Medicinal herbs in the prevention and treatment of osteoporosis.

Am. J. Chin. Med. 2014.42:1-22. Downloaded from www.worldscientific.com by NATIONAL TAICHUNG UNIVERSITY OF SCIENCE AND TECHNOLOGY on 04/23/14. For personal use only.

The American Journal of Chinese Medicine, Vol. 42, No. 1, 1–22 © 2014 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X14500013

Medicinal Herbs in the Prevention and Treatment of Osteoporosis Chenrui Li,*,a Qiang Li,†,a Ruijun Liu,* Yinbo Niu,* Yalei Pan,* Yuankun Zhai* and Qibing Mei* *Key Laboratory for Space Biosciences and Biotechnology School of Life Sciences, Northwestern Polytechnical University Xi’an, Shanxi, China †

Department of Radiology, Tangdu Hospital The Fourth Military Medical University Xi’an, Shaanxi, China

Abstract: Osteoporosis is a common disease with wide prevalence, especially in the elderly population. Osteoporosis induced fractures not only decrease the patient’s life quality, but also cause heavy financial burden to the society. Although current medications for osteoporosis are effective, numerous adverse effects have been observed accompanying their clinical applications. Effective prevention and therapy strategies with high safety are critical, which benefit both individual patients and the whole society. Traditional Chinese medicines have been used for thousands of years to treat bone related diseases in China and a number of modern preparations have been developed that are currently commercially available. In addition, several medicinal herbs demonstrated therapeutic effects against osteoporosis in animal models. This paper reviewed the anti-osteoporotic effects of traditional Chinese formulas, medicinal herbs and bioactive constituents based on clinical trials and in vivo animal studies. Due to the lack of rigorous studies to compare the effectiveness with conventional interventions, traditional formulas are recommended as alternative medications or supplements to treat osteoporosis at the current stage. Although there are abundant natural resources with anti-osteoporotic effects, either in the form of medicinal herbs or bioactive components, much work need to be accomplished before they are developed into potential drugs. Keywords: Osteoporosis; Traditional Formulas; Medicinal Herbs; Phytoestrogens; Bisphosphonates; Hormone Replacement Therapy; Review.

Correspondence to: Dr. Qibing Mei, Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyixi Road, Xi’an, Shaanxi 710072, China. Tel/Fax: (+86) 29-8846-0543, E-mail: [email protected] a These authors contributed equally to this work.

1

2

C. LI et al.


Introduction Osteoporosis is a chronic progressive skeleton disorder characterized by the decrease in bone mass and deterioration of bone microarchitecture. One of the most serious outcomes of osteoporosis is the increased susceptibility to fracture, especially the fractures in hip, spine and wrist (CDC, 1993). The study by Johnell and Kanis, revealed that an estimated 9.0 million osteoporotic fractures occurred worldwide in the year of 2000, with the highest incidence of osteoporotic fracture (34.8%) in Europe (Johnell and Kanis, 2006). As for patients, fracture lowers their quality of life and is associated with increased morbidity and mortality in the elderly. Moreover, it results in heavy financial burden and healthcare costs to the society. The estimated medical cost for osteoporosis and fractures in the United States was up to 22 billion dollars in 2008 (Blume and Curtis, 2011). A number of interventions are effective to prevent and treat osteoporosis, such as physical exercise, supplements of calcium, and medications. However, not all the interventions are effective and potential adverse effects were observed, particularly for bisphosphonates and hormone replacement therapy (Shang, 2006; Bolam et al., 2013; Knopp-Sihota et al., 2013). With the wide prevalence of osteoporosis and the aggravation of aging problem, developing effective therapies with low toxicity is essential and imperative. Herbal medicines have been used for thousands of years in China and several classic formulas have been successfully proposed and validated for the treatment of bonerelated diseases. Notably, epidemiologic evidences and clinical trials showed the relationship between a dietary intake of green tea and soy with the reduced the incidence of osteoporosis (Liu et al., 2009a; Shen et al., 2009). Besides, phytoestrogens, including isoflavones, lignans and coumestans, exhibit beneficial effects against postmenopausal osteoporosis due to their structural similarity to estrogen (Chiang and Pan, 2013). Therefore, it is important to find effective medications derived from natural resources for the prevention and treatment of osteoporosis. This review article aimed to discuss the in vivo evidence regarding the therapeutic effects of traditional formulas, herbal extracts and single ingredients against different types of osteoporosis. Perspectives about future investigations were also proposed. Risk Factors of Osteoporosis Osteoporosis is classified into two categories: primary osteoporosis, and secondary osteoporosis. The primary type is associated with age and hormone fluctuation. Most people reach bone mass peak in their middle 20s, and their bone density and quality undergo an undetectable decline with age (Clarke and Khosla, 2010). Estrogen deficiency is found to be the main reason for the bone loss and osteoporosis in postmenopausal women. Secondary osteoporosis is likely to be induced by conditions such as chronic inflammatory diseases, medications such as corticosteroids, anticonvulsants, cyclosporine A, methotrexate, and thyroid hormones (Gates et al., 2009). In addition, a lack of mechanical loading (disuse induced osteoporosis) also contributes to the secondary osteoporosis, such as unloading during space flight, immobilization or prolonged bed rest

