Part Ⅲ Therapeutic Anabolic And Anticatabolic Benefits Of Natural Chinese Medicines For The Treatment Of Osteoporosis

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In vivo studies using rodent models of postmenopausal estrogen deficiency-induced osteoporosis have shown that Cistanches deserticola-extract (CDE) could provide therapeutic benefits for the treatment of osteoporosis (Liang et al., 2011; Liang et al., 2013). Findings indicate that Cistanche Deserticola Extract could dose-dependently enhance the femoral BMD and BMC in OVX rats, and improve biomechanical femur parameters of loading and auto break including maximum load, maximum displacement, and stress (Liang et al., 2011). In comparison with OVX rats, Cistanche Deserticola Extract-treatment rats showed biochemical differences including decreased blood calcium, zinc, and copper levels (Liang et al., 2011). Further in vivo investigation of the molecular mechanisms behind the antiosteoporosis effect of CDE indicate that the attenuation of bone degeneration is associated with the regulation of genes involved with bone metabolism, including Smad1, Smad5, TGF-β1, and TIEG1 (Liang et al., 2013). Additionally, in vivo investigation of the effects of CD compound, Cistanoside, on OVX rats indicates that Cistanche Deserticola may contain both osteogenic and antiosteoclastic properties (Xu et al., 2017). In addition to increasing bone strength, BMD, and improving trabecular microstructure, Cistanoside may also decrease the activity of bone resorption markers including TRAP, DPD, and cathepsin K (Xu et al., 2017). These effects appear to be mediated by down-regulation of TNF-receptor associated factor 6 (TRAF6), which downstream mediates both the inactivation of NF-κB, to inhibit osteoclast activity, and the stimulation of the PI3K/Akt osteogenic pathway (Xu et al., 2017).

Epimedium brevicornum Maxim

Epimedium brevicornum Maxim (EBM, “Yin Yang Huo”) is a very popular natural drug been traditionally used to treat bone diseases, pregnancy, and gonad dysfunction in Chinese medicine for thousands of years. It could relieve postmenopausal symptoms and inhibit osteoporosis and other bone loss diseases, while few hyperplastic effects on the uterus were found. These antiosteoporotic effects may be related to the estrogenic properties by the intrinsic phytoestrogens including some of the flavonoids, lignans, sterols, etc. (Wang et al., 2007; Xu et al., 2016). In the systems pharmacology study, there are 77 components in Epimedium possessing the analogous structure to estrogen (Xu et al., 2016). Many of these phytoestrogenic compounds have the beneficial effects to inhibit osteoporosis, including icariin, epimedin A, epimedin B, epimedin C, acaricide II and icariin, epimedoside C, baohuoside I, baohuoside II, etc. (Meng et al., 2005; Huang et al., 2007; Zhai et al., 2013; Liu et al., 2014b; Wang et al., 2016b; Liu et al., 2017b). Among these ingredients, icariin is the main compound of Epimedium brevicornum Maxim. Now, there have been many studies and reviews focusing on its anabolic and anticatabolic effects. Certain studies found that icariin has better antiosteoporotic effects than other compounds (Ma et al., 2011; Wang et al., 2018). This review would emphatically introduce the potential effects of icariin to treat osteoporosis, being represented for Epimedium brevicornum Maxim.

Flavonoid

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Icariin, a prenylated flavonol glycoside, was one of the main effective compounds in Epimedium. With the instinct estrogen biosynthetic effect (Yang et al., 2013), it had potential osteogenic and anti osteoclastogenic effects in vitro and in vivo, and antiosteoporotic effects in clinical.

