bone remodeling occurs throughout life via synthesis of bone matrix through the action of two major bone cells : osteoblasts and osteoclasts [ 1 - 3 ] .
the proper functioning of these cells is necessary for the maintenance of bone mass as well as bone mineral density ( bmd ) . during old age and especially postmenopause
there is excessive bone resorption relative to bone formation due hormone deficiencies , which reduces bone mass and ultimately causes bone diseases and osteoporosis . osteoporosis is a widespread health dilemma and its occurrence is projected to rise in the upcoming decades due to the aging of many societies .
it is a bone disease that is thought to cause stumpy bone mass and micro - architectural weakening of bone materials , enhance bone brittleness , decrease bone strength , and subsequently increase the threat of fracture .
osteoporosis causes distress throughout the united states , europe , china , japan and the rest of the world . according to the world health organization
, almost 75 million people in the united states , europe , and japan are affected by osteoporosis .
primary osteoporosis is usually associated with aging and low levels of reproductive hormones , especially estrogen , which leads to reduced gonadal activity in the elderly .
secondary osteoporosis has other causes , including deficiencies of calcium , vitamin d , and parathyroid hormone .
an understanding of the molecular mechanisms and anabolic and catabolic activity of bone is important in the development of new drugs for treating bone diseases , especially osteoporosis . for osteoporosis ,
the search for new therapeutic agents is mostly concerned with the control of bone resorption and the induction of bone formation by osteoclasts and osteoblasts , respectively .
the main molecular factors involved in osteoporosis are the receptor activator of nuclear factor kappa - b ligand ( rankl ) , osteoprotegerin ( opg ) and the receptor activator of nuclear factor kappa - b ( rank ) .
osteoclasts are multinucleate and highly specialized giant cells that have the ability to work in perfect synchronization with osteoblasts to retain the skeletal system .
. the discoveries of the rankl and opg have altered our understanding of the primary mechanisms involved in osteoclast differentiation and activity .
rankl , a transmembrane protein , belongs to the tumor necrosis factor superfamily member 11 , and a ligand for opg is produced by osteoblast and stromal cells [ 15 - 17 ] .
rankl binds with the membrane bound protein rank that is expressed by osteoclasts ( oc ) with the combination of tumor necrosis factor ( tnf)-receptor - associated factor-6 ( traf-6 ) and activates different downstream signaling pathways ( fig .
consequently , it plays an important role in osteoclast differentiation and bone resorption , which leads to osteoporosis .
opg belongs to tumor necrosis factor receptor superfamily member 11b , which has the ability to restrain osteoclast differentiation / formation by preventing rankl from binding to rank .
the most important factor in osteoclast activation is a protein known as rankl , which brings these osteoclasts and osteoblasts in contact by inserting itself into the external membrane of osteoclasts , thereby triggering its receptor rank , which is then responsible for bone resorption .
the coupling of rankl to rank is facilitated by the nuclear factor ( nf)-b signaling pathway .
the traf family of proteins ( traf , 2 - 6 ) comprises the most significant factors involved in osteoclastogenesis when rankl binds to rank .
a pivotal role is played by traf6 via the regulation and activation of downstream signaling pathways , such as the nf-b pathway , the inhibitor of nf-b kinase pathway , the c - jun n - terminal kinase ( jnk ) pathway , and the p38 pathway .
these pathways ultimately prop - up osteoclast differentiation and bone resorption by stimulating different transcriptional factors such as activator protein-1 and the nf-b pathways .
however , it is not clear how these factors are activated by traf6 or how they lead to bone resorption by activating osteoclast - specific markers such as tartrate - resistant acid phosphatase ( trap ) , cathepsin , 3 integrin , and calcitonin receptors [ 21 - 23 ] .
recently it has been suggested that , among the proteases , matrix metallopeptidases ( mmps ) are responsible for the deprivation of bone extracellular matrix .
in particular , mmp-9 is strongly expressed in osteoclasts since it is stimulated by the action of the rankl signaling pathway and it plays a vital role in bone resorption . at the molecular level , however , little is known about how rankl induces mmp-9 gene stimulation .
osteoblasts are mononucleate cells that are derived from mesenchymal stem cells , which have the ability to suppress osteoclast activity and increase bone formation by secreting a bone mineralization organic matrix such as collagen - i ( col - i ) in the osteoid . in osteoblast differentiation ,
the wnt canonical signaling pathway and the bone morphogenetic protein ( bmps ) pathways are the most pivotal .
