http://informahealthcare.com/phb ISSN 1388-0209 print/ISSN 1744-5116 online Editor-in-Chief: John M. Pezzuto Pharm Biol, 2014; 52(9): 1223–1228 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2014.884606
REVIEW ARTICLE
Chinese herbal medicine for bone health Emmanuel Mukwaya1,2, Fei Xu2, Man-Sau Wong3,4, and Yan Zhang1,2,3,4 Center for Systems Biomedical Sciences and 2School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, PR China, 3State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen, PR China, and 4 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China Pharmaceutical Biology Downloaded from informahealthcare.com by University of Newcastle on 09/26/14 For personal use only.
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Abstract
Keywords
Context: Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years. They are cost-effective with fewer side effects and are more suitable for long-term use compared with chemically synthesized medicines. Objective: Chinese herbal formula prescribed among the CHMs is safe, and it is an alternative medicine for bone-related diseases such as osteoporosis. Methods: Science Direct and Google Scholar were used to search articles published. The input key words were CHM, osteoporosis, Chinese herbal formula, traditional Chinese medicine, single herb, multiple-herbs, and bone health. CHMs (single herb and formula) lacking sufficient proof and evidence in the literature were excluded and only those with high citation were retained. Results: A brief review was summarized to indicate the application and the potential mechanism of single herb formula and multi-herb formula in treating the common bone-related diseases such as inflammation, fracture, osteopenia, and osteoporosis. Conclusion: In order to ensure safety and efficacy of all these CHMs, the prescriptions with single herb and multi-component formula must be verified and ensured by reliable pharmacological and toxicological methods. Much more effort needs to be done for studying the standardization, safety evaluation, and mechanism exploration of herb formula as well as confirming the compatibility of these herbs which make one.
Fracture, herbal formula, inflammation, osteoblast, osteoclast, osteoporosis
Introduction Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years and they are a cost-effective alternative to commercial pharmaceutical products. More than 130 countries in the world are using CHM (Hsiao, 2007), which relies on the use of topical herbal pastes, by which, the herbal essence is believed to go directly into the underlying tissues and initiates, for metabolic enhancements of tissue repairs (Ma, 1998). During the development of herbal therapy, single herb formula is the original form of herb prescriptions, and the multi-herb formula is developed gradually by adding one or more herbs to the pre-existing single herb formula (Yi & Chang, 2004). When several herbal medicines are mixed in a certain proportion, they display superiority over a single drug in the treatment of a disease (Qin et al., 2008). Thus multiherbal formula is used to achieve the mutual enhancement, mutual assistance, mutual restraint, mutual suppression, or
Correspondence: Yan Zhang, Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, PR China. Tel: +86 21 65710369. Fax: +86 21 65710108. E-mail: [email protected]
History Received 17 November 2013 Revised 18 December 2013 Accepted 14 January 2014 Published online 18 June 2014
mutual antagonism (Chan, 1995). The most fundamental and the simplest form of multi-herb therapy is herb pair which is the combination of two relatively fixed herbs (Wang et al., 2012). More than 100 000 formulas have been accumulated over the past 2000 years (Qiu, 2007), and among them, more than 80 single herbs have been reported to be effective in treating osteoporosis (Zhao et al., 2012). In this review, we will give a brief review on single herb formula and multi-herb formula which are used to treat the common bone-related diseases such as inflammation, fracture, osteopenia, and osteoporosis.
CHMs and fracture healing Fracture healing is a complex physiological process, starting after local bleeding and inflammation, followed by the complicated activities of mesenchymal precursor cells that lead to the formation of soft extracellular matrix tissue, cartilage, and the new bone (Matsuyama et al., 2005). It consists of a well-orchestrated sequence of events which leads to the proliferation and differentiation from osteoprogenitor cells to endothelial cells and to osteoblasts which form vascular tissues and bone tissues, respectively. According to the traditional Chinese medicine (TCM) theory, pathological syndromes of bone fracture include
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redness and pain in the fracture area, swelling and stagnation of circulation, and slow bone healing. The fracture healing could be, therefore, improved with herbs that could control inflammation, promote blood circulation, and stimulate bone regeneration. A paste obtained by a combination of three herb pairs, known by their activity of anti-inflammation (Rhizoma Rhei and Fructus Gardeniae), circulation promotion (Rhizoma Notoginseng and Flos Carthami), and bone forming (Radix Dipsaci and Ramulus Sambucus Willamsii), successfully healed the closed fracture in the rabbit model, and this healing effect was due to the direct influence of this paste on bone formation, blood vessels formation, and inhibition of nitric oxide (NO) production (Peng et al., 2010).
