Saturday, 19 May 2018

Dietary nutraceuticals as backbone for bone health

JournalsBooks Download PDF Advanced Outline Abstract Keywords 1. Introduction 2. Signaling pathways in osteoblasts 3. Signaling pathways in osteoclasts 4. Potential of natural agents against bone loss 5. Clinical trials 6. Conclusions References Figures (2) Fig. 1. Biochemical mechanism for bone loss/formation Fig. 2. Structure of Nutraceuticals linked with suppressing bone loss Tables (2) Table 1 Table 2 Elsevier Biotechnology Advances Available online 27 March 2018 In Press, Corrected ProofWhat are Corrected Proof articles? Biotechnology Advances Research review paper Author links open overlay panelManoj K.PandeyaSubash C.GuptabDeepkamalKareliacPatrick J.GilhooleyaMehdiShakibaeidBharat B.Aggarwale Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA b Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India c Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA d Musculoskeletal Research Group and Tumour Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Ludwig-Maximilian-University, Munich, Germany e Inflammation Research Center, San Diego, CA, USA Get rights and content Abstract Bone loss or osteoporosis, is a slow-progressing disease that results from dysregulation of pro-inflammatory cytokines. The FDA has approved number of drugs for bone loss prevention, nonetheless all are expensive and have multiple side effects. The nutraceuticals identified from dietary agents such as butein, cardamonin, coronarin D curcumin, diosgenin, embelin, gambogic acid, genistein, plumbagin, quercetin, reseveratrol, zerumbone and more, can modulate cell signaling pathways and reverse/slow down osteoporosis. Most of these nutraceuticals are inexpensive; show no side effect while still possessing anti-inflammatory properties. This review provides various mechanisms of osteoporosis and how nutraceuticals can potentially prevent the bone loss. Keywords Phytoestrogens Bone loss Nutraceuticals Osteoclastogenesis Bone remodeling Osteoporosis Pro-inflammatory cytokines 1. Introduction Bone loss or osteoporosis is an aggravating factor for the precipitation of bone disease. Bone loss accounts for nearly 8.9 million fractures annually (Looker et al., 2017; Rachner et al., 2011). In the United States approximately 53 million people are at risk of developing bone loss (Looker et al., 2017). It is estimated that over 200 million women are suffering from osteoporosis (Looker et al., 2017), and by 2025 there will be three million fractures because of bone loss, which will amount to a staggering $25.3 billion annual economic cost. The characteristic feature of osteoporosis is a decrease in density, and strength of bone (Adler, 2014; Iniguez-Ariza and Clarke, 2015). The hallmark of healthy bone is the ‘honeycomb’ like structure seen on gross examination of specimen. However, an erosion of bone structure leads to an increase in pore diameter of the structural “honeycomb”, causing the bone to lose density and eventually strength (Adler, 2014; Iniguez-Ariza and Clarke, 2015). Factors including health problems, lifestyle, medical procedures, and medication can all contribute to bone loss. Additionally, rheumatoid arthritis (RA), lupus, inflammatory bowel disease (IBD), breast cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, Parkinson’s disease, diabetes, hyperparathyroidism, Cushing’s syndrome, irregular periods, premature menopause, low levels of testosterone and estrogen in men, and chronic obstructive pulmonary disease (COPD) can all lead to osteoporosis (Adler, 2014; Clementini et al., 2014; Khanna et al., 2007; Kling et al., 2014). Furthermore, medical procedures such as weight loss surgery, gastrectomy, and gastrointestinal bypass surgery, and medicines including aromatase inhibitors, chemotherapeutic drugs, gonadotropin releasing hormone (GnRH), methotrexate, steroids (glucocorticoids), and thyroid hormones contribute to osteoporosis (Adler, 2014; Clementini et al., 2014; Khanna et al., 2007; Kling et al., 2014). Bone remodeling takes place continuously, (Iniguez-Ariza and Clarke, 2015; Kobayashi et al., 2003) and tightly maintained by both osteoblasts (OBs) the bone forming cells, and osteoclasts (OCs) the bone resorbing cells (Chambers, 2000; Iniguez-Ariza and Clarke, 2015; Rachner et al., 2011; Roodman, 1999). The transition of mesenchymal stem cells (MSCs) into differentiating OBs and monocyte/macrophage precursors into differentiating OCs are the main events in osteogenesis and bone remodeling (Boyle et al., 2003; Teitelbaum, 2000). A number of signaling pathways play critical role in controlling the commitment and differentiation of lineages by modulating the expression of genes (Iniguez-Ariza and Clarke, 2015; Khanna et al., 2007). The imbalance at any stage of differentiation will impair function of these two cell types results in bone diseases including, osteopetrosis, periodontal problems, and bone cancer metastases (Chen et al., 2010; Iniguez-Ariza and Clarke, 2015; Sethi and Aggarwal, 2007). Current treatment for bone loss includes; estrogens, estrogen receptor modulators, bis-phosphonates, and calcitonin. The US Food and Drug Administration (US FDA) has approved number of drugs, however, most of them are associated with severe side effects as reflected in Table 1, (Sethi and Aggarwal, 2007). Recently, antibodies against receptor activator of nuclear factor kappa-B ligand (RANKL), Denosumab, showed promising response by inhibiting bone resorption in postmenopausal women (Maricic, 2007), though Denosumab exhibited undesirable side effects (Table 1). Extensive studies on agents derived from natural sources demonstrated that natural agents are efficacious in the treatment of bone-related diseases. Importantly, these agents are safe and inexpensive (Fig. 1, Table 2). By utilizing various in vitro and in vivo models, number of studies demonstrated that agents derived from natural sources exhibit anti- osteoclastogenesis potential (Ichikawa et al., 2007; Sethi and Aggarwal, 2007). For example, 1'-acetoxychavicol acetate (ACA, from Alpina galangal, commonly called thai ginger) (Ichikawa et al., 2006a), acetyl-11-keto-beta-boswellic acid (AKBA, from Boswellia serrata, commonly known as salai guggul) (Takada et al., 2006), butein (from cashew) (Sung et al., 2011), curcumin and calebin A (from turmeric) (Bharti et al., 2004; Kim et al., 2012; Tyagi et al., 2016), cardamonin (from Alpinia katsumadai, commonly called cardamonin) (Sung et al., 2013), coronarin D (from Hedychium coronarium, commonly