Recent in vitro studies have demonstrated that icariin could enhance the ALP activity, osteogenic differentiation and improve the maturation and mineralization of MSCs and osteoblasts including hFOB 1.19 cells, MC3T3-E1, UMR 106 cells (Chen et al., 2007b; Mok et al., 2010; Fan et al., 2011; Cao et al., 2012; Liang et al., 2012). Icariin could also have a pronounced ability to promote the differentiation of osteoblast even with the absence of dexamethasone (Ma et al., 2013). Correspondingly, the mRNA expression of osteogenesis-related genes including COL1a2, OSX, RUNX-2, BMP-2, Smad4, Notch2, and OPG/RANKL ratio was significantly increased (Xiao et al., 2005; Zhao et al., 2008; Hsieh et al., 2010; Ma et al., 2011; Bian et al., 2012; Cao et al., 2012; Liang et al., 2012; Li et al., 2013b). Extra studies found that icariin treatment could significantly induce the activation of ERK, JNK, and p38 kinase, and their respective inhibitors would dramatically attenuate icariin-stimulated osteogenic effects. Ye et al. found that TAZ (the transcriptional coactivator with PDZ-binding motif) depletion could significantly block the promoting proliferation and osteogenic differentiation induced by icariin treatment (Ye et al., 2017). These studies indicated the involvement of Wnt/β-catenin-BMP2, Notch, MAPK, and RhoA-TAZ signaling pathways in the osteogenic effects of icariin (Song et al., 2013; Wu et al., 2015a; Ye et al., 2017). Additionally, the osteogenic differentiation ability of BMSCs from OVX rats would be significantly decreased compared with that in the sham operation group. While icariin treatment could act to protect and increase the osteogenic differentiation and mineralization via the estrogen pathway (Luo et al., 2015). Icariin could also protect osteoblast's cell cycle and suppress their apoptosis induced by oxidative stress. There was less production of reactive oxygen species and malondialdehyde, and more superoxide dismutase activity with the treatment of icariin (Liu et al., 2012a). Therefore, icariin could effectively preserve potential osteogenic differentiation of the cells in hypoxic conditions, with the increased levels of RUNX-2, OSX, and BMP-2 gene expression, and the functions of ALP activity, and mineralized nodules (Liu et al., 2012a).

Icariin not only stimulated osteogenic differentiation but also suppressed the osteoclastogenesis and inhibited bone resorption activity in vivo. It was found that icariin could effectively control the proliferation and differentiation of hemopoietic cells which could develop into osteoclasts at the concentration of 10 mM. With the exposure of icariin, the TRAP-positive multinuclear cells appeared to be fewer. The formed bone resorption pits were inhibited and the osteoclastogenesis-related expressions of TRAP, RANK, and CTR genes were controlled by icariin (Chen et al., 2007a). Huang reported that icariin could suppress the bone resorption functions of osteoclasts via the affection on cytosolic free calcium, actin rings, and superoxide generation (Huang et al., 2007). The positive activities of TRAcP and the activities of osteoclasts formation and bone resorption stimulated by LPS were diminished by icariin. Correspondingly, the synthesis of cyclo-oxygenase type-2, prostaglandin E2, hypoxia-inducible factor-1, and the activation of p38 and JNK were inhibited (Hsieh et al., 2011). Additionally, icariin could inhibit Ti particles-stimulated increase of RNA expressions of the RANKL, CTSK, TRAcP, and MMP9 in RAW264.7 cells. The expressions of IL-1β and TNF-α were increased induced by Ti particles of RAW264.7 cells had also been inhibited (Cui et al., 2014). These experiments indicate the potential inhibitory effects of icariin on the prevention of inflammatory bone loss diseases.