MEDICINAL HERBS ON OSTEOPOROSIS

3


(Watanabe et al., 2004; Blaber et al., 2010). The major risk factors for osteoporosis are summarized as female sex, premature menopause, age, primary or secondary amenorrhoea, primary and secondary hypogonadism in men, Asian or white ethnic origin, glucocorticoid therapy, poor visual acuity, low bodyweight, and long-term immobilization (Kanis, 2002). Diagnosis and Treatment of Osteoporosis The occurrence of osteoporosis is usually very subtle and patients are unaware of the situation until a serious fracture takes place. A timely diagnosis of osteoporosis at an early stage of osteoporosis may contribute significantly to the prevention and reduction of fracture. However, there is no available way to effectively assess bone quality. The currently available method for osteoporosis diagnosis is mainly based on the assessment of bone mineral density by dual X-ray absorptionmetry (Genant et al., 1996). According to the criteria of the World Health Organization, osteoporosis is diagnosed as the condition with a T-score 2.5 SDs below the mean (NIHCDP, 2001). Based on the risk factors of osteoporosis fractures, a number of precautions have been proposed and recommended for the potential population of osteoporosis, such as the adequate intake of calcium and vitamin D, regular weight-bearing exercise, fall prevention, and the avoidance of tobacco use and excessive alcohol intake (Gates et al., 2009). Moreover, medications are necessary for most osteoporosis patients. It is estimated that at least 34% of US white men and 72% of US white women aged above 65 and 49% of men and 93% of women aged above 75 would need drug therapies (Donaldson et al., 2009). The anti-osteoporotic drugs are classified into two categories, i.e., the antiresorptive drugs and the anabolic drugs. Medications that are commercially available include bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid), parathyroid hormone (teriparatide), selective estrogen receptor modulators (raloxifene), calcitonin, as well as hormone replacement therapy (estrogen and/or progesterone) (Pinkerton and Dalkin, 2007). Since the osteoporosis therapy normally requires long-term medication, it is important to evaluate their safety during the long-term clinical application. A high occurrence of serious upper gastrointestinal bleeding accompanying the oral administration of bisphosphonates was observed and reported in a population-based nested cohort study (Knopp-Sihota et al., 2013). Besides, osteonecrosis of the jaw has also been reported during the application of bisphosphonates (Durie et al., 2005; Khosla et al., 2007). Additionally, long-term intake of hormone intake was shown to result in high risk of mammary gland cancer, endometrium cancer and breast cancer (Orija and Mehta, 2003; Wiseman, 2004; Shang, 2006). More importantly, a low adherence and persistence with anti-osteoporotic medications has been observed and it has been reported that 50–75% of osteoporosis patients discontinued their medication within one year (Huybrechts et al., 2006; Rabenda et al., 2008; Imaz et al., 2010). Thus, finding alternative strategies with improved compliance and lower toxicity is significantly critical and beneficial.

4

C. LI et al.


Natural Products and Their Anti-Osteoporosis Effect Based on in vivo Evidence A number of clinical trials were conducted to compare the efficacy of commercial traditional formula products with that of placebo or standard anti-osteoporotic therapy in the treatment of osteoporosis. Based on the nosogenesis, animal models were established to simulate the conditions of osteoporosis including ovariectomization, orchidectomization, corticosteroid induction, and retinoic acid induction (Wu et al., 1996). Estrogen deficiency is the major reason for osteoporosis, which is characterized by increased bone reabsorption and induces osteoporosis in postmenopausal women (Binder et al., 2009). Female rats/mice treated by ovariectomization could develop similar skeletal physiology to postmenopausal women such as accelerated bone turnover and greater loss of cancellous bone than cortical (Chiang and Pan, 2013). These mice/rat models are extensively employed to evaluate the anti-osteoporotic effect. Other operations such as hindlimb suspension, wrapping or casting the legs, tenotomy, neurotomy, neurectomy and hemicordotomy as well as injection of Clostridium botulinum toxin were also conducted in animals to generate immobilization induced osteoporosis. Herbal Formulas and Randomized Controlled Trials (RTCs) In the theory of traditional Chinese medicine, the kidney is related to the skeletal system and a number of kidney-tonifying formulas showed beneficial effects for the maintenance of bone strength and health. Table 1 lists representative traditional formulas and their bioactive constituents whose anti-osteoporotic effects were evaluated in vivo. The antiosteoporotic effects of traditional formulas might be due to their direct effects on osteoblast/ osteoclast, estrogen-like effect, the balance of trace elements, and the modulation of Ca/P metabolism etc. (Zhao and Wang, 2003; Wang et al., 2006a). More importantly, several proprietary traditional Chinese medicine products have been developed and modified based on traditional formulas. Wang et al. summarized 12 randomized controlled trials (RCTs) and evaluated the effectiveness of commercial antiosteoporotic herbal products in 1816 osteoporosis patients (Wang et al., 2013b). The results of Meta-analysis indicated the lumbar spine bone mineral density (BMD) was significantly increased by these traditional anti-osteoporotic herbal products, which include Migu tablet, Xian Ling Gubao capsule, Bo-gu Ling capsules, Yigu capsule, Qiang-Gu capsule, Jiangu granule, Bu Shen Sheng Sui soup, Gu Kang Oral liquid, Gushukang capsule, Gushukang granules, and Jinwugutong capsule. In a five-year multi-center clinical trial, Fufang BZG composed of Herba Epimedii, Rehmannia Glutinosa, Dioscorea Batatas, Cornus Officinalis, Cinnamomum Cassia, Drynaria Fortumei, and Morinda Officinalis, significantly increased the BMD of the distal radius in 155 postmenopausal women aged 47 to 70 years old (Deng et al., 2012). A positive effect has been observed in these clinical trials. The tested herbal formulas showed beneficial effects on the skeleton and they could increase the BMD in the lumbar spine or hip of subjects. Although these studies suggest the promising prospects of herbal products in the treatment of osteoporosis, there are limitations with the current clinical trials