known white ginger lily) (Kunnumakkara et al., 2008), diosgenin (from fenugreek) (Shishodia and Aggarwal, 2006a, 2006b), embelin (from Embelia ribes, known as false black pepper) (Reuter et al., 2010), gambogic acid (from mangosteen) (Ma et al., 2015; Pandey et al., 2014), gossypin (from Hibiscus vitifolius, called as rose mallow) (Kunnumakkara et al., 2007), guggulsterone (from guggul tree Commiphora mukul) (Ichikawa and Aggarwal, 2006), honokiol (from Magnolia officinalis, common name hou po) (Ahn et al., 2006), isodeoxyelephantopin (from medicinal plant Elephantopus scaber Linn., commonly called elephant foot) (Ichikawa et al., 2006b), indole-3 carbinol (from Brassica species) (Takada et al., 2005), plumbagin (from Chitrak) (Sung et al., 2012), reseveratrol (from grapes) (Shakibaei et al., 2011; Zhao et al., 2014), simvastatin (Ahn et al., 2008), thiocolchicoside (from Gloriosa superba, common name flame lily) (Reuter et al., 2012), withanolides (from Ashwagandha) (Ichikawa et al., 2006c), zerumbone (from subtropical ginger) (Sung et al., 2009), zyflamend (polyherbal preparation) (Sandur et al., 2007) have been shown to inhibit osteoclastogenesis induced by RANKL (Fig. 1). This review summarizes the recent advancements in the understanding of the role of natural agents, particularly those derived from dietary resources, in bone remodeling. Table 1. FDA approved drugs used for bone loss and their side effects. Drug Chemical class Mechanism of action Side effects References Alendronate/risedronate/ibandronate/zoledronic acid Bisphosphonates Inhibits osteoclast GI toxicity, weight loss, bone pain, low calcium levels Gao et al. (2017), Grigg et al. (2017), Lai et al. (2005), Lange et al. (2017), Lindsay et al. (1999), Lu et al. (2016), Monda et al. (2017), Sharma and Pradeep (2012), Shimizu et al. (2017), Shin et al. (2017); Watanabe et al. (2016) Estrogen Sex steroid Inhibits osteoclast development Endometrial cancer, stroke Goetz et al. (2017), Khalid and Krum (2016), Sapir-Koren and Livshits (2017), Southmayd and De Souza (2017), Streicher et al. (2017), Wu et al. (2018) Raloxifene Estrogen mimic Inhibits osteoclast development Leg cramps, hot flashes Beekman et al. (2017)Das and Crockett (2013), Fernandez-Garcia et al. (2008), Gomes-Filho et al. (2015) Estren Estrogen derivative Inhibits osteoblast apoptosis Breast cancer Denosumab RANKL antibody Inhibits osteoclast development Nausea, diarrhea, cramps Cummings et al. (2018), Meier et al. (2017), Nakamura et al. (2017), Nakatsukasa et al. (2017) Calcitonin Peptide hormone Inhibits osteoclasts Nausea, skin redness, diarrhea Atbinici et al. (2015), Bandeira et al. (2016), Binkley et al. (2014), Liu et al. (2014), Mandema et al. (2014), Shohrati et al. (2015) Teriparatide Peptide Induces bone formation Pain, headache, diarrhea, hypercalcemia Canalis (2018), Dempster et al. (2018), Greenspan et al. (2018), Kaneko et al. (2017), Langdahl et al. (2017), Lu et al. (2017), Suzuki et al. (2018) Abaloparatide (TYMLOS) Peptide Induces bone formation, maintains BMD Headache, dizziness, nausea, hypercalcemia Reginster et al. (2017), Shirley (2017), Tella et al. (2017) Table 2. List of nutraceuticals connected with bone health. Natural agents Source Mechanism Models Reference Resveratrol Vitis vinifera (red grapes) ↓IL1, ↓IL-6, ↓(COX-2), ↓RANKL, ↓Wnt, ↓PPAR-γ, ↓TNF-α, ↓VEGF, ↓lamin, ↓NF-κB, ↑FOXO1, ↑HO-1, ↑Sirt1, ↑Runx2, ↑osterix, ↑p-ERK1/2, ↑AMPK, ↑ALP, ↑osteocalcin In vivo and in vitro Ke et al. (2015), Lee et al. (2017), Matsuda et al. (2018), Mobasheri and Shakibaei (2013), Tou (2015), Zhao et al. (2015) Curcumin Curcuma longa (turmeric) ↓NF-κB, ↓RANKL, ↓MMP-13, ↓CTX, ↓ROS levels, ↓PPAR-γ, ↓C/EBP alpha, ↓ERK, ↓JNK, ↓p38, ↓NFAT2, ↓NF-κB, ↑osteocalcin, ↑Wnt-signaling pathway, ↑Runx2, ↑Osterix, ↑Col1A1, ↑Osteonectin, ↑HO-1, ↑ALP In vitro and in vivo Bharti et al. (2004), Chen et al. (2016), Gu et al. (2012), Hou et al. (2016), Kim et al. (2011b), Oh et al. (2008), TenBroek et al. (2016), von Metzler et al. (2009)Wang et al. (2016), Xin et al. (2015) Quercetin Allium cepa (onions) ↓p-AKT, ↓RANKL, ↓PGE2, ↓TRAF6, ↓COX-2, ↓Bcl-2, ↓NF-κB, ↓Smad, ↓AP-1, ↑ER-α, ↑ALP, ↑ERK, ↑p38, ↑MAPK, ↑Osx, ↑Runx2, ↑BMP-2, ↑Col-1, ↑OPN, ↑OCN, ↑Bax, ↑Bcl-2 In vitro and in vivo Casado-Diaz et al. (2016), Derakhshanian et al. (2013), Gomez-Florit et al. (2015), Guo et al. (2012), Kim et al. (2006), Masuhara et al. (2016), Wang et al. (2014b), Wattel et al. (2004), Yamaguchi and Weitzmann (2011), Zhou and Lin (2014), Zhou et al. (2015) Withanolide (Withaferin A) Acnistus arborescens (hollow heart) ↓RANKL, ↓Smurf2, ↓NF-κB, ↑Runx2 In vitro and in vivo Khedgikar et al. (2013) Silibinin Silybum marianum (milk thistle) ↓ERK, ↓JNK, ↓p38, ↓NFATc1, ↓NF-κB, ↓OSCAR, ↓MMP-9, ↓TRAP, ↓PSCAR, ↓cathepsin-K, ↓AP-1, ↑Col-1, ↑CTGF, ↑BMP-2, ↑p-AKT In vitro Kavitha et al. (2014), Kim et al. (2009), Kim et al. (2012a), Ying et al. (2015) Rosmarinic acid Rosmarinus officinalis (rosemary) ↓NFATc1, ↓MMP-9, ↓TRAP, ↓cathepsin-K, ↓NF-κB In vitro Hsu et al. (2011), Omori et al. (2015) Lupeol Senegalia visco, Abronia villosa, Mangifera (Mango) ↓NF-κB, ↓NFATc1, ↓c-Fos In vitro and in vivo Im et al. (2016) Syringetin Lysimachia congestiflora (Creeping Jenny) ↓AKT, ↓mTOR, ↓RANKL In vitro Tsai et al. (2015) Oleanolic acid Phytolacca Americana, olive oil ↑osteocalcin, and ↑Runx2 In vivo Bian et al. (2012) Indole-3-carbinol cruciferous vegetables ↓iNOS, ↓IL-6, ↓NF- κB, ↓TNF-α, ↓IL-1, ↓NO, ↓PGE2 In vivo Dong et al. (2010), Yu et al. (2015) Obovatol Magnolia obovate (Japanese big leaf) ↓NF-κB, ↓JNK, ↓ERK, ↓c-Fos, ↓NFATc1 In vitro and in vivo Kim et al. (2014a) Gambogic acid Garcinia hanburyi (false mangosteen) ↓NF-κB, ↓CXCR4, ↓p-Akt, ↓p38, ↓Erk1/2, ↓IL-6 In vitro Pandey et al. (2014) Harpagoside Harpagophytum procumbens (wood spider) ↓ERK, ↓JNK, ↓Syk-Btk-PLCγ2-Ca(2+), ↓c-Fos, and ↓NFATc1 In vitro and in vivo Chung et al. (2017), Kim et al. (2015b) Wedelolactone Eclipta alba (false daisy) ↓PLCγ2, ↓GSK3β activity, ↓NFATc1, ↓NF- κB, ↓c-Src, ↓c-Fos, ↓Cathepsin-K, ↓NF- κB/c-Fos/NFATc1, ↑β-catenin, ↑Runx2, ↑Wnt/GSK3β/β-catenin In vitro and in vivo Liu et al. (2016a), Liu et al. (2016b) Celastrol Tripterygium wilfordii (thunder of god vine) ↓PGE2, ↓BMP-2, ↓Col 1, ↓Runx-2, ↓osteocalcin, ↓PGE-2, ↓AKT, ↓PI3K, ↓β-catenin, ↑GSK-3β In vitro Zou et al. (2016) Theaflavin-3,3′-digallate Camellia sinensis (tea shrub) ↓RANKL, ↓ERK, ↓c-Fos, ↓NFATc1, ↓TRAP, ↓CTSK, ↓Oscar In vitro and in vivo Hu et al. (2017) Zerumbone Zingiber zerumbet (bitter ginger) ↓NF- κB In vitro and in vivo Sung et al. (2009) Ursolic