CHMs and anti-inflammatory activity Inflammation is a common response to tissue injury. Acute or chronic inflammation locally leads to serious bone diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammation-induced osteoporosis (Andreassen et al., 1997; Deodhar & Woolf, 1996; Landry et al., 2000; Will et al., 1989). Inflammation in response to injury of bone and soft tissue can be harmful to bone healing, or even result in more serious bone disease. For example, wounding of soft tissue generates inflammatory mediators leading to the delay of bone fracture healing (Landry et al., 2000). During inflammation, immune cells produce great amounts of reactive oxygen species (ROS). As the mediators of inflammatory cytokine effects, ROS play an important role in the pathophysiology of inflammation-induced tissue injury. Hydrogen peroxide (H2O2) and NO, produced by osteoblasts or activated mononuclear phagocytes, are two critical ROS involved in inflammatory lesions (Dannenberg et al., 1994; Heck et al., 1992; Sterner-Kock et al., 1999), both of them could suppress osteoblastic metabolism and viability (Mogi et al., 1999; Nicholson et al., 1998; Suzuki et al., 1997). This suppression results in the delay of bone fracture healing and leads to the occurrence of bone resorption, osteopenia, and even osteoporosis (Armour et al., 1999; Frost et al., 1999; Krempien et al., 1988). Therefore, the elevation of intracellular oxidative stress that results from bone disease-induced acute inflammation is toxic to osteoblasts and harmful to bone healing. Recently, more attention has been focused on CHMs research and their anti-inflammatory efficacy, which results from their multi-component features including the ability to affect multiple targets and levels signaling pathways and their multiple mechanisms of mitigating inflammation (Drayton et al., 2006). Gusuibu (Drynaria fortunei J. Sm) is a traditional Chinese herb that has been claimed to have therapeutic effects on bone healing (Ma et al., 1996). Studies on rat osteoblasts had revealed that water extract from Gusuibu at 10 mg/mL had an antioxidant effect on osteoblasts and this antioxidant activity protected rat osteoblasts from hydrogen peroxide-induced death and had promoted bone recovery (Liu et al., 2001). Many other CHMs, such as Cynanchum wilfordii Hemsley, Scutellaria baicalensis Georgi, and Tinospora tuberculata Beumee, have also been shown to have anti-inflammatory activity by scavenging H2O2
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or NO to reduce their induced oxidative stress (Gao et al., 1999; Hong et al., 1992; Yokozawa et al., 1999).
CHMs and anti-osteoporotic activity Osteoporosis (OP) is a major public health problem which is characterized by a reduction in and deterioration of the microarchitecture of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures (Genant et al., 2007; Renno et al., 2006). Hormone replacement therapy (HRT) is one of the most common and effective strategies for decreasing the risk of developing osteoporosis. However, HRT increases the risk of endometrial, breast and ovarian cancers, not to mention thromboembolic events and vaginal bleeding (Beral & Million Women Study Collaborators, 2003; Lacey et al., 2002). Thus, there are efforts to explore naturally occurring substances, especially those of plant origin, which could prevent osteoporosis and are free from any adverse effects (Liu et al., 2009). In recent years, CHM have achieved many effects on the prevention and treatment of OP (Yue et al., 2009; Zhang & Li, 2012). Thus, many single herbs such as Herba epimedii (HEP), Fructus Ligustri Lucidi (FLL), Rhizoma Drynariae Rhizoma (DR), and Cortex Eucommiae, etc, are frequently prescribed by TCM practices either as single herb or the major component in multi-herbs formula. Additionally, many multi-herb formulas such as Er-Xian decoction (EXD), Xian Ling Gu Bao capsule (XLGB), Er-Zhi-Wan (EZW), Danggui Buxue Tang, and Bu-zhong-yi-qi-tang etc, are used to treat osteoporosis. HEP HEP is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China (Qin et al., 2005). HEP as a single herbal extract or as a multiherb formula could reduce bone loss in ageing or ovariectomized (OVX) rat model (Wang et al., 2000). Clinical