Qiang-Gu capsule

Jinwugutong capsule

Bo-gu Ling capsule

Bu Shen Sheng Sui Soup

Jiangu granules

Yigu capsule

Xian ling Gubao capsule

Migu tablet

Formula Name

Herba Epimedii, Frutus Ligustri Lucidi, Fructus Psoraleae Cibotium barometz, Zaocys Dhumnade, Herba Epimedii, Fructus Psoraleae, Radix Clematidis, Rhizoma Curcumae longae, Codonopsis Pilosula, Radix Achyranthis bidentatae, Fructus Chaenomelis lagenariae, Radix Puerariae Radix Dipsaci, Radix Salviae Miltiorrhizae, Astragalus Mongholicus, Radix Achyranthis bidentatae, Fructus Corni, Radix Rehmanniae Preparata, Radix Polygoni Multiflori, Rhizoma Dioscoreae

Herba Epimedii, Cortex Eucommniae, Fructus Psoraleae, Semen Juglandis Herba Epimedii, Radix Dipsaci, Fructus Psoraleae, Radix Salviae Miltiorrhizae, Rhizoma Anemarrhenae, Radix Rehmanniae Recens Herba Epimedii, Fructus Lycii, Radix Angelicae sinensis, Radix Achyranthis bidentatae blume Rhizoma Atractylodis Macrocephalae, Codonopsis Pilosula, Fructus Psoraleae, Herba Pyrolae, Pilose Antler Fructus Psoraleae, Herba Epimedii, Cortex Eucommniae, Fructus Ligustri Lucidi

Compositions

PMO women PMO women

PMO women

N.A.

Estradiol valerate

(Ruan et al., 2006)

(Zheng et al., 2007)

(Leung et al., 2011)

(Liao et al., 2004)

PMO women

Conjugated estrogens and medroxyprogesteronum N.A.

(Du et al., 2008)

PMO women

Gusongbao

(Zhang et al., 2005)

(Dai and Shen, 2007; Dai et al., 2007) (Wu et al., 2009)

References

PMO women

CIO patients

PMO women

Subjects

Calciferol

Xian ling Gubao capsule and calcium Calcitriol and Caltrate D 600

Positive Control

Table 1. Summary of Composition and Anti-Osteoporotic Effect of Representative Traditional Chinese Formulas


MEDICINAL HERBS ON OSTEOPOROSIS 5

Bushen Ningxin Decoction

Er-Zhi-Wan NR/CAL/06

Er-Xian decoction

Qing’E formula

Saikokaryukotsuboreito

ELP

Yijung-tang

Gushukang capsule

Gukang Oral Liquid

Formula Name

Fructus Psoraleae, Herba Epimedii, Radix Polygoni Multiflori, Radix Rehmanniae Recens, Radix Paeoniae Alba, Astragalus Mongholicus, Semen Cuscutae, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, Fructus Ziziphi Jujubae Herba Epimedii, Fructus Psoraleae, Radix Salviae Miltiorrhizae, Astragalus Mongholicus, Radix Rehmanniae Radix Ginseng, Radix Zingiberis, Radix Atractylodis Alba, Radix Glycyrrhizae Herba Epimedii, Fructus Ligustri Lucidi, Fructus Psoraleae Bupleurum root, Pinelliae tuber, Cinnamon bark, Poria sclerotium, Scutellariae root, Jujube, Ginseng, Ostreae shell, Longgu, Ginger Cortex Eucommniae, Fructus Psoraleae, Juglandis Semen, Garlic Rhizoma Epimedium sagittatum Maxim., Curculigo orchioides Gaertn., Morinda officinalis How, Angelica sinensis Diels, Phellodendron chinense Schneid, Anemarrhena asphodeloides Bunge Fructus Ligustri Lucidi, Herba Ecliptae Hibiscus rosasinensis, Cestrum diurnum, Glycyrrhiza glabra Radix Rehmanniae, Herba Epimedii, Rhizoma Anemarrhenae, Fructus Psoraleae, Cuscuta australis R.Br, Semen Ziziphi Spinosae, Cortex Phellodendri, Radix Glycyrrhizae

Compositions

Patients with primary ostoporosis

Gushukang granules

N.A.