acid Ocimum sanctum (holy basil) ↓NFATc1, ↓NF- κB, ↓JNK, ↓TRAP, ↓CTSK, ↓MMP-9, ↓c-Fos, ↓NFAT In vitro and in vivo Jiang et al. (2015a)Xu et al. (2016) Piperine Piper nigrum (Black pepper) ↓p38 MAPK kinase, ↓c-Fos, ↓NFATc1, ↓p38/NFATc1/c-Fos In vitro Deepak et al. (2015b) Gingerol Zingiber officinale (Ginger) ↓IL-6, ↓NF- κB, ↑Collagen type I, ↑ALP, ↑ALP activity in vitro Fan et al. (2015) Embelin Ardisia japonica (Marlberry) ↓NF- κB In vitro Reuter et al. (2010) Andrographolide Andrographis paniculata (king of bitters) ↓calcitonin receptors, ↓cathepsin-K, ↓NF-κB, ↓p-TGF-β-activated kinase 1, ↓p-IκBα, ↓ERK/MAPK signaling pathway, ↓TRACP, ↓NFATc1, ↑Wnt/β-catenin, ↑ALP, ↑BSP, ↑OCN, ↑Runx2 In vitro and in vivo Jiang et al. (2015b), Ren and Zhou (2015)Wang et al. (2015)Zhai et al. (2014) Butein Toxicodendron vernicifluum (Chinese lacquer) ↓RANKL, ↓NF-κB, ↓PGE2, ↓iNOS, ↓TNF-α, ↓IL-6, ↓COL-2, ↓COX-9, ↓ADAMTS-4, ↓ADAMTS-5 In vitro and in vivo Sung et al. (2011), Zheng et al. (2017) Sulforaphane cruciferous vegetables ↓NF-κB, ↓OSCAR, ↓NDATc1, ↓cathepsin-K, ↓DC-STAMP, ↓OC-STAMP, ↑STAT1 In vitro (Kim et al. (2005b), Takagi et al. (2017) Silymarin Silybum marianum (milk thistle) ↓NF-κB, ↓JNK, ↓p38, ↓ERK, ↓NFATc1, ↓OSCAR, ↑collagen secretion, ↑osteocalcin, ↑BMP, ↑SMAD1/5/8, ↑Runx2, ↑BMP/SMAD/Runx2 In vitro and in vivo Kim et al. (2009), Kim et al. (2012b) Plumbagin Drosera and Nepenthes (pitcher plants) ↓NF-κB, ↓MAPK, ↓RANKL In vitro and in vivo Li et al. (2012), Sung et al. (2012) Honokiol Magnolia grandiflora (bull bay) ↓p-p38 MAPK, ↓ERK, ↓JNK, ↓NFATc1, ↓IL-6, ↓RANKL, ↓TNF-α, ↓NF-κB, ↑BMP-2, ↑Smad In vitro Choi (2011), Hasegawa et al. (2010), Yamaguchi et al. (2011) Fisetin Acacia greggiil, Acacia berlandieri, Quebracho colorado (Cat claw) ↓p38 MAPK, ↓c-Fos, ↓NFATc1, ↓DC-STAMP, ↓cathepsin-K, ↓ERK, ↓Akt, ↓JNK, ↓NF-κB, ↓TRAF6, ↓c-Src-2, ↓osteocalcin, ↑HO-1, ↑MKP-1, ↑Runx-1, ↑Col1A1 In vitro and in vivo Choi et al. (2012), Kim et al. (2014b), Leotoing et al. (2014), Leotoing et al. (2013), Sakai et al. (2013) Ellagic acid Juglans regia (Walnut) and many other fruits and vegetables ↓p38 MAPK In vitro Rantlha et al. (2017) Betulinic acid Betula pubescens (downy birch) ↓MMP-2, ↓MMP-9, ↓cathepsin-K In vitro and in vivo Park et al. (2014) Emodin Rheum emodi (Himalayan rhubarb) ↓RANKL, ↓PPARγ, ↓C/EBPα, ↑Runx2, ↑osterix, ↑COL1, ↑osteocalcin, ↑ALP In vitro and in vivo Chen et al. (2017), Kang et al. (2014), Yang et al. (2014) Caffeic acid Eucalyptus globulus (blue gum) ↓ERK1/2, ↓p38, ↓JNK, ↓AP-1, ↓c-Fos, ↓p-Akt.↓NFATc1, ↓TRAP, ↓cathepsin-K, ↓c-Src, ↑Runx2 In vitro and in vivo Duan et al. (2014), Tolba et al. (2017), Wu et al. (2012), Zawawi et al. (2015) Apigenin Petroselinum crispum (parsley), Thymus vulgaris (thyme) ↓ IL-6, ↓RANTES, ↓MCP-1, ↓MCP-3, ↓MCP-1, ↓RANKL, ↓c-Fms, ↑BMP-6, ↑Osteopontin, ↑Runx2, ↑p-JNK, ↑p-p38 In vitro Bandyopadhyay et al. (2006), Goto et al. (2015), Zhang et al. (2015) Luteolin Found in many cruciferous vegetables, fruits and herbs ↓ATF2, ↓p38 MAPK, ↓NFATc1, ↓TNF-α, ↓CTX, ↑Dnajb1, ↑Hsp90b1 In vitro Crasto et al. (2013), Kwon et al. (2016), Lee et al. (2009), Shin et al. (2012) Genistein Genista tinctoria (dyer’s broom) ↓osteocalcin, ↓TNF-α, ↓PPARγ, ↓adipsin, ↓NF-κB, ↑ALP, ↑ACP, ↑osteocalcin, ↑ALP, ↑TGFβ1, ↑Estrogen Receptor, ↑p38MAPK-Runx2, ↑NO/cGMP, ↑OPG, ↑SMAD5, ↑BMP2 In vitro and in vivo Dai et al. (2013), Heim et al. (2004), Li and Yu (2003), Ming et al. (2013), Zhang et al. (2016) Berberine Berberis vulgaris (barberry) ↓NF-κB, ↓Akt, ↑osteopontin, ↑osteocalcin, ↑Runx2, ↑p38 MAPK, ↑COX-2, ↑Wnt/β-catenin In vitro Hu et al. (2008), Lee et al. (2008)/Tao et al. (2016)Xu et al. (2010) Lycopene Solanum lycopersicum (tomato) ↓ALP, ↓IL-6, In vivo Ardawi et al. (2016), Iimura et al. (2014), Liang et al. (2012) Fig. 1 Download high-res image (896KB)Download full-size image Fig. 1. Biochemical mechanism for bone loss/formation. Chemical structure of common dietary agents. The main sources of the natural agents are indicated in the parenthesis. These agents can also be derived from other natural sources. 2. Signaling pathways in osteoblasts Signaling pathways are pivotal in the commitment and differentiation of OBs and OCs. A number of studies have identified the key players in the process of osteogenesis (Iniguez-Ariza and Clarke, 2015). 2.1. TGF-β-Smad signaling The TGF-β superfamily members bind and signal through dual type I and II transmembrane receptors, which contain serine/threonine kinase domains. Smad proteins play key role in transmitting signals from receptor to nucleus (Derynck and Zhang, 2003; Miyazono et al., 2000). One of the member of TGF-β superfamily, bone morphogenetic proteins (BMPs) is critical in osteogenesis (Chen et al., 2012; Wozney, 1992; Zhang et al., 2014). Existing in various isoforms, BMPs mediate variety of activities in skeleton tissues (Rahman et al., 2015). For example, BMP-2, -6, and -7, and -9 promotes bone formation (Kochanowska et al., 2007), while BMP-3 inhibits bone formation (Kokabu et al., 2012; Wang et al., 2014a). The BMP mediated signaling pathways are both Smad-dependent and - independent (Derynck and Zhang, 2003). Upon BMP stimulation transcription factor Runx2 and Smads physically interact and regulate the transcription of genes which facilitates differentiation of mesenchymal stem cells (MSCs) to osteoblast (Javed et al., 2008; Phimphilai et al., 2006). How BMP modulates the expression of Runx2 is not clear. Recent studies have shown that BMP does not directly regulate Runx2 expression in mesenchymal cells (Lee et al., 2003), but instead it modulates the expression of distal less homeobox 5 (DLX5) in osteoblasts (Lee et al., 2003; Ryoo et al., 1997), which induces Runx2 in osteo-progenitor cells (Lee et al., 2003). Additionally, BMP signaling also regulates genes critical in osteoblastic differentiation such as Hairy/enhancer of split related with YRPW motif 1 (Hey1; also called HesR1 and Herp2), Tcf7, ITF-2 (Tcf4), and interferon regulatory factor 8 (ICSBP) (Chen et al., 2012; Franceschi et al., 2003). The activation of MAPKs including ERK, JNK, and p38 is regulated by BMP-2 in osteoblastic cells. The BMP signaling induced MAPKs have distinct roles in regulation of osteocalcin expression (Aubin et al., 2004; Broege et al., 2013; Rahman et al., 2015). Furthermore, BMP activated p38 MAPK and Smads controls the MSCs differentiation by Runx2 (Aubin et al., 2004). Additionally, studies using mouse progenitor cells and chondrocytes have demonstrated that BMP-2 induces Osterix (Osx) expression (Matsubara et al., 