Isoflavones Potentials for the Treatment of Osteoporosis: An Update on In-vivo Studies

Main Article Content

Hamid Reza Chaboki
Farideh Akbarian
Hossein Kazemi Mehrjerdi

Abstract

In plant-derived compounds, phytoestrogens are biologically active substances that exhibit various estrogenic and antiestrogenic effects. With the increasing prevalence of osteoporosis among older women caused by estrogen deficiency, identifying natural substances that can potentially treat the disease is of utmost significance. This review study aimed to explore how phytoestrogen metabolites mimic mammalian estrogens and prevent bone loss following menopause. Phytoestrogens derived from plants have gained considerable attention due to their similarity to mammalian estrogens and lower impact on sensitive tissues, such as the uterus and breasts. One well-established approach to simulate postmenopausal conditions is by using ovariectomized rats or mice (OVX). The administration of phytoestrogens in the OVX murine model has inhibited osteoclast differentiation, activation, and Pyridinoline secretion. Furthermore, these compounds have been shown to enhance bone formation and increase bone mineral density and the expression levels of various osteoblast markers, such as alkaline phosphatase, osteocalcin, osteopontin, and alpha-1 collagen. Several natural phytoestrogen compounds in plants possess a chemical structure akin to 17 beta-estradiol, a steroid hormone. In postmenopausal women with osteoporosis, isoflavones, a type of phytoestrogen, can potentially treat the disease by binding to estrogen receptors on the surface of target cells. Mechanistic investigations have demonstrated that phytoestrogens can retard bone resorption and promote bone formation. Novel approaches in phytoestrogen research could involve investigating the synergistic effects of combining different phytoestrogen compounds, exploring their interactions with other signaling pathways, or assessing their effects on various bone types. Furthermore, identifying novel sources of phytoestrogens could lead to the discovery of new compounds with potent osteoprotective effects.

Article Details

How to Cite
Chaboki, H. R., Akbarian, F., & Kazemi Mehrjerdi, H. (2022). Isoflavones Potentials for the Treatment of Osteoporosis: An Update on In-vivo Studies. Journal of Lab Animal Research, 1(1), 20–25. https://doi.org/10.58803/jlar.v1i1.10
Section
Review Article

References

Pignolo RJ, Law SF, and Chandra A. Bone aging, cellular senescence, and osteoporosis. JBMR plus. 2021; 5(4): e10488. DOI: https://doi.org/10.1002/jbm4.10488

Yu B, and Wang CY. Osteoporosis and periodontal diseases-an update on their association and mechanistic links. Periodontology. 2022; 89(1): 99-113. DOI: https://doi.org/10.1111/prd.12422

Shevroja E, Cafarelli FP, Guglielmi G, and Hans D. DXA parameters, Trabecular Bone Score (TBS) and Bone Mineral Density (BMD), in fracture risk prediction in endocrine-mediated secondary osteoporosis. Endocrinology. 2021; 74: 20-28. DOI:10.1007/s12020-021-02806-x

Genazzani AR, Monteleone P, Giannini A, and Simoncini T. Hormone therapy in the postmenopausal years: Considering benefits and risks in clinical practice. Human Reprod Update. 2021; 27(6): 1115-1150. DOI: https://doi.org/10.1093/humupd/dmab026

Ringe JD. Plain vitamin D or active vitamin D in the treatment of osteoporosis: Where do we stand today?. Arch Osteoporos. 2020; 15: 1-10. DOI: https://doi.org/10.1007/s11657-020-00842-0

Rizzoli R, and Biver E. Are probiotics the new calcium and vitamin D for bone health?. Cur Osteoporos Rep. 2020; 18: 273-284. DOI: https://doi.org/10.1007/s11914-020-00591-6

Bhattarai HK, Shrestha S, Rokka K, and Shakya R. Vitamin D, calcium, parathyroid hormone, and sex steroids in bone health and effects

of aging. J Osteoporos. 2020; 2020: 9324505. DOI: https://doi.org/10.1155/2020/9324505