In vivo studies with OVX rats, the flavonoids treatment of Epimedium Brevicornum could increase the level of serum osteocalcin and decrease the TRAcP with the comparison to untreated rats. The micro-CT result indicated that the parameters of BMD, BV/TV, Conn.D, and other similar indicators in flavonoids-treated OVX rats were obviously better. The bone histomorphometric parameters of OS/BS, MAR, and BFR/BS were improved. In mechanical testing, the OVX would induce the reduction of the failure force. However, it was effectively inhibited by flavonoids treatment. While no increase in uterus weight was found during the treatment progress (Zhang et al., 2006; Peng et al., 2009; Liang et al., 2012). The experiments in vivo with C57BL/6 mice found that icariin could prevent decreased BMD and bone strength in the femur by estrogen deficiency after ovariectomy surgery (Mok et al., 2010). The ratio of OPG/RANKL expression in the tibia has been improved (Mok et al., 2010). In the OVX rat experiment, orally treated rats with icariin at the concentration of 125 mg/kg body weight enhanced the activity of bone mineralization and formation, obtaining higher BMD, biomechanical, and histopathological parameters. And the decreased concentrations of Ca2+, P, and E2 in the serum were prevented (Nian et al., 2009). In the glucocorticoid-induced osteoporosis (GIOP) model study, icariin significantly attenuated the bone deteriorations, less BMD, hypocalcemia, and hypercalciuria of the glucocorticoid positive group. The bone formation level of ALP, calcium, OCN, and fibroblast growth factor-23 in serum was increased. The bone resorption markers of carboxyterminal collagen cross-links, C-terminal telopeptide of type I collagen, and TRAP were reduced (Feng et al., 2013; Zhang et al., 2015). The antiosteoporotic effects by icariin maybe act via involvement of the ERK, PI3K/Akt/GSK3b/β-catenin integrated signaling pathways (Feng et al., 2013; Zhang et al., 2015). Liu et al. found that icariin had beneficial effects for osteoporotic rats via the inhibition of peroxisome proliferator-activated receptor γ (PPARγ) and Notch2 mRNA expression (Liu et al., 2017a). And Ma et al. found that icariin appears to be a therapeutic drug to manage glucocorticoid-induced bone loss via the activation of microRNA-186-mediated suppression on cathepsin K (Ma et al., 2018). Additionally, icariin could significantly reduce particle-induced bone resorption by suppressing osteoclast formation (Shao et al., 2015). Oral administration of icariin improved the abilities of bone formation with higher BMD in the regenerated bone area during the distraction osteogenesis of mandibular, indicating the icariin might be a potential medicine that could shorten the course and improve the activity of distraction osteogenesis (Wei R. et al., 2011).

In clinical, a double-blind placebo-controlled clinical trial showed that the flavonoids treatment (containing the compounds of icariin, daidzein, and genistein in Epimedium) possessed the beneficial ability to inhibit serious bone loss in postmenopausal women. The BMD could be maintained at 12 and 24 months with treatment. However, no significant changes in serum estradiol or uterus tissue were found, indicating the safety of the endometrium during the application (Zhang et al., 2007a).

Therefore, being the main ingredient of E. brevicornum, icariin could act as a potential useful medicine to affect the imbalance of bone metabolism by increasing osteogenesis and inhibiting bone resorption. More importantly, despite the low number of clinical trials with Chinese medicine compounds, and three kinds of flavonoids in the Epimedium treated group, it has effectively indicated the antiosteoporotic effects of Epimedium Brevicornum Maxim clinically. Numerous studies in this review based on osteoporotic animal models, osteoblasts, and osteoclasts cells have deeply and consistently confirmed the potential effects and mechanisms by which icariin regulates bone metabolism to treat osteoporosis. Furthermore, high-quality clinical research is needed to test the antiosteoporotic effects of the single compound and to compare their representative effects.

Pueraria montana (Lour.) Merr

The Chinese herb of Pueraria Montana (Lour.) Merr. (PM, “Ge Gen”) has been famously used for the daily diet and medicine in China and other Asia countries from ancient years. Being a classical and antioxidant agent, it had more recently exhibited benefits for the treatment of angina pectoris and hypertension (Yang et al., 2010b; Tan et al., 2017), neurological health (Gao et al., 2009), blood glucose homeostasis (Prasain et al., 2012), and bone metabolism (Manonai et al., 2008).