2008). Several studies have demonstrated that BMP signaling is implicated in pathogenesis of variety of bone disorders such as bone metastasis, brachydactyly type A2, and osteoarthritis (Dathe et al., 2009; Katz et al., 2013; Shen et al., 2014). The group of Phimphilai et al. (2006) showed that suppression of BMP signaling disrupt the osteoblast differentiation (Phimphilai et al., 2006). Another studies of Tsuji et al. (2006) augmented the role of BMP-2 fracture repair (Tsuji et al., 2006). Overall, studies suggest that BMP-2 signaling is required for bone remodeling. Several studies have illustrated that natural agents induce the osteoblast specific differentiation through TGFβ-Smad signaling pathways. Along these lines it is shown that quercetin, celastrol, andrographolide, silymarin, and honokiol reduce the TGFβ-Smad signaling pathways thus induces the osteoblast specific differentiation (Casado-Diaz et al., 2016; Kim et al., 2006; Zou et al., 2016) (Choi, 2011; Kim et al., 2012a). 2.2. Fibroblast growth factor signaling The fibroblast growth factors (FGFs) are a family of secreted polypeptides. FGFs bind to FGF tyrosine kinase receptors (FGFRs) and regulate a number of biological events critical in endochondral and intramembranous ossification (Ornitz, 2005; Su et al., 2014). During embryonic development, FGFRs are expressed in the condensing mesenchyme, perichondrium and periosteum, which evolve in cartilage, osteoblasts, and cortical bone, respectively (Ornitz and Marie, 2015; Teven et al., 2014). Mutations in FGFRs are linked with pathological conditions in humans including cranio synostosis and chondrodysplasia syndromes (Johnson and Wilkie, 2011; Ko, 2016). However, the role of FGFR 1 signaling in OBs differentiation is contradictory, as it is also reported that this signaling suppresses differentiation of OBs. Probably, FGFR1 signaling does act in a stage-specific manner (Jacob et al., 2006). Nonetheless, it has been demonstrated that FGF activates the transcription factor Runx2 by MAPK pathways, and thus regulates bone formation (Park et al., 2010). Studies have shown that apigenin, berberine, curcumin, emodin, genistein, oleanolic acid, quercetin, resveratrol, silymarin, wedelolactone, and withanolide activate the transcription factor Runx2 through MAPK pathways, therefore regulate the bone formation (Goto et al., 2015; Gu et al., 2012; Khedgikar et al., 2013; Kim et al., 2012a; Lee et al., 2008; Zhang et al., 2015). 2.3. Wnt signaling pathway The Wnt/β-catenin pathway is particularly important for bone cell signaling (Baron and Kneissel, 2013; Wang et al., 2014c). Based on the various genetic models, it is unequivocally established that embryonic skeletal development and adult skeletal remodeling requires Wnt signaling (Wang et al., 2014c). The studies of Krishnan et al in 2006, first showed that Wnt signaling plays a critical role in bone formation. These studies demonstrated that mutation in LRP5 a co-receptor of Wnt is the main cause of alternation in bone mass (Krishnan et al., 2006). Eight missense mutations in LRP5 have been identified as causing high bone mass (Balemans et al., 2007; Niziolek et al., 2015), while several homozygous or heterozygous nonsense, frameshift, and missense mutations have been identified in osteoporosis-pseudo glioma patients leading to low bone density (Cheung et al., 2006; Laine et al., 2011). It has been suggested that canonical Wnt/β-catenin signaling increase bone mass through upregulating the development of OBs (Regard et al., 2012; Yavropoulou and Yovos, 2007). High levels of β-catenin signaling upregulate the expression of genes implicated in differentiation of OBs (Zhang et al., 2013). This evidence is derived from studies utilizing conditional knockout mouse model, where knock out of β-catenin causes ectopic chondrogenesis and abnormal osteoblast differentiation (Usami et al., 2016). Additional studies further strengthen the role of Wnt signaling in OBs induction, suppression of chondrocytic differentiation in early osteochondroprogenitors (Day et al., 2005; Glass II et al., 2005; Hill et al., 2005). It was shown that Wnt induced OBs stimulated the production of osteoprotegerin (OPG) which inhibit the OCs formation and induces the OBs differentiation (Day et al., 2005; Glass II et al., 2005; Hill et al., 2005). A recent study revealed that Wnt/β-catenin signaling allows activation of transcription factors important in osteoblastogenesis by suppressing CCAAT/enhancer binding protein alpha (C/EBPa) and peroxisome proliferator activated receptor gamma (PPARγ) (Kang et al., 2007). Knockout of C/EBPa or PPARγ expression in ST2 cells and mouse embryonic fibroblasts reduced adipogenic potential and caused spontaneous formation of osteoblasts (Song et al., 2012). Recently, a study using Col1a1- and an OCN-Cre genetic model demonstrated that β-catenin is required in postnatal bone homeostasis (Burgers and Williams, 2013). The non-canonical Wnt signaling is also reported to play a role in osteoblastogenesis (Okamoto et al., 2014). Tu et al. has shown that Wnt3a and Wnt7b each function in osteoblastogenesis through a protein kinase C delta (PKCδ) pathway (Tu et al., 2007). Among the natural agents that modulate the Wnt signaling pathways and regulate the osteoblast differentiations are curcumin, wedelolactone, celastrol, andrographolide, and berberine. These agents have been used to demonstrate their effect on osteoblastogenesis. Furthermore studies suggest that these agents induce osteoblast differentiation by modulating the Wnt/β-catenin signaling pathways (Chen et al., 2016; Jiang et al., 2015b; Liu et al., 2016b; Tao et al., 2016; Zou et al., 2016). 2.4. Ephrin signaling Ephrins mediates bidirectional signaling (Pasquale, 2008). There are two classes of ephrins, class A and B. The B class molecules include (ephrin B1 to B3) ligands for EphB tyrosine kinase receptors (B1 to B6), whereas the class A ephrins (A1 to A5) are ligands for glycosyl phosphatidylinositol (GPI) - anchored EphA receptors (A1 to A10) (Lisabeth et al., 2013). The axis of ephrin B/EphB receptors control patterning of the developing skeleton. The unregulated ephrin signaling is associated with cranio frontonasal syndrome (Edwards and Mundy, 2008; Wieland et al., 2004). The ephrin signaling is critical in communication between OCs and OBs (Zhao et al., 2006). This bidirectional communication is mediated by ephrinB2 ligand in OCs and EphB4, a tyrosine kinase receptor, in OBs (Zhao et al., 2006). Notably, reverse signaling from EphB4 in osteoblasts to ephrinB2 in OC progenitors lead to the inhibition of osteoclast differentiation (Takyar et al., 2013). EphB4 induces osteogenic regulatory factors, such as Dlx5, Osx, and Runx2, in calvarial osteoblasts, suggesting that EphB4 is upstream in the regulation of osteoblast differentiation (Zhao et al., 2006). As a whole, these studies establish the concept that ephrin-Eph signaling is important in maintaining bone homeostasis. A number of laboratories have shown that resveratrol, curcumin, quercetin, oleanolic acid, wedelocatone, celastrol, fisetin, emodin, genistein, and berberine induce osteoblast differentiation, thus preventing bone decay (Bian et al., 2012; Casado-Diaz et al., 2016; Dai et al., 2013; Lee et al., 2008; Leotoing et al., 2014; Liu et al., 2016a; Mobasheri and Shakibaei, 2013; Zhou and Lin, 2014; Zou et al., 2016). 