studies have demonstrated that HEP extract could prevent bone loss and increase osteocalcin and E2 levels. Total flavonoid fraction of HEP improved bone mineral density, and enhanced the E2 level and decreased the circulating IL-6 level in OVX rats (Jiang et al., 2012). HEP flavonoids promoted cell proliferation and increased alkaline phosphatase (ALP) activity in the primary rat calvarial osteoblasts (Han et al., 2003; Li et al., 2002; Wang et al., 2002). Icariin, a marker flavonoid glycoside in HEP, is believed to be the major active ingredient that accounts for its bone protective actions (Wong & Zhang, 2013). A recent study (Mok et al., 2010) characterized the in vivo bone protective effects of icariin in which OVX C57BL/6 mice were orally treated with icariin (0.3 mg/g d) for 6 weeks. It was found that icariin suppressed the loss of bone mass and strength in distal femur in OVX mice. FLL As a single herb, FLL is also commonly prescribed for detoxifying kidney and strengthening the bones (Huang & Yang, 2003; Wang et al., 2003). FLL extract increased bone mineral density and bone mechanical strength at the diaphysis of both tibias and femurs as well as the lumbar vertebra
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(LV-2) in ovariectomized rats fed either with low calcium diet (0.1% Ca) or normal calcium diet (0.6% Ca) (Zhang et al., 2008c). In fact, FLL regulates calcium balance by modulating the parathyroid hormone–vitamin D axis, and increases vitamin D-dependent calcium absorption in vivo (Zhang et al., 2008b), suggesting FLL could be an alternative medicine for improving calcium balance in postmenopausal women. Although oleanolic acid, the major compound with high amount in FLL, exerted an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulated the osteoblastic differentiation of bone mesenchymal stem cells in vitro (Bian et al., 2012), we need to further investigate whether this compound contributes to the regulation of FLL on calcium homeostasis. Eucommia ulmoides Oliv (EUO) Extracts from the cortex and leaf of EUO are also reported to be capable of preventing osteolysis and bone mineral loss and stimulating osteogenesis. By testing the therapeutic efficacy of these extracts, such as methanol extract, n-hexane, chloroform, ethyl acetate, butanol, and aqueous fractions, on osteoporosis, Ha et al. (2003) found that the components in a part of the fractions of Eucommiae cortex participate in each step of the mechanism for activating osteoblast to facilitate osteogenesis, and suppressing osteoclast activity to inhibit osteolysis. Research to evaluate the action of EUO in OVX rats has shown that the oral administration of EUO over a 16 weeks period in adult OVX rats could prevent the loss of estrogen deficiency-induced bone minerals and deterioration of trabecular micro-architecture, thereby maintaining biomechanical competence of the bone (Zhang et al., 2009b), furthermore, EUO extract has been found to induce the release of GH regulating bone maturation and bone remodeling (Ha et al., 2003), suggesting that EUO might be a potential alternative medicine for the treatment of postmenopausal osteoporosis. DR The single herb DR, which is commonly used to manage disorders of orthopedics, also has the therapeutic effects on osteoporosis (Sun et al., 2002). The effect of DR on osteoporosis has also been confirmed by the fact that it prevented the progression of bone loss induced by ovariectomy in rats and preserved the fine particle surface of the trabecular bone (Lee, 2002). DR extract was also shown to be the potent inhibitors on the cathepsin K-induced degradation of denaturated collagen by suppressing cathepsin K activity in an in vitro model (Jeong et al., 2005). In addition, naringin, naturally occurring in DR and one of its active ingredients, is a flavonoid which possess estrogenic activity (Jeong et al., 2003). Naringin by activating estrogen receptor phosphorylation in osteoblasts, consequently, could inhibit the retinoic acid-induced osteoporosis in rats (Wei et al., 2007), increase BMP-2 expression, induce bone formation (Wu et al., 2008), and enhance the proliferation and osteogenic differentiation of human bone mesenchymal stem cells (BMSCs) (Zhang et al., 2009a).
