p-ISSN 1693-5683; e-ISSN 2527-7146 41 Vol. 19, No. 1, May 2022, pp. 41-52 Review Article Systematic Review: Anti-Osteoporosis Potential Activities Of Phytoestrogen Compounds In Chrysophyllum cainito L., Elaeis guineensis Jacq., Lannea acida Rich., Marsilea crenata Presl., and Medicago sativa L. Burhan Ma’arif*, Suryanto, Faisal Akhmal Muslikh, Arief Suryadinata, Begum Fauziyah Department of Pharmacy, Faculty of Medical and Health of Science, Islamic State University Maulana Malik Ibrahim, Malang, East Java, 65151, Indonesia https://doi.org/10.24071/jpsc.003166 J. Pharm. Sci. Community, 2022, 19(1), 41-52 Article Info ABSTRACT Received: 02-03-2021 Revised: 21-05-2021 Accepted: 10-06-2021 *Corresponding author: Burhan Ma’arif email: burhan.maarif@farmasi- uin.malang.ac.id Keywords: Chrysophyllum cainito L.; Elaeis guineensis Jacq.; Lannea acida Rich.; Marsilea crenata Presl.; Medicago sativa L. Phytoestrogens are compounds from plants that have a structure and function similar to estrogen (17β-estradiol). Phytoestrogens can be found in Chrysophyllum cainito L., Elaeis guineensis Jacq., Lannea acida Rich., Marsilea crenata Presl., and Medicago sativa L. This systematic review aimed to prove that all of these five plants have phytoestrogens which were observed with several instruments, and to assess activities and bone forming mechanisms from these five plants in the female mice (Mus musculus) and female rats (Rattus norvegicus). This systematic review was done by identifying articles in several databases (Google Scholar, PubMed, and Science Direct). The process of selecting the articles used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to create a flowchart with inclusion and exclusion study criteria. Meta-synthesis was done to analyze, identify, and interpret all of the data in the articles systematically. 31 articles in total were obtained from the selection process, with 27 articles containing a discussion about chemical compound content and 4 articles describing research results for in vivo testing of the plants that were reviewed. The results showed that these five plants have phytoestrogens and by in vivo testing have the activity in increasing trabecular bone density in the experimental animals. INTRODUCTION Osteoporosis is a condition where the bones become thinner, fragile, porous, and easily broken because of decreasing bone density which happens over a long time. Osteoporosis in postmenopausal women happens because of an imbalance between the bone erosion process and bone formation due to estrogen deficiency (Wahjudi and Putriana, 2014; Afni and Hanafi, 2019; Sugiritama and Adiputra, 2019). Today, the osteoporosis prevalence in the world is more than 200 million people. Recent research conducted by the International Osteoporosis Foundation in 2015 revealed that 1 out of 4 women in Indonesia with the age range 50-80 years old have osteoporosis risk 4 times higher than men (Kemenkes, 2015; Sozen et al., 2017). Estrogen deficiency is one of the essential factors that cause an imbalance in the bone remodeling process which involves increasing bone resorption that induces osteoporosis. First-line therapy in osteoporosis is hormone replacement therapy (HRT), but the long-term application may evoke severe side effects for the body, like emboli cancer, breast cancer, and stroke. Accordingly, using HRT as osteoporosis therapy has been limited and discontinued (Chen et al., 2015; Agarwal et al., 2018). Phytoestrogens are compounds from plants that have a structure like estrogen or may replace estrogen’s function. Structurally, phytoestrogen is divided into two groups, which http://issn.pdii.lipi.go.id/issn.cgi?daftar&1180428136&1&& http://issn.pdii.lipi.go.id/issn.cgi?daftar&1465346481&1&& https://e-journal.usd.ac.id/index.php/JFSK/index https://creativecommons.org/licenses/by/4.0/ https://doi.org/10.24071/jpsc.003166 Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 42 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 are flavonoid and non-flavonoid. Not only is the phytoestrogen compound group easy to obtain and has no side effects, but it also has the efficacy to raise bone density (Schröder et al., 2016; Ma’arif et al., 2019). Plants that contain phytoestrogen compounds are Chrysophyllum cainito (C. caimito) L., Elaeis guineensis (E. guineensis) Jacq., Lannea acida (L. acida) Rich., Marsilea crenata (M. crenata) Presl., and Medicago sativa (M. sativa) L. (Figure 1). Plants such as C. cainito, E. guineensis, L. acida, and M. sativa, empirically have been utilized as rheumatic medication and plant-like M. crenata has been applied as an anti- osteoporosis treatment, when rheumatic symptoms and osteoporosis occur due to estrogen deficiency disorder in postmenopausal women (Muhaisen, 2013; Shailajan and Gurjar, 2014; Widjayant, 2016; Febrina and Febriyanti, 2017; Rafińska et al., 2017). C. cainito is a plant that is often found in tropical areas. Research of the methanol extract from C. cainito leaves indicated it has the potential to reduce inflammation reactions in the joints because of the anti-inflammatory effects from triterpenoid compounds (Meira et al., 2014). Furthermore, research of methanol extract in E. guineensis leaves identified 28 derivates of flavonoids that have been observed with liquid chromatograph mass spectrometry (LC-MS) instrument (Tahir et al., 2012). Additionally, an in vivo study identified the 96% ethanol extract from L. acida bark which was induced in MCF-7 cells has the potential to raise the marker from bone formation, which is alkaline phosphatase (ALP) (Oumarou et al., 2017). Various research has been conducted on M. crenata leaves that have potential as anti- osteoporosis. One in silico study showed the compounds in M. crenata leaves have a high affinity to ER-β, while, an in vitro study of MC3T3- E1 