2.5. Hedgehog signaling Studies have implicated the role of hedgehog (Hh) in skeletal signaling pathways (Yang et al., 2015). During skeletogenesis, Indian hedgehog (Ihh) and sonic hedgehog (Shh) are involved in patterning the axial, appendicular, and facial skeleton (Pan et al., 2013; St-Jacques et al., 1999). It has been illustrated that Ihh is expressed by prehypertrophic chondrocytes and coordinates growth and differentiation of chondrocytes (Chung et al., 2001). In humans, mutation in the Hh pathway leads to many skeletal deformities such as brachydactyly type A1, and Gorlin syndrome (Onodera et al., 2017). The effect of homozygous mutation of Ihh is thought to be associated primarily with a deregulation of chondrocyte homeostasis (Cai and Liu, 2016). Recent studies of Sreekumar V et al, showed that resveratrol induces osteogenic differentiation (Sreekumar et al., 2017), through the inhibition of hedgehog signaling. Few natural agents have been explored for their osteogenic potential through hedgehog signaling pathways. More studies are needed to confirm whether natural agents induce bone formation by modulating the Hh signaling. 2.6. Parathyroid hormone signaling Parathyroid hormone (PTH) can be targeted therapeutically to build bone (Morley et al., 2001). PTH has been used as an effective treatment for osteoporosis due to the fact that PTH exerts either a catabolic or anabolic effect, depending on the method of administration (Morley et al., 2001; Thomas, 2006). Recent insights into the structure of PTH, parathyroid hormone-related protein (PTHrP), and PTH/PTHrP receptor have further enhanced the understanding of its role in calcium and bone biology (Mundy and Edwards, 2008). Although it is well establish that PTH/PTHrP axis play a critical role in bone metabolism, further studies are needed in order to demonstrate whether agents derived from natural agents modulate PTH/PTHrP axis for bone metabolism. Additionally, it has been identified that phytoestrogens inhibits osteoporosis in menopausal group (Kotecha and Lockwood, 2005). In summation, these studies strongly suggest that natural agents have the potential to induce osteogenesis by modulating various signaling pathways integral in bone metabolism. However, more clinical trials and various models are needed to fully understand the potential of natural agents. 3. Signaling pathways in osteoclasts A recent study has shed light on the role of osteocytes in bone remodeling. A number of signaling pathways associated with osteoclastogenesis have been discovered. Thus the understanding of each step in the differentiation of OC is important in order to develop novel agents to prevent bone loss (Fig. 2). Fig. 2 Download high-res image (408KB)Download full-size image Fig. 2. Structure of Nutraceuticals linked with suppressing bone loss. Steps involved in the bone formation and bone resorption. Bone remodeling is a dynamic process, which is controlled by a variety of chemokines, growth factors, and transcription factors. The agents derived from natural resources either induce the bone formation or inhibit the process of bone resorption. MSCs, mesenchymal stem cells; FGFs, fibroblast growth factors; BMPs, bone morphogenetic proteins; TGF-β, transforming growth factor-β; FGFRs, fibroblast growth factor receptors; Runx-2, runt-related transcription factor 2; CFU-S, colony forming unit-spleen; M-CSF, macrophages colony stimulating factor; RANKL, receptor activator of nuclear factor kappa-B ligand. 3.1. RANKL signaling RANKL is an important member of TNF superfamily. RANKL is also known as TNF-related activation-induced cytokine (TRANCE), osteoprotegrin ligand (OPGL), or OC differentiation factor (ODF) (Boyce and Xing, 2007; Darnay et al., 1998). Mice deficient in RANK demonstrated profound osteopetrosis resulting from lack of OC differentiation, suggesting that RANK is required for OC differentiation (Dougall et al., 1999). The binding of extracellular signaling factor RANKL to RANK activates signaling cascades by recruiting the adapter protein TRAF6 which leads to multiple downstream events such as activation of MAPK (ERK, p38, and JNK), NF-κB, Src, and AKT (Armstrong et al., 2002; Kim and Kim, 2016). The RANKL induced signaling is negatively regulated by osteoprotegrin (OPG), which is encoded by TNF Receptor Superfamily Member 11b (TNFRSF 11b). The pre-OCs and OCs express OPG and competes with RANKL for binding to RANK. In humans autosomal recessive osteopetrosis involves mutations in the RANKL gene, which results in low numbers of osteoclasts (Pangrazio et al., 2012). The role of RANKL in rheumatoid arthritis has recently been elucidated at sites of pannus invasion into bone. Pettit et al. found that RANKL and RANK expressing OC precursor cells were confined to the erosion sites of pannus-bone (Pettit et al., 2006). OPG protein expression, on the other hand, was limited at sites of bone erosion. These results implicate RANKL in the pathogenesis of rheumatoid arthritis, and show that it provides a conducive environment that favors the activity and differentiation of OCs (Pettit et al., 2006). A variety of nutraceuticals have been shown to inhibit bone loss by modulating RANKL signaling, some of these are resveratrol, curcumin, quercetin, and plumbagin (Bharti et al., 2004; Sung et al., 2012; Wattel et al., 2004; Zhao et al., 2015). Using in vitro and animal models, studies have demonstrated that these natural agents inhibit osteoclastogenesis induced by RANKL, suggesting that natural agents have the potential to inhibit the bone loss. 3.2. NF-κB signaling The inactive dimers of NF-κB are sequestered in cytoplasm by binding with inhibitory protein IκB (Aggarwal, 2004; Hayden and