the bmps belong to the transforming growth factor ( tgf)- superfamily and bmp-2 plays an especially significant role in osteoblastogenesis .
when bmp-2 binds to a transmembrane protein such as a bone morphogenetic protein receptor ii , it phosphorylates type i receptor , and hence activates the smad complex ( smad 1 , 4 , 5 , and 8) signaling pathways [ 26 - 29 ] , which can aid in the activation of osteoblast - specific transcriptional regulation genes involved in bone formation , such as osteocalcin ( ocn ) , collagen type i , osteonectin , osteopontin , osterix , and bone sialoprotein ( bsp ) ( fig .
recently it has been suggested that retinoblastoma binding protein 1 may be the co - activator of runt - related transcription factor 2 ( runx2 ) .
different therapeutic agents have been used for the treatment , management , and prevention of osteoporosis , including denosumab , bisphosphonate , raloxifene , calcitonin , teriparatide , strontium ranelate , and hormone replacement therapy , but these drugs may have side effects .
recently , it has been found that bisphosphonate causes esophagitis , esophageal cancer , and atypical femur fractures when it is used for more than five years .
similarly , it has been suggested that hormone replacement therapy may cause breast cancer , coronary heart disease , stroke , and venous thromboembolism [ 32 - 35 ] .
modern pharmacological therapy is costly and produces many side effects , resulting in significant patient non - compliance .
thus , there is a strong need to explore alternative therapies , particularly from herbal sources as these are cost - effective and have minimal side effects . over the past decades , herbal medicine has become a topic of global importance , making an impact on both world health and international trade .
medicinal plants continue to play a central role in the healthcare of much of the world population .
as much as 2000 years ago the roots of american ginseng ( p. quinquefolius ) and korean ginseng ( p. ginseng meyer ) were traditionally used for the treatment of many diseases . among the 15 panax species ,
4 different species include p. ginseng , p. notoginseng , p. japonicus , p. quinquefolius were used commercially .
the ginseng plant contains many active ingredients , including steroidal saponins with a dammarane skeleton as well as protopanaxadiol and protopanaxatriol , commonly known as ginsenosides , which is the energetic part of glycoside plus an aglycone .
although ginsenosides have been reported to possess antioxidant , anti - cancer , anti - diabetic , anti - adipocyte , and sexual enhancement properties , very few studies have been conducted on their anti - osteoporotic activity [ 56 - 60 ] .
cell and animal studies of the anti - osteoporotic activities of different ginsenosides have been conducted .
protopanaxadiol - type saponins ( rb1 , rg3 , rd , and rh2 ) , protopanaxatriol - type saponins ( re and rg1 ) , p. notoginseng saponins ( pns ; rg1 , rb1 , and r1 ) , and ginseng mixtures have been reported to show anti - osteoporotic activity in these studies ( table 1 ) .
effects of ginseng on different molecular pathways related to osteoporosis in cell line and animal studies alp , alkaline phosphatase ; ocn , osteocalcin ; opn , osteopontin ; osx , ostrex ; col - i , collagen i ; oc , osteoclast ; pkd , protein kinase d ; rankl , receptor activator of nuclear factor kappa - b ligand ; nf-b , nuclear factor kappa - b ; jnk , c - jun n - terminal kinases ; ampk , amp - activated protein kinase ; nfatc1 , nuclear factor of activated t - cells , cytoplasmic 1 ; bmp-2 , bone morphogenetic protein 2 ; pns , panax notoginseng saponins ; opg , osteoprotegerin ; cbfa1 , core binding factor alpha-1 ; ppar 2 , peroxisome proliferator - activated receptors 2 ; erk , extracellular - signal - regulated kinases ; bmd , bone mineral density ; camp , cyclic adenosine monophosphate ; tnf- , tumor necrosis factor - alpha ; il-6 , interleukin-6 ; trap , tartrate - resistant acid phosphatase ; nk , natural killer cells ; inos , isoform nitric oxide synthases ; no , nitric oxide ; ovx , ovariectomised rats ; dpd / cr , urinary deoxypyridinoline / creatinine ; bv / tv , trabecular bone volume over total bone volume ; conn.d , connectivity density ; tb.n , trabecular number ; tb.th , trabecular thickness ; bmscs , bone marrow stromal cells ; runx 2 , runt - related transcription factor 2 ; bsp , bone sialoprotein . even though the exact mechanisms of ginseng s anti - osteoporotic effects are not fully understood , in vitro and in vivo data suggest three possibilities : 1 ) modulation of osteoblastogenesis and bone formation , 2 ) modulation of osteoclastogenesis and bone resorption , and 3 ) modulation of osteoporosis .