Peraza-Delgado A, Sánchez-Gómez MB, Gómez-Salgado J, Romero-Martín M, Novo-Muñoz M, and Duarte-Clíments G. Non-pharmacological interventions towards preventing the triad osteoporosis-falls risk-hip fracture, in population older than 65. Scoping Review. J Clin Med. 2020; 9(8): 2329. DOI: https://doi.org/10.3390/jcm9082329

Cai Xy, Zhang ZJ, Xiong JL, Yang M, and Wang ZT. Experimental and molecular docking studies of estrogen-like and anti-osteoporosis activity of compounds in Fructus Psoraleae. J Ethnopharmacol. 2021; 276: 114044. DOI: https://doi.org/10.1016/j.jep.2021.114044

Auréal M, Machuca-Gayet I, and Coury F. Rheumatoid arthritis in the view of osteoimmunology. Biomolecules. 2020; 11(1): 48. DOI: https://doi.org/10.3390/biom11010048

Kravvariti E, Kasdagli M-I, Diomatari KM, Mouratidou P, Daskalakis K, Mitsikostas DD, et al. Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice. Osteoporos Int. 2023: 1-14 .DOI: 10.1007/s00198-022-06658-7

Langer R, Hodis H, Lobo R, and Allison M. Hormone replacement therapy-where are we now?. Climacteric. 2021; 24(1): 3-10. DOI: https://doi.org/10.1080/13697137.2020.1851183

Martiniakova M, Babikova M, and Omelka R. Pharmacological agents and natural compounds: Available treatments for osteoporosis. J Physiol Pharmacol. 2020; 71(3): 307-320. DOI: https://doi.org/10.26402/jpp.2020.3.01

Yoon KH, Cho DC, Yu SH, Kim KT, Jeon Y, and Sung JK. The change of bone metabolism in ovariectomized rats: Analyses of microCT scan and biochemical markers of bone turnover. J Korean Neurosurg Soc. 2012; 51(6): 323-327. DOI: https://doi.org/10.3340/jkns.2012.51.6.323

Zheng X, Zhang Y, Guo S, Zhang W, Wang J, and Lin Y. Dynamic expression of matrix metalloproteinases 2, 9 and 13 in ovariectomy induced osteoporosis rats. Exp Ther Med. 2018; 16(3): 1807-1813. DOI: https://doi.org/10.3892/etm.2018.6356

Chalvon-Demersay T, Blachier F, Tomé D, and Blais A. Animal models for the study of the relationships between diet and obesity: A focus on dietary protein and estrogen deficiency. Front Nut. 2017; 4: 5. DOI: https://doi.org/10.3389/fnut.2017.00005

Coffman AA, Basta‐Pljakic J, Guerra RM, Ebetino FH, Lundy MW, Majeska RJ, et al. A bisphosphonate with a low hydroxyapatite binding affinity prevents bone loss in mice after ovariectomy and reverses rapidly with treatment cessation. JBMR plus. 2021; 5(4): e10476. DOI: https://doi.org/10.1002/jbm4.10476

Macari S, Duffles LF, Queiroz-Junior CM, Madeira MF, Dias GJ, Teixeira MM, et al. Oestrogen regulates bone resorption and cytokine production in the maxillae of female mice. Arch Oral Biol. 2015; 60(2): 333-341. DOI: https://doi.org/10.1016/j.archoralbio.2014.11.010

Sadr S, Ghafouri SA, Ghaniei A, Jami Moharreri D, Zeinali M, Qaemifar N, et al. Treatment of Avian Trichomoniasis by Tannin-based Herbal mixture (Artemisia Annua, Quercus infectoria, and Allium Sativum). J World’s Poult Sci. 2022; 1(2): 32-39. Available at: https://jwps.rovedar.com/article_163137_a229fe401769f4f7908398db5b8ec0e0.pdf

Sadr S, Ahmadi Simab P, Kasaei M, Landi MG, Borji H, and Adhami G. Potential of anthelmintic herbal drugs against gastrointestinal nematodes in farm animals: A review. Farm Anim Health

Nut. 2022; 1(1): 26-30 available at: https://fahn.rovedar.com/article_160944_3e6c82b5703b82558f72d30827da6569.pdf