Ghosh, 2008). The upstream kinase, IκB kinase (IKK), phosphorylates IκB, which induces the degradation of inhibitory protein (Aggarwal, 2004; Hayden and Ghosh, 2008). Once inhibitory protein is degraded, dimer released from complex and translocate to nucleus (Aggarwal, 2004; Karin and Lin, 2002). Patients suffering from X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, harbor a X420W point mutation in IKKγ, thus constitutively activated NF-κB, leads to severe osteopetrosis (Boyce et al., 2015; Roux et al., 2002; Walsh and Choi, 2014). Several studies using genetically engineered mouse models suggest that NF-κB pathway is key in RANKL induced osteoclast development and function. RANKL can induce both classical and alternative NF-κB activation in OCs and their precursors (Novack, 2011). Deletion of IKK2 (IKK2−/−) in transgenic mice caused defective osteoclastogenesis in OC precursors in response to RANKL, TNF-α, or IL-1β, which resulted in osteopetrosis (excessive bone formation) and resistance to inflammatory-associated bone loss in vivo (Ruocco et al., 2005). Osteopetrosis and impaired osteoclastogenesis were reported in the transgenic mice with p50/p52 deletion, and the phenotypes were rescued by bone marrow cell transplantation (Franzoso et al., 1997; Iotsova et al., 1997). The pro-inflammatory cytokines, IL-1β and TNF-α, induced osteoclastogenesis via direct activation of OC precursor cells, or indirect induction of RANKL secretion in bone marrow stromal cells (McLean, 2009; Schett, 2011). Nevertheless, the dependence of RANKL/RANK signaling in the OC activation process is still a highly debated topic. Kobayashi et al. first reported that murine bone marrow myeloid cells differentiated into TRAP+ OCs in the presence of M-CSF and TNF-α (Kobayashi et al., 2000). The bone-resorption ability in OCs and RANKL secretion in OBs stimulated by TNF-α was dependent on IL-1β (Kobayashi et al., 2000; Wei et al., 2005; Zwerina et al., 2007). Antibodies against TNF-α receptors but not RANKL were observed to inhibit this process, suggesting that the TNF-α-mediated OC activation is independent of RANKL/RANK signaling. Inhibition of RANKL by OPG at an earlier stage of OC differentiation (exposed to M-CSF alone) augmented TNF-α-mediated OC activation. Interestingly, bone marrow myeloid cells deficient in RANK can differentiate into OCs by TNF-α stimulation; this demonstrated the existence of RANKL/RANK-independent pathway of OC activation (Kim et al., 2005a). It is clear from afore mentioned studies that agents inhibiting NF-κB signaling would have beneficial effects on bone loss. Several nutraceuticals have been identified for example resveratrol, curcumin, quercetin, withanolide, silibinin, rosemarinic acid, obovatol, gambogic acid, wedelolactone, zerumbone, ursolic acid, embelin, butein, silymarin, plumbagin, honokiol, fisetin, and berberine modulate NF-κB signaling pathways thus control bone loss (Bharti et al., 2004; Hu et al., 2008; Jiang et al., 2015a; Kavitha et al., 2014; Khedgikar et al., 2013; Kim et al., 2014a; Kim et al., 2009; Leotoing et al., 2013; Liu et al., 2016b; Mobasheri and Shakibaei, 2013; Omori et al., 2015; Pandey et al., 2014; Reuter et al., 2010; Sung et al., 2011; Sung et al., 2009; Sung et al., 2012; Wattel et al., 2004; Yamaguchi et al., 2011). 3.3. Macrophage-colony stimulating factor The macrophage-colony stimulating factor (M-CSF), facilitates the commitment of MSCs to pre-OCs (Qiao et al., 1997; Udagawa et al., 1990), which is one of the main events in OCs differentiation. Studies have established that proliferation, differentiation, and survival of hematopoietic cells are all dependent on M-CSF signaling (Feng and Teitelbaum, 2013). Furthermore, M-CSF also regulates cytoskeletal changes (Boyle et al., 2003). The studies demonstrated that M-CSF deficient osteopetrotic (op/op) mutant mouse exhibit osteopetrotic phenotype, which strongly suggests that M-CSF is required for OC differentiation (Takatsuka et al., 1998; Umeda et al., 1996), because these deficiencies can be reversed by injecting M-CSF (Umeda et al., 1996). How M-CSF stimulates the commitment of MSCs to pre-OCs is still poorly understood, nonetheless it is reported that binding of M-CSF to its receptor c-Fms recruits variety of adapter proteins and kinase which further activates downstream signaling pathways. Similarly, the studies of Cappellen et al. illustrate that M-CSF induces RANK, TRAF2A, PI3-kinase, and MEKK3 which are critical in regulation of OCs differentiation (Cappellen et al., 2002). Moreover, M-CSF stimulates the survival of OCs precursors by activation of survival protein Bcl-xL (Boyce, 2013). As discussed above, the role of M-CSF on the osteoclastogenesis is not fully understood. Nonetheless, studies on natural agents suggest that quercetin (Casado-Diaz et al., 2016), syringetin (Tsai et al., 2015), caffeic acid (Wu et al., 2012) may inhibit the commitment of MSCs to pre-OCs by modulating PI3K kinase pathways. However, more studies are required to fully delineate the mechanism. 3.4. Src Src belongs to the non-receptor tyrosine kinase (NRTK) family (Boggon and Eck, 2004). The evidence suggests that Src plays critical role in osteoclastogenesis was demonstrated in genetically engineered mouse models. These mice lack functional Src and produce an osteopetrotic skeletal phenotype (Marzia et al., 2000). The absence of Src affects the bone-resorbing activity of mature OCs, but does not affect OC formation (Miyazaki et al., 2004). A key function of Src in OCs is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin-based attachment structures of OCs and other highly motile cells (Destaing et al., 2008). All together, these studies have demonstrated that Src is essential for bone resorption. It has been demonstrated that wedellactone (Liu et al., 2016a), and fisetin (Choi et al., 2012) inhibit bone loss through the inhibition of Src. 4. Potential of natural agents against bone loss It is evident from the section above that a balance of OBs and OCs is necessary in order to maintain healthy bone. Thus, agents that can modulate the expression of key players involved in bone metabolism would be of great interest. As noted in Table 2, agents derived from natural resources regulate the expression of key players. Some of these natural agents, which have been tested in the context of bone loss, are discussed below. The chemical structures of these agents are shown in Fig. 1. 