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Erythrina Variegate (EV) Some CHMs like EV could maintain bone health by suppressing bone resorption. EV is a leguminous tree which is used to treat rheumatic joint pain, spasm of the limbs as well as lower back and knee pain, and to stimulate lactation and menstruation for women (Kawashima et al., 2004). An animal study showed that the bark extract of EV could suppress bone resorption in vivo, so it could suppress the high rate of bone turnover induced by estrogen deficiency (Zhang et al., 2007). The protective effects of EV on bone properties are likely to be mediated by its inhibitory actions on the process of bone resorption via the suppression of osteoclast differentiation and maturation (Zhang et al., 2010). The osteoprotective effect of EV is associated to its isoflavones (Hidaka et al., 2003; Lee et al., 2004) which have chemical structures similar to the mammalian estrogens and which have received considerable attention for their preventive actions on bone loss (Mathey et al., 2004). EXD EXD is a multi-herb formula composed of six herbs including Rhizome curculiginis, H. epimedii, Radix morindae officinalis, Rhizome anemarrhenae, Cortex phellodendri, and Radix angelicae sinensis (Sze et al., 2009). It has long been used for the treatment of osteoporotic disorders (Wang et al., 1998), perimenopausal syndrome (Liu et al., 2005), and aging diseases (Shen et al., 1995) in elderly patents. It is clinically effective in relieving menopausal syndrome via increasing the circulatory estradiol level. EXD relieved the menopausal syndrome involved an increase of endocrine and antioxidant function through, at least, the activation of aromatase and catalase (CAT) detoxifying pathways (Sze et al., 2009). EXD contributed significantly to the prevention or treatment of the development of bone loss induced by ovariectomy in rats and has shown the anti-osteoporotic effects similar to those of estrogens. It has positive effects on bone while only displaying minor effects on the uterus, indicating the safety of EXD when used to manage bone health (Nian et al., 2006). XLGB XLGB is another multi-herb formula composed of six herbal medicines, Epimedii Herba (1167 g), Dipsaci Asperoidis Radix (167 g), Psoraleae Fructus (83 g), Anemarrhenae Rhizoma (83 g), Salviae Miltiorrhizae Radix (83 g), and Rehmanniae Radix (83 g) for every 1000 capsules (State Food and Drug Administration of China, 2002). Studies have shown that BMD of lumbar spine was significantly improved by 2.11% after treating postmenopausal women with XLGB for 6 months, which was more significant than that in the control group (Zhu et al., 2012). XLGB played a dual role in regulating bone metabolism by increasing the contents of ALP, BGP, and IGF-1 and reducing serum IL-6, TNF-a, and type I collagen levels of postmenopausal women (Zhang et al., 2004).
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Danggui Buxue Tang (DBT)
References
DBT, a TCM formula used to treat woman with menopausal irregularity, contains two herbs, Radix Astragali and Radix Angelicae Sinensis (Dong et al., 2006). Application of DBT in osteoblastic cells triggered the activations of signaling cascades including the ERK-dependent and ER-dependent pathways, which could result in stimulating osteoblastic proliferation and differentiation and mRNA transcription of a set of target genes (Gao et al., 2007). Pharmacological results indicated that DBT has the ability to promote hematopoietic functions, stimulate cardiovascular circulation, prevent osteoporosis, increase anti-oxidation activity, and stimulate the immune system (Huang et al., 2005).
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EZW EZW, a common multi-herb formula, contains two herbs, namely, FLL. and Herba Ecliptae. An equal weight ratio (1:1) of FLL to Herba Eclipta is widely used to prevent and treat various kidney and bone diseases by nourishing the kidney and strengthening tendon and bone (Lu, 2007). EZW could prevent and treat osteoporosis by restraining osteoclastic bone resorption (Zhang et al., 2008a). The daily oral administration of EZW over a 26-week period in the adult female OVX rats prevented the estrogen deficiency-induced bone loss. This result proved that EZW could be used as a remedy for the treatment of postmenopausal osteoporosis (Cheng et al., 2011).
Conclusion Multi-herb formulas have been developed gradually by adding one or more herbs to the pre-existing single herb formula (Yi & Chang, 2004), since many diseases are regulated by multiple pathogenic factors and it is hard to deal with them with the potency of a single herb which is modest and cannot address the complicated and multivariate conditions of patients. Each formula is devised according to the situation of one certain disease, thus the herbs selected should be compatible with others and help to enhance the desired therapeutic effects. Much effort is yet required in order to study the pharmacology of each herb formula and to confirm the compatibility of these herbs which make one formula. In order to ensure the safety and efficacy of CHMs, single herbs and multi-component prescriptions must be verified and ensured by reliable pharmacological and toxicological methods and standards and by clinical trials, and modern technology must be applied to establish quality controls and standardize herbal products using biological and chemical markers.
