{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:15:06Z","timestamp":1790615706607,"version":"4.1.0"},"reference-count":72,"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\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Osteoporosis, the most common bone disease, is associated with compromised bone strength and increased risk of fracture. Previous studies have shown that oxidative stress contributes to the progression of osteoporosis. Specifically, for postmenopausal osteoporosis, the reduction in estrogen levels leads to increased oxidative stress in bone remodeling. Tocotrienol, a member of vitamin E that exhibits antioxidant activities, has shown potential as an agent for the treatment of osteoporosis. Most studies on the osteoprotective effects of tocotrienols had used the oral form of tocotrienols, despite their low bioavailability due the lack of transfer proteins and high metabolism in the liver. Several bone studies have utilized tocotrienol combined with a nanocarrier to produce a controlled release of tocotrienol particles into the system. However, the potential of delivering tocotrienol\u2013nanocarrier combination through the intraosseous route has never been explored. In this study, tocotrienol was combined with a nanocarrier, poly lactic-co-glycolic acid (PLGA), and injected intraosseously into the bones of ovariectomized rats to produce targeted and controlled delivery of tocotrienol into the bone microenvironment. This new form of tocotrienol delivery was compared with the conventional oral delivery in terms of their effects on bone parameters. Forty Sprague\u2013Dawley rats were divided into five groups. The first group was sham operated, while other groups were ovariectomized (OVX). Following 2\u00a0months, the right tibiae of all the rats were drilled at the metaphysis region to provide access for intraosseous injection. The estrogen group (OVX + ESTO) and tocotrienol group (OVX + TTO) were given daily oral gavages of Premarin (64.5\u00a0mg\/kg) and annatto-tocotrienol (60\u00a0mg\/kg), respectively. The locally administered tocotrienol group (OVX + TTL) was given a single intraosseous injection of tocotrienol\u2013PLGA combination. After 8\u00a0weeks of treatment, both OVX + TTO and OVX + TTL groups have significantly lower bone markers and higher bone mineral content than the OVX group. In terms of bone microarchitecture, both groups demonstrated significantly higher trabecular separation and connectivity density than the OVX group (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). Both groups also showed improvement in bone strength by the significantly higher stress, strain, stiffness, and Young\u2019s modulus parameters. In conclusion, daily oral tocotrienol and one-time intraosseous injection of tocotrienol\u2013PLGA combination were equally effective in offering protection against ovariectomy-induced bone changes.<\/jats:p>","DOI":"10.3389\/fphar.2021.706747","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T07:57:12Z","timestamp":1637222232000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Osteoprotective Effects in Postmenopausal Osteoporosis Rat Model: Oral Tocotrienol vs. Intraosseous Injection of Tocotrienol-Poly Lactic-Co-Glycolic Acid Combination"],"prefix":"10.3389","volume":"12","author":[{"given":"Nurul \u2018Izzah","family":"Ibrahim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasnul \u2018Iffah","family":"Mohd Noor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Naqib","family":"Shuid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharlina","family":"Mohamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Maaruf","family":"Abdul Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Putri Ayu","family":"Jayusman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Nazrun","family":"Shuid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isa","family":"Naina Mohamed","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":"680834","DOI":"10.1155\/2012\/680834","article-title":"Effects of Low-Dose versus High-Dose \u03b3-Tocotrienol on the Bone Cells Exposed to the Hydrogen Peroxide-Induced Oxidative Stress and Apoptosis","volume":"2012","author":"Abd Manan","year":"20122012","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"960742","DOI":"10.1155\/2012\/960742","article-title":"Effects of Tocotrienol and Lovastatin Combination on Osteoblast and Osteoclast Activity in Estrogen-Deficient Osteoporosis","volume":"2012","author":"Abdul-Majeed","year":"2012","journal-title":"Evid Based. Complement. Altern. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1124\/dmd.109.031567","article-title":"Intestinal Absorption of Gamma-Tocotrienol Is Mediated by Niemann-Pick C1-like 1: In Situ Rat Intestinal Perfusion Studies","volume":"38","author":"Abuasal","year":"2010","journal-title":"Drug Metab. Dispos"},{"key":"B4","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/1743-7075-11-52","article-title":"Pharmacological Potential of Tocotrienols: a Review","volume":"11","author":"Ahsan","year":"2014","journal-title":"Nutr. Metab. (Lond)"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12050406","article-title":"Polymer-Drug Conjugate, a Potential Therapeutic to Combat Breast and Lung Cancer","volume":"12","author":"Alven","year":"2020","journal-title":"Pharmaceutics"},{"key":"B7","first-page":"247","article-title":"Effects of Palm Tocotrienols on Oxidative Stress and Bone Strength in Ovariectomised Rats","volume":"3","author":"As","year":"2008","journal-title":"Med. Health"},{"key":"B8","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/s11914-016-0321-4","article-title":"Advances in Controlled Drug Delivery for Treatment of Osteoporosis","volume":"14","author":"Asafo-Adjei","year":"2016","journal-title":"Curr. Osteoporos. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/s00223-010-9393-9","article-title":"Association of Oxidative Stress with Postmenopausal Osteoporosis and the Effects of Hydrogen Peroxide on Osteoclast Formation in Human Bone Marrow Cell Cultures","volume":"87","author":"Baek","year":"2010","journal-title":"Calcif Tissue Int."},{"key":"B10","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.redox.2013.05.003","article-title":"Sex Hormones Modulate Circulating Antioxidant Enzymes: Impact of Estrogen Therapy","volume":"1","author":"Bellanti","year":"2013","journal-title":"Redox Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.fct.2012.09.021","article-title":"A Review on Antioxidants, Prooxidants and Related Controversy: Natural and Synthetic Compounds, Screening and Analysis Methodologies and Future Perspectives","volume":"51","author":"Carocho","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"569563","DOI":"10.1155\/2014\/569563","article-title":"Oxidative Stress and Bone Resorption Interplay as a Possible Trigger for Postmenopausal Osteoporosis","volume":"2014","author":"Cervellati","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0153120","DOI":"10.1371\/journal.pone.0153120","article-title":"Biomechanical Characteristics of Osteoporotic Fracture Healing in Ovariectomized Rats: A Systematic Review","volume":"11","author":"Chen","year":"2016","journal-title":"PloS one"},{"key":"B14","doi-asserted-by":"publisher","first-page":"143","DOI":"10.3390\/nu9020143","article-title":"The Effects of Tocotrienol and Lovastatin Co-supplementation on Bone Dynamic Histomorphometry and Bone Morphogenetic Protein-2 Expression in Rats with Estrogen Deficiency","volume":"9","author":"Chin","year":"2017","journal-title":"Nutrients"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.2147\/CIA.S67016","article-title":"Effects of Annatto-Derived Tocotrienol Supplementation on Osteoporosis Induced by Testosterone Deficiency in Rats","volume":"9","author":"Chin","year":"2014","journal-title":"Clin. Interv. Aging"},{"key":"B16","doi-asserted-by":"publisher","first-page":"S222","DOI":"10.4103\/0019-5545.161483","article-title":"Postmenopausal Syndrome","volume":"57","author":"Dalal","year":"2015","journal-title":"Indian J. Psychiatry"},{"key":"B17","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.bone.2014.07.006","article-title":"\u03b3-Tocotrienol Protects against Ovariectomy-Induced Bone Loss via Mevalonate Pathway as HMG-CoA Reductase Inhibitor","volume":"67","author":"Deng","year":"2014","journal-title":"Bone"},{"key":"B18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.11138\/ccmbm\/2017.14.1.209","article-title":"Oxidative Stress in Bone Remodeling: Role of Antioxidants","volume":"14","author":"Domazetovic","year":"2017","journal-title":"Clin. Cases Miner Bone Metab."},{"key":"B19","volume-title":"Intraosseous Vascular Access","author":"Dornhofer","year":"2021"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5157","DOI":"10.1074\/jbc.M110.180919","article-title":"Neogenin, a Receptor for Bone Morphogenetic Proteins","volume":"286","author":"Hagihara","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"726590","DOI":"10.1155\/2014\/726590","article-title":"Effects of Nrf2 Deficiency on Bone Microarchitecture in an Experimental Model of Osteoporosis","volume":"2014","author":"Ib\u00e1\u00f1ez","year":"2014","journal-title":"Oxid Med. Cel Longev"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e115595","DOI":"10.1371\/journal.pone.0115595","article-title":"Targeted Delivery of Lovastatin and Tocotrienol to Fracture Site Promotes Fracture Healing in Osteoporosis Model: Micro-computed Tomography and