preosteoblast cells found the n-hexane extract and its fraction can increase proliferation process and differentiation in MC3T3-E1 preosteoblast cells (Ma’arif et al., 2018). Moreover, research of the methanol extract from M. sativa leaves observed with ultra-high performance liquid chromatography (U-HPLC) instrument, found phytoestrogen compounds from flavonoid group which have the potential as anti-osteoporosis agents (Chiriac et al., 2020). These five plants had been studied in vivo to find out their estrogenic effect. This systematic review aimed to study the phytoestrogen compounds from these five plants that have been observed with numerous instruments, and to study the mechanism of bone formation in increasing trabecular bone density in the experimental animals. Therefore, this systematic review may be considered as a primary contribution and source of scientific information for further research related to the development of these five plants as anti-osteoporosis agents. Figure 1. (a). Kenitu leaves (C. cainito) (b). Kelapa sawit leaves (E. guineensis) (c). Faruhi bark (L. acida) (d). Semanggi leaves (M. crenata) (e). Alfalfa leaves (M. sativa) (Source: Agil et al., 2021; Plantsoftheworldonline.org; TopTropicals.com) Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... Review Article 43 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Figure 2. Flow diagram of the study selection process following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines METHODS Materials Criteria of collecting data Inclusion criteria used to select the articles were: (i) Studies that referred to in vivo research models that focused on osteoporosis; (ii) Studies that used plants which contain phytoestrogens; and (iii) Studies that reported the benefits of phytoestrogens in bone formation. The exclusion criteria applied to each article were: (i) Article in another language besides English and Indonesian; (ii) Research article that published before the last ten years; and (iii) article that was not in full text or could not be fully accessed. Collecting strategy and article selection Article searching used the electronic databases of Google Scholar, ScienceDirect, and PubMed in January 2021. The keywords used were “Chemical content, leaves or bark, Chrysophyllum cainito or Elaeis guineensis or Lannea acida or Marsilea crenata or Medicago sativa, phytoestrogen and in vivo antiosteoporotic”. After that step, by screening the title and abstract from the articles that were considered compatible with the research, article screening was done based on the inclusion and exclusion criteria that were developed for this research. Furthermore, the article was selected to be a discussion analysis objective or primary article. Any article that was considered relevant could be used as a supported analysis in this systematic review. Methods This review literature with a systematic review used the Meta-Synthesis methods with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Selcuk, 2019; Snyder, 2019). Data extraction Collected data from all of the studies were organized and analyzed using the PRISMA guidelines and Meta-Synthesis methods. Moreover, data that met the inclusion criteria were arranged in a table and the articles were analyzed to match the aim of this systematic review. file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Snyder Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 44 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Table 1. Investigation results for phytoestrogens articles from plants C. cainito, E. guineensis, L. acida, M. crenata, and M. sativa No. First Author, Year of Publication Material / Extract Phytochemical Components (Phytoestrogens) Observation Method 1 (Ningsih et al., 2016) 70% ethanol extract of C. cainito leaves Flavonoids UV-Vis 2 (Arrijal et al., 2018) Ethyl acetate extract of C. cainito leaves Flavonoids Color test 3 (Ma’arif et al., 2019) Methanol extract of C. cainito leaves Myricetin, dibutyl phthalate UPLC-QToF- MS/MS 4 (Arana-Argáez et al., 2017; Sayed et al., 2019) Methanol extract of C. cainito leaves Flavonoids, Terpenoids GC-MS 5 (Soundararajan and Sreenivasan, 2012) Methanol extract of E. guineensis leaves Flavonoids FTIR analysis 6 (Vargas et al., 2016; Zain et al., 2020) 95% ethanol extract of E. guineensis leaves Flavonoids UHPLC-MS/MS 7 (Tahir et al., 2012) Methanol extract of E. guineensis leaves Apigenin, Luteolin LC−MS 8 (Yin et al., 2013; Ajayi et al, 2016) Methanol extract of E. guineensis leaves Flavonoids, Terpenoids Color test 9 (Soundararajan and Sreenivasan, 2012) Methanol extract of E. guineensis leaves Flavonoids FTIR analisis 10 (Vargas et al., 2016; Zain et al., 2020) 95% ethanol extract of E. guineensis leaves Flavonoids UHPLC-MS/MS 11 (Tahir et al., 2012) Methanol extract of E. guineensis leaves Apigenin, Luteolin LC−MS 12 (Yin et al., 2013; Ajayi et al, 2016) Methanol extract of E. guineensis leaves Flavonoids, Terpenoids Color test 13 (Muhaisen, 2013) Acetone extract of L. acida bark Flavonoids UV-Vis 14 (Ogunsina, 2020; Olatunji et al., 2020; Olusola et al., 2020) Methanol extract of L. acida bark Flavonoids Color test 15 (Ma’arif et al., 2019) 96% ethanol extract of M. crenata leaves Prochlorperazine, 12- Aminododecanoic acid, 1- methyl-2-[(4- methylpiperazin-1- yl)methyl]benzimidaol-5- amine. UPLC-QToF- MS/MS 16 (Ma’arif et al., 2016) n-hexane extract of M. crenata leaves Monoterpenoid, diterpenoid, and palmitic acid GC-MS 17 (Ma’arif et al., 2019) n-hexane extract of M. crenata leaves Triterpenoid UV-Vis 18 (Puspitasari et al., 2015) n-hexane fraction of M. crenata leaves Terpenoids 1H-NMR 19 (Nurjanah et al., 2012; Hardoko et al., 2019) Methanol extract of M. crenata leaves Flavonoids Color test 20 (Susilowati et al., 2014; Widyowati et al, 2014) 70% ethanol extract and 96% ethanol extract of M. sativa leaves Flavonoids TLC 21 (Rodrigues et al.,2014) Methanol extract of M. sativa leaves Flavonoids HPLC 22 (Krakowska et al., 2017) 70% ethanol extract of M. sativa leaves Flavonoids HPLC-MC 23 (Doss et al., 2011) Ethanol extract of M. sativa leaves Flavonoids Color test Notes: UV-Vis (Ultraviolet-Visible),UPLC-QToF-MS/MS (Ultra-High Performance Liquid Chromatography with Quadrupole Time-of-Flight Mass Spectrometry), 1H-NMR (Proton Nuclear Magnetic Resonance), GC-MS (Gas Chromatography Mass Spectrometry), FTIR (Spektrofotometer Fourier Transform Infra Red),UHPLC-MS/MS (Ultra- High Performance Liquid Chromatography with Mass Spectrometry), LC−MS (Liquid Chromatography-Mass Spectrometry), TLC (Thin Layer Chromatography), HPLC (High Performance Liquid Chromatography). Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... Review Article 45 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Figure 3. Total of article publications in the 2011- 2020 period RESULTS AND DISCUSSION Article selection Articles in this systematic review study were selected using the PRISMA guidelines to create a flowchart diagram as shown in Figure 2. There were 31 articles obtained from the database searching. Among them, 16 articles were from Google Scholar, 6 articles were from ScienceDirect, and 3 articles were from PubMed. After identifying the titles, abstracts, and article discussions that were relevant to the research, there were 31 articles that met the inclusion criteria, and 29 articles that did not meet the inclusion criteria or exclusion criteria. From the 31 articles analyzed, 26 articles discussed phytochemical component analysis that was observed with various instruments, and 5 articles used the in vivo research model; all of which were published within the last 10 years (Figure 3). The articles were discussed with the Meta-Synthesis method which involves analyzing, identifying, and interpreting article data that were presented systematically. Article characteristics The primary characteristics of the articles that were included in this review discussion are summarized in Tables 1 and 2, with a total of 31 articles or primary analyzed data. There are 5 articles involving in vivo research models from the 5 plants that have potential as anti- osteoporosis agents. Also, the articles that focus on phytoestrogen content in C. cainito leaves are 5 articles, 4 articles on E. guineensis leaves, 4 articles on L. acida bark, 3 articles on M. crenata leaves and 4 articles on M. sativa leaves. Phytoestrogen as anti-osteoporosis agents Phytoestrogens are chemical compounds from plants that have a similar structure as estrogen or can replace the function of estrogen. Structurally, phytoestrogens are divided into two main groups based on their chemical structure. There are flavonoid compounds including isoflavones (genistein, daidzein, glycitein, biochanin A, and formonoetin), coumestans (equol), prenyflavonoids, and non-flavonoid compounds including lignans (pinoresinol, 4- methoxy pinoresinol, and eudesmin), and terpenoids (α-amyrin, and β-amyrin) (Virk- Baker et al., 2010; Zhou et al., 2014; Kiyama, 2017; Křížová et al., 2019) (Table 3). A chemical compound will have similar pharmacological properties as phytoestrogen if it has similar pharmacophore distances, and has a similarity of the type of bound amino acids (Ma’arif et al., 2019). Estrogen biological effect in bone formation begins when estrogen (as a ligand) diffuses into cells then binds with estrogen receptor (ER). The receptor will be activated and form an estrogen-receptor complex that is able to penetrate the nucleus (translocation). This estrogen-receptor complex will bind to a particular part in the DNA, which is called estrogen-response-element (ERE). This process is followed by complex genetic transcription, which causes an estrogenic effect in bones which includes forming osteoblast cells and inhibiting the overproduction of osteoclast cells (Sihombing et al., 2012). Since phytoestrogens have a similar structure or activity with the estrogen hormone in the body, phytoestrogens potentially can replace the function of estrogen to induce the estrogenic effect in bone formation. Phytoestrogen compound from plants C. cainito, E. guineensis, L. acida, M. crenata, and M. sativa C. cainito leaves chemically contains phytoestrogen from the flavonoid compound group and terpenoids that was observed with color test, ultra-violet (UV)-Vis Instrument, UPLC-QToF-MS/MS, and gas-chromatography and mass spectrometry (GC-MS) (Table 1). Myricetin and dibutyl phthalate are compounds that are found in methanol extract of C. cainito leaves, where the compounds are derivates from flavonoids (Mayanti et al., 2017; Ma’arif et al., 2019; Yahmin et al., 2019). Remarkably, the GC- MS instrument identified C. cainito leaves have 7 derivate compounds of flavonoids: 3//galloyl myricitrin, rutin, quercitrin, myrecetrin, myricetin, and quercetin. Also, there are 3 terpenoid compounds, are α–amyrin, β–amyrin, and lupeol (Arana-Argáez et al., 2017; Sayed et al., 2019). The UV-Vis instrument identified C. cainito leaves have flavonoid total content of 14.039 ± 0.030 mg gallic acid equivalent (GAE)/g extract (Ningsih et al., 2016). Additionally, the qualitative chemical test which is the flavonoid file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Kiyama file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Kiyama file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Křížová file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bagawan file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bagawan file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Sihombing file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Mayanti file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bagawan