Declaration of interest The authors have no potential conflicts of interest to declare. This work was sponsored by National Natural Science Foundation of China (No. 81202894), the National Key Basic Research Development Plan (973 plan, 2012CB723506), Hong Kong Scholars Program (XJ2011022) and China Postdoctoral Science Foundation funded project (2012M511115).
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REVIEW ARTICLE
Chinese herbal medicine for bone health Emmanuel Mukwaya1,2, Fei Xu2, Man-Sau Wong3,4, and Yan Zhang1,2,3,4 Center for Systems Biomedical Sciences and 2School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, PR China, 3State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen, PR China, and 4 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China Pharmaceutical Biology Downloaded from informahealthcare.com by University of Newcastle on 09/26/14 For personal use only.
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Abstract
Keywords
Context: Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years. They are cost-effective with fewer side effects and are more suitable for long-term use compared with chemically synthesized medicines. Objective: Chinese herbal formula prescribed among the CHMs is safe, and it is an alternative medicine for bone-related diseases such as osteoporosis. Methods: Science Direct and Google Scholar were used to search articles published. The input key words were CHM, osteoporosis, Chinese herbal formula, traditional Chinese medicine, single herb, multiple-herbs, and bone health. CHMs (single herb and formula) lacking sufficient proof and evidence in the literature were excluded and only those with high citation were retained. Results: A brief review was summarized to indicate the application and the potential mechanism of single herb formula and multi-herb formula in treating the common bone-related diseases such as inflammation, fracture, osteopenia, and osteoporosis. Conclusion: In order to ensure safety and efficacy of all these CHMs, the prescriptions with single herb and multi-component formula must be verified and ensured by reliable pharmacological and toxicological methods. Much more effort needs to be done for studying the standardization, safety evaluation, and mechanism exploration of herb formula as well as confirming the compatibility of these herbs which make one.
Fracture, herbal formula, inflammation, osteoblast, osteoclast, osteoporosis
Introduction Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years and they are a cost-effective alternative to commercial pharmaceutical products. More than 130 countries in the world are using CHM (Hsiao, 2007), which relies on the use of topical herbal pastes, by which, the herbal essence is believed to go directly into the underlying tissues and initiates, for metabolic enhancements of tissue repairs (Ma, 1998). During the development of herbal therapy, single herb formula is the original form of herb prescriptions, and the multi-herb formula is developed gradually by adding one or more herbs to the pre-existing single herb formula (Yi & Chang, 2004). When several herbal medicines are mixed in a certain proportion, they display superiority over a single drug in the treatment of a disease (Qin et al., 2008). Thus multiherbal formula is used to achieve the mutual enhancement, mutual assistance, mutual restraint, mutual suppression, or
Correspondence: Yan Zhang, Center for Systems Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai 200093, PR China. Tel: +86 21 65710369. Fax: +86 21 65710108. E-mail: [email protected]
History Received 17 November 2013 Revised 18 December 2013 Accepted 14 January 2014 Published online 18 June 2014
mutual antagonism (Chan, 1995). The most fundamental and the simplest form of multi-herb therapy is herb pair which is the combination of two relatively fixed herbs (Wang et al., 2012). More than 100 000 formulas have been accumulated over the past 2000 years (Qiu, 2007), and among them, more than 80 single herbs have been reported to be effective in treating osteoporosis (Zhao et al., 2012). In this review, we will give a brief review on single herb formula and multi-herb formula which are used to treat the common bone-related diseases such as inflammation, fracture, osteopenia, and osteoporosis.
CHMs and fracture healing Fracture healing is a complex physiological process, starting after local bleeding and inflammation, followed by the complicated activities of mesenchymal precursor cells that lead to the formation of soft extracellular matrix tissue, cartilage, and the new bone (Matsuyama et al., 2005). It consists of a well-orchestrated sequence of events which leads to the proliferation and differentiation from osteoprogenitor cells to endothelial cells and to osteoblasts which form vascular tissues and bone tissues, respectively. According to the traditional Chinese medicine (TCM) theory, pathological syndromes of bone fracture include
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redness and pain in the fracture area, swelling and stagnation of circulation, and slow bone healing. The fracture healing could be, therefore, improved with herbs that could control inflammation, promote blood circulation, and stimulate bone regeneration. A paste obtained by a combination of three herb pairs, known by their activity of anti-inflammation (Rhizoma Rhei and Fructus Gardeniae), circulation promotion (Rhizoma Notoginseng and Flos Carthami), and bone forming (Radix Dipsaci and Ramulus Sambucus Willamsii), successfully healed the closed fracture in the rabbit model, and this healing effect was due to the direct influence of this paste on bone formation, blood vessels formation, and inhibition of nitric oxide (NO) production (Peng et al., 2010).