Biomechanical Evaluation","volume":"9","author":"Ibrahim","year":"2014","journal-title":"PloS one"},{"key":"B23","doi-asserted-by":"publisher","first-page":"12958","DOI":"10.3390\/ijerph121012958","article-title":"The Effects of Targeted Deliveries of Lovastatin and Tocotrienol on Ossification-Related Gene Expressions in Fracture Healing in an Osteoporosis Rat Model","volume":"12","author":"Ibrahim","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B24","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1590\/0103-6440201801979","article-title":"Use of Micro-computed Tomography for Bone Evaluation in Dentistry","volume":"29","author":"Irie","year":"2018","journal-title":"Braz. Dent J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.2147\/IJN.S127683","article-title":"A Review of Drug Delivery Systems Based on Nanotechnology and green Chemistry: green Nanomedicine","volume":"12","author":"Jahangirian","year":"2017","journal-title":"Int. J. Nanomedicine"},{"key":"B26","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1002\/jor.20750","article-title":"Effects of Ovariectomy on Bone Turnover, Porosity, and Biomechanical Properties in Ovine Compact Bone 12 Months Postsurgery","volume":"27","author":"Kennedy","year":"2009","journal-title":"J. Orthop. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1177\/0300060516662402","article-title":"Relationship between Bone mineral Density and Dietary Intake of \u03b2-carotene, Vitamin C, Zinc and Vegetables in Postmenopausal Korean Women: a Cross-Sectional Study","volume":"44","author":"Kim","year":"2016","journal-title":"J. Int. Med. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1146\/annurev-chembioeng-073009-100847","article-title":"Polymers for Drug Delivery Systems","volume":"1","author":"Liechty","year":"2010","journal-title":"Annu. Rev. Chem. Biomol. Eng."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1210\/jc.2002-021496","article-title":"Marked Decrease in Plasma Antioxidants in Aged Osteoporotic Women: Results of a Cross-Sectional Study","volume":"88","author":"Maggio","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B30","first-page":"489","article-title":"Oral Supplementation with Antioxidant Agents Containing Alpha Lipoic Acid: Effects on Postmenopausal Bone Mass","volume":"39","author":"Mainini","year":"2012","journal-title":"Clin. Exp. Obstet. Gynecol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1111\/j.1742-7843.2008.00241.x","article-title":"Palm Tocotrienol Exerted Better Antioxidant Activities in Bone Than Alpha-Tocopherol","volume":"103","author":"Maniam","year":"2008","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.3390\/ijms17111682","article-title":"Biological Properties of Tocotrienols: Evidence in Human Studies","volume":"17","author":"Meganathan","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23102527","article-title":"Polymeric Nanocarriers for the Delivery of Antimalarials","volume":"23","author":"Mhlwatika","year":"2018","journal-title":"Molecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"111368","DOI":"10.1016\/j.biopha.2021.111368","article-title":"Therapeutic Potential of Annatto Tocotrienol with Self-Emulsifying Drug Delivery System in a Rat Model of Postmenopausal Bone Loss","volume":"137","author":"Mohamad","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B35","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.biopha.2018.04.083","article-title":"Effects of Tocotrienol from Bixa Orellana (Annatto) on Bone Histomorphometry in a Male Osteoporosis Model Induced by Buserelin","volume":"103","author":"Mohamad","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B36","doi-asserted-by":"publisher","first-page":"372878","DOI":"10.1155\/2012\/372878","article-title":"Tocotrienol Supplementation Improves Late-phase Fracture Healing Compared to Alpha-Tocopherol in a Rat Model of Postmenopausal Osteoporosis: A Biomechanical Evaluation","volume":"2012","author":"Mohamad","year":"2012","journal-title":"Evid. Based Complement. Alternat Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.6061\/clinics\/2013(10)08","article-title":"Tocotrienol Supplementation in Postmenopausal Osteoporosis: Evidence from a Laboratory Study","volume":"68","author":"Muhammad","year":"2013","journal-title":"Clinics (Sao Paulo)"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.96451","article-title":"Tocotrienol: An Underrated Isomer of Vitamin E in Health and Diseases IntechOpen","volume-title":"Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects","author":"Musa","year":"2021"},{"key":"B39","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s002640050207","article-title":"Stimulation of Bone Formation by Intraosseous Injection of Basic Fibroblast Growth Factor in Ovariectomised Rats","volume":"22","author":"Nakamura","year":"1998","journal-title":"Int. Orthop."