file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bagawan file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yahmin file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Arana file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Sayed file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Sayed file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Ningsih Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 46 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 test showed a changing of orange color indicating there are flavonoid compound groups derived from C. cainito leaves (Arrijal et al., 2018). The compounds from E. guineensis leaves contain phytoestrogens from the flavonoid compound group, including flavone, apigenin, and luteolin which were observed with the color test, Fourier-transform infrared spectroscopy (FTIR) instrument, UPHPLC-MS/MS, and LC-MS (Table 1). Flavonoid compounds from E. Table 2. Search results for articles containing in vivo analysis from plants C. cainito, E. guineensis, L. acida, M. crenata, and M. sativa No First Author, Year of Publication Material Animal Model Osteoporos is Model Observed section Analysis Results (Histomorfo- metri) Bone Remodelling Mechanism 1 (Utaminingt yas et al., 2018) 70% ethanol extract of C. cainito leaves Female Mice (M. musculus) Induction with the drug dexametha sone Trabecular Vertebra Has activity in increasing trabecular bone vertebrae of female mice (M. musculus) with an optimum dose of 400 mg / kgB /day. ↑Osteoblastogen esis ↓Osteoclastogen esis 2 (Bakhsh et al., 2013) 50% ethanol extract of E. guineensis leaves Female Rat (R. norvegicus) Sprague Dawley OVX Trabecular Femur At a dose of 300 mg/ kgBW/day from the leaves extract of E. guineensis, it increased the trabecular bone density of female rats (R. norvegicus). ↑ ALP activity ↑ Calcium deposition ↑Ekspression mRNA of Runx2 ↑ Protein osteocalcin ↓ Cytokines IL1, IL6, dan IL7 ↓ TNF production ↓ Ekspression COX-2 of RANKL 3 (Oumarou et al., 2017) 95% ethanol extract of L. acida bark Female Rat (R. norvegicus) Albino Wistar OVX Trabecular Femur Trabecular bone density of female rats (R. norvegicus) increased due to the induction of L. acida leaves ethanol extract at a dose of 200 mg/kgBW/day. ↑ ERβ activition ↑ Production of osteoblasts cell 4 (Agil et al., 2019) n-hexane extract of M. crenata leaves Female Rat (R. norvegicus) Induction with the drug dexametha- sone Trabecular Vertebra In the n-hexane fraction of M. crenata has activity in increasing the trabecular bone density of female rats (R. norvegicus), at a dose of 3.08 mg/20gBW ↑ Production of osteoblasts cell ↓ Production of osteoclasts cell 5 (Jdidi et al., 2020) Ethanol extract of M. sativa leaves Female Mice (M. musculus) OVX Trabecular Femur There was an increase in the trabecular bone density of the female mice (M. musculus) which was induced by the ethanol extract of M. sativa leaves at a dose of 0.75 g/kgBW/ day. ↑ Production of osteoblasts cell ↓ Lipid and protein oxidation biomarkers file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Arrijal Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... Review Article 47 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 guineensis leaves were found in the FTIR instrument analysis that showed stretching vibrations from flavonoids and other minor flavone groups with wave range 100-1700 cm-1 (Soundararajan and Sreenivasan, 2012). Apigenin and luteolin derivate compounds from E. guineensis had been identified with the UPHLC-MS/MS instrument (Vargas et al., 2016; Zain et al., 2020). Moreover, the LC-MS instrument identified that E. guineensis leaves have 28 flavonoid derivate compounds (Tahir et al., 2012). In qualitative phytochemical screening analysis, the yellow color from the Shinoda test shows that there are the flavonoid compound group and terpenoid compounds in E. guineensis leaves (Yin et al., 2013; Ajayi et al, 2016). The compounds in L. acida bark are flavonoid compounds that have been observed with the UV-Vis instrument and by chemical qualitative methods (Table 1). There were 4 flavonoid compounds found with the UV-Vis instrument, 6,7-(2”,2”-dimethyl chromeno)-8- γ,γ-dimethyl allyl flavanone, 3’,4’dihydroxy-7,8 (2”,2”- dimethyl chromeno)-6-γ,γ dimethyl allyl flavanol, 7-methyltectorigenin, and Irisolidone (Muhaisen, 2013). Additionally, the flavonoid qualitative analysis test showed a yellow color meaning there is a flavonoid compound group (Ogunsina, 2020; Olatunji et al., 2020; Olusola et al., 2020). The content of M. crenata leaves was observed with UPLC-QToF-MS/MS, GC-MS, and UV-Vis instrument which identified several phytoestrogens (Table 1). The UPLC-QToF- MS/MS instrument found Prochlorperazine,12- Aminododecanoic acid, and1-methyl-2- (4- methyl piperazine-1-yl) methyl benzimidazole- 5-amine components, that are potentially active as phytoestrogen compounds due to their similar affinity that has been predicted in silico. Monoterpenoid, diterpenoid, and palmitic acid compounds are compounds that had been found with the GC-MS instrument, whereas monoterpenoid and terpenoid are terpenoid groups. Palmitic acid is a fatty acid group that has a mechanism to increase osteogenesis (Ma’arif et al., 2016). In the UV-Vis instrument, there is a triterpenoid component that was found in M. crenata with maximum absorption in λ 232 nm and 242 nm wavelength. Identification M. crenata with spectroscopy 1H-NMR showed terpenoid compounds, due to the result of analysis contains signals on δH 0.8 to 1.3 ppm, which indicated that these are isolated terpenoid compounds because it has a long-chain altakane group (Puspitasari et al., 2015). Moreover, the flavonoid qualitative test of M. crenata leaves shows yellow color, which is a characteristic of the flavonoid compound group (Nurjanah et al., 2012; Hardoko et al., 