Mondal S, Soumya NPP, Mini S, and Sivan SK. Bioactive compounds in functional food and their role as therapeutics. Bioact Compd Health Dis. 2021; 4(3): 24-39. DOI: https://doi.org/10.31989/bchd.v4i3.786

Słupski W, Jawień P, and Nowak B. Botanicals in postmenopausal osteoporosis. Nutrients. 2021; 13(5): 1609. DOI: https://doi.org/10.3390/nu13051609

Gupta C, Prakash D, and Gupta S. Phytoestrogens as pharma foods. Adv Food Technol Nutr Sci Open J. 2016; 2(1): 19-31. DOI: https://doi.org/10.17140/AFTNSOJ-2-127

Rietjens IM, Louisse J, and Beekmann K. The potential health effects of dietary phytoestrogens. British J Pharmacol. 2017; 174(11): 1263-1280. DOI: https://doi.org/10.1111/bph.13622

Tripathi G, Raja N, and Yun H. Effect of direct loading of phytoestrogens into the calcium phosphate scaffold on osteoporotic bone tissue regeneration. J Mater Chem B. 2015; 3(44): 8694-703 DOI: https://doi.org/10.1039/C5TB01574J

Sirotkin AV, and Harrath AH. Phytoestrogens and their effects. Eur J Pharmacol. 2014; 741: 230-236. DOI: https://doi.org/10.1016/j.ejphar.2014.07.057

Vitale DC, Piazza C, Melilli B, Drago F, and Salomone S. Isoflavones: Estrogenic activity, biological effect and bioavailability. Eur J drug Metab Pharmacokinet. 2013; 38: 15-25. DOI:10.1007/s13318-012-0112-y

Wood CL, Lane LC, and Cheetham T. Puberty: Normal physiology (brief overview). Best Pract Res Clin Endocrinol Metab. 2019; 33(3): 101265. DOI: https://doi.org/10.1016/j.beem.2019.03.001

Mills EG, Yang L, Nielsen MF, Kassem M, Dhillo WS, and Comninos AN. The relationship between bone and reproductive hormones beyond estrogens and androgens. Endocr Rev. 2021; 42(6): 691-719. DOI: https://doi.org/10.1210/endrev/bnab015

Hadji P, Colli E, and Regidor PA. Bone health in estrogen-free contraception. Osteoporos Int. 2019; 30(12): 2391-2400. DOI: https://doi.org/10.1007/s00198-019-05103-6

Song S, Guo Y, Yang Y, and Fu D. Advances in pathogenesis and therapeutic strategies for osteoporosis. Pharmacol Ther. 2022: 108168. DOI: https://doi.org/10.1016/j.pharmthera.2022.108168

Emerton K, Hu B, Woo A, Sinofsky A, Hernandez C, Majeska R, et al. Osteocyte apoptosis and control of bone resorption following ovariectomy in mice. Bone. 2010; 46(3): 577-583. DOI: https://doi.org/10.1016/j.bone.2009.11.006

Thent ZC, Das S, Mahakkanukrauh P, and Lanzotti V. Osteoporosis: Possible pathways involved and the role of natural phytoestrogens in bone metabolism. Sains Malays. 2019; 48(9): 2007-2019. DOI: https://doi.org/10.17576/jsm-2019-4809-22

Martín-Millán M, and Castaneda S. Estrogens, osteoarthritis and inflammation. Joint Bone Spine. 2013; 80(4): 368-373. DOI: https://doi.org/10.1016/j.jbspin.2012.11.008

Xiao W, Li S, Pacios S, Wang Y, and Graves DT. Bone remodeling under pathological conditions. Tooth Movement. 2016; 18: 17-27. DOI: https://doi.org/10.1159/000351896

Rozenberg S, Bruyère O, Bergmann P, Cavalier E, Gielen E, Goemaere S, et al. How to manage osteoporosis before the age of 50. Maturitas. 2020; 138: 14-25. DOI: https://doi.org/10.1016/j.maturitas.2020.05.004

Liu T, Li N, Yan Yq, Liu Y, Xiong K, Liu Y, et al. Recent advances in the anti‐aging effects of phytoestrogens on collagen, water content, and oxidative stress. Phytother Res. 2020; 34(3): 435-447 DOI: https://doi.org/10.1002/ptr.6538