OVX BALB/c mice

OVX rats OVX rats

OVX rats

Nylestriol

Estradiol valerate Raloxifene

OVX mice

OVX mice

N.A.

Nylestriol

HLS male SD rats

N.A.

OVX rats

Patients with primary ostoporosis

Xian ling Gubao capsule

17-estradiol

Subjects

Positive Control

Table 1. (Continued) References

(Wang et al., 2009)

(Cheng et al., 2011) (Srikanta et al., 2011)

(Nian et al., 2006)

(Xu et al., 2010)

(Hattori et al., 2010)

(Siu et al., 2013)

(Kim et al., 2013)

Wang et al., 2006a

Yang et al., 2007


6 C. LI et al.

Herba Cistanches, Fructus Psoraleae, Placenta Hominis, Pilose Antler, Dendrobe, Morifolium Dendranthema, Lopha Cristagalli Radix Astragali, Radix Angelicae sinensis, Folium Epimedii

Radix Angelica, Radix Paeony, Cortex Cinnamon, Rhizome Cnidium, Cortex Moutan, Hoelen, Atractylodis Lancea Rhizome, Bitter Orange Peel, Radix Rehmanniae, Cyperus Rhizome, Glycyrrhiza, Semen Persicae, Cotidis Rhizome, Ginseng, Ginger, Clove Herba Epimedii, Fructus Corni, Codonopsis Pilosula, Rhizoma Drynariae, Rhizoma Dioscoreae, Tortoise Plastron, Orange Peel, Carthamus Tinctorious Tortoise Plastron, Radix Rehmanniae Preparata, Herba Epimedii, Lycium chinensis Herba Epimedii, Rhizome Cnidium

Compositions

OVX rats

Gusongbao granule

Conjugated equine estrogens

N.A.

N.A.

OVX rats

CIO male rats

CIO male rats

OVX rats

OVX rats

17β-oestradiol

Calcium

Subjects

Positive Control

Note: OVX: ovariectomized; PMO: postmenopausal osteoporosis; CIO: corticosteroid-induced osteoporosis; HLS: hind-limb suspension.

Danggui Buxue Tang

Xianzhen Gubao capsule Kidney-Tonifying Recipe

Gui-Di powder

Jiangu granule

Chujo-to

Formula Name

Table 1. (Continued) References

(Xie et al., 2012)

(Shen et al., 1998)

(Hu et al., 1999)

(Wang et al., 2000)

(Lin et al., 2004)

(Hidaka et al., 1999)




8

C. LI et al.

of traditional formulas. Most of the studies were conducted in a Chinese population and the efficacy of these formulas in other populations remains to be verified. Another limitation with current clinical studies is the lack of comparison with classic anti-osteoporotic drugs with respect to their osteoporotic effect is another limitation of current clinical studies. More pharmacovigilant information is required to elucidate the efficacy and safety of traditional formulas. Single Herb Extract Several medicinal herbs have been frequently employed in the traditional formulas, such as Herba Epimedii, Cortex Eucommniae, and Fructus Psoraleae. The in vivo anti-osteoporotic effects of herbal extracts have been investigated and their impacts on bone mass and biochemical parameters were quantified, as summarized in Table 2. As the base for osteoporosis diagnosis, BMD is an important index and employed by most studies to determine the impact of drug administration on bone strength (Cummings et al., 2002). Serum ALP and urinary DPD/Cr are two sensitive biochemical markers to indicate bone formation and reabsorption, respectively (Yin et al., 2006; Park et al., 2008). Therefore, these three parameters are selected to indicate their anti-osteoporotic effects in the present study. Although herbs are traditionally processed by water decoction, extraction by various organic solvents is commonly employed nowadays to produce high extraction yield (Table 2). Nevertheless, the use of different solvents for extraction might lead to different ingredients in the formula. Moreover, the content of each ingredient may be different, which may result in varying degrees of anti-osteoporotic effects. In addition to the information in Table 2, the osteogenetic effects of herbal extracts are confirmed by other indices. The supplement of Labisia pumila var. arata water decoction at 17.5 mg/kg for eight weeks was proven to increase the osteoclacin level and decrease C-terminal telopeptide of type I collagen levels in OVX Wistar rats (Shuid et al., 2011). The crude extract of Pueraria candollei var. mirifica significantly down-regulated the expression of RANKL mRNA in OVX mice (Udomsuk et al., 2012). Bioactive Components in Medicinal Herbs Over the past decades, phytoestrogens have been extensively investigated for their therapeutic effects against postmenopausal syndromes and osteoporosis (Bedell et al., 2012). Chemically, they are classified into isoflavones, lignans, coumestans. Daidzein and genistein are two representative soy-derived isoflavones. However, the in vivo results regarding their anti-osteoporosis effect are quite controversial. Genistein significantly improved femoral mechanical properties and alleviated bone turnover induced by ovariectomization (Miao et al., 2012). Genistein, daidzein and equol, the metabolite of daidzein, at 10 g/g body weight/day could significantly enhance the total BMD in OVX rats (Mathey et al., 2007). However, oral administration of genistein as a daily dietary supplement did not improve the cancellous and cortical bone mass and architecture either in virgin OVX Long-Evans rats at seven months of age or in aged retired-breeder OVX rats at

90 days, p.o.