2019). Table 3. Structure of phytoestrogens such as flavonoid and non-flavonoid (Virk-Baker et al., 2010; Zhou et al., 2014 Křížová et al., 2019) Flavonoid Structure R1 R2 R3 R4 Genistein (isoflavones) OH H OH OH Daidzein (isoflavones) H H OH OCH3 Glycitein (isoflavones) H OCH3 OH OCH3 Formonoetin (isoflavones) H H OCH3 OH Biochanin A (isoflavones) OH H OCH3 OH Equol (coumestans) H H OH OH Non-Flavonoid Structure R1 R2 R3 R4 Pinoresinol (lignans) H CH3 H CH3 4-methoxy pinoresinol (lignans) H CH3 CH3 CH3 Eudesmin (lignans) CH3 CH3 CH3 CH3 α-amyrin (terpenoids) H CH3 β-amyrin (terpenoids) CH3 H file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Soundararajan file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Vargas file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Zain file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Tahir file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Tahir file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yin file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Ajayi file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Muhaisen file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Ogunsina file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Olatunji file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Olusola file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Olusola file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Laswati file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Laswati file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Puspitasari file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Nurjanah file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Nurjanah file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Hardoko Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 48 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Phytoestrogen compounds from M. sativa leaves are a flavonoid compound group that was observed with the thin-layer chromatography (TLC), HPLC, and HPLC-MC instruments (Table 1). The content of M. sativa that has been observed with TLC densitometry shows a spot yellow color, which is a characteristic of the flavonoid compound group (Susilowati et al., 2014; Widyowati et al., 2014). The HPLC instrument identified that the average content of isoflavone is about 2.3 (mg/kg/db) (Rodrigues et al., 2014). Also, the HPLC-MC instrument showed that there are derivate compounds from flavonoids, such as apigenin, luteolin, and quercetin (Krakowska et al., 2017). The qualitative phytochemical analysis screening in M. sativa leaves also showed there is a flavonoid compound group (Doss et al., 2011). Activities of bone formation from plants C. cainito, E. guineensis, L. acida, and M. sativa for in vivo Table 2 explains that in vivo research results from plants C. cainito, E. guineensis, L. acida, M. crenata, and M. sativa have anti- osteoporosis potential because of their phytoestrogen content. There are two kinds of osteoporosis models that are used in these five plants, which are ovariectomy (OVX) and induced by medicine. OVX is an ovary removal method in a female experimental animal, so the ovary cannot produce estrogen (Yuliawati et al., 2019; Yousefzadeh et al., 2020). This model had been applied to in vivo study of E. guineensis leaves, M. sativa leaves, and L. acida bark. Furthermore, the osteoporosis model by inducing experimental animals with medicine was used in the research conducting in vivo study of C. cainito leaves and M. crenata leaves, where the experimental animal is given the medicine that is proved to have a side effect of osteoporosis; one of which is dexamethasone. Dexamethasone is a synthetic substance from the corticosteroid group that has high glucocorticoid content which may cause side effects, and this higher glucocorticoid content will cause inhibition of bone formation from long-term use (Agil et al., 2019). Moreover, in observations of bone density in experimental animals from the in vivo study, histomorphometry has been used. Cells or tissue measurement methods to study the changing shape and activity of the cells are done through volume, thickness, length, and wide measurement with an optic microscope, for example, using the Carl Zeiss teaching, Olympus cellsens (Yanti et al., 2019). Histomorphometry observation in bone density was done by observing the quantity or sign marker of bone formation. This method was performed by in vivo study of E. guineensis leaves (in U/L), increasing quantity of bone inorganic matrix in L. acida bark, and M. sativa leaves (in mg/g or mmol/L). Also, it is used to measure growth by directly counting on bone specimen thickness value for an in vivo study of C. cainito and M. crenata leaves (in µm). Giving ethanol extract in C. cainito leaves with 400 mg dose to mice (M. musculus) has activity in increasing the vertebrate trabecular bone density which has the average bone specimen thickness of 626.96 µm. This research suggests increases in bone density occurs because phytoestrogen compounds in the C. cainito leaves potentially replace the estrogen function in binding with ER. As a result, its binding causes decreasing in osteoclastogenesis and bone resorption. Also, it causes an increase in osteoblastogenesis and bone formation (Utaminingtyas et al., 2018). Giving E. guineensis leaves extract with 300 mg/kg BW/day dose to female rats (R. norvegicus) revealed increasing femur bone density with alkaline phosphatase (ALP) (U/L) 272.33± 3.80 because the phytoestrogen compounds from this plant are able to raise ALP activity, increase calcium deposition, increase mRNA expression from runx2, and increase osteocalcin protein in increment bone formation. Moreover, the phytoestrogen compounds from E. guineensis potentially suppress the inflammation cytokines: interleukin (IL)-1, 