Puerarin is an active and famous isoflavone compound extracted from the classical Chinese medicine P. Montana. Puerarin treatment with intragastric administration protected against the decreased levels of BMD and BMC, and the poor structure of femur trabecular bone in ovariectomized rats was improved (Wang et al., 2012a). In the in vivo study with orchidectomized (ORX) osteoporotic model, the BMD of the femur was significantly decreased. PM treatment of diet intake effectively decreased the impaired BMD, and the analysis of the femoral metaphysis indicated that PM significantly decreased the levels of BV/TV and trabecular number. And the enhancement of trabecular separation in ORX mice was restored (Wang et al., 2005; Yuan et al., 2016). In the experiment with natural menopausal monkeys, the treatment of 1000 mg/kg body weight of Puerarin powder for 16 months could significantly alleviate the loss of cortical bone. And the bone turnover levels of serum ALP and osteocalcin were decreased (Kittivanichkul et al., 2016). Puerarin 6’’-O-xyloside (PXY), one of the major isoflavones of the P. Montana had the beneficial effects to improve the levels of calcium, phosphorus, ALP activity, and OPG which had been decreased after OVX surgery in ICR mice serum. The destructive femur osseous tissues of enlarged bone marrow cavity and sparse trabecular bone were alleviated with PXY treatment. Correspondingly, PXY effectively improved the proliferation of osteoblasts via the improvement in the expression of the OPG/ RANKL ratio (Li et al., 2016b).

In the vitro study, Puerarin could stimulate and improve the proliferation and differentiation of osteoblast cells (Wang et al., 2013a; Wang et al., 2014). The stimulation of osteoprotegerin and inhibition of RANKL and interleukin-6 production may act via the classic estrogen response element (ERE) pathway in MG-63 cells (Wang et al., 2014). And the expression of OPG mRNA was increased by Puerarin in MC3T3-E1 osteoblast cells (Yuan et al., 2016). Puerarin at the dose of 2.5-100 µM would increase the growth of human BMSCs concentration-dependently (Lv et al., 2015). The osteoblastic maturation would be stimulated with the increased ALP activity, as well as the formation of mineralized nodules by Puerarin (Wang et al., 2012a; Lv et al., 2015; Zeng et al., 2018). The signaling pathways of classical ER, MAPK, and Wnt/β-catenin were involved in the osteogenesis and bone formation effects stimulated by Puerarin treatment (Wang et al., 2012a). Lv, et al. found that the osteogenesis marker expressions of Runx2, osterix, and osteocalcin were enhanced via the increased nitric oxide production and cyclic guanosine monophosphate content in hBMSCs (Lv et al., 2015). And Zeng et al. reported that the expression of transient receptor potential Melastatin 3 (TRPM3) and miR‐204 were decreased and the activation of Runx2 was promoted following puerarin treatment in MC3T3‐ E1 osteoblastic cells (Zeng et al., 2018). Additionally, Puerarin opposed the apoptosis of human osteoblast cells induced by cisplatin or in serum-free conditions. The expression of Bcl-xL and Bcl-2 was up-regulated and Bax has decreased via the activation of MEK/ERK and PI3K/Akt signaling (Liu et al., 2013; Wang et al., 2013a).

PM could also inhibit the formation of osteoclasts in vitro. Pueraria Montana extract (PME) could dose-dependently inhibit osteoclast differentiation and formation from the precursor cells. Consistently, the expression of osteoclast differentiation markers including c-Fos and NFATc1 genes were downregulated (Park et al., 2017). MAPK activity induced by RANKL had also been effectively inhibited by PME treatment (Park et al., 2017). In the vitro experiment with RAW 264.7 cells, PM reduced the formation of TRAP-positive cells induced by the stimulation of RANKL. Correspondingly, the mRNA expression of RANKL was inhibited (Yuan et al., 2016)

These results strongly suggest that P. Montana could act as both effective promotors of osteogenesis and inhibitor of RANKL-induced osteoclastogenesis, and it appears the isoflavone compounds of Puerarin and PXY have the great promotion on osteogenesis ability in the in vivo and in vitro studies. Even Pueraria Montana may be a potential therapeutic agent for the treatment of bone loss diseases, while the definite extracts of PM to inhibit osteoclastogenesis were still not well known and studied. Further research is necessary to characterize the bioactive compounds of CM which contain anti-catabolic or anabolic benefits for the treatment of osteoporosis, and their molecular mechanisms providing the antiosteoporotic effects.

Salvia miltiorrhiza Bunge

Salvia miltiorrhiza Bunge (SMB, “Dan Shen”) has been widely and classically used in clinical practice and trial for the treatment and prevention of vascular diseases in the liver and heart, as well as commonly used for treating trauma wounds and fractures and correcting blood stasis in TCM for its antioxidant properties (Chen et al., 2017b; Zhang et al., 2017a; Chen et al., 2019b). The application of Salvianolate, Salvianolic acid B on the treatment of osteoporosis has been deeply studied (Guo et al., 2014).

