Table 2: Antiosteoporotic compounds isolated from medicinal plants.

CompoundPharmacological activityreference

Flavonoids
IcariinSee Section 3.1.1[2326]
GenisteinSee Section 3.1.2[29]
Daidzeinprevent bone loss in ovariectomized rats and orchidectomized rats;
inhibit osteoclastic differentiation and bone resorption by increasing the activity of mature osteoblasts via ERβ, regulating RUNX 2/Cbfα1 production, and stimulating the secretion osteoprotegerin.
[31, 32]
Kaempferolincrease ALP activity in cultured human MG-63 osteoblasts through ERK and ER pathway;
prevent antimycin A-induced cell damage in mitochondrial membrane potential dissipation, complex IV inactivation, ROS production through activation of PI3K (phosphoinositide 3-kinase), Akt (protein kinase B), CREB (cAMP-response element-binding protein) in MC3T3-E1.
[72]
Quercetinreverse the decreased biomechanical quality and the impaired microarchitecture of the femurs in diabetic rats through improving antioxidant capacity;
inhibit osteoclastic differentiation and bone resorption via inducing apoptosis and involving NF- B and AP-1.
[73, 74]
Naringinprotect against retinoic acid-induced osteoporosis and improve bone quality in rats;
perturb osteoclast formation and bone resorption by inhibiting RANK-mediated NF- B and ERK signaling;
induce bone morphogenetic protein-2 expression via PI3K, Akt, c-Fos/c-Jun and AP-1 pathway in osteoblasts;
prevent hydrogen peroxide-induced dysfunction in osteoblastic MC3T3-E1 cells.
[7577]
Hesperidinprotect bone loss in OVX rats, improve BMD and femoral load in intact rats[78]
Linarinprotect osteoblasts against hydrogen peroxide-induced osteoblastic dysfunction, exert antiresorptive actions via the reduction of RANKL and oxidative damage[79]
Bavachalconeinhibit osteoclastogenesis by interfering with the ERK and Akt signaling pathways and the induction of c-Fos and NFATc1.[36]
Rutininhibit ovariectomy—induced trabecular bone loss in rats by slowing down resorption and increasing osteoblastic activity.[80]
(+)-Catechinenhance cell survival, alkaline phosphatase activity, decrease bone-resorbing cytokines (TNF-α and IL-6) production and apoptosis in osteoblasts.[81]
Nobiletinprevent bone loss in ovariectomized rats;
suppress formation and bone resorption of osteoclast induced by interleukin-1;
suppress the expression of cyclooxygenase-2, NF-κB-dependent transcription, and prostaglandin E production in osteoblasts.
[82]
Luteolinincrease bone mineral density and bone mineral content of trabecular and cortical bones in the femur of OVX rats;
inhibit the differentiation of both bone marrow mononuclear cells and RAW 264.7 cells into osteoclasts and the bone resorptive activity of osteoclasts.
[83]
Baicaleininhibit the differentiation and bone resorptive activity of osteoclasts by inhibiting RANKL-induced activation of signaling molecules (Akt, ERK/MAP kinase and NF- B) and mRNA expression of osteoclast-associated genes TRAP, matrix metalloproteinase 9 and c-Src, c-Fos, Fra-2 and NFATc1.[84]
Baicalinpromote osteoblastic differentiation via Wnt/β-catenin signaling and enhance the mRNA expression of osteoprotegerin[85]
Xanthohumolupregulate ALP activity and expression of osteogenic marker genes by activation of RUNX2 via mechanisms related to the p38 MAPK and ERK signaling pathway[86]
Coumarins
Psoralenpromote osteoblast differentiation by up-regulation of expressions of osteoblast-specific marker through the activation of BMP signaling[35]
Ostholeprevent bone loss and improve bone microarchitecture, histomorphometric parameters, and biomechanical properties in OVX rats;
stimulate osteoblast proliferation and differentiation through β-catenin/BMP signaling.
[87]
Lignan
Honokiolincrease cell growth, alkaline phosphatase activity, collagen synthesis, mineralization, glutathione content, and osteoprotegerin release in the osteoblast;
decrease the production of TNF-α, IL-6, and RANKL in the presence of antimycin A;
stimulate osteoblastogenesis by suppressing NF-κB activation.
[88, 89]
Isotaxiresinolimprove bone mineral content, bone mineral density, and bone strength indexes in OVX control rats;
slightly increase bone formation and significantly inhibit bone resorption
[90]
Magnololcause a significant elevation of cell growth, alkaline phosphatase activity, collagen synthesis, mineralization, and glutathione content in osteoblast;
decrease the production of osteoclast differentiation inducing factors such as RANKL, TNF-α, and IL-6 in the presence of antimycin A
[91]
Polyphenol
Resveratrolprevent osteoporosis induced by cyclosporin A;
inhibit the differentiation and bone resorbing activity of osteoclasts through inhibition of ROS production;
promote the formation of osteoblasts by induction of bone morphogenetic protein-2 through Src kinase-dependent estrogen receptor activation;
promote osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis.
