Escin is a natural mixture of triterpene saponins extracted from the seeds of Aesculus chinensis Bge. or Aesculus wilsonii Rehd. Escin has been reported to exhibit pharmacological effects similar to those associated with glucocorticoid administration. For example, oral escin (5 and 10 mg/kg, p.o.) intake has been found to suppress carrageenan-induced paw edema and to inhibit prostaglandin E2 (PGE2) production (30). Notably, when compared with glucocorticoids, escin (2 mg/kg, i.v.) has been shown not to induce thymic or splenic immune cell apoptosis in mice, nor does it promote the enhanced secretion of endogenous corticosterone (31). Zhang et al. found that the sustained administration of escin (0.45 and 0.9 mg/kg for a period of 10 days, i.v.) in the context of post-surgical bone fracture healing has no adverse impact on wound or bone healing processes (32). There is also evidence that glucocorticoids and escin (2 mg/kg, i.v.) exhibit synergistic anti-inflammatory activity when administered in vitro and in vivo at low doses, suggesting at least partial overlap in the pharmacological pathways impacted by these compounds (33). Combination glucocorticoid and escin(5 and 10 mg/kg for a period of 16 days, i.g.) treatment can significantly decrease synovial inflammatory infiltration, synovial hyperplasia, and bone erosion in a rat model of adjuvant-induced arthritis (AIA) rats while reversing some of the adverse effects of glucocorticoid treatment alone such as reductions in boy weight and increases in the spleen index relative to untreated rats (34). Administering escin (10 mg/kg for a period of 14 days, p.o.) together with a low dose of dexamethasone (Dex) has been shown to markedly suppress paw swelling, joint pathology, arthritic index scores, and immune organ pathology in an animal model, all while reducing the necessary Dex dose and thus decreasing the rate of adverse effects associated with Dex administration (35). The anti-edema and anti-inflammatory properties of escin may be attributable to its ability to bind to the glucocorticoid receptor (GR), consistent with glucocorticoid-like activity (36). Escin (1.8 and 3.6 mg/kg, i.v.) may additionally augment the antioxidant capacity of tissue in the context of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and endotoxin-induced liver injury by suppressing the production of inflammatory compounds including NO, TNF-α, and IL-1β while simultaneously promoting GR upregulation in the liver and lungs (37, 38).

Ginsenosides are the primary active ingredients isolated from ginseng, and they have been reported to exhibit anti-inflammatory activity in vitro and in vivo owing to their structural similarity to steroid hormones. Compound K is a ginsenoside that has, in vitro, been shown to suppress TNF-α-induced fibroblast-like synoviocyte (FLS) migration, proliferation, and secretion, consistent with joint-protective activity (80 mg/kg for a period of 14 days, i.g.) (39). In a rat model of myocardial infarction (MI), ginsenoside Rg3 (30 mg/kg for a period of 7 days, i.g.) reduces inflammation via the inhibition of the NF-κB pathway (40). Combining the ginsenosides Rh1 (20 mg/kg, i.p.) and Rg2 (20 mg/kg, i.p.) can suppress LPS-induced tissue damage and inflammation by interfering with the ability of LPS to bind to and trigger the activation of TLR4 (41). Ginsenoside Rb1 (10 and 20 mg/kg, i.p.) markedly alleviates LPS- or cantharidin-induced acute kidney injury, LPS-induced septicemia, and dimethyl benzene-induced ear edema in mice (42). Ginsenoside treatment is also not associated with any significant adverse reactions. In mice overexpressing TNF-α, ginsenoside Rg1 (20 mg/kg, i.g.) can prevent bone erosion, inhibit synovial inflammation, and reduce serum levels of both IL-6 and TNF-α, and treatment for 12 weeks with ginsenoside Rg1 was not associated with any liver or kidney damage (43). Ginsenoside Rd (10 mg/kg, i.p.) can suppress ischemia-induced microglial activation and inhibit proinflammatory cytokine production while inducing fewer severe side effects as compared to glucocorticoids (44). Importantly, these ginsenosides can also work in synergy with glucocorticoids to inhibit inflammation. For example, combining corticosterone with low concentrations of Rg1 can suppress the LPS-induced production of NO and TNF-α by RAW264.7 macrophages while simultaneously promoting GR upregulation (45). Ginsenosides can also shape cellular responses in a GR-mediated manner, as in the case of Rg1 (12.5 mg/kg, i.p.), which suppresses LPS-induced NF-κB nuclear translocation and inflammatory cytokine production in a GR-dependent fashion. Notably, Rg1 (20 mg/kg for a period of 21 days, i.g.) has no adverse impact on murine osteoblast differentiation or proliferation (46). In a murine collagen-induced arthritis (CIA) model system, the ginsenoside Rh1 (10 mg/kg for a period of 10 days, i.p.) was also able to augment the anti-inflammatory activity of Dex by enhancing GR expression and binding without inducing hyperglycemia (47). Ginsenoside CK (112 mg/kg for a period of 24 days, i.g.) can also activate GR to suppress β-arrestin2 expression, thereby inhibiting inflammation (48).