Salvianolate could control the metabolism of bones in glucocorticoid-treated lupus-prone mice. Lupus mice usually have a marked bone loss and deterioration due to an imbalance of bone formation and resorption. Glucocorticoid treatment would deeply restrain their bone formation. After the treatment, Salvianolate increased the trabecular qualities of BV/TV, Conn.D, and Tb. Th, and decreased the SMI number in both the untreated and GC-treated lupus mice. The mechanical parameters of bone ultimate load, yield load, and stiffness in treated lupus mice were significantly improved (Liu et al., 2016). Correspondingly, the bone resorption marker of serum TRAcP was down-regulated and the OPG level was increased. The expression of RANKL, IL-6, ROS, and PPARγ was inhibited, while the Runx2 expression was increased in the mice. These results indicated that Salvianolate treatment significantly affected bone metabolism to inhibit bone loss in lupus mice (Liu et al., 2016). The compound of Salvianolic acid B could prevent glucocorticoid-induced decreased BMD, bone strength, and serious architecture, and could effectively enhance the bone formation rate and the local microcirculation with more capillary dilation (Cui et al., 2012).

There are many compounds in S. miltiorrhiza having pro-osteogenesis abilities including water solution, Salvianic acid A, Salvianolic acid B, Tanshinol, and Tanshinone IIA. The water solution of Salvia miltiorrhiza improved bone remodeling by enhancing the gene expression of ALP, OCN, and OPG (Chin et al., 2011). Salvianolic acid A protected bone metabolism from serious impairment by the stimulation on osteogenesis and the depression of adipogenesis induced by prednisone (Cui et al., 2009). It was reported that Salvianolic acid B had the potential to stimulate the ALP activity of osteoblastic cells (Liu et al., 2007). It could also protect BMSCs differentiation and increase osteoblast activities via the increase of Runx2 mRNA expression even with the exposure of glucocorticoid. The glucocorticoid-associated adipogenic differentiation was decreased by the regulation of PPARγ mRNA expression (Cui et al., 2012). In the Vivo study with rat tibia fracture model, Salvianolic acid B could accelerate the early-stage fracture healing for that the callus growth in the fractured bone was significantly greater in the Salvianolic acid B treated group. And the serum ALP level of the fracture rats was enhanced at weeks 1 and 3 postfracture. These findings indicate that Salvianolic acid B is a potential candidate to treat bone fracture and osteoporosis by promoting effects on bone formation (He and Shen, 2014). In another experiment with zebrafish in vivo, dexamethasone exposure had a series of serious impairments to bone formation, bone mass, and osteoblast-specific genes. While Tanshinol protectively promoted bone formation and bone mass via the inhibition of oxidative stress, and the osteoblast-specific genes expression of Runx2, osteocalcin, ALP, and osterix were stimulated (Luo et al., 2016). Additionally, Tanshinone IIA blocked the apoptosis of osteoblasts induced by glucocorticoids via the inhibition of the Nox4-derived overexpressed reactive oxygen species activities (Li et al., 2015a). And Tanshinone IIA enhanced the differentiation of C2C12 cells to osteoblasts via activating the signaling pathways of p38, BMP2/Smad, and Runx2 (Kim and Kim, 2010). It could also enhance the osteogenic differentiation of human periodontal ligament stem cells via enhancing the activation of both ERK and Runx2 (Liu et al., 2019).