CHMs and anti-inflammatory activity Inflammation is a common response to tissue injury. Acute or chronic inflammation locally leads to serious bone diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammation-induced osteoporosis (Andreassen et al., 1997; Deodhar & Woolf, 1996; Landry et al., 2000; Will et al., 1989). Inflammation in response to injury of bone and soft tissue can be harmful to bone healing, or even result in more serious bone disease. For example, wounding of soft tissue generates inflammatory mediators leading to the delay of bone fracture healing (Landry et al., 2000). During inflammation, immune cells produce great amounts of reactive oxygen species (ROS). As the mediators of inflammatory cytokine effects, ROS play an important role in the pathophysiology of inflammation-induced tissue injury. Hydrogen peroxide (H2O2) and NO, produced by osteoblasts or activated mononuclear phagocytes, are two critical ROS involved in inflammatory lesions (Dannenberg et al., 1994; Heck et al., 1992; Sterner-Kock et al., 1999), both of them could suppress osteoblastic metabolism and viability (Mogi et al., 1999; Nicholson et al., 1998; Suzuki et al., 1997). This suppression results in the delay of bone fracture healing and leads to the occurrence of bone resorption, osteopenia, and even osteoporosis (Armour et al., 1999; Frost et al., 1999; Krempien et al., 1988). Therefore, the elevation of intracellular oxidative stress that results from bone disease-induced acute inflammation is toxic to osteoblasts and harmful to bone healing. Recently, more attention has been focused on CHMs research and their anti-inflammatory efficacy, which results from their multi-component features including the ability to affect multiple targets and levels signaling pathways and their multiple mechanisms of mitigating inflammation (Drayton et al., 2006). Gusuibu (Drynaria fortunei J. Sm) is a traditional Chinese herb that has been claimed to have therapeutic effects on bone healing (Ma et al., 1996). Studies on rat osteoblasts had revealed that water extract from Gusuibu at 10 mg/mL had an antioxidant effect on osteoblasts and this antioxidant activity protected rat osteoblasts from hydrogen peroxide-induced death and had promoted bone recovery (Liu et al., 2001). Many other CHMs, such as Cynanchum wilfordii Hemsley, Scutellaria baicalensis Georgi, and Tinospora tuberculata Beumee, have also been shown to have anti-inflammatory activity by scavenging H2O2
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or NO to reduce their induced oxidative stress (Gao et al., 1999; Hong et al., 1992; Yokozawa et al., 1999).
CHMs and anti-osteoporotic activity Osteoporosis (OP) is a major public health problem which is characterized by a reduction in and deterioration of the microarchitecture of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures (Genant et al., 2007; Renno et al., 2006). Hormone replacement therapy (HRT) is one of the most common and effective strategies for decreasing the risk of developing osteoporosis. However, HRT increases the risk of endometrial, breast and ovarian cancers, not to mention thromboembolic events and vaginal bleeding (Beral & Million Women Study Collaborators, 2003; Lacey et al., 2002). Thus, there are efforts to explore naturally occurring substances, especially those of plant origin, which could prevent osteoporosis and are free from any adverse effects (Liu et al., 2009). In recent years, CHM have achieved many effects on the prevention and treatment of OP (Yue et al., 2009; Zhang & Li, 2012). Thus, many single herbs such as Herba epimedii (HEP), Fructus Ligustri Lucidi (FLL), Rhizoma Drynariae Rhizoma (DR), and Cortex Eucommiae, etc, are frequently prescribed by TCM practices either as single herb or the major component in multi-herbs formula. Additionally, many multi-herb formulas such as Er-Xian decoction (EXD), Xian Ling Gu Bao capsule (XLGB), Er-Zhi-Wan (EZW), Danggui Buxue Tang, and Bu-zhong-yi-qi-tang etc, are used to treat osteoporosis. HEP HEP is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China (Qin et al., 2005). HEP as a single herbal extract or as a multiherb formula could reduce bone loss in ageing or ovariectomized (OVX) rat model (Wang et al., 2000). Clinical