Dean M, Murphy BT, and Burdette JE. Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products. Mol Cell Endocrinol. 2017; 442: 98-105. DOI: https://doi.org/10.1016/j.mce.2016.12.013

Taylor M. Complementary and alternative approaches to menopause. Endocrinol Metabol Clinics. 2015; 44(3): 619-648. DOI: https://doi.org/10.1016/j.ecl.2015.05.008

Toda T, Sugioka Y, and Koike T. Soybean isoflavone can protect against osteoarthritis in ovariectomized rats. J food Sci Technol. 2020; 57: 3409-3414. DOI: https://doi.org/10.1007/s13197-020-04374-w

Hu C, Wong WT, Wu R, and Lai WF. Biochemistry and use of soybean isoflavones in functional food development. Crit Rev Food Sci Nutr. 2020; 60(12): 2098-2112. DOI: https://doi.org/10.1080/10408398.2019.1630598

Xie CL, Park KH, Kang SS, Cho KM, and Lee DH. Isoflavone‐enriched soybean leaves attenuate ovariectomy‐induced osteoporosis in rats by anti‐inflammatory activity. J Sci Food Agric. 2021; 101(4): 1499-1506. DOI: https://doi.org/10.1002/jsfa.10763

Hooshiar SH, Tobeiha M, and Jafarnejad S. Soy isoflavones and bone health: Focus on the RANKL/RANK/OPG pathway. BioMed Res Int. 2022. 2022: 8862278. DOI: https://doi.org/10.1155/2022/8862278

Abdelrazek H, Mahmoud M, Tag HM, Greish SM, Eltamany DA, and Soliman MT. Soy isoflavones ameliorate metabolic and immunological alterations of ovariectomy in female Wistar rats: Antioxidant and estrogen sparing potential. Oxid Med Cell Longev. 2019; 2019: 5713606. DOI: https://doi.org/10.1155/2019/5713606

Zullkiflee N, Taha H, and Usman A. Propolis: Its role and efficacy in human health and diseases. Molecules. 2022; 27(18): 6120. DOI: https://doi.org/10.3390/molecules27186120

Ali Reza A, Nasrin MS, Hossen MA, Rahman MA, Jantan I, Haque MA, et al. Mechanistic insight into immunomodulatory effects of food-functioned plant secondary metabolites. Crit Rev Food Sci Nutr. 2021. p. 1-31. DOI: https://doi.org/10.1080/10408398.2021.2021138

Thangavel P, Puga-Olguín A, Rodríguez-Landa JF, and Zepeda RC. Genistein as potential therapeutic candidate for menopausal symptoms and other related diseases. Mol. 2019; 24(21): 3892. DOI: https://doi.org/10.3390/molecules24213892

Wang J, Shang F, Jiang R, Liu L, Wang S, and Hou J, et al. Nitric oxide-donating genistein prodrug: Design, synthesis, and bioactivity on MC3T3-E1 cells. J Pharmacol Sci. 2007; 104(1): 82-89. DOI: https://doi.org/10.1254/jphs.FP0061549

Sakai E, Farhana F, Yamaguchi Y, and Tsukuba T. Potentials of natural antioxidants from plants as antiosteoporotic agents. Stud Nat Prod Chem. 2022; 72: 1-28. DOI: https://doi.org/10.1016/B978-0-12-823944-5.00002-8

Zhang Y, Li Q, Li X, Wan HY, and Wong MS. Erythrina variegata extract exerts osteoprotective effects by suppression of the process of bone resorption. Br J Nut. 2010; 104(7): 965-971. DOI: https://doi.org/10.1017/S0007114510001789

Hertrampf T, Schleipen B, Offermanns C, Velders M, Laudenbach U, and Diel P. Comparison of the bone protective effects of an isoflavone-rich diet with dietary and subcutaneous administrations of genistein in ovariectomized rats. Toxicol let. 2009; 184(3): 198-203. DOI: https://doi.org/10.1016/j.toxlet.2008.11.006