Glycyrrhizic acid (also known as glycyrrhizin) is the primary glycoside derivative of licorice, and it has been ascribed a range of anti-inflammatory activities. By suppressing signaling through the Smad3 and MAPK pathways, for example, glycyrrhizin (30 and 100 mg/kg for a period of 28 days, i.g.) has been shown to reduce the severity of bleomycin-induced inflammation and pulmonary fibrosis in mice (49). Glycyrrhizin (10 mg/kg for once every day in the first 3 weeks following by given once every 3 days until the twelfth week, intra-articular knee injection) treatment can also alleviate inflammation and the degeneration of cartilage tissue in a rat model of osteoarthritis via regulating the TLR4/NF-κB and HMGB1 pathways (50). In vivo, glycyrrhizic acid undergoes hydrolysis to yield glycyrrhetinic acid, which is structurally similar to steroid hormones such that it is able to exert a range of biological effects including glucocorticoid-like anti-inflammatory activity through interactions with steroid hormone receptors and metabolic enzymes. For example, in a murine ALI model system, glycyrrhetinic acid (10, 20 and 40 mg/kg for a period of 7 days, i.g.) was able to reduce injury severity by suppressing NLRP3 inflammasome activation through the ROS-PI3K/AKT pathway (51). Glycyrrhetinic acid (40 μM) may also be hepatoprotective in the context of chronic liver inflammation, functioning by suppressing the phosphorylation of IκBα phosphorylation and the nuclear translocation of p65 so as to reduce iNOS expression, thus alleviating inflammation (52). Glycyrrhetinic acid and glycyrrhizic acid can interact with GR as ligands, modulating glucocorticoid resistance can also prevent inflammation by disrupting the GR-HSP90 (53, 54). As a relatively weak glucocorticoid-like drug, glycyrrhizic acid can enhance the effects of glucocorticoids while antagonizing the adverse effects associated with high-dose glucocorticoid treatment. Licorice (75 mg/kg for a period of 5 days) can also suppress 11 beta-hydroxysteroid dehydrogenase mRNA expression while potentiating glucocorticoid activity (55). Therefore, glycyrrhizic acid and glycyrrhetinic acid seem to be able to exert glucocorticoid-like anti-inflammatory activity without a significant risk of negative glucocorticoid-related side effects such as GIOP.

Icariin is the main active ingredient of epimedium, which is a natural compound that has been increasingly studied in the context of osteoporosis treatment and prevention, as it has been shown to simultaneously suppress bone resorption and expedite bone formation (56). Icariin (125 mg/kg for a period of 14 days, i.g.) can promote primary osteoblast maturation and associated bone remodeling, inducing osteoblast mineralization and the expression of key markers of terminal differentiation such as alkaline phosphatase (ALP) and type I collagen (57–60). Icariin(0.1 μM) also exhibits robust anti-apoptotic activity, promoting BMSC proliferation and osteogenic differentiation via Wnt/β-catenin pathway activation (61).

With respect to the symptoms of GIOP, icariin (5 μM for a period of 48 h) can enhance trabecular bone density in the context of glucocorticoid exposure, promoting osteogenic differentiation via the suppression of Notch signaling (62). Through the enhancement of autophagic activity, icariin (50 mg/kg for a period of 30 days, i.p.) can reduce OVX-induced bone loss in animal model systems (63), in addition to disrupting the Dex-induced apoptotic death of osteocytes (58). Icariin can also activate the ERK and ER pathways to control bone homeostasis, promoting OPG expression and Wnt pathway activation. Inhibiting osteoclastogenesis is at least partially responsible for the anti-osteoporotic activity of icariin and compounds derived therefrom. The levels of the osteoclast differentiation marker tartrate-resistant acid phosphatase (TRAP) are reduced in a dose-dependent manner when osteoclast precursor cells are treated with icariin (10 nM, every 3 days) (64). Icariin (10 μM) is also able to directly suppress RANKL-induced hemopoietic cell differentiation into osteoclasts (65). In addition to regulating osteoclastogenesis, icariin (50 and 100 μM) can arrest cell cycle progression in osteoclast precursors, thereby inducing their apoptotic death (66). It can further reverse deleterious Dex-induced trabecular phenotypes while stimulating bone remodeling, increasing bone calcium, OCN, and FGF-23 levels while reducing the levels of bone resorption markers including CTX and TRAP-5b. Indeed, in GIOP model mice, icariin (100 mg/kg for a period of 6 or 12 weeks, p.o.) treatment has been shown to protect against bone degeneration, hypercalciuria, and hypocalcemia (67). As such, icariin may be a valuable tool for use in the induction of bone regeneration owing to its potent osteogenic bioactivity.

