"2001","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1515\/pjfns-2017-0023","article-title":"The effect of quercetin on bone mineral status and markers of bone turnover in retinoic acid-induced osteoporosis","volume":"68","author":"Nemrava","year":"2018","journal-title":"Pol. J. Food Nutr. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"27285","DOI":"10.1074\/jbc.M702810200","article-title":"Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids","volume":"282","author":"Almeida","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1515\/cclm-2015-0807","article-title":"Oxidative damage and the pathogenesis of menopause related disturbances and diseases","volume":"54","author":"Cervellati","year":"2016","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s11010-005-9077-3","article-title":"All-trans retinoic acid induces free radical generation and modulate antioxidant enzyme activities in rat sertoli cells","volume":"285","author":"Behr","year":"2006","journal-title":"Mol. Cell Biochem."},{"key":"ref_24","first-page":"1559","article-title":"Oxidative Stress as a Risk Factor of Osteoporotic Model Induced by Vitamin A in Rats","volume":"3","author":"Fahmy","year":"2009","journal-title":"Aust. J. Basic Appl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1093\/jn\/116.4.578","article-title":"Hypervitaminosis A and calcium-regulating.hormones in the rat","volume":"116","author":"Frankel","year":"1986","journal-title":"J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.0906-6705.2004.00112.x","article-title":"Retinol, at concentrations greater than the physiological limit, induces oxidative stress and apoptosis in human dermal fibroblasts","volume":"13","author":"Gimeno","year":"2004","journal-title":"Exp. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1210\/endo-122-6-2933","article-title":"Effects of hypervitaminosis A on the bone and mineral metabolism of the rat","volume":"122","author":"Hough","year":"1988","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/BF00310266","article-title":"Inhibitory effects of 9-cis and all trans retinoic acid on 1, 25 (OH) vitamin D-induced bone resorption","volume":"57","author":"Kindmark","year":"1995","journal-title":"Calcif. Tissue Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.bone.2004.11.006","article-title":"Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents","volume":"36","author":"Kneissel","year":"2005","journal-title":"Bone"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.tem.2012.03.008","article-title":"Estrogen and the Skeleton","volume":"23","author":"Khosla","year":"2012","journal-title":"Trends Endocrinol. MeTab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1081\/ERC-120018674","article-title":"Effects of different nylestriol\/levonorgestrel dosages on bone metabolism in female Sprague-Dawley rats with retinoic acid-induced osteoporosis","volume":"29","author":"Liao","year":"2003","journal-title":"Endocr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1172\/JCI117026","article-title":"Retinoic acid suppresses parathyroid hormone (PTH) secretion and PreproPTH mRNA levels in bovine parathyroid cell culture","volume":"93","author":"MacDonald","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.cccn.2005.04.014","article-title":"Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats","volume":"360","author":"Muthusami","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/8756-3282(90)90072-7","article-title":"Retinoic acid and 1, 25-dihydroxy vitamin D stimulate osteoclast formation by different mechanisms","volume":"11","author":"Scheven","year":"1990","journal-title":"Bone"},{"key":"ref_35","first-page":"20","article-title":"Bone quality and bone strength: Benefits of the bone-forming approach","volume":"11","author":"Iolascon","year":"2014","journal-title":"Clin. Cases Miner. Bone Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"C\u00e1diz-Gurrea, M.L., Borr\u00e1s-Linares, I., Lozano-S\u00e1nchez, J., Joven, J., Fern\u00e1ndez-Arroyo, S., and Segura-Carretero, A. (2017). Cocoa and Grape Seed Byproducts as a Source of Antioxidant and Anti-Inflammatory Proanthocyanidins. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020376"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.4103\/1673-5374.194722","article-title":"Protective effect of ginkgo proanthocyanidins against cerebral ischemia\/reperfusion injury associated with its antioxidant effects","volume":"11","author":"Cao","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hozayen, W.G., El-Desouky, M.A., Soliman, H.A., Ahmed, R.R., and Khaliefa, A.K. (2016). Antiosteoporotic effect of Petroselinum crispum, Ocimum basilicum and Cichorium intybus L. in glucocorticoid-induced osteoporosis in rats. BMC Complement. Altern. Med., 16.","DOI":"10.1186\/s12906-016-1140-y"},{"key":"ref_39","first-page":"399","article-title":"Nondigestible oligosaccharides increase calcium absorption and suppress bone resorption in ovariectomized rats","volume":"134","author":"Zafar","year":"2004","journal-title":"Int. J. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1210\/edrv-15-3-301","article-title":"Estrogen effects on calcitropic hormones and calcium homestasis","volume":"15","author":"Hoenderop","year":"1994","journal-title":"Endocr. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/nm.4481","article-title":"Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity","volume":"24","author":"Bartelt","year":"2018","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, F., Gao, B., Dong, H., Shi, J., and Fang, D. (2015). Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119955"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/mnfr.201200463","article-title":"Grape seed proanthocyanidin extracts alleviate oxidative stress and ER stress in skeletal muscle of low dose streptozotocin- and high-carbohydrate\/high-fat diet-induced diabetic rats","volume":"57","author":"Ding","year":"2013","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_44","first-page":"35","article-title":"The effects of sustained delivery of alendronate on the kidney in ovariectomized female rats","volume":"48","author":"Benghuzzi","year":"2012","journal-title":"Biomed. Sci. Instrum."},{"key":"ref_45","first-page":"CD002010","article-title":"Bisphosphonates for osteoporosis in people with cystic fibrosis","volume":"18","author":"Conwell","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/ki.2008.356","article-title":"Bisphosphonate Nephrotoxicity","volume":"74","author":"Perazzella","year":"2008","journal-title":"Kidney Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plefa.2004.04.005","article-title":"Gastroprotective effect of leukotriene receptor blocker montelukast in alendronat-induced lesions of the rat gastric mucosa","volume":"72","author":"Sener","year":"2005","journal-title":"Prostag. Leukot. Essent. Fatty Acids"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.toxlet.2010.08.013","article-title":"Pro-IL-1\u03b2 accumulation in macrophages by alendronate and its prevention by clodronate","volume":"199","author":"Shikama","year":"2010","journal-title":"Toxicol. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1001\/jama.2011.190","article-title":"Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women","volume":"305","author":"Mamdani","year":"2011","journal-title":"JAMA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.intimp.2006.09.009","article-title":"Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFalpha, macrophages, and T-cells","volume":"7","author":"Deng","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3858\/emm.2011.43.10.062","article-title":"Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis","volume":"43","author":"Woo","year":"2011","journal-title":"Exp. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cbi.2016.06.027","article-title":"Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid","volume":"256","author":"Kukolj","year":"2016","journal-title":"Chem. Biol. Interact."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2746\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:20:19Z","timestamp":1760196019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,13]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["ijms19092746"],"URL":"https:\/\/doi.org\/10.3390\/ijms19092746","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,13]]}}}