Part Ⅰ Therapeutic Anabolic And Anticatabolic Benefits Of Natural Chinese Medicines For The Treatment Of Osteoporosis
Mar 04, 2022
For more information:ali.ma@wecistanche.com
Jianbo He1, Xiaojuan Li, Ziyi Wang2, Samuel Bennett, Kai Chen, Zhifeng Xiao, Jiheng Zhan, Shudong Chen, Yu Hou, Junhao Chen, Shaofang Wang, Jiake Xu and Dingkun Lin
1 Guangzhou University of Chinese Medicine, Guangzhou, China,
2 The School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia,
3 The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China,
4 Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China,
5 Centre for Legumes in Mediterranean Agriculture, University of Western Australia, Perth, WA, Australia
Osteoporosis is a bone disease characterized by increasing osseous fragility and fracture due to reduced bone mass and microstructural degradation. Primary pharmacological strategies for the treatment of osteoporosis, hormone replacement treatment (HRT), and alendronate therapies may produce adverse side effects and may not be recommended for long-term usage. Some classic and bone-specific natural Chinese medicine are very popularly used to treat osteoporosis and bone fracture effectively in clinical with their potential value in bone growth and development, but with few adverse side-effects. Current evidence suggests that the treatments appear to improve bone metabolism and attenuate the osteoporotic imbalance between bone formation and bone resorption at a cellular level by promoting osteoblast activity and inhibiting the effects of osteoclasts. The valuable therapies might, therefore, provide an effective and safer alternative to primary pharmacological strategies. Therefore, the purpose of this article is to comprehensively review these classic and bone-specific drugs in natural Chinese medicines for the treatment of osteoporosis that had been deeply and definitely studied and reported with both bone formation and antiresorptive effects, including Gynochthodes Officinalis (F.C.How) Razafim. & B.Bremer (syn. Morinda officinalis F.C.How), Curculigo orchioides Gaertn., Psoralea corylifolia (L.) Medik Eucommia ulmoides Oliv., Dipsacus inermis Wall. (syn. Dipsacus asperoides C.Y.Cheng & T.M.Ai), Cibotium barometz (L.) J. Sm., Velvet Antler, Cistanche deserticola Ma, Cistanche tubulosa Cuscuta Chinensis Lam., Cnidium monnieri (L.) Cusson, Epimedium brevicornum Maxim, Pueraria montana (Lour.) Merr. and Salvia miltiorrhiza Bunge., thus providing evidence for the potential use of alternative Chinese medicine therapies to effectively treat osteoporosis.
Click to Cistanche UK products
Cistanche is a well-known tonic herb that can nourish and protect the kidneys. In traditional Chinese medicine theory, Cistanche is the best herb for kidneys.Cistanche is rich in echinacoside, acteoside, and flavonoids.These effective ingredients in Cistanche can reduce kidney cell apoptosis and increase kidney cell proliferation
Keywords: osteoporosis, natural Chinese medicine, osteogenesis, osteoclastogenesis, anti bone resorption, therapeutic, osteoblasts, osteoclasts
INTRODUCTION
Osteoporosis may result from imbalanced bone metabolism leading to a systemic deterioration in bone mass and bone microstructure, characterized by skeletal fragility and an increased risk of bone fracture (Albright, 1947; Rachner et al., 2011). Almost one in three women and one in five men would experience one bone fracture in their life after 50 years of age, resulting from osteoporosis (Sozen et al., 2017). Furthermore, the risk of additional fractures will rise exponentially with each incidence of fracture (Lorentzon and Cummings, 2015). Osteoporosis is, therefore, a debilitating disease for sufferers, leading to reduced quality of life, and placing a large economic burden on society (Curtis et al., 2016). Thus, medical intervention is imperative to provide adequate care for patients and improve societal health. Moreover, it is necessary to continue research leading to the development of a medical treatment that may effectively treat and potentially prevent osteoporosis (Wang et al., 2017b).
Currently, there are numerous pharmacological products used for the treatment of osteoporosis in the clinic (Pavone et al., 2017). Hormone replacement therapy (HRT) and bisphosphonates are the primary therapeutic strategies for bone loss diseases including osteoporosis (He et al., 2017). Long-term HRT may significantly increase the risk of endometrial and mammary cancer, coronary heart disease, and other cardiovascular diseases (Dinger et al., 2016a; Dinger et al., 2016b). While bisphosphonates may lead to osteonecrosis of the long bones and jaws (Spivakovsky, 2017; Lungu et al., 2018). These adverse side-effects limit the clinical use of HRT and bisphosphonates. Therefore, alternative therapeutic agents are required to develop medicines for the treatment of osteoporosis that are less likely to have adverse side effects.
