Recent Advances in Anti-osteoporosis Effects and Drug Delivery System of Icaritin
ZHANG Jun1, REN Yue-ming1*, ZHANG Shuang-qing2*
1. Chinese Pharmacopeia Commission, Beijing 100061, China; 2. National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing 100050, China
Abstract：Osteoporosis is a common chronic degenerative bone disease, which has become a global health problem. Icaritin is an intestinal metabolite of traditional benefiting-bone herb Epimedium, and is also an enzymatic product of icariin, the active flavonoid ingredient of Epimedium. Icaritin exhibits an excellent anti-osteoporotic activity, however its poor solubility, bioavailability and poor bone-targeted property restrain its clinical application. Poor drug target to bone tissue/cell is also a common problem in the treatment of osteoporosis. Based on research progress of icaritin, the review covers the anti-osteoporosis characteristics, action mechanism, and drug delivery system especially the bone-targeted drug delivery system, which provide a basis for the anti-osteoporosis clinical application and drug development.
CHINA HEALTH PROMOTION FOUNDATION OSTEOPOROSIS PREVENTION AND CONTROL COMMITTEE OF THE WHITE PAPER. White paper on osteoporosis in China [J]. Chin J Health Manage (中华健康管理学杂志), 2009, 3(3): 148-154.
[2]
MA Y Z, WANG Y M, LIU Q, et al. 2018 China guideline for the diagnosis and treatment of senile osteoporosis [J]. Chin J Gerontol (中国老年学杂志), 2019, 39(11): 2557-2575.
[3]
FAIENZA M F, VENTURA A, MARZANO F, et al. Postmenopausal osteoporosis: the role of immune system cells [J]. Clin Dev Immunol, 2013, 2013: 575936.
[4]
ZHANG G, QIN L, SHI Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double blind and placebo-controlled trial [J]. J Bone Miner Res, 2007, 22(7): 1072-1079.
[5]
WONG S P, SHEN P, LEE L, et al. Pharmacokinetics of prenylflavonoids and correlations with the dynamics of estrogen action in sera following ingestion of a standardized Epimedium extract [J]. J Pharm Biomed Anal, 2009, 50(2): 216-223.
[6]
ZHANG G, QIN L, SHENG H, et al. A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner [J]. Bone, 2009, 44(2): 345-356.
[7]
HAN H, SHAN Q, ZHOU F J, et al. Research progress in metabolites of active constitutes from Epimedii Herba [J]. Drugs Clin (现代药物与临床), 2013, 28(1): 78-82.
[8]
WU D W, CI X Y, WEI Z H, et al. Inhibition effects of anhydroicaritin on important clinical drug transporters [J]. Drug Eval Res (药物评价研究), 2018, 41(6): 986-991.
[9]
NAN M L, LI S C, ZHAO Y W, et al. Preparation method and pharmacological activity of anhydroicaritin [J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2015, 21(7): 227-231.
[10]
JIANG J, LI J, JIA X. The antiosteoporotic activity of central-icaritin (CIT) on bone metabolism of ovariectomized rats [J]. Molecules, 2014, 19(11):18690-18704.
[11]
JIANG J, FENG L, SUN E, et al. Metabolic profiling of isomeric aglycones central-icaritin (c-IT) and icaritin (IT) in osteoporotic rats by UPLC-QTOF-MS [J]. Drug Test Anal, 2015, 7(4): 309-319.
[12]
WANG C, ZHANG K, LI W, et al. Effects of anhydroicaritin microemulsion formulation on the immunologic bocytopenic purpura mice [J]. Chin J New Drugs (中国新药杂志), 2017, 26(5): 555-561.
[13]
CHEN J. The pharmaceutical research of anhydroicaritin capsule [D]. Tianjin: Tianjin Medical University, 2017.