In the in vivo study, after SMB treatment at the concentration of 5 g/kg for 14 weeks, the unbalanced levels of serum ALP, OPG, TRAcP, and RANKL of OVX rats were attenuated. The decreased BMD and bone strength were inhibited, and the impaired bone microstructures were improved. Moreover, the decreased expression of p‐LRP6, IGF‐1, ALP, and OPG was enhanced. While the increased expression of RANKL and CTSK in the tibias and femurs of OVX rats was effectively inhibited by SMB treatment (Liu et al., 2018). Tanshinone VI, extracted from the root of S. miltiorrhiza, could greatly inhibit osteoclast differentiation and bone resorption by disrupting the formation of the actin ring. Tanshinone VI appears to prevent osteoclast differentiation by the downregulation of RANKL expression (Nicolin et al., 2010). Kwak et al. reported that Tanshinone IIA inhibited the osteoclast differentiation from the precursors via the down-regulation of RANKL-induced high levels of c-Fos and NFATc1 (Kwak et al., 2006). Additionally, in the natural drug screening experiment, maybe tanshinone 1, cryptotanshinone, and 15,16-dihydrotanshinone I diterpenoids and other unknown compounds had a synergistic effect with tanshinone, possessing the anti osteoclastogenesis effects by reducing the formation and function of TRAP-positive multinuclear osteoclasts (Lee et al., 2005; Kim et al., 2008).

These studies highlight the antiosteoporotic effects of S. miltiorrhiza in vivo and in vitro. Most of the compounds of S. miltiorrhiza including Salvianolate, Salvianic acid A, Salvianolic acid B, Tanshinol, and Tanshinone IIA, and so on, have potential antiosteoporosis effects by promoting bone formation via increased expression of osteogenesis-related genes and proteins, and by decreasing bone resorptive osteoclastogenesis through the inhibition of reactive oxygen species activity. Compounds in the research of Kim et al. also have the anti osteoclastogenic effects which are not further studied. More research is needed to provide evidence of the herb and its potent compounds to target osteoporosis in clinical trials, including their mode of application and mechanisms of action.

DISCUSSION

In summary, with the increasingly aging population worldwide, osteoporotic fracture has become a major health and social issue. The side effects caused by hormone therapy and alendronate antiosteoporotic agents have prompted researchers to study natural therapeutic compounds, which may be effective and safe for the treatment of osteoporosis, and with fewer adverse side effects.

The pathophysiology of osteoporosis is complicated in terms of occurrence, development, and progression, including much more numerous mechanisms of mechanistic/ mammalian target of rapamycin (mTOR), autophagy, and notch involved (Shen et al., 2016; Zanotti et al., 2018; Hiraiwa et al., 2019), except for RANKL, MAPK, Wnt, and Smad signaling pathways discussed above. Natural Chinese medicine may contain compounds that are effective for the treatment of osteoporosis and this review documents current evidence as to their potential bio-pharmacological effects and possible mechanisms of action. A summary of the in vivo and in vitro antiosteoporosis effects of the natural herbs reviewed by this article is presented in Table 1 and Table 2, respectively. Natural Chinese medicine appears to promote bone formation activity, including the osteogenesis of MSCs and osteoblasts. Some medicines could protect them from oxidative damage due to ROS activity. Additionally, the bone resorption activity of osteoclasts may be significantly inhibited by certain herbal compounds, thus potentially alleviating the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. Figure 3 summarizes the signaling pathways that appear to mediate the antiosteoporotic effects of the natural medicine reviewed by this article.