Traditional Chinese medicine (TCM) has become increasingly popular due to its effectiveness in treating diseases, with fewer side effects. Natural Chinese medicine has been widely and effectively used to treat a variety of orthopedic diseases, including bone fractures, rheumatism, and osteoporosis (Mukwaya et al., 2014; He et al., 2017; Suvarna et al., 2018). Some TCMs are the most classical and bone-specific of drugs when applied to the treatment of bone loss and bone fracture diseases, with the effects on the growth and development of skeleton tissue (Shu et al., 2015; Wang et al., 2019a). Recent scientific reports suggest that these natural Chinese medicine therapies appear to have both the anabolic and anticatabolic effects for the treatment of osteoporosis by promoting bone formation and attenuating imbalanced bone resorption, leading to improved bone mineral density and biomechanical properties, and reduced bone microstructural degradation (Figure 1) (He et al., 2017; Wang et al., 2017b; Suvarna et al., 2018). Further, in vitro findings indicate that these natural medicines may enhance the proliferation and survival of osteoblasts, and they could induce the differentiation of osteoblast cells from bone mesenchymal stem cells (MSCs). While the bone catabolic effects of osteoclastogenesis and bone resorption were effectively inhibited (Figure 2).
Therefore, we selected the natural Chinese medicines, which are the classical bone-specific drugs for bone loss and fracture diseases in the clinic, including Gynochthodes Officinalis (F.C.How) Razafim. & B.Bremer (syn. Morinda officinalis F.C.How), Curculigo orchioides Gaertn., Psoralea corylifolia (L.) Medik, Eucommia ulmoides Oliv., Dipsacus inermis Wall. (syn. Dipsacus asperoides C.Y.Cheng & T.M.Ai), Cibotium barometz (L.) J. Sm., Velvet Antler, and so on. Then, according to the literature search of PubMed, each natural Chinese medicine was searched with the keywords of bone, osteoporosis, bone loss, osteolysis, bone formation, skeleton, osteogenesis, osteoclastogenesis, anti bone resorption, bone resorption, bone absorption, therapeutic, osteoblasts, osteoclasts, bone mesenchymal stem cell, differentiation, apoptosis, formula, and combination, accompanied with the Boolean connectors of “AND”, “OR”, and “NOT”. After careful reading, the medicines with both anabolic and anticatabolic effects were included and reviewed. Medicines without osteoporosis-related research, without both anabolic and anticatabolic benefits, or with flaws in experimental design were excluded. Despite the massive amount of experimental data regarding antiosteoporotic effects by the natural Chinese medicines from the in vivo and in vitro studies, high-quality clinical trials are lacking. Additionally, this review highlights and evaluates the scientific evidence for the potential use of natural Chinese medicines in the treatment of osteoporosis with both therapeutic anabolic and anticatabolic benefits, and their potential mechanisms of action.
NATURAL CHINESE MEDICINES
Gynochthodes officinalis (F.C.How) Razafim. & B.Bremer (syn. Morinda Officinalis F.C.How)
Gynochthodes officinalis (F.C.How) Razafim. & B.Bremer (syn. Morinda Officinalis (F.C.How) (MO, “Ba-Ji-Tian”) is a famous natural herb in Chinese medicine, containing many bioactive components including oligosaccharides, iridoid glycosides, and bajijiasu (Chen et al., 2014; Wu et al., 2015b; Li et al., 2016a). Recent studies have found that it could enhance sexual and reproductive function; and may ameliorate Alzheimer’s disease via the microbiota-gut-brain axis, providing benefits including improved memory and learning abilities (Wu et al., 2015b; Chen et al., 2017a). Additionally, the components of polysaccharides, monocropping, and bajijiasu could act as potential agents to treat osteoporosis.