6, and 7) protein production and osteoclast activity thereby inhibiting tumor necrosis factor (TNF) production, and cyclooxygenase expression (COX-2) in RANKL expression (Bakhsh et al., 2013). Giving the extract of L. acida bark with 200 mg/kg BW/day doses to female rats (R. norvegicus) showed increasing in femur bone formation in the experimental animals which was characterized by increasing of inorganic bone matrix quantities: specifically, Calcium (Ca) 0.043 ± 0.005 mmol/L, and Phosphorus (P) 4.30 ± 0.482 mmol/L. In this study, phytoestrogen content from L. acida potentially increased the inorganic bone matrix. Osteoblast cells are the cells that form the bone matrix. Consequently, a phytoestrogen in L. acida affects bone formation through ERβ localized activity on osteoblast cells (Oumarou et al., 2017). The n-hexane extract from M. crenata leaves with 3.08 mg/20g BW dose which was given to female rats (R. norvegicus) showed an file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Susilowati file:///C:/Users/suryanto/AppData/Roaming/Downloads/,%202014 file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Widyowati file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Rodrigues file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Krakowska file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Doss file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yuliawati file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yuliawati file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yousefzadeh file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Agil file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Yuliawati file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Utaminingtyas file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bakhsh file:///D:/Side%20Jobs/Translate/Burhan%20Ma'arif/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Bakhsh file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Oumarou Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... Review Article 49 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 increasement of vertebrate bone density with the result of average bone thickness ± standard deviation (SD): 8.0 ± 0.3 µm. This occurs due to the content of phytoestrogen in M. crenata leaves. Phytoestrogen compounds bind ER in the main cells, thereby decreasing osteoclastogenesis and bone resorption, while also increasing osteoblastogenesis and bone formation (Agil et al., 2019). In addition, giving ethanol extract of M. sativa leaves with 0.75 g/kg BW/day dose also had activity on femur bone density in the female mice (M. musculus), which was indicated by increasing inorganic bone matrix quantities (mg/g): specifically, Calcium (Ca) 21.942 ± 0.133, Phosphorus (P) 7.530 ± 0.056, and Magnesium (Mg) 0.423 ± 0.010. This article explained that increasing bone matrix density occurs because there is a growth of the inorganic matrix, which is an indicator of higher bone replacement. Accordingly, the phytoestrogen content from M. sativa leaves may lower oxidation lipid and protein biomarkers due to high levels of oxidant production that disturb the balance of normal redox and shift the cells into oxidative stress condition (Jdidi et al., 2020). CONCLUSIONS Anti-osteoporosis activity from plants C. cainito, E. guineensis, L. acida, M. crenata, and M. sativa can affect trabecular bone density in the experimental animals by different mechanisms, but in general, it occurs because there is an increase in bone formation and a decrease in bone resorption due to the phytoestrogen content from each plant. REFERENCES Afni, R., Hanafi, A., 2019. Risiko osteoporosis pada lansia Di UPT Panti Sosial Tresna Werdha Khusnul Khotimah Pekanbaru. Risiko Osteoporosis Pada Lansia Di Upt Panti Sosial Tresna Werdha Khusnul Khotimah Pekanbaru. 3(1), 16–21. Agarwal, S., Alzahrani, F. A., Ahmed, A., 2018. Hormone replacement therapy: would it be possible to replicate a functional ovary? International Journal of Molecular Sciences, 19(10), 3160. Agil, M., Ma’arif, B., Aemi, N.Y., 2019. Aktivitas antiosteoporosis fraksi n-heksana daun Marsilea crenata Presl. dalam meningkatkan kepadatan tulang trabekular vertebra mencit betina. Jurnal Tumbuhan Obat Indonesia, 11(2), 7. Agil, M., Laswati, H., Purwitasari, N., Ma'arif, B., 2021. Analysis of heavy metal contents of Marsilea crenata Presl. leaves and soils from East Java Province, Indonesia. Pharmacognosy Journal, 13(1), 17-21 Ajayi, O., Awala, S., Ogunleye, A., Okogbue, F., 2016. Antimicrobial screening and phytochemical analysis of Elaeis guineensis (Ewe Igi Ope) against Salmonella strains. British Journal of Pharmaceutical Research, 10(3), 1–9. Arana-Argáez, V.E., Chan-Zapata, I., Canul- Canche, J., Fernández-Martín, K., Martín- Quintal, Z., Torres-Romero, J.C., Ramírez- Camacho, M.A., 2017. Immunosuppresive effects of the methanolic extract of Chrysophyllum cainito leaves on macrophage functions. African Journal of Traditional, Complementary, and Alternative Medicines, 14(1),179–186. Arrijal, I.M.H., Ma’arif, B., Suryadinata, A., 2018. Activity of ethyl acetate extract from Chrysophyllum cainito L. leaves in decreasing blood sugar level in male Wistar rats. Journal of Islamic Pharmacy, 3(1), 31. Bakhsh, A., Mustapha, N.M., Mohamed, S., 2013. Catechin-rich oil palm leaf extract enhances bone calcium content of estrogen-deficient rats. Nutrition, 29(4), 667–672. Chen, M.N., Lin, C.C., Liu, C.F., 2015. Efficacy of phytoestrogens for menopausal symptoms: a meta-Analysis and systematic review. Climacteric, 18(2), 260–269. Chiriac, E.R., Chi, C.L., Borda, D., Lupoae, M., 2020. Comparison of the polyphenolic profile high-resolution mass spectrometry. Molecules, 25, 1–19. Chrysophyllum cainito leaves - Top Tropicals., 2021. Retrieved June 14, 2021, from https://toptropicals.com/html/toptropica