},{"key":"B40","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1001\/jama.285.6.785","article-title":"Prevention, Diagnosis, and Therapy","volume":"285","year":"2001","journal-title":"Jama"},{"key":"B41","first-page":"533","article-title":"Low Dose of Tocotrienols Protects Osteoblasts against Oxidative Stress","volume":"162","author":"Nizar","year":"2011","journal-title":"Clin. Ter"},{"key":"B42","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000442714","article-title":"The Biomechanical Testing for the Assessment of Bone Quality in an Experimental Model of Chronic Kidney Disease","volume":"132","author":"Oksztulska-Kolanek","year":"2016","journal-title":"Nephron"},{"key":"B43","doi-asserted-by":"publisher","first-page":"e698","DOI":"10.1038\/cddis.2013.226","article-title":"Inhibition of Rac1 Promotes BMP-2-Induced Osteoblastic Differentiation","volume":"4","author":"Onishi","year":"2013","journal-title":"Cell Death Dis"},{"key":"B44","doi-asserted-by":"publisher","first-page":"S11","DOI":"10.1016\/S0020-1383(16)47003-8","article-title":"Bone Mechanical Properties and Changes with Osteoporosis","volume":"47","author":"Osterhoff","year":"2016","journal-title":"Injury"},{"key":"B45","doi-asserted-by":"publisher","first-page":"369s","DOI":"10.1093\/jn\/131.2.369S","article-title":"Molecular Aspects of Alpha-Tocotrienol Antioxidant Action and Cell Signalling","volume":"131","author":"Packer","year":"2001","journal-title":"J. Nutr."},{"key":"B46","doi-asserted-by":"publisher","first-page":"11230","DOI":"10.1016\/s0021-9258(18)82115-9","article-title":"Tocotrienols Regulate Cholesterol Production in Mammalian Cells by post-transcriptional Suppression of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase","volume":"268","author":"Parker","year":"1993","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s13054-016-1277-6","article-title":"Use of Intra-osseous Access in Adults: a Systematic Review","volume":"20","author":"Petitpas","year":"2016","journal-title":"Crit. Care"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3283","DOI":"10.3390\/molecules23123283","article-title":"The Potential Use of Plant Natural Products and Plant Extracts with Antioxidant Properties for the Prevention\/Treatment of Neurodegenerative Diseases: In Vitro, In Vivo and Clinical Trials","volume":"23","author":"Pohl","year":"2018","journal-title":"Molecules"},{"key":"B49","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.trsl.2007.03.012","article-title":"Potential Role of the Antioxidant N-Acetylcysteine in Slowing Bone Resorption in Early post-menopausal Women: a Pilot Study","volume":"150","author":"Sanders","year":"2007","journal-title":"Transl Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"144","DOI":"10.2106\/JBJS.D.02453","article-title":"rhBMP-2\/calcium Phosphate Matrix Accelerates Osteotomy-Site Healing in a Nonhuman Primate Model at Multiple Treatment Times and Concentrations","volume":"88","author":"Seeherman","year":"2006","journal-title":"J. Bone Jt. Surg Am"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1016\/j.lfs.2005.12.001","article-title":"Tocotrienols: Vitamin E beyond Tocopherols","volume":"78","author":"Sen","year":"2006","journal-title":"Life Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.jbspin.2009.02.005","article-title":"Antioxidant Status in Patients with Osteoporosis: A Controlled Study","volume":"76","author":"Sendur","year":"2009","journal-title":"Jt. Bone Spine"},{"key":"B53","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s11746-009-1526-9","article-title":"The Antioxidant Functions of Tocopherol and Tocotrienol Homologues in Oils, Fats, and Food Systems","volume":"87","author":"Seppanen","year":"2010","journal-title":"J. Am. Oil Chem. Soc."},{"key":"B54","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/0891-5849(91)90033-y","article-title":"Free Radical Recycling and Intramembrane Mobility in the Antioxidant Properties of Alpha-Tocopherol and Alpha-Tocotrienol","volume":"10","author":"Serbinova","year":"1991","journal-title":"Free Radic. Biol. Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/0076-6879(94)34105-2","article-title":"Antioxidant Properties of Alpha-Tocopherol and Alpha-Tocotrienol","volume":"234","author":"Serbinova","year":"1994","journal-title":"Methods Enzymol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.bone.2017.06.010","article-title":"Body Composition by DXA","volume":"104","author":"Shepherd","year":"2017","journal-title":"Bone"},{"key":"B57","doi-asserted-by":"publisher","first-page":"846","DOI":"10.4103\/2230-8210.192914","article-title":"Bone Turnover Markers: Emerging Tool in the Management of Osteoporosis","volume":"20","author":"Shetty","year":"2016","journal-title":"Indian J. Endocrinol. Metab."