The protective effects of MO root extract on ovariectomy-induced bone loss have been reported (Li et al., 2009). Findings indicate that MO root extract could enhance the bone mineral content (BMC) and bone mineral density (BMD) of the tibia in ovariectomized (OVX) rats (Li et al., 2009). The levels of serum phosphorus (P), calcium(Ca), and osteoprotegerin (OPG) increased, and the levels of serum deoxypyridinoline crosslinks to creatinine ratio (DPD/Cr), tartrate-resistant acid phosphatase (TRAcP), adrenocorticotropin (ACTH), and corticosterone decreased but did not reverse the levels of serum alkaline phosphatase (ALP), tumor necrosis factor-α (TNF-α), or interleukin-6 (IL-6) (Li et al., 2009). Correspondingly, MO capsules attenuated the ovariectomy-induced loss of bone mass by enhancing bone strength and reducing further deterioration of the trabecular microarchitecture of the femurs in rats, which was associated with increased serum osteocalcin (OC) levels (Li et al., 2014b). Polysaccharides are the extract isolated from MO that could significantly elevate whole femoral BMD as compared with the osteoporosis group. The mineral levels of Ca, P, Mg, Zn, Mn, Cu, and Fe in the femur were enhanced dose-dependently (Zhu et al., 2008). Monotropein is a natural compound extracted from MO that appears to exhibit antiosteoporotic effects by increasing BMC, BMD, bone volume fraction (BVF), and attenuating trabecular microstructural degradation in OVX rodents (Zhu et al., 2008; Zhang et al., 2016c). In vivo findings from a disuse-model of osteoporosis indicate that MO driedroot extracts exhibit both bone formation activity and appear to suppress bone resorption. Mornidae Radix (MR), the dried-root of MO, was found to inhibit the osteoporosis-induced decrease of hind limb thickness, tibia failure load, BMD, and tibia Ca and P levels (Seo et al., 2005). Histomorphometry results indicated that it could remarkably protect tibiae’s bone parameters, including volume, length, and cortical and trabecular thickness. Furthermore, both preventive and therapeutic studies indicated that the effects of MR appear to be favorable for both the prevention and treatment of osteoporosis (Seo et al., 2005).
Consistently, in vitro studies have found that MO and its bioactive components appear to provide potentially therapeutic treatment for osteoporosis and that the molecular mechanisms appear to act via receptor activator of nuclear factor kappa-B ligand (NF-κB, or RANKL) signaling pathways. For example, rubidium-1-methyl ether (RBM, a natural anthraquinone compound isolated from the root of MO) may effectively inhibit osteoclastic bone resorption by blocking the NF-κB pathway (He et al., 2018). Bajijiasu was found to inhibit osteoclast formation and bone resorption via the mediation of RANKL signaling pathways (Hong et al., 2017a). Expression of RANKL-induced marker genes, including cathepsin K (CTSK), nuclear factor of activated T cells cytoplasmic 1 (NFATc1), TRAcP, vacuolar-type H+-ATPase V0 subunit D2 (V-ATPase d2), and matrix metalloproteinase-2 (MMP-2) was inhibited by Bajijiasu (Hong et al., 2017a). Further in vitro studies of anthraquinones isolated from MO have identified these molecules as potential inhibitors of osteoclastic bone resorption and enhancers of osteoblastic bone-forming activity (Wu et al., 2009; Bao et al., 2011). MO-anthraquinones have demonstrated the ability to decrease the formation of bone resorption pits, the number of multinucleated osteoclasts, and the activity of tartrate-resistant acid phosphates (TRAP) in an osteoblastbone marrow coculture system, in addition to expediting the apoptosis of osteoclasts (Bao et al., 2011). MO-anthraquinones also appear to promote osteoblastic bone-forming activity by increasing osteoblast proliferation and ALP activity (Wu et al., 2009). Investigation of the polysaccharides extracted from MO revealed that osteogenic inulins of MO promote the proliferation, differentiation, and mineralization of osteoblast cells, as confirmed by the up-regulation of marker genes, including runt-related transcription factor 2, osterix, osteocalcin, bone sialoprotein, and OPG (Jiang et al., 2018).
Taken together, these findings suggest that MO and its bioactive components might provide an important therapeutic role for the treatment and prevention of osteoporosis. MO appears to provide potentially effective treatment for osteoporosis by the attenuation of bone loss and trabecular microstructural degradation, the enhancement of bone mineral density and bone mass, the promotion of osteoblastic bone-forming activity, and the inhibition of osteoclastic bone resorption by direct effects on osteoclasts and effects mediated via known signaling pathways. In the in vitro research, the effective concentration of Bajijiasu compound was found to be 0.8 mM (Hong et al., 2017a), which may be higher than compounds in other in vitro experiments, and the clinical usage may be increased to get better curative effects, therefore, a careful caution of the safety should be observed. Further research is needed to develop the therapeutic potential of this natural medicine.
Curculigo orchioides Gaertn
There are more than 20 species of Curculigo plants in the world. They are native to the tropical and subtropical regions of Asia, Africa, South America, and Oceania (Nie et al., 2013). Curculigo orchioides Gaertn (CO, “Xian Mao”), one of the curculio species, is used to relieve the symptoms of limb weakness, lumbar and knee joint arthritis, and diarrhea in Chinese medicine (Tan et al., 2019). Recent studies have found that CO also appears to have antioxidant properties and anticancer potential, and may be used as an antiosteoporotic herb (Cao et al., 2008; Ramchandani et al., 2014; Hejazi et al., 2018).