[9295]
Curcuminimprove bone microarchitecture and mineral density in APP/PS1 transgenic mice;
improve bone strength and biochemical marker in ovariectomized mature rat model;
inhibit OVX-induced bone loss by reducing osteoclastogenesis through increasing antioxidant activity and impairing RANKL signaling.
[9698]
Tea polyphenols (including epigallocatechin-3-gallate, epigallocatechin epi-catechin epicatechin-3-gallate)attenuate trabecular and cortical bone loss through increasing bone formation while suppressing bone resorption due to its antioxidant capacity;
inhibit the formation and differentiation of osteoclasts via inhibition of matrix metalloproteinases.
[99, 100]
Anthraquinones
Rubiadin;
2-hydroxy-1-methoxy-anthraquinone;
1,3,8-trihydroxy-2-methoxy-anthraquinone
decrease bone resorption, the number of multinucleated osteoclasts, and the activity TRAP and cathepsin K of osteoclast;
induce the apoptosis of osteoclasts through improving the ratio of OPG and RANKL in osteoblasts, interfering with the JNK and NF-κB signal pathway, and reducing the expression of calcitonin receptor and carbonic anhydrase/II in osteoclasts.
[71]
Alkaloids
Harmineprevent bone loss in ovariectomized osteoporosis model mice;
inhibit osteoclast formation and bone resorption via downregulation of c-Fos and NFATc1 induced by RANKL.
[101]
Coptisineinhibit RANKL-induced NF- B phosphorylation in osteoclast precursors;
suppress the formation, differentiation and bone resorption of osteoclast through regulation of RANKL and OPG gene expression in osteoblastic cells
[102]
Palmatineinhibit osteoclast formation and bone resorption in the co-culture system with mouse bone marrow cells (BMC) and osteoblasts;
induce disruption of actin ring formation in mature osteoclasts with an impact on cell viability
[103]
Berberineprevent bone loss in SAMP6 senile osteoporosis model and ovariectomized rats;
inhibit formation and differentiation of osteoclast;
promote osteoblast differentiation through activation of Runx2 by p38 MAPK.
[104, 105]
Other compounds
Curculigosideinhibit bone loss in ovariectomized mice;
promote the proliferation and differentiation of osteoblast;
prevent hydrogen peroxide-induced dysfunction and oxidative damage in calvarial osteoblasts;
inhibit the formation, differentiation and bone resorption of osteoclast.
[106, 107]
Asperosaponin VIinduce osteoblast maturation and differentiation, and bone formation via increasing BMP-2 synthesis and activating p38 and ERK1/2 pathway[108]
Limonoid 7-oxo-deacetoxygedunin inhibit RANKL-induced osteoclastogenesis by suppressing activation of the NF- B and MAPK pathways[109]
Zerumboneabolish RANKL-induced NF- B activation, inhibit osteoclastogenesis, and suppress human breast cancer—induced bone loss in athymic nude mice[110]
Costunolide stimulate the growth and differentiation of osteoblastic MC3T3-E1 cells, which may be associated with ER, PI3K, PKC, and MAPK signaling pathway[111]
Lycopenereduce oxidative stress and the levels of bone turnover markers in postmenopausal women;
stimulate proliferation and alkaline phosphatase activity of osteoblasts;
inhibit osteoclasts formation and bone resorption activity.
[112, 113]
Tanshinone IIAinhibit osteoclast differentiation and bone resorption through disruption of the actin ring by inhibiting c-Fos and NFATc1 expression.[49, 50]
Salvianic acid Aprevent bone loss from long-term administration of prednisone in rats;
protect bone from glucocorticoid—induced bone marrow impairment by stimulating osteogenesis and depressing adipogenesis in bone marrow stromal cells.
[51]
Salvianolic acid Bprevent glucocorticoid—induced cancellous bone loss and decrease adipogenesis;
stimulate bone marrow stromal cell differentiation to osteoblast and increase osteoblast activities;
decrease glucocorticoid—induced associated adipogenic differentiation through regulating the mRNA expression of PPAR-γ, Runx2, Dickkopf-1 and β-catenin in MSC
[52]
Alisol-Bprevent bone loss in mice;
inhibit osteoclastogenesis by inhibiting the phosphorylation of JNK, and expression of NFATc1 and c-Fos;
suppresses 2-methylene-19-nor-(20S)-1α, 25(OH)2D3—induced hypercalcemia as resulting from the inhibition of osteoclastogenesis
[114]
Maslinic acidsuppress osteoclastogenesis and prevent ovariectomy-induced bone loss by regulating RANKL-mediated NF- B and MAPK signaling pathway[115]