4.1. Curcumin (Curcuma longa) Curcumin is a main coloring component of turmeric (Curcuma longa). Traditionally, curcumin has been used as a spice in Indian subcontinent for many years (Aggarwal et al., 2006). The ancient use of this agent is described in Ayurveda, which is an Indian system of medicine. Several bodies of evidence using in vitro and in vivo models suggest that curcumin may be used against bone loss. Many have demonstrated that curcumin downregulates the activation of NF-κB, Wnt/β-catenin, RANKL, and TNF-α all are linked with bone loss (Kim et al., 2012; Singh and Aggarwal, 1995; von Metzler et al., 2009). The cytokines RANKL, M-CSF, and recently discovered high mobility group box 1 (HMGB1), a chromatin protein, play a critical role in OCs differentiation. Curcumin can inhibit the osteoclastogenesis by inhibiting HMGB1 release in a P38-MAPK dependent mechanism (Sakai et al., 2012). The work of our group demonstrated that curcumin inhibits RANKL induced osteoclastogenesis (Bharti et al., 2004). Furthermore, we also demonstrated that turmeric possess the potential to inhibit bone loss (Kim et al., 2012). Another study by von Metzler et al demonstrated that curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated IκB kinase (von Metzler et al., 2009). Several studies from other laboratories have illustrated that curcumin protects against ovariectomy-induced bone loss (Kim et al., 2011b). The curcumin analog UBS109 prevents breast cancer induced bone loss (Yamaguchi et al., 2015). Studies by Wang et al., 2016, demonstrated that curcumin enhances the osteoblast differentiation of human adipose-derived MSCs by inhibiting Wnt/β-catenin signaling, suggesting curcumin may control the bone metabolism (Wang et al., 2016). 4.2. Resveratrol (Vitis vinifera) Resveratrol was first isolated from white hellebore roots (Veratrum grandiflorum O. Loes). Since then, resveratrol has been isolated from various plants including grapes, berries, and peanuts. The work from our laboratory has shown that resveratrol suppresses the NF-κB activation (Manna et al., 2000), a key player of bone loss. Recent studies indicate that this stilbene may play a role in the prevention and treatment of bone loss; for example, Zaianbadi et al showed that by inducing SIRT1, resveratrol regulates RUNX2 thus inducing the differentiation of OBs (Zainabadi et al., 2017). Another study demonstrated that analogs of resveratrol inhibit osteoclasotogenesis by deacetylating FoxOs in a murine model (Kim et al., 2015a). Similarly, using in vivo model, Lee et al showed that resveratrol inhibits methotrexate induced bone loss (Lee et al., 2017). Various animal models further demonstrate that resveratrol supplementation retards bone loss. Nonetheless, additional clinical trials are needed to fully comprehend the utility of this stilbene against bone loss (Dosier et al., 2012; Tou, 2015; Zhao et al., 2015). 4.3. Quercetin (Allium cepa) Quercetin is a flavonoid found in a variety of fruits and vegetables, and has an especially high concentration in onions. The name quercetin was used in 1857, when this flavonoid was isolated from oak tree (Quercus sp.). This flavonoid is believed to either activate osteoblast or inhibit the OC differentiation, thus regulating bone metabolism (Casado-Diaz et al., 2016). Quercetin induces OB differentiation by activating Smad (Yamaguchi and Weitzmann, 2011), and P38 MAPK (Zhou et al., 2015), and inhibiting WNT/β-Catenin pathways (Casado-Diaz et al., 2016). Furthermore, studies have demonstrated that quercetin inhibit RANKL induced osteoclastogenesis through inhibition of NF-κB activation (Yamaguchi and Weitzmann, 2011). The studies of Tsuji et al have demonstrated that supplementation of quercetin can inhibit bone loss in an ovariectomy mouse model (Tsuji et al., 2009). All these studies suggest that this flavonoid has great potential to be used as a bone health supplement. However, further clinical studies are needed to fully elucidate the utility of this natural agent. 4.4. Genistein (Glycine max) Genistein an isoflavone, was first isolated in 1899 from the dyer's broom, Genista tinctoria. Although found mostly in soy, isoflavone is also found in a wide variety of foods. A number of in vitro and in vivo studies have demonstrated that genistein has the potential to prevent bone loss (An et al., 2016; King et al., 2015; Zhang et al., 2016). Along the same line of thinking, several mechanisms have been proposed. For example, isoflavone was found to induce osteoblast differentiation by upregulating PPARγ (Zhang et al., 2016), BMP2, Wnt/β-catenin (Kushwaha et al., 2014), Smad5, Runx2 (Dai et al., 2013), oestrogen and oestrogen receptors (ERs) (Liao et al., 2014). Isoflavone also inhibit osteoclastogenesis by either inhibiting number of transcription factors, which are critical in bone loss such as NF-κB, AP-1 (Liao et al., 2014) or bone loss associated cytokines such as IGF-1 and TGFβ (Joo et al., 2004). These studies clearly demonstrate that dietary supplementation of soy product can be beneficial in the prevention of bone loss. 4.5. Other natural agents Several other natural compounds have been found to exhibit anti-osteoporosis potential. Studies from our laboratory and by others have shown that 1'-acetoxychavicol acetate (ACA) (Ichikawa et al., 2006a), acetyl-11-keto-beta-boswellic acid (AKBA) (Takada et al., 2006), apigenin (Goto et al., 2015), betullinic acid (Park et al., 2014), berberine (Wei et al., 2009), butein (Sung et al., 2011), capsaicin (Kobayashi et al., 2012), catechin gallate (Shen et al., 2009), caffeic acid (Zawawi et al., 2015), curcumin and calebin A (Bharti et al., 2004; Kim et al., 2012; Tyagi et al., 2016), coronarin D (Kunnumakkara et al., 2008), diosgenin (Shishodia and Aggarwal, 2006a, 2006b), embelin (Reuter et al., 2010), emodin (Chen et al., 2017), eugenol (Deepak et al., 2015a), fisetin (Leotoing et al., 2014), gambogic acid (Ma et al., 2015; Pandey et al., 2014), gossypin (Kunnumakkara et al., 2007), guggulsterone (Ichikawa and Aggarwal, 2006), γ-tocotrienol (Deng et al., 2014), harpagoside (Kim et al., 2015b), honokiol (Ahn et al., 2006), isodeoxyelephantopin (Ichikawa et al., 2006b), luteolin (Kim et al., 2011a), lycopene (Iimura et al., 2015), obovatol (Kim et al., 2014a), oleanolic acid (Zhao et al., 2011), plumbagin (Sung et al., 2012), reseveratrol (Shakibaei et al., 2011; Zhao et al., 2014), rosmarinic acid (Lee et al., 2015), silymarin (Mohd Fozi et al., 2013), thiocolchicoside (Reuter et al., 2012), wedelolactone (Liu et al., 2016b), withanolides (Ichikawa et al., 2006c), zerumbone (Sung et al., 2009), and zyflamend (Sandur et al., 2007) all have tremendous potentials to inhibit osteoclastogenesis. 