Many clinical studies have shown that Chinese medicine containing epimedium has achieved good clinical effects in the treatment of GIOP patients. Hugu Capsules (comprised of epimedium, polygonum multiflorum, rehmannia glutinosa and other traditional chinese medicines) can significantly increase the bone mass of 51 patients with GIOP, improve bone turnover, and relieve pain (68). Through observation of 50 GIOP patients, Wu et al. found that taking Xianling Gubao capsule while using glucocorticoids treatment can increase the BMD of the patient’s lumbar spine and proximal femur, thereby reducing the incidence of osteoporotic fractures and having fewer adverse reactions (69). Through clinical observation of 66 patients with GIOP, Shi et al. found that Bugu Capsules (including epimedium) can significantly reduce the impact of OP caused by glucocorticoids, reduce blood calcium, parathyroid hormone levels, and increase bone density (70).

Tanshinone IIA, extracted from Salvia miltiorrhiza Bunge, is a perennial herbal plant widely used as a folk remedy in Asian countries. Several studies have proved that Tanshinone IIA possesses many biological activities, such as anti-inflammatory, free-radical scavenging abilities, antioxidant properties, liver protection, and anti-cancer properties. Tanshinones are compounds that can also simultaneously inhibit osteoclastogenesis and bone resorption while promoting more robust bone formation with concomitant osteoblastogenesis. These tanshinones (2, 5 μg/ml) suppress osteoclast development through the disruption of RANKL-mediated NF-κB, MAPK, Akt, and M-CSF/c-Src signaling pathway activation (71, 72). Tanshinone IIA, for example, can inhibit osteoclastogenesis through the inhibition of RANKL-induced c-Fos and NFAT c1 (71), with Tanshinone IIA (20 μg/mL for a period of 30 min) pretreatment reportedly reducing the fusion, actin ring formation, and resorptive activity of osteoclasts in a co-culture system containing M-CSF and RANKL-treated calvarial osteoblasts and BMCs (73). Mechanistically, Tanshinone IIA (10 μg/mL) can function as a selective COX-2 inhibitor to suppress PGE2 and to thereby modulate OPG and RANKL expression (74), all of which are related to osteoclast function. Tanshinones (1 μM for a period of 24 h) can also disrupt the apoptotic death of osteoblasts and consequent osteoporosis observed upon glucocorticoid treatment by inactivating Nox4 (75). In osteoporosis model mice, Tanshinone IIA (10 mg/kg for a period of 6 weeks, p.o.) was able to decrease the incidence of fractures and severe osteopenia while augmenting bone strength, mineral levels, and collagen in the bone matrix (76). Tanshinone (10 mg/kg for a period of 21 days, i.v.) was also able to upregulate phosphoglycerate dehydrogenase and to thereby suppress OVX-induced osteoporosis and BMSC senescence (77). Tanshinone can alleviate the adverse effects of Dex treatment and consequence cellular injuries such as caspase-9-dependent apoptosis, increased cytosolic cytochrome c and Nox levels, and increased ROS generation (75). Current preclinical evidence suggests that these Tanshinones preserve skeletal integrity primarily by suppressing bone resorption and osteoclast formation, underscoring their potential value for the treatment of GIOP.

Many other herbal medicines have also been found to reduce GIOP incidence or severity through a range of mechanisms. For example, celastrol can suppress GIOP incidence in rats by modulating the Wnt and PI3K/AKT signaling pathways (78), while KRG can induce the apoptotic death of osteoblasts, highlighting its potential therapeutic utility as a tool to delay the onset of osteoporosis (79). Osthole has been shown to prevent Dex-induced osteoporosis in female rats, potentially by normalizing hormone and cytokine homeostasis through increases in TGF-β1 production (80) ( Table 1 ).