it is obvious from the table 1 that rh2 , rd , rh2(s ) , and ( tr ) ginsenosides stimulate the secretion and phosphorylation of alkaline phosphatase ( alp ) , ocn , osteopontin , ostrex , col - i , bmp-2 , protein kinase d ( pkd)/amp - activated protein kinase , pkd / p38 , and camp and increase bone mineral density .
li et al .   demonstrated that p. notoginseng has the ability to affect the mrna level of alp , bsp , core - binding factor subunit alpha-1 , and opg , increases phosphorylation of extracellular - signal - regulated kinases and p38 , and inhibits the secretion of peroxisome proliferator - activated receptors  2 ( ppar2 ) and rankl . on the other hand ,
ginsenosides rh2(r ) , rb1 , rh2 , and rg1 may have the ability to suppress the secretion and activity of osteoclasts , rankl , nf - kb , jnk , c - fos , nfatc1 , and tnf- , interleukin ( il)-6 , and lipopolysaccharide .
monroe et al . , kim et al . , and yovel et al .   suggest that red ginseng acidic polysaccharide can increase the tumoricidal activity of isoform nitric oxide synthases of natural killer cells in ovariectomised rats ( ovx ) , while it may increase tnf- , nitric oxide , and il-1 expression by peritoneal macrophages .
however , calcium and hydroxyproline secretion in the urine of male wistar rats was significantly suppressed by treatment with a liquid extract from siberian ginseng ( eleutherococcus senticosus ) , while also increasing the strength of femoral diaphyses and vertebrae . according to kim et al .
, the ginseng mixture ( her - s ) has the ability to induce the deposition of bmd , increase femoral trabecular width and estrogen levels , and decrease trap activity in ovx .
and li et al .   reported that pns decreased the loss of bmd , ppar2 , microstructure corrosion in trabecular bone , and urinary deoxypyridinoline / creatinine , while increasing trabecular bone volume over total bone volume , connectivity density , trabecular number , trabecular thickness , alkaline phosphatase , runx2 , oc , and bsp levels in bone marrow stromal cells .
kim et al .   found clinically that treatment of postmenopausal osteoporosis patients with korean red ginseng together with maltose capsules had no significant consequences .
ginseng that is used as a folk and conventional medicine for the treatment of different diseases for decades has been recognized as one of the valuable source in drug discovery and development .
many studies demonstrate that ginsenosides can decrease osteoporosis by inhibiting production of nf - kb , stimulate alp , col - i , runx2 , increase blood circulation , and enhance memory .
furthermore many studies indicate that ginsenosides have a huge number of activities in both pathological and physiological circumstances concerning with bone disease .
however the effects and mechanisms of action of ginsenosides are still not yet entirely understood .
data from in vitro and in vivo studies have revealed that ginseng saponins ( ginsenosides ) have beneficial effects in the treatment of osteoporosis and may increase the osteogenesis of bone marrow stromal cells and pre - osteoblast cells . even though some ginsenosides have been studied for the treatment of osteoporosis , their functions at the pharmacokinetic and pharmacodynamic levels are not well understood , and are important for understanding the inhibition of bone resorption and osteoclastogenesis .
future studies about osteoporosis with ginsenosides should include detailed mode of action and mechanisms both in vitro and in vivo .
 the ginseng plant ( panax ginseng meyer ) has a large number of active ingredients including steroidal saponins with a dammarane skeleton as well as protopanaxadiol and protopanaxatriol , commonly known as ginsenosides , which have antioxidant , anticancer , antidiabetic , anti - adipocyte , and sexual enhancing effects . 
 though several discoveries have demonstrated that ginseng saponins ( ginsenosides ) as the most important therapeutic agent for the treatment of osteoporosis , yet the molecular mechanism of its active metabolites is unknown . in this review , we summarize the evidence supporting the therapeutic properties of ginsenosides both in vivo and in vitro , with an emphasis on the different molecular agents comprising receptor activator of nuclear factor kappa - b ligand , receptor activator of nuclear factor kappa - b , and matrix metallopeptidase-9 , as well as the bone morphogenetic protein-2 and smad signaling pathways . 
INTRODUCTION
TYPES OF OSTEOPOROSIS
PATHOPHYSIOLOGY OF OSTEOPOROSIS
OSTEOCLASTOGENESIS/OSTEOCLAST DIFFERENTIATION
OSTEOBLASTOGENESIS/OSTEOBLAST DIFFERENTIATION
CONCLUSION