OVX Wistar rats

95% ethanol followed by ether, hexane and silica gel 70% ethanol Water and 50% ethanol 50% methanol

Erythrina variegate L. Curculigo orchioides Eucommia ulmoides Oliv Radix Dipsaci Pueraria mirifica

Berberis aristata

Cibotium barometz Cordyceps sinensis

OVX SD rat OVX SD rat

OVX SD rat


65% ethanol 75% ethanol

60% ethanol

60% ethanol N.A.

OVX SD rat

OVX SD rat HLS male SD rat

5 weeks, p.o.

OVX ICR mice Prednisolone treated ICR mice OVX Swiss mice

Methanol ethanol, n-hexane, ethyl acetate n-hexane

Curcuma comosa Roxb. Wedelia calendulacea Less.

OVX rat

n-butanol

16 weeks, p.o. 90 days, p.o.

16 weeks, p.o.

14 weeks, p.o. 12 weeks,

42 days, p.o.

16 weeks, p.o. 8 weeks, p.o.

12 weeks, p.o. 4 weeks, p.o.

6 weeks, p.o.

16 weeks, p.o.

OVX SD rat

60% ethanol

Duration

Achyranthes bidentata root Achyranthes bidentataroot Magnoliae Flos Poncirus trifoliata

Animal Model

Extraction Solvent

Herbs

100/300/500 10/100/1000

100/300/500

300/600 500/1000/2000

100/300/500

100/300/500 100/300/500

500/750

250/500

0.1/1 100

25/50/100

100/300/500

Dosage (mg/kg/day)

N.A. N.A. 0/þ/þ (TT)

N.A. /0 / /

//

17β-estradiol 17-ethinylestradiol

0// N.A.

0// N.A.

0/þ/þþ (RF) þ= þ =þ (TM)

0/þþ/þþ (RF)

0/þþ/þþ (RF) 0/þ/þ

// N.A.

0// 0/0/

0//

N.A.

N.A.

N.A./þ (RF)

0/þ (FT) þþ (WB)

þ=0

0/ 0/0/0


References

(Liu et al., 2009b) (Urasopon et al., 2008)


(Yogesh et al., 2011) (Zhang et al., 2007) (Cao et al., 2008)

(Zhao et al., 2011) (Qi et al., 2012)

(Weerachayaphorn et al., 2011) (Annie et al., 2006)

(Jun et al., 2012) (Kim et al., 2011)

þ= þ = þ þ (LS) (He et al., 2010)

0/þ/þþ (RF)

N.A.

N.A. N.A.

N.A.

0//

BMD

0/

0/ N.A.

N.A.

0//

Urinary DPD/Cr

Biochemical Parameters Serum ALP

17-ethinylestradiol //

17β-estradiol Nylestriol

Standard estrogen

17β-estradiol Alendronate

Raloxifen

17β-estradiol

17β-estradiol SrCl2

Ethinylestradiol

17β-ethinylestradiol

Positive Control

Table 2. Studies of Representative Medicinal Herbs with Anti-Osteoporotic Effects in Animal Models



N.A. N.A. Dichloromethane and methanol followed by water

N.A.

Extraction Solvent

ORX mice OVX mice OVX Wistar rat

ORX SD rat

Animal Model 10/100/1000

Dosage (mg/kg/day)

4 weeks, p.o. 5, 10 and 20% of diet 4 weeks, p.o. 5, 10 and 20% of diet 6 month, p.o. 300

90 days, p.o.

Duration

17β-estradiol 17β-estradiol N.A.

17-ethinylestradiol

Positive Control

N.A. N.A. N.A.

N.A. N.A. N.A. N.A.

N.A.

Urinary DPD/Cr

Biochemical Parameters Serum ALP

þ= þ =þ (TF) þ= þ =þ (TF) þ þ þ (PT)

0/þ/þ (PT)

BMD

(Urasopon et al., 2007) (Wang et al., 2005) (Wang et al., 2003) (Dontas et al., 2006)

References

Note: OVX: ovariectomized; ORX: orchidectomized; HLS: hind limb suspended; TM: proximal tibia; TT: tibial trabecula; TF: femoral trabecula; TF: total femur; RF: right femur; LS: lumbar spine; WB: whole body. Comparison was made between drug treatment group versus solvent vehicle. 0: no significant difference; : p < 0:05; : p < 0:01; : p < 0:001 (decrease from vehicle control), þ: p < 0:05; þþ: p < 0:01; þ þ þ: p < 0:001 (increase from vehicle control).