ls/plant_wk/cainito.html. Doss, A., Parivugunam, V., Vijayasanthi, M., Surendran, S., 2011. Antibacterial evaluation and phytochemical analysis of Medicago sativa L. against some microbial pathogens. Indian Journal of Science and Technology, 4(5), 550–552. Elaeis guineensis leaves - Top Tropicals., 2021. Retrieved June 14, 2021, from https://toptropicals.com/catalog/uid/elae is guineensis.htm Febrina, D., Febriyanti, R. and Zumarni, 2017. Isolasi senyawa bioaktif antimikroba dari pelepah kelapa sawit (Elaeis guineensis Jacq). Laporan Penelitian, UIN Sultan Syarif Kasim Riau. Feng, X., Mcdonald, J.M., 2011. Disorders of bone remodeling. Annual Review of Pathology, 6, 121–145. file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Agil file:///D:/La%20Penna/%5bNew-Draft%20Jurnal%20Review%5d%20Systematic%20Review-5%20Tanaman%20(1).docx%23Jdidi Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 50 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Glisic, M., Kastrati, N., Musa, J., Milic, J., Asllanaj, E., Portilla Fernandez, E., Muka, T., 2018. Phytoestrogen supplementation and body composition in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Maturitas, 115, 74–83. Hardoko, Gunawan, W.L., Handayani, R., 2019. Aktivitas inhibisi ekstrak daun semanggi air (Marsilea crenata) terhadap enzim HMG-KoA reduktase. Jurnal Sains Dan Teknologi, 3(1), 45–57. Jdidi, H., Ghorbel Koubaa, F., Aoiadni, N., Elleuch, A., Makni-Ayadi, F., El Feki, A., 2020. Effect of Medicago sativa compared to 17β- oestradiol on osteoporosis in ovariectomized mice. Archives of Physiology and Biochemistry, 20, 1–8. Kenkre, J., Bassett, J., 2017. The bone remodelling cycle. Annals of Clinical Biochemistry, 6, 3– 44. Kemenkes., 2015. Data dan Kondisi Penyakit Osteoporosis di Indonesia. Retrieved February 9, 2021, from Pusat Data dan Informasi Kementrian Kesehatan Republik Indonesia https://pusdatin.kemkes.go.id/article/vie w/16010400003/data-dan-kondisi- penyakit-osteoporosis-di-indonesia.html Kiyama, R., 2017. Estrogenic terpenes and terpenoids: pathways, functions and applications. European Journal of Pharmacology, 815, 405–415. Krakowska, A., Rafińska, K., Walczak, J., Kowalkowski, T., Buszewski, B., 2017. Comparison of various extraction techniques of Medicago sativa: yield, antioxidant activity, and content of phytochemical constituents. Journal of AOAC International, 100(6), 1681–1693. Křížová, L., Dadáková, K., Kašparovská, J., Kašparovský, T., 2019. Isoflavones. Molecules, 24(6), 1076. Lannea acida bark - Plants of the world online., 2021. Retrieved June 14, 2021, from http://www.plantsoftheworldonline.org/t axon/urn:lsid:ipni.org:names:69738-1 Ma’arif, B., Aditama, A., Muti’ah, R., Bagawan, W.S., Amiruddin, R., Rukiana, R., 2019. Profil metabolit berbagai ekstrak daun Chrysophyllum cainito L. menggunakan UPLC-QTOF-MS/MS. Jurnal Tumbuhan Obat Indonesia, 12(1), 10–24. Ma’arif, B., Agil, M., Laswati, H., 2016. Phytochemical assessment on n-hexane extract and fractions of Marsilea crenata Presl. leaves through GC-MS. Traditional Medicine Journal, 21(2), 77–85. Ma’arif, B., Agil, M., Laswati, H., 2018. Alkaline phosphatase activity of Marsilea crenata Presl. extract and fractions as marker of MC3T3-E1 osteoblast cell differentiation. Journal of Applied Pharmaceutical Science, 8(3), 55-59 Ma’arif, B., Agil, M., Widyowati, R., 2019. Isolation of terpenoid compound of n-hexane extract of Marsilea crenata Presl.. Farmasains: Jurnal Farmasi Dan Ilmu Kesehatan, 4(2),27–31. Ma’arif, B., Mirza, D.M., Suryadinata, A., Muchlisin, M.A., Agil, M., 2019. Metabolite profiling of 96% ethanol extract from Marsilea crenata Presl. leaves using UPLC-QToF-MS/MS and anti-neuroinflammatory predicition activity with molecular docking. Journal of Tropical Pharmacy and Chemistry, 4(6), 261–270. Mayanti, T., Wahyuni, A., Indriyani, I., Darwati, Herlina, T., and Supratman, U., 2017. Senyawa-senyawa aromatik dari ekstrak daun dan kulit batang Dysoxylum parasiticum serta toksisitasnya terhadap Artemia salina. Chimica et Natura Acta, 5(3), 124–131. Medicago sativa leaves - Plants of the world online., 2021. Retrieved June 14, 2021, from http://www.plantsoftheworldonline.org/t axon/urn:lsid:ipni.org:names:30234961-2 Meira, N.A., Klein, L.C., Rocha, L.W., Quintal, Z.M., Monache, F.D., Cechinel Filho, V., Quintão, N.L.M., 2014. Anti-inflammatory and anti- hypersensitive effects of the crude extract, fractions and triterpenes obtained from Chrysophyllum cainito leaves in mice. Journal of Ethnopharmacology, 151(2), 975–983. Muhaisen, H.M.H., 2013. Chemical constituents from the bark of Lannea acida Rich (Anacardiaceae). Der Pharma Chemica, 5(5), 88–96. Ningsih, I.Y., Zulaikhah, S., Hidayat, M.A., Kuswandi, B., 2016. Antioxidant activity of various Kenitu (Chrysophyllum cainito L.) leaves extracts from Jember, Indonesia. Agriculture and Agricultural Science Procedia, 9, 378–385. Nurjanah, Azka, A., Abdullah, A., 2012. Aktivitas antioksidan dan komponen bioaktif semanggi air. J. Inovasi Dan Kewirausahaan, 1(3), 152–158. Ogunsina, O.I., 2020. Antibacterial activities and time-killing kinetics of Lannea acida extracts against selected microbes. Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... Review Article 51 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Agricultural and Biological Sciences Journal, 6(3), 129–136. Olatunji, O.A., Ihediuche, C.I., Bolaji, O.W., Akala, A.O., Edet, S.E., Oladipo, A.D., 2020. Phytochemical screening and antimicrobial activities of Lannea acida (a. Rich) stem bark extract. Journal of Advances in Biology and Biotechnology, 23(7), 21–26. Olusola, A.O., Olabode Ogunsina, I., Samson Ayedogbon, O., Olusola Adesayo, O., 2020. In vivo Antimalarial activity of bark extracts of Lannea acida (Anacardiaceae) and chloroquine against Plasmodium berghei in mice. International Journal of Biomedical and Clinical Sciences, 5(3), 229–235. Oumarou, M.R., Zingue, S., Bakam, B.Y., Ateba, S.B., Foyet, S.H., Mbakop, F.T.T., Njamen, D., 2017. Lannea acida A. Rich. (Anacardiaceae) ethanol extract exhibits estrogenic effects and prevents bone loss in an ovariectomized rat model of osteoporosis. Evidence-Based Complementary and Alternative Medicine. Puspitasari, Y., Suciati, Agil, M., 2015. Isolasi senyawa terpenoid dari fraksi N-heksana daun Marsilea crenata Presl. pada hasil Kcv fraksi no.2. Jurnal Farmasi Dan Ilmu Kefarmasian Indonesia, 2(1), 16–18. Rafińska, K., Pomastowski, P., Wrona, O., Górecki, R., Buszewski, B., 2017. Medicago sativa as a source of secondary metabolites for agriculture and pharmaceutical industry. Phytochemistry Letters, 20, 520–539. Rodrigues, F., Almeida, I., Sarmento, B., Amaral, M.H., Oliveira, M.B.P.P., 2014. Study of the isoflavone content of different extracts of Medicago spp. as potential active ingredient. Industrial Crops and Products, 57, 110–115. Sayed, D.F., Nada, A.S., Abd El Hameed Mohamed, M., Ibrahim, M.T., 2019. Modulatory effects of Chrysophyllum cainito L. extract on gamma radiation induced oxidative stress in rats. Biomedicine and Pharmacotherapy, 111, 613–623. Schröder, L., Richter, D.U., Piechulla, B., Chrobak, M., Kuhn, C., Schulze, S., Weissenbacher, T., 2016. Effects of phytoestrogen extracts isolated from elder flower on hormone production and receptor expression of trophoblast tumor cells JEG-3 and BEWO, as well as MCF7 breast cancer cells. Nutrients, 8(10), 616. Selcuk, A. A., 2019. A guide for systematic reviews: PRISMA. Turkish Archives of Otorhinolaryngology, 57(1), 57–58. Shailajan, S., Gurjar, D., 2014. Pharmacognostic and phytochemical evaluation of Chrysophyllum cainito. International Journal of Pharmaceutical Sciences Review and Research, 26(17), 106–111. Sihombing, I., Wangko, S., Kalangi, S.J.R., 2012. Peran estrogen pada remodeling tulang. Jurnal Biomedik, 4(3), 18–28. Snyder, H., 2019. Literature review as a research methodology: an overview and guidelines. Journal of Business Research, 104(July), 333–339. Soundararajan, V., Sreenivasan, S., 2012. Antioxidant activity of Elaeis guineensis leaf extract: an alternative nutraceutical approach in impeding aging. APCBEE Procedia, 2, 153–159. Sozen, T., Ozisik, L., Calik Basaran, N., 2017. An overview and management of osteoporosis. European Journal of Rheumatology, 4(1), 46–56. Sugiritama, I.W., Adiputra, I.N., 2019. Potensi antosianin dalam manajemen menopause. Jurnal Kesehatan Andalas, 8(1), 158. Susilowati, M.C., Budiarti., Agnes, S.N., 2014. Identifikasi kandungan senyawa kimia ekstrak etanol herba alfalfa (Medicago Sativa, L). Media Farmasi Indonesia, 9(2), 732-742. Tahir, N.I., Shaari, K., Abas, F., Parveez, G.K.A., Ishak, Z., Ramli, U.S., 2012. Characterization of apigenin and luteolin derivatives from oil palm (Elaeis guineensis Jacq.) leaf using LC- ESI-MS/MS. Journal of Agricultural and Food Chemistry, 60(45), 11201–11210. Utaminingtyas, N.I., Ma’arif, B., Megawati, D.S., Atmaja, R.R.D., 2018. Activity of 70% ethanol extract of Chrysophyllum cainito in increasing vertebrae trabecular bone density in female mice. Majalah Obat Tradisional, 23(3), 119. Vargas, L.H.G., Neto, J.C.R., de Aquino Ribeiro, J.A., Ricci-Silva, M.E., Souza, M.T., Rodrigues, C.M., Abdelnur, P.V., 2016. Metabolomics analysis of oil palm (Elaeis guineensis) leaf: evaluation of sample preparation steps using UHPLC–MS/MS. Metabolomics, 12(153). Virk-Baker, M.K., Nagy, T.R., Barnes, S., 2010. Role of phytoestrogens in cancer therapy. Plant Med, 76(11), 1132-1142. Wahjudi, P., Putriana, M.F., 2014. Karakteristik dan status kesehatan jamaah haji kabupaten Banyuwangi tahun 2012. Jurnal Ikesma, 10(1), 1–12. Widjayant, Y., 2016. Gambaran keluhan akibat penurunan kadar hormon estrogen pada masa menopause. Adi Husada Nursing Review Article Journal of Pharmaceutical Sciences and Community Systematic Review: Anti-Osteoporosis Potential Activities... 52 Ma’arif et al. J. Pharm. Sci. Community, 2022, 19(1), 41-52 Journal, 2(1), 96–101. Widyowati, H., Ulfah, M., Sumantri., 2014. Uji aktivitas antioksidan ekstrak etanolik herba alfalfa (Medicago sativa L.) dengan metode DPPH (1,1-Diphenyl-2 Picrylhidrazyl). Jurnal Ilmu Farmasi Dan Farmasi Klinik, 11(1), 25–33. Yahmin, Y., Faqih, K., Suharti, S., 2019. Skrining turunan flavonoid sebagai kandidat inhibitor protease nsP2 dari virus chikungunya menggunakan molecular docking. JC-T (Journal Cis-Trans): Jurnal Kimia Dan Terapannya, 3(1), 34–44. Yin, N.S., Abdullah, S., Phin, C.K., 2013. Phytochemical constituents from leaves of Elaeis guineensis and their antioxidant and antimicrobial activities. International Journal of Pharmacy and Pharmaceutical Sciences, 5(Suppl.4), 137–140. Yousefzadeh, N., Kashfi, K., Jeddi, S., Ghasemi, A., Physiology, E., Sciences, B., Blvd, D., 2020. Ovariectomized rat model of osteoporosis: a practical guide. EXCLI Journal, 19, 89–107. Yuliawati, D., Astuti, W.W., Yuniarti, F., 2019. Pengaruh ovariektomi terhadap kadar estradiol dalam darah tikus (Rattus novergicus) model menopause. Jurnal Ilmu Kesehatan, 10(2), 95–100. Yusof, N.Z., Gani, S.S.A., Siddiqui, Y., Mokhtar, N.F.M., Hasan, Z.A.A., 2016. Potential uses of oil palm (Elaeis guineensis) leaf extract in topical application. Journal of Oil Palm Research, 28(4), 520–530. Zain, M.S.C., Lee, S.Y., Teo, C.Y., Shaari, K., 2020. Adsorption and desorption properties of total flavonoid from oil palm (Elaeis guineensis Jacq.) mature leaf on macroporous adsorption resins. Molecules, 25(4), 1–17. Zhou, J., Chen, Y., Wang, Y., Gao, X., Qu, D., 2014. A comparative study on the metabolism of Epimedium koreanum Nakai-prenylated flavonoids in rats by an intestinal enzyme (lactase phlorizin hydrolase) and intestinal flora. Molecules, 19, 177–203.