The natural Chinese medicines in this review are classic and bone-specific medicines. As we know, clinical experiences are very important to Chinese medicine. Chinese medicines were classified into different categories with special functions according to the rich practices and experiences in the clinic and the Chinese medicine theories. Some of them were the classic and bone-specific drugs to treat skeleton fractures and bone loss diseases for their beneficial improvement on bone formation. Most of them have the effects and functions to tonify the “Yang” in traditional Chinese medicine, which has an improvement in bone development and metabolism. “Yang-tonifying” medicines are the most popular and classic kind of natural drugs to treat osteoporosis in Chinese medicine (Ju et al., 2014; Li et al., 2015b). Furthermore, all of them are deeply studied possessing both anabolic and anticatabolic effects. They have potential bone-formation effects by enhancing the proliferation and differentiation of osteoblasts and BMSCs, improving the activity of ALP and mineralization formation. Some of them could protect osteoblasts and BMSCs from apoptosis induced by oxidative stress (Liu et al., 2013). While the osteoclastogenesis and bone-resorption function of osteoclasts was inhibited by the treatment of these medicines (Wang et al., 2014). Interestingly, they have phytoestrogenic or phytoandrogenic effects which might act as the natural and potential alternatives for hormone replacement treatment or alendronate therapies to significantly inhibit bone loss and improve skeleton development of osteoporotic patients. It has been reported that testosterone played a vital basic and clinical role in the homeostasis of skeletal tissue (Ebeling, 2010). In vivo study indicated that the androgen deficiency would significantly lead to an increase of osteopenia in the aged male rats (Erben et al., 2000). Clinically, testicular malfunction induced by androgen deficiency may cause osteoporosis in old men with increasing bone resorption (Foresta et al., 1984). Numerous studies indicated that these bone-specific drugs contain phytoestrogens (Edouard et al., 2014), which could act as a natural and potential alternative for testosterone replacement therapy (TRT). They could effectively restore the level of serum testosterone and thus significantly improve the bone health and physical condition of patients (George and Henkel, 2014). Some studies found that the compounds from these classical drugs may also possess phytoestrogenic effects (Jiao et al., 2009; Ma et al., 2011; Zhang et al., 2016b), having a similar structure of estrogen conformation and capabilities to bind with estrogen receptors. Therefore, they may regulate bone remodeling via the estrogen receptor pathway (Wiseman, 2000). More importantly, the application of these drugs exhibiting phytoestrogen and phytoestrogen effects do not appear to cause obvious or harmful side-effects including cardiovascular disease, prostate cancer, and breast cancer, which might be induced by the long-term and large dosage use of testosterone or estrogen replacement therapy (Wiseman, 2000).

However, the development of osteoporosis is very complex in postmenopausal women, elderly men, glucocorticoidoveruse patients, and other patients with metabolic diseases. The mechanisms of action of natural Chinese medicines effective for the treatment of osteoporosis have not yet been well investigated, thus indicating the need for further studies (Ju et al., 2014). Besides, large dosages or long-term usage warrants caution, and certain methodologies should be observed. Further research to isolate and characterize the bioactive antiosteoporotic compounds from the classical and bone-specific drugs is necessary to extensively profile compounds for pharmacological usage, especially their safety, efficacy, and potential chemical interactions with other drugs. Studies to determine the special and targeted cellular and molecular mechanisms of natural Chinese medicine compounds are required to develop their potential application for the treatment of osteoporosis, as an effective, safe alternative to primary therapeutic strategies, or in combination with current primary pharmacological treatments. Additionally, few high-quality clinical studies have documented the antiosteoporosis effects of structure well-known compounds, for example, Epimedium-derived phytoestrogen flavonoids were used to treat and inhibit osteoporosis and bone loss of the postmenopausal women in a clinical trial (Zhang et al., 2007a). There are still some limitations and deficiencies of these clinical drug findings, which are studied together with combined medicines in traditional formulas, due to the potential for unknown interactions between the various drugs and nonspecific compounds in this medicine (Wei H. et al., 2011; Wei R. et al., 2011; Shi et al., 2012). Therefore, more high-quality clinical studies with natural Chinese medicines possessing the anabolic and anticatabolic effects are needed in the future.

CONCLUSION

Recent in vivo and in vitro findings suggest that natural Chinese medicine may provide potential therapeutic benefits for the treatment of osteoporosis. Further research is necessary to ensure the safety, efficacy, and specificity of the compounds in Chinese medicines to develop their therapeutic potential. More high-quality clinical research with these natural medicines is needed to provide greater evidence for the candidate to beneficial and safer antiosteoporotic application.

AUTHOR CONTRIBUTIONS

JH, XL, and ZW contributed equally to this work. JH and XL conceived the idea and wrote the manuscript. ZW, SB, and KC helped modify the language and the revision. ZX collected the literature. JX, DL, and SW helped supervise the research and contribute to the final draft of the paper. We thanked JZ, SC, YH, and JC for the help with this review. All authors reviewed and approved the final manuscript.

FUNDING

This work was supported by the National Natural Science Foundation of China (No. 81673992), National Natural Science Foundation of China Youth Fund (No. 81904091), and Fundamental Research Funds for the Central Universities (No. 21619307).