Puerariae radix Puerariae radix Onobrychis ebenoides

Pueraria mirifica

Herbs

Table 2. (Continued)


10 C. LI et al.



11

ages of 16 or 22 months, respectively (Turner et al., 2013). In a randomized double-blind placebo-controlled study, genistein at 54 mg/day for one year significantly increased femoral BMD (3:6 3%), which was even higher than HRT control (2:4 2%) in healthy, ambulatory women of 47–57 years old (Morabito et al., 2002). On the contrary, daily administration of isoflavone tablets (91 mg of genistein and 103 mg of daidzein) for two years failed to prevent bone loss and menopausal symptoms in women aged 45 to 60 years (Levis et al., 2011). Similar results were observed in another clinical trial in post-menopausal women aged 45 to 65 years. The treatment of isoflavone at 300 mg/kg containing 172.5 mg genistein and 127.5 mg daidzein could not prevent lumbar spine and total proximal femur BMD compared with the placebo control group (Tai et al., 2012). It was speculated that the menopausal stage, interventions and ability of equal production would contribute to the inconsistent results (Park and Weaver, 2012). In addition to daidzein and genistein, icariin, which is isolated from Herba Epimedium, has been extensively studied recently. It shares the chemical structure of flavonol and its osteogenetic effect has been confirmed in OVX animal models and glucocorticoid induced osteoporosis (Table 3). Lignans and coumestans have not been extensively studied and most studies concentrated on flavonoids. Flavonoids undergo extensive first-pass metabolism in vivo, and therefore, it is of great necessity to elucidate their pharmacokinetic profiles and the specific functional group responsible for the onset of the anti-osteoporotic effect. In particular, the efficacy might be enhanced by a special group in the chemical structure, such as the prenyl group. For instance, the 8-prenylnaringenin with 8-prenyl group shows higher osteogenetic capacity than naringenin (Ming et al., 2013). The investigation in structure activity relationship would contribute significantly to the modification of compounds for improved anti-osteoporotic effect. The Pros and Cons of Natural Products in Their Application to Treat Osteoporosis Medicinal herbs have a long history of application in China and other Asian countries. Recently, their uses as alternative and supplementary medicines have also increased in western societies. Although they are of natural origin and proposed to be harmless, their safety is still a critical issue during their clinical application. As the most popular natural alternatives to Hormone Replacement Therapy (HRT), the safety and adverse reactions of phytoestrogen have been reviewed (Bedell et al., 2012). Being effective to treat climacteric symptoms such as vasomotor symptoms, vaginal atrophy, insomnia and osteoporosis, phytoestrogen has shown neither to increase the risk of breast cancer nor to enhance the incidence of endometrial hyperplasia. More importantly, natural products are ubiquitous in our daily diets and they are inevitably taken with other pharmaceuticals as well as alternative products, which might induce herb-drug or herb-herb interactions (Singh et al., 2012). As for the herbal medicines of anti-osteoporosis effect, the reports about their safety and interactions with other pharmaceuticals are limited. Decoction of Pueraria lobata root could significantly increase the AUC0t and prolong MRT of methotrexate (Chiang et al., 2005). Genistein could significantly increase the AUC and Cmax of

Epimedium brevicornum Maxim Epimedium pubescens Herba Epimedii

Epimedii Herba Soy

Soy

Soybeans and soybased products Soybeans Soy

Icariin

Icariin Icariin

Icariin Genistein

Genistein

Genistein

Huaijiao (Sophora japonica – Leguminosae) Soy

Soy

Soy bean

Genistein

Genistein

NO-Genistein

Genistein

Genistein Genistein

Herba epimedii

Herbal Resources

Icariin

Compound

OVX SD rat

OVX Wistar rat 12 weeks, p.o.

12 weeks, sc

4 weeks, i.p.

12 weeks, p.o.

OVX SD rat

OVX balb/c mice

15 weeks p.o. 12 weeks, p.o.

3 months, p.o.

12 weeks, p.o.

12 weeks, p.o. 5 months, p.o.

3 months, p.o. 6 weeks, p.o.

12 weeks, p.o.

12 weeks, p.o.

Duration

OVX C57BL/6J mice OVX SD rat OVX Wistar rats

OVX SD rat

OVX SD rat OVX C57BL/6J mice OVX SD rat OVX Long-Evans rats

Glucocorticoid induced SD rat OVX SD rat

Animal Model

Genistein

17β-estradiol

17β-estradiol

Nilestriol

17β-estradiol 17β-estradiol

Estradiol benzoate

Nilestriol

Nylestriol N.A

Premarin 17b-oestradiol

Nylestriol,

Alendronate

Positive Control

4.5/9/18

10

0.1/0.5/1.5 /3.0

4.5/9/18

5 10

3

4.5/9/18

5/25/125 1.6/3.2

12 300

20

125

Dosage (mg/kg/day)

(Liu et al., 2012) (Mok et al., 2010)

þ (LS) þþ (DF)