[14]
ZENG H T, GUO J, CHEN Y. Research progress on pharmacology effects and new drug delivery system of icaritin [J]. Chin Tradit Herb Drugs (中草药), 2020, 51(20): 5372-5380.
[15]
HOU K M, LI Q R, YANG Q, et al. Effect of icaritin on proliferation and apoptosis of human ovarian cancer cells SKOV3 [J]. China J Chin Mater Med (中国中药杂志), 2021,46(1):183-189.
[16]
XU Y M, XU H G, GAO Z, et al. Icaritin protects the ICMT-induced degeneration of endplate chondrocytes via inhibiting Hedgehog signaling pathway [J]. Chin J Clin Pharmacol Ther (中国临床药理学与治疗学), 2017, 22(4): 373-380.
[17]
LIU H P, MENG F H, GUO J F, et al. Pharmacokinetics of icaritin in rats [J]. Chin Pharm J (中国药学杂志), 2010, 45(7):539-543.
[18]
LIU H P, MENG F H, GUO J F, et al. Determination of icaritin in rat plasma by HPLC-MS/MS [J]. Acta Pharm Sin (药学学报), 2009, 44(10): 1140-1144.
[19]
MA H, HE X, YANG Y, et al. The genus Epimedium: an ethnopharmacological and phytochemical review [J]. J Ethnopharmacol, 2011, 134(3): 519-541.
[20]
HUANG Z W, YANG Y X, HUANG L H, et al. Pharmacokinetics and metabolism of icaritin in rats by UPLC-MS/MS [J]. Food Sci Nutr, 2019, 7(12): 4001-4006.
[21]
PENG S, ZHANG G, ZHANG B T, et al. The beneficial effect of icaritin on osteoporotic bone is dependent on the treatment initiation timing in adult ovariectomized rats [J]. Bone, 2013, 55(1): 230-240.
[22]
TAN E M, LI L, INDRAN I R, et al. TRAF6 mediates suppression of osteoclastogenesis and prevention of ovariectomy-induced bone loss by a novel prenylflavonoid [J]. J Bone Miner Res, 2017, 32(4): 846-860.
[23]
LIM R, LI L, CHEW N, et al. The prenylflavonoid icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3 (STAT-3) regulation of C-X-C chemokine receptor type 4 (CXCR4) expression [J]. Bone, 2017, 105: 122-133.
[24]
YE H Y, LIU J, LOU Y J. Preparation of two derivatives from icariin and investigation of their estrogen-like effects [J]. J Zhejiang Univ(Med Sci) (浙江大学学报:医学版), 2005, 34(2): 131-136.
[25]
RACHNER T D, KHOSLA S, HOFBAUER L C. Osteoporosis: now and the future [J]. Lancet, 2011, 377(9773): 1276-1287.
[26]
TAKAYANAGI H. New developments in osteoimmunology [J]. Nat Rev Rheumatol, 2012, 8(11): 684-689.
[27]
HOFBAUER L C, KHOSLA S, DUNSTAN C R, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells [J]. Endocrinology, 1999, 140(9): 4367-4370.
[28]
HUANG J, YUAN L, WANG X, et al. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro [J]. Life Sci, 2007, 81(10): 832-840.
[29]
YAO D, XIE X H, WANG X L, et al. Icaritin, an exogenous phytomolecule, enhances osteogenesis but not angiogenesis—an in vitro efficacy study [J]. PLoS One, 2012, 7(8): e41264.
[30]
LUO G, XU B, WANG W, et al. Study of the osteogenesis effect of icariside II and icaritin on canine bone marrow mesenchymal stem cells [J]. J Bone Miner Metab, 2018, 36(6): 668-678.
[31]
CHAU J F, LEONG W F, LI B. Signaling pathways governing osteoblast proliferation, differentiation and function [J]. Histol Histopathol, 2009, 24(12): 1593-1606.
[32]
BURGERS T A, WILLIAMS B O. Regulation of Wnt/β-catenin signaling within and from osteocytes [J]. Bone, 2013, 54(2): 244-249.