},{"key":"B58","doi-asserted-by":"publisher","first-page":"532862","DOI":"10.1155\/2012\/532862","article-title":"Palm Tocotrienol Supplementation Enhanced Bone Formation in Oestrogen-Deficient Rats","volume":"2012","author":"Soelaiman","year":"2012","journal-title":"Int. J. Endocrinol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"25054","DOI":"10.1074\/jbc.M605575200","article-title":"Insig-dependent Ubiquitination and Degradation of 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase Stimulated by delta- and Gamma-Tocotrienols","volume":"281","author":"Song","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B60","doi-asserted-by":"publisher","first-page":"46","DOI":"10.5152\/eurjrheum.2016.048","article-title":"An Overview and Management of Osteoporosis","volume":"4","author":"S\u00f6zen","year":"2017","journal-title":"Eur. J. Rheumatol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s40824-020-00190-7","article-title":"Recent Advances in Polymeric Drug Delivery Systems","volume":"24","author":"Sung","year":"2020","journal-title":"Biomater. Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"10692","DOI":"10.1021\/bi00091a020","article-title":"Structural and Dynamic Membrane Properties of Alpha-Tocopherol and Alpha-Tocotrienol: Implication to the Molecular Mechanism of Their Antioxidant Potency","volume":"32","author":"Suzuki","year":"1993","journal-title":"Biochemistry"},{"key":"B63","doi-asserted-by":"publisher","first-page":"9081686","DOI":"10.1155\/2020\/9081686","article-title":"Antioxidant Potential Overviews of Secondary Metabolites (Polyphenols) in Fruits","volume":"2020","author":"Swallah","year":"2020","journal-title":"Int. J. Food Sci."},{"key":"B64","volume-title":"Small Animal Clinical Techniques","author":"Taylor","year":"2020"},{"key":"B65","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/s0168-3659(98)00146-1","article-title":"Modification of Release Rates of Cyclosporin A from polyl(L-Lactic Acid) Microspheres by Fatty Acid Esters and Iin-Vvivo Evaluation of the Microspheres","volume":"58","author":"Urata","year":"1999","journal-title":"J. Control. Release"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.2147\/DDDT.S168935","article-title":"Annatto-derived Tocotrienol Stimulates Osteogenic Activity in Preosteoblastic MC3T3-E1 Cells: a Temporal Sequential Study","volume":"12","author":"Wan Hasan","year":"2018","journal-title":"Drug Des. Devel Ther."},{"key":"B67","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3389\/fendo.2015.00080","article-title":"Using Micro-CT Derived Bone Microarchitecture to Analyze Bone Stiffness - A Case Study on Osteoporosis Rat Bone","volume":"6","author":"Wu","year":"2015","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B68","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/BF00675627","article-title":"Increased Bone Growth by Local Prostaglandin E2 in Rats","volume":"52","author":"Yang","year":"1993","journal-title":"Calcif Tissue Int."},{"key":"B69","doi-asserted-by":"publisher","first-page":"351895","DOI":"10.1155\/2013\/351895","article-title":"Tanshinol Attenuates the Deleterious Effects of Oxidative Stress on Osteoblastic Differentiation via Wnt\/FoxO3a Signaling","volume":"2013","author":"Yang","year":"20132013","journal-title":"Oxid Med. Cel Longev"},{"key":"B70","first-page":"15","article-title":"Tocotrienol and Tocopherol Contents of Annatto Seed Accessions","volume":"10","author":"Yong","year":"2014","journal-title":"J. Sci. Technol. Trop."},{"key":"B71","doi-asserted-by":"publisher","first-page":"323","DOI":"10.3340\/jkns.2012.51.6.323","article-title":"The Change of Bone Metabolism in Ovariectomized Rats : Analyses of MicroCT Scan and Biochemical Markers of Bone Turnover","volume":"51","author":"Yoon","year":"2012","journal-title":"J. Korean Neurosurg. Soc."},{"key":"B72","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1186\/s13018-019-1512-3","article-title":"The BMP Signaling Pathway Enhances the Osteoblastic Differentiation of Bone Marrow Mesenchymal Stem Cells in Rats with Osteoporosis","volume":"14","author":"Zhao","year":"2019","journal-title":"J. Orthop. Surg. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.706747\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T07:57:22Z","timestamp":1637222242000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.706747\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":72,"alternative-id":["10.3389\/fphar.2021.706747"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.706747","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"article-number":"706747"}}