//

//

N.A //

//

N.A

N.A

N.A N.A

N.A

N.A

N.A

N.A N.A

N.A

N.A N.A

// N.A

N.A

N.A

N.A N.A

þ= þ þ= þ þ (LF)

0/þþ/0/þþ (TF) þþ (TT)

þ þ = þ þ= þ þ (TF)

þ (LS) þ (TT)

þ= þ =þ (LF) þþ=þþ (Total tibia) þ þ = þ þ= þ þ (LF) þ þ þ (MT)

(Xue et al., 2012)

þ (LF)

0

(Park and Weaver, 2012) (Hertrampf et al., 2009) (Udomsuk et al., 2012)

(Sehmisch et al., 2010) (Dai et al., 2008) (Hertrampf et al., 2007) (Wang et al., 2006b)

(Miao et al., 2012)

(Nian et al., 2009) (Turner et al., 2013)

(Feng et al., 2013)

þ (PF)

N.A

References

BMD

Urinary DPD/Cr

Serum ALP

Biochemical Parameters

Table 3. Studies of Bioactive Constituent Derived from Medicinal Herbs with Anti-Osteoporotic Effects in Animal Models


12 C. LI et al.

Soy

Soybean clover or alfalfa sprouts, oilseeds Soy

Daidzein

Daidzein

Isotaxiresinol

Puerarin Oleuropein

Ferutinin Ferutinin

Echinacoside

OVX Wistar rat

OVX SD rat OVX Wistar rat 6 weeks, p.o.

12 weeks, p.o. 100 days, p.o.

60 days, p.o. 30 days, p.o.

12 weeks, p.o.

OVX SD rat


12 weeks, p.o.

OVX SD rat

Cistanche tubulosa (Schrenk) R. Wight Cistanche tubulosa (Schrenk) R. Wight Ferula hermonis root Root of Ferula hermonis Boiss Radix Puerariae Olives and their derivates Taxus yunnanensis Cheng et LK Fu (Taxaceae)

Echinacoside

6 weeks, p.o.

N.A.

Equol

OVX SD rat

OVX C57BL/6 mice 12 weeks, p.o.

N.A.

3 months, p.o.

OVX Wistar rat

Soy products

12 weeks, p.o.

3 months, p.o.

OVX Wistar rat

OVX C57BL/6 rat

8 weeks, p.o.

5 or 10 weeks, p.o.

Duration

OVX Wistar rat

OVX SD rat

Animal Model

Daidzein/equol/genistein Equol

DaidzeinþCa

Soy

Herbal Resources

Daidzein

Compound

17β-estradiol

N.A N.A

Estradiol benzoate Estradiol benzoate

17β-estradiol

17β-estradiol

Estradiol benzoate

Estradiol benzoate

N.A

Calcium

17-ethinylestradiol

17β-estradiol

Estradiol-17β-benzoate

Positive Control


50/100

20 2.5/5/10/15

2 0.5/1/2

30/90/270

30/90/270

400

4000

10

100/200

10

10

50

Dosage (mg/kg/day)

N.A þ þ þ= þ þ þ = þ þþ N.A //

N.A

N.A

N.A

N.A

þ= þ = þ þ

N.A

N.A

N.A

þ (LF) þ þ = þ þ= þ þ (PF) þ þ =0 (TM)

N.A N.A

þ þ = þ þ= þ þ (TF)

þ= þ = þ þ (RF)

þ (LS)

0 (TM)

þ= þ =þ (LF)

N.A

þ (LF)

þþ (RF)

N.A

þ (TF)

N.A

N.A

N.A

N.A

N.A

N.A

BMD þ (LS)

N.A

N.A

N.A

Urinary DPD/Cr

Serum ALP

Biochemical Parameters


References

(Yin et al., 2006)

(Wang et al., 2013a) (Puel et al., 2006)

(Ferretti et al., 2010) (Cavani et al., 2012)

(Yang et al., 2013)

(Fonseca and Ward, 2004) (Mathey et al., 2007) (Sehmisch et al., 2010) (Rachon et al., 2007) (Li et al., 2013a)

(Komrakova et al., 2011) (Om and Shim, 2007) (Picherit et al., 2000)


Ubiquitous Ubiquitous Dioscorea spp.

Resveratrol Apigenin Diosgenin

OVX SD rat HLS male Fischer 344 Brown Norway male rats HLS male SD rats OVX SD rat OVX SD rat


Animal Model

45 days, p.o. 15 weeks, p.o 4 weeks. p.o

90 days, p.o 21 days, p.o.

4weeks, s.c. 2 months, p.o

Duration

N.A. 17β-estradiol Isoflavone

Diethylstilbestrol N.A.

Estradiol N.A.

Positive Control

400 10 0.15/0.3/20/40

5/15/45 12.5

10/50/100 60/300/1500

Dosage (mg/kg/day)

N.A. þ= þ = þ =0

N.A. N.A N.A

N.A N.A.

N.A N.A

// N.A N.A N.A.