Kawakita S, Marotta F, Naito Y, Gumaste U, Jain S, Tsuchiya J, et al. Effect of an isoflavones-containing red clover preparation and alkaline supplementation on bone metabolism in ovariectomized rats. Clin Interv Aging. 2009; 4: 91-100. DOI: https://doi.org/10.2147/CIA.S4164

Bitto A, Burnett B, Polito F, Marini H, Levy R, Armbruster M, et al. Effects of genistein aglycone in osteoporotic, ovariectomized rats: A comparison with alendronate, raloxifene and oestradiol. Brit J Pharmacol. 2008; 155(6): 896-905. DOI: https://doi.org/10.1038/bjp.2008.305

Sarasquete C, Úbeda Manzanaro M, and Ortiz Delgado JB. Effects of the isoflavone daidzein in Senegalese sole, Solea senegalensis: Modulation of the oestrogen receptor-β, apoptosis and enzymatic signalling pathways. Histol Histopathol. 2019; 34: 875-887. DOI: https://doi.org/10.14670/HH-18-090

Liu Zm, Chen B, Li S, Li G, Zhang D, and Ho SC, et al. Effect of whole soy and isoflavones daidzein on bone turnover and inflammatory markers: A 6-month double-blind, randomized controlled trial in Chinese postmenopausal women who are equol producers. Ther Adv Endocrinol Metab. 2020; 11: 1-4. DOI: 2042018820920555

Liu X, Jia H, and Xia H. Reduction of intra-articular adhesion by topical application of Daidzein following knee surgery in rabbits. Afr J Tradit Complement Altern Med. 2017; 14(4): 265-271. DOI: https://doi.org/10.21010/ajtcam.v14i4.29

57. Alshehri MM, Sharifi-Rad J, Herrera-Bravo J, Jara EL, Salazar LA, Kregiel D, et al. Therapeutic potential of isoflavones with an emphasis on daidzein. Oxid Med Cell Longev. 2021; 2021: 6331630. DOI: https://doi.org/10.1155/2021/6331630

Sun MY, Ye Y, Xiao L, Rahman K, Xia W, and Zhang H. Daidzein: A review of pharmacological effects. Afr J Tradit Complement Altern Med. 2016; 13(3): 117-132. DOI: https://doi.org/10.21010/ajtcam.v13i3.15

Hussain A, Tabrez ES, Muhammad A, and Peela JR. The mechanisms of dietary phytoestrogen as a potential treatment and prevention agent against Alzheimer's disease. Crit Rev Eukaryot Gene Express. 2018; 28(4): 321-327. DOI: https://doi.org/10.1615/CritRevEukaryotGeneExpr.2018025847

Ajdžanovic VZ, Trifunovic S, Miljic D, Šošic-Jurjevic B, Filipovic B, Miler M, et al. Somatopause, weaknesses of the therapeutic approaches and the cautious optimism based on experimental ageing studies with soy isoflavones. EXCLI J. 2018; 17: 279-301. DOI: https://doi.org/10.17179/excli2017-956

Křížová L, Dadáková K, Kašparovská J, and Kašparovský T. Isoflavones. Molecules. 2019; 24(6): 1076. DOI: https://doi.org/10.3390/molecules24061076

Mayo B, Vázquez L, and Flórez AB. Equol: A bacterial metabolite from the daidzein isoflavone and its presumed beneficial health effects. Nutrients. 2019; 11(9): 2231. DOI: https://doi.org/10.3390/nu11092231

Lund TD, Munson DJ, Haldy ME, Setchell KD, Lephart ED, and Handa RJ. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reproduc. 2004; 70(4): 1188-1195. DOI: https://doi.org/10.1095/biolreprod.103.023713

Canivenc-Lavier MC, and Bennetau-Pelissero C. Phytoestrogens

and Health Effects. Nutrients. 2023; 15(2): 317. DOI: https://doi.org/10.3390/nu15020317

Stojanov S, and Kreft S. Gut microbiota and the metabolism of phytoestrogens. Rev Bras Farmacogn. 2020; 30: 145-154. DOI: https://doi.org/10.1007/s43450-020-00049-x