studies have demonstrated that HEP extract could prevent bone loss and increase osteocalcin and E2 levels. Total flavonoid fraction of HEP improved bone mineral density, and enhanced the E2 level and decreased the circulating IL-6 level in OVX rats (Jiang et al., 2012). HEP flavonoids promoted cell proliferation and increased alkaline phosphatase (ALP) activity in the primary rat calvarial osteoblasts (Han et al., 2003; Li et al., 2002; Wang et al., 2002). Icariin, a marker flavonoid glycoside in HEP, is believed to be the major active ingredient that accounts for its bone protective actions (Wong & Zhang, 2013). A recent study (Mok et al., 2010) characterized the in vivo bone protective effects of icariin in which OVX C57BL/6 mice were orally treated with icariin (0.3 mg/g d) for 6 weeks. It was found that icariin suppressed the loss of bone mass and strength in distal femur in OVX mice. FLL As a single herb, FLL is also commonly prescribed for detoxifying kidney and strengthening the bones (Huang & Yang, 2003; Wang et al., 2003). FLL extract increased bone mineral density and bone mechanical strength at the diaphysis of both tibias and femurs as well as the lumbar vertebra
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(LV-2) in ovariectomized rats fed either with low calcium diet (0.1% Ca) or normal calcium diet (0.6% Ca) (Zhang et al., 2008c). In fact, FLL regulates calcium balance by modulating the parathyroid hormone–vitamin D axis, and increases vitamin D-dependent calcium absorption in vivo (Zhang et al., 2008b), suggesting FLL could be an alternative medicine for improving calcium balance in postmenopausal women. Although oleanolic acid, the major compound with high amount in FLL, exerted an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulated the osteoblastic differentiation of bone mesenchymal stem cells in vitro (Bian et al., 2012), we need to further investigate whether this compound contributes to the regulation of FLL on calcium homeostasis. Eucommia ulmoides Oliv (EUO) Extracts from the cortex and leaf of EUO are also reported to be capable of preventing osteolysis and bone mineral loss and stimulating osteogenesis. By testing the therapeutic efficacy of these extracts, such as methanol extract, n-hexane, chloroform, ethyl acetate, butanol, and aqueous fractions, on osteoporosis, Ha et al. (2003) found that the components in a part of the fractions of Eucommiae cortex participate in each step of the mechanism for activating osteoblast to facilitate osteogenesis, and suppressing osteoclast activity to inhibit osteolysis. Research to evaluate the action of EUO in OVX rats has shown that the oral administration of EUO over a 16 weeks period in adult OVX rats could prevent the loss of estrogen deficiency-induced bone minerals and deterioration of trabecular micro-architecture, thereby maintaining biomechanical competence of the bone (Zhang et al., 2009b), furthermore, EUO extract has been found to induce the release of GH regulating bone maturation and bone remodeling (Ha et al., 2003), suggesting that EUO might be a potential alternative medicine for the treatment of postmenopausal osteoporosis. DR The single herb DR, which is commonly used to manage disorders of orthopedics, also has the therapeutic effects on osteoporosis (Sun et al., 2002). The effect of DR on osteoporosis has also been confirmed by the fact that it prevented the progression of bone loss induced by ovariectomy in rats and preserved the fine particle surface of the trabecular bone (Lee, 2002). DR extract was also shown to be the potent inhibitors on the cathepsin K-induced degradation of denaturated collagen by suppressing cathepsin K activity in an in vitro model (Jeong et al., 2005). In addition, naringin, naturally occurring in DR and one of its active ingredients, is a flavonoid which possess estrogenic activity (Jeong et al., 2003). Naringin by activating estrogen receptor phosphorylation in osteoblasts, consequently, could inhibit the retinoic acid-induced osteoporosis in rats (Wei et al., 2007), increase BMP-2 expression, induce bone formation (Wu et al., 2008), and enhance the proliferation and osteogenic differentiation of human bone mesenchymal stem cells (BMSCs) (Zhang et al., 2009a).