5. Clinical trials Clinical trials have been conducted for several natural products, as well as formulations containing combinations of these agents. One of the most widely studied nutraceutical curcumin, has demonstrated potential for a number of bone related problems such as arthritis, rheumatoid arthritis (RA), and osteoarthritis. In a recent study, curcumin was found to inhibit osteoclastogenesis in PBMCs derived from rheumatoid arthritis patients (Shang et al., 2016). The effectiveness of a surface controlled water dispersible form of curcumin named Theracurmin was also assessed among the patients suffering from knee osteoarthritis (Nakagawa et al., 2014). A randomized, double blind, placebo-controlled prospective study was performed in fifty patients. Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks and knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks. Additionally, blood analysis was performed to monitor for adverse effects. The study clearly demonstrated that after 8 weeks of treatment knee osteoarthritis was effective without any adverse side effects (Nakagawa et al., 2014). Studies of Riva et al., 2017a, 2017b further establish that curcumin-based supplementation in combination of healthy lifestyle may be beneficial in osteopenia (low bone density). In this study oral formulation of turmeric was used in patients (n=57) suffering from osteopenia (Riva et al., 2017a, 2017b). Several other clinical trials further suggest that curcumin has a tremendous potential for the prevention of bone loss, importantly curcumin exhibits no side effects (Belcaro et al., 2010; Chandran and Goel, 2012; Chin, 2016; Daily et al., 2016; Henrotin et al., 2014; Panahi et al., 2014; Rahimnia et al., 2015). A randomized double-blind placebo controlled study was performed on genistein to evaluate its effect on bone loss in postmenopausal women compared to hormone-replacement therapy (HRT) (Morabito et al., 2002). Studies by Cotter A., et al confirmed that genistein reduces bone resorption and increases bone formation in postmenopausal women (Cotter and Cashman, 2003). Another randomized, placebo-controlled, double-blind pilot study by Lappe J et al further confirmed that genistein in combination with polyunsaturated fatty acids, and vitamins D3 and K1 inhibits the bone loss in postmenopausal women. The paramount importance of these studies was derived from the fact that no toxicities were observed (Lappe et al., 2013). Though the use of various phytoestrogens derived from various sources inducing soya (genistein), red cloves, dietary products have beneficial effects on bone loss, however controversial results also been observed (Abdi et al., 2016). Thus more detailed studies and clinical trial are needed in order to gain more insight into the advantages of natural non-toxic agents (Abdi et al., 2016). Studies by Lamb J et al demonstrated that the anti-inflammatory agent berberine, a combination of hop rho iso-alpha acids, vitamin D₃, and vitamin K inhibits the bone loss in postmenopausal women with metabolic syndrome (Lamb et al., 2011). Similarly, supplementation of lycopene can significantly increase antioxidant capacity and decrease oxidative stress and the bone resorption marker N-telopeptide (NTx) in postmenopausal women (Mackinnon et al., 2011). In this study sixty postmenopausal women, 50-60 years old, were recruited. Participants either consumed regular tomato juice, lycopene-rich tomato juice, tomato Lyc-O-Mato lycopene capsules, or placebo capsules, twice daily for total lycopene intakes of 30, 70, 30, and 0 mg/day respectively for 4 months (Mackinnon et al., 2011). Serum collected and assayed for cross-linked aminoterminal N-telopeptide, carotenoid content, total antioxidant capacity (TAC), lipid, and protein oxidation. Remarkably, there were no toxicities were reported in 4 months of study (Mackinnon et al., 2011). There are several other natural extracts or herbal therapies, which have been successfully used against the bone loss. For example, use of Yin and Yang tonic formula in the treatment of osteopenia (Yang et al., 2011). This formulation was used in patients aged 55 to 75 with low bone mineral density. It was concluded that classic Yin and Yang tonic formula could increase the bone mass without any adverse effects (Yang et al., 2011). 6. Conclusions Compunds that provide effective prevention and therapy strategies with few side effects are highly desirable, in the patients suffering from bone loss. The traditional treatment of bone loss requires a life-long regimen of drugs, which can have a significant impact on patient's quality of life. Although there are numerous pharmacological treatments for bone loss, none seem to have a desirable level of efficacy without either high financial cost or side effects. Plant-derived products offer a promising alternative to traditional pharmacotherapy. Studies from our group and others from around the globe on natural agents have provided concrete evidence that natural agents have potential to either enhance the bone formation or prevent the bone loss. Several molecules derived from natural agents were found effective in either bone formation or prevention of bone loss such as resveratrol, curcumin, quercetin, withanolide, silibinin, wedelolactone, and silymarin. A number of natural agents are already in clinical trials and many more studies are underway. In addition, several medicinal herbs demonstrated therapeutic effects against osteoporosis in animal models. This is encouraging development for scientific community as well as for patients. Nonetheless many more agents require extensive investigation in various preclinical and clinical settings to prove their usefulness. One of the biggest challenges associated with natural agents are lack of studies on pharmacokinetics, formulation, and off target effects, in addition often time these agents fail in clinical trials. In addition to above challenges the American and International legal code, which prohibit the patenting of natural compounds, therefore, pharmaceutical industry has shown little motivation to pursue studies on natural agents. Perhaps, in years to come federal agencies will be more considerate about supporting such studies. Henceforth, scientist and medical researchers alike can begin to investigate natural products as the backbone for bone health. References Abdi et al., 2016 F. Abdi, Z. Alimoradi, P. Haqi, F. 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