Fonseca D, and Ward WE. Daidzein together with high calcium preserve bone mass and biomechanical strength at multiple sites in ovariectomized mice. Bone. 2004; 35(2): 489-497. DOI: https://doi.org/10.1016/j.bone.2004.03.031

Cheng CH, Chen LR, and Chen KH. Osteoporosis due to hormone imbalance: An overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. Int J Mol Sci. 2022; 23(3): 1376. DOI: https://doi.org/10.3390/ijms23031376

Kim IS. Current perspectives on the beneficial effects of soybean isoflavones and their metabolites for humans. Antioxidants. 2021; 10(7): 1064. DOI: https://doi.org/10.3390/antiox10071064

Loo YT, Howell K, Chan M, Zhang P, and Ng K. Modulation of the human gut microbiota by phenolics and phenolic fiber‐rich foods. Com Rev in Food Sci and Food Safety. 2020; 19(4): 1268-1298. DOI: https://doi.org/10.1111/1541-4337.12563

Watanabe S, and Uehara M. Health effects and safety of soy and isoflavones. The role of functional food security in global health. 2019. p. 379-394. DOI: https://doi.org/10.1016/B978-0-12-813148-0.00022-0

Harahap IA, and Suliburska J. Probiotics and isoflavones as a promising therapeutic for calcium status and bone health: A narrative review. Foods. 2021; 10(11): 2685. DOI: https://doi.org/10.3390/foods10112685

Mayo Pérez B, Vázquez L, and Flórez García AB. Equol: A bacterial metabolite from the daidzein isoflavone and its presumed beneficial health effects. Nutrients. 2019; 11(9): 2231. DOI: https://doi.org/10.3390/nu11092231

David K, Narinx N, Antonio L, Evenepoel P, Claessens F, Decallonne B, et al. Bone health in ageing men. Rev Endocr Metab Disord. 2022; 23: 1173-1208. DOI: https://doi.org/10.1007/s11154-022-09738-5

Vigneswaran K, and Hamoda H. Hormone replacement therapy-Current recommendations. Best Pract Res Clin Obstet Gynaecol. 2022; 81: 8-21. DOI: https://doi.org/10.1016/j.bpobgyn.2021.12.001

Azeez JM, Susmi TR, Remadevi V, Ravindran V, Sujatha AS, Ayswarya RNS, et al. New insights into the functions of progesterone receptor (PR) isoforms and progesterone signaling. Ame J of Can Res. 2021; 11(11): 5214. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640821/

Parasuraman S, Thing GS, and Dhanaraj SA. Polyherbal formulation: Concept of ayurveda. Pharmacogn Rev. 2014; 8(16): 73-80. DOI: https://doi.org/10.4103/0973-7847.134229

Swathi Krishna S, Kuriakose BB, and Lakshmi P. Effects of phytoestrogens on reproductive organ health. Arch Pharma Res. 2022; 45: 849-864.. DOI: https://doi.org/10.1007/s12272-022-01417-y

Júnior L, Silva K, Oliveira F, and Nisar S. The most abundant isoflavone contained in soy beans and its effects on menopausal symptoms and related pathophysiologies: A review. Int J Chem Biochem Sci.

; 21: 22-35. Available at: https://www.iscientific.org/wp-content/uploads/2022/04/3-IJCBS-22-21-3.pdf

Lagari VS, and Levis S. Phytoestrogens in the prevention of postmenopausal bone loss. J Clin Densitom. 2013; 16(4): 445-449. DOI: https://doi.org/10.1016/j.jocd.2013.08.011

Sathyapalan T, Aye M, Rigby AS, Fraser WD, Thatcher NJ, Kilpatrick ES, et al. Soy reduces bone turnover markers in women during early menopause: A randomized controlled trial. J Bone Min Res. 2017; 32(1): 157-164. DOI: https://doi.org/10.1002/jbmr.2927

Oseni T, Patel R, Pyle J, and Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta medica. 2008; 74(13): 1656-1665. DOI: https://doi.org/10.1055/s-0028-1088304

Pilšáková L, Riečanský I, and Jagla F. The physiological actions of isoflavone phytoestrogens. Physiol Res. 2010; 59(5): 651-664. DOI: https://doi.org/10.33549/physiolres.931902