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Erythrina Variegate (EV) Some CHMs like EV could maintain bone health by suppressing bone resorption. EV is a leguminous tree which is used to treat rheumatic joint pain, spasm of the limbs as well as lower back and knee pain, and to stimulate lactation and menstruation for women (Kawashima et al., 2004). An animal study showed that the bark extract of EV could suppress bone resorption in vivo, so it could suppress the high rate of bone turnover induced by estrogen deficiency (Zhang et al., 2007). The protective effects of EV on bone properties are likely to be mediated by its inhibitory actions on the process of bone resorption via the suppression of osteoclast differentiation and maturation (Zhang et al., 2010). The osteoprotective effect of EV is associated to its isoflavones (Hidaka et al., 2003; Lee et al., 2004) which have chemical structures similar to the mammalian estrogens and which have received considerable attention for their preventive actions on bone loss (Mathey et al., 2004). EXD EXD is a multi-herb formula composed of six herbs including Rhizome curculiginis, H. epimedii, Radix morindae officinalis, Rhizome anemarrhenae, Cortex phellodendri, and Radix angelicae sinensis (Sze et al., 2009). It has long been used for the treatment of osteoporotic disorders (Wang et al., 1998), perimenopausal syndrome (Liu et al., 2005), and aging diseases (Shen et al., 1995) in elderly patents. It is clinically effective in relieving menopausal syndrome via increasing the circulatory estradiol level. EXD relieved the menopausal syndrome involved an increase of endocrine and antioxidant function through, at least, the activation of aromatase and catalase (CAT) detoxifying pathways (Sze et al., 2009). EXD contributed significantly to the prevention or treatment of the development of bone loss induced by ovariectomy in rats and has shown the anti-osteoporotic effects similar to those of estrogens. It has positive effects on bone while only displaying minor effects on the uterus, indicating the safety of EXD when used to manage bone health (Nian et al., 2006). XLGB XLGB is another multi-herb formula composed of six herbal medicines, Epimedii Herba (1167 g), Dipsaci Asperoidis Radix (167 g), Psoraleae Fructus (83 g), Anemarrhenae Rhizoma (83 g), Salviae Miltiorrhizae Radix (83 g), and Rehmanniae Radix (83 g) for every 1000 capsules (State Food and Drug Administration of China, 2002). Studies have shown that BMD of lumbar spine was significantly improved by 2.11% after treating postmenopausal women with XLGB for 6 months, which was more significant than that in the control group (Zhu et al., 2012). XLGB played a dual role in regulating bone metabolism by increasing the contents of ALP, BGP, and IGF-1 and reducing serum IL-6, TNF-a, and type I collagen levels of postmenopausal women (Zhang et al., 2004).
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Danggui Buxue Tang (DBT)
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EZW EZW, a common multi-herb formula, contains two herbs, namely, FLL. and Herba Ecliptae. An equal weight ratio (1:1) of FLL to Herba Eclipta is widely used to prevent and treat various kidney and bone diseases by nourishing the kidney and strengthening tendon and bone (Lu, 2007). EZW could prevent and treat osteoporosis by restraining osteoclastic bone resorption (Zhang et al., 2008a). The daily oral administration of EZW over a 26-week period in the adult female OVX rats prevented the estrogen deficiency-induced bone loss. This result proved that EZW could be used as a remedy for the treatment of postmenopausal osteoporosis (Cheng et al., 2011).
Conclusion Multi-herb formulas have been developed gradually by adding one or more herbs to the pre-existing single herb formula (Yi & Chang, 2004), since many diseases are regulated by multiple pathogenic factors and it is hard to deal with them with the potency of a single herb which is modest and cannot address the complicated and multivariate conditions of patients. Each formula is devised according to the situation of one certain disease, thus the herbs selected should be compatible with others and help to enhance the desired therapeutic effects. Much effort is yet required in order to study the pharmacology of each herb formula and to confirm the compatibility of these herbs which make one formula. In order to ensure the safety and efficacy of CHMs, single herbs and multi-component prescriptions must be verified and ensured by reliable pharmacological and toxicological methods and standards and by clinical trials, and modern technology must be applied to establish quality controls and standardize herbal products using biological and chemical markers.
Declaration of interest The authors have no potential conflicts of interest to declare. This work was sponsored by National Natural Science Foundation of China (No. 81202894), the National Key Basic Research Development Plan (973 plan, 2012CB723506), Hong Kong Scholars Program (XJ2011022) and China Postdoctoral Science Foundation funded project (2012M511115).
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