CO is used in Chinese medicine for the treatment of postmenopausal osteoporosis and the antiosteoporotic effects of CO have been investigated in vivo (Cao et al., 2008). Administration of CO prevented trabecular bone loss in the tibia of ovariectomized rats by inhibiting bone resorption and increasing serum phosphorus, calcium, and OPG levels, without affecting the body or uterus mass (Cao et al., 2008). The serum levels of bone resorption related makers, DPD/Cr, TRAcP, ACTH, and corticosterone were decreased following CO administration (Cao et al., 2008). CO may also enhance bone formation upon induction during wound healing (Wong et al., 2007a).
Curculigoside (CCG, a phenolic glycoside) is the main bioactive compound of CO and appears to have both osteogenic and antiosteoclastic effects (Liu et al., 2014a). A recent in vitro study evaluated the effect of CCG on osteogenic differentiation of human amniotic fluid-derived stem cells (hAFSCs) and found that CCG up-regulated osteogenic activity in a dose-dependent manner, including increased expression of osteopontin (OPN) and Collagen I, increased ALP activity, and calcium deposition (Liu et al., 2014a). Furthermore, the ratio of OPG to RANKL increased, indicating that osteoclastogenesis was inhibited. The simultaneous up-regulation of β-catenin and Cyclin-D1 indicate that these effects appear to be mediated via the Wnt/β-catenin signaling pathway (Liu et al., 2014a). The in vitro effect of CCG on osteogenic differentiation has also been investigated in relation to BMSCs, and the data indicate that CCG may promote the proliferation and osteogenic differentiation of BMSCs (Shen et al., 2013).
The antioxidant properties of CO are also thought to be attributable to CCG and may play a critical role in attenuating osteoporosis pathophysiology (Wang et al., 2012b). The antioxidant protective effects of CCG have therefore been investigated in rat calvarial osteoblasts exposed to hydrogen peroxide (H2O2), and findings indicate that CCG significantly reduces the cytotoxic effects of H2O2 by reducing the production of reactive oxygen species (ROS) by osteoblasts, and recovering the levels of osteoblast differentiation markers, including ALP, calcium deposition, and runt-related protein 2 (Runx2) (Wang et al., 2012b). CCG has also been shown to protect rat calvarial osteoblasts from dexamethasone (DEX) induced cytotoxicity by regulating osteoblast proliferation, differentiation, and proinflammatory cytokine levels (Zhu et al., 2015). The effects of DEX on the levels of osteoblast differentiation markers, including ALP, OPG, β-catenin, and RANKL was reversed, indicating that CCG may be a suitable compound for the treatment of osteoporosis (Zhu et al., 2015). Accordingly, metabolic analysis indicates that CCG via its main metabolite, M2, could produce these antiosteoporotic effects (Wang et al., 2017a).
Further in vitro and rat calvarial studies have shown that compounds isolated from CO appear to have antiosteoporotic properties, including the promotion of osteoblast proliferation and differentiation, increased bone-forming activity, and the inhibition of osteoclastic bone resorption. The bioactive compounds isolated from MO include novel homogeneous polysaccharides, COP90-1 and COP70-3, and phenolic glycosides (Jiao et al., 2009; Wang et al., 2013b; Wang et al., 2017c; Wang et al., 2019b)
Briefly, the promotion of the osteogenesis of C. orchioides might be the beneficial effect leading to attenuation of osteoporosis, and the inhibition of reactive oxygen species is a great property of this medicine. Additionally, some compounds isolated from CO exhibit the suppression of osteoclastic bone resorption. Further research is necessary to discover the molecular mechanisms, signaling pathways, and bioactive constituents of CO; and to determine the molecular basis of the potential relationship between the antioxidant effects of CCG and osteoporosis pathophysiology in osteoclasts and osteoblasts.
Psoralea corylifolia (L.) Medik
Psoralea corylifolia (L.) Medik (PC, “Bu Gu Zhi”) is widely used in Asia for medicinal purposes; the dried ripe seeds are the active component of the plant. PC is used in Chinese pharmacopeia and TCM formulas for the treatment of skin diseases, cardiovascular disease, nephritis, and osteoporosis (Zhang et al., 2016a). The primary bioactive compounds of PC are coumarins (e.g., psoralen), flavonoids (e.g., neobavaisoflavone, bavachalcone, baldachin, and storyline), and meroterpenes (e.g., bakuchiol) (Zhang et al., 2016a). Additional components of PC have immunoregulatory, antioxidant, and neuroprotective properties for the treatment of Parkinson’s disease (Jing et al., 2017). PC may also have therapeutic potential for the treatment of prostate cancer (Lin et al., 2018).