[33]
SHENG H, RUI X F, SHENG C J, et al. A novel semisynthetic molecule icaritin stimulates osteogenic differentiation and inhibits adipogenesis of mesenchymal stem cells [J]. Int J Med Sci, 2013, 10(6): 782-789.
[34]
HOLMEN S L, ZYLSTRA C R, MUKHERJEE A, et al. Essential role of beta-catenin in postnatal bone acquisition [J]. J Biol Chem, 2005, 280(22): 21162-21168.
[35]
ZHANG S Q, ZHANG S Z. Oral absorption, distribution, metabolism and excretion of icaritin in rats by Q-TOF and UHPLC-MS/MS [J]. Drug Test Analysis, 2017, 9(10): 1604-1610.
[36]
ZHANG S Q. Dynamic biodistribution of icaritin and its phase II metabolite in rat tissues by ultra-high performance liquid chromatography-tandem mass spectrometry [J]. Anal Sci, 2016, 32(5): 631-637.
[37]
ZHANG S Q. Ultra-high performance liquid chromatography-tandem mass spectrometry for the quantification of icaritin in mouse bone [J]. J Chromatogr B, 2015, 978(1): 24-28.
[38]
ZHANG S Q. Biodistribution evaluation of icaritin in rats by ultra-performance liquid chromatography-tandem mass spectrometry [J]. J Ethnopharmacol, 2014, 155(2): 1382-1387.
[39]
JIA Z, ZHANG Y, CHEN Z X, et al. Pharmacokinetics of icaritin active bone-targeting nanoparticles in rats [J]. J Hygiene Res (卫生研究), 2019, 48(5): 847-849.
[40]
WU L. Study on preparation and dissolution rate of icaritin-poloxamer 188 solid dispersion [J]. China Pharm (中国药房), 2015, 26(19): 2702-2704.
[41]
LI Y, SUN S, CHANG Q, et al. A strategy for the improvement of the bioavailability and antiosteoporosis activity of BCS IV flavonoid glycosides through the formulation of their lipophilic aglycone into nanocrystals [J]. Mol Pharm, 2013, 10(7): 2534-2542.
[42]
HUANG H, LIU X G, CHEN S D, et al. Preparation and characterization of icaritin solid lipid nanoparticle [J]. J Chin Med Mater (中药材), 2015, 38(6): 1312-1314.
[43]
LI J, LIU C F, ZHONG X Y, et al. Protective effect of icaritin liposome against hepatic ischemia reperfusion injury in rats and its mechanism [J]. Acad J Sec Mil Med Univ (第二军医大学学报), 2017, 38(6): 739-745.
[44]
FENG Q, XU J, ZHANG K, et al. Dynamic and cell-infiltratable hydrogels as injectable carrier of therapeutic cells and drugs for treating challenging bone defects [J]. ACS Cent Sci, 2019, 5(3): 440-450.
[45]
YANG J G, ZHANG J, CHEN X J, et al. Stable loading and delivery of icaritin using PEG-PCL micelles for effective treatment of oral squamous cell carcinoma [J]. Curr Drug Deliv, 2020, doi: 10.2174/1567201818999201210211636.
[46]
SHAN S, YAO J, XU L, et al. Preparation of icaritin-loaded mPEG-PLA micelles and evaluation on ischemic brain injury [J]. J Biomed Nanotechnol, 2019, 15(4): 674-685.
[47]
CHENG H, CHAWLA A, YANG Y, et al. Development of nanomaterials for bone-targeted drug delivery [J]. Drug Discov Today, 2017, 22(9):1336-1350.
[48]
CHEN S, ZHENG L, ZHANG J, et al. A novel bone targeting delivery system carrying phytomolecule icaritin for prevention of steroid-associated osteonecrosis in rats [J]. Bone, 2018, 106: 52-60.
2021, Vol. 56 