Urinary DPD/Cr

Biochemical Parameters Serum ALP BMD

þ (Total tibia) N.A þ= þ = þ =þ (DF)

þ=0=0 (TT) þ þ = þ þ= þ þ (RF) 0/þ/þ (TF) 0

References

(Habold et al., 2011) (Park et al., 2008) (Chiang et al., 2011)

(Lin et al., 2005) (Durbin et al., 2012)

(Kapur et al., 2008) (Li et al., 2013b)

Note: OVX: ovariectomized; ORX: orchidectomized; HLS: hind limb suspended; TM: proximal tibia; TT: tibial trabecula; TF: femoral trabecula; TF: total femur; LF: left femur; RF: right femur; LS: lumbar spine; WB: whole body; PF: proximal femurs; MT: metaphyseal tibia; DF: distal femur. Comparison was made between drug treatment group versus solvent vehicle group. 0: no significant difference; : p < 0:05; : p < 0:01; : p < 0:001 (decrease from vehicle control), þ: p < 0:05; þþ: p < 0:01; þ þ þ: p < 0:001 (increase from vehicle control).

Resveratrol Resveratrol

T. cordifolia Grapefruit and Rhizoma Drynariae Ubiquitous Ubiquitous

Herbal Resources

Tinosporacordifolia Naringin

Compound



14 C. LI et al.


15


paclitaxel (Li and Choi, 2007). Besides, berberine could modulate the expression of CYPs by either suppression or enhancement of CYPs’ levels, which might influence the metabolism of CYPs substrates (Chatuphonprasert et al., 2012). Since the medication time of anti-osteorporosis drugs are relatively long, the incidence of potential interactions with other pharmaceuticals is high and their safety and should be carefully investigated. Summary In summary, due to the adverse effects and low persistence of most current antiosteoporotic drugs, new drug candidates from natural resources are highly demanded. Traditional formulas, herbal extracts and bioactive components, which were proven to efficiently increase BMD and improve bone microarchitecture in both in vivo studies and clinical trials, suggest their great potential in primary and secondary osteoporosis treatment. Moreover, clinical trials should be carried out to compare the efficacy and toxicity of proprietary traditional Chinese medicine products with those of classic anti-osteoporotic drugs. The anti-osteoporosis effects of their metabolites should also be studied in vivo. Acknowledgments The work was supported by the China Postdoctoral Science Foundation Grant (2012M521806) and the National Natural Science Foundation of China (81202457 and 81201081). References Annie, S., R.G. Prabhu and S. Malini. Activity of Wedelia calendulacea Less. in post-menopausal osteoporosis. Phytomedicine 13: 43–48, 2006. Bedell, S., M. Nachtigall and F. Naftolin. The pros and cons of plant estrogens for menopause. J. Steroid Biochem. Mol. Biol. 139: 225–236, 2014. Binder, N.B., B. Niederreiter, O. Hoffmann, R. Stange, T. Pap, T.M. Stulnig, M. Mack, R.G. Erben, J.S. Smolen and K. Redlich. Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis. Nat Med. 15: 417–424, 2009. Blaber, E., H. Marcal and B.P. Burns. Bioastronautics: the influence of microgravity on astronaut health. Astrobiology 10: 463–473, 2010. Blume, S.W. and J.R. Curtis. Medical costs of osteoporosis in the elderly Medicare population. Osteoporos. Int. 22: 1835–1844, 2011. Bolam, K.A., J.G. van Uffelen and D.R. Taaffe. The effect of physical exercise on bone density in middle-aged and older men: a systematic review. Osteoporos. Int. April 4, 2013. Cao, D.P., Y.N. Zheng, L.P. Qin, T. Han, H. Zhang, K. Rahman and Q.Y. Zhang. Curculigo orchioides, a traditional Chinese medicinal plant, prevents bone loss in ovariectomized rats. Maturitas 59: 373–380, 2008. Consensus development conference (CDC): diagnosis, prophylaxis, and treatment of osteoporosis. Am. J. Med. 94: 646–650, 1993.


16

C. LI et al.

Cavani, F., M. Ferretti, G. Carnevale, L. Bertoni, M. Zavatti and C. Palumbo. Effects of different doses of ferutinin on bone formation/resorption in ovariectomized rats. J. Bone Miner. Metab. 30: 619–629, 2012. Chatuphonprasert, W., N. Nemoto, T. Sakuma and K. Jarukamjorn. Modulations of cytochrome P450 expression in diabetic mice by berberine. Chem. Biol. Interact. 196: 23–29, 2012. Cheng, M., Q. Wang, Y. Fan, X. Liu, L. Wang, R. Xie, C.C. Ho and W. Sun. A traditional Chinese herbal preparation, Er-Zhi-Wan, prevent ovariectomy-induced osteoporosis in rats. J. Ethnopharmacol. 138: 279–285, 2011. Chiang, H.M., S.H. Fang, K.C. Wen, S.L. Hsiu, S.Y. Tsai, Y.C. Hou, Y.C. Chi and P.D. Chao. Lifethreatening interaction between the root extract of Pueraria lobata and methotrexate in rats. Toxicol. Appl. Pharmacol. 209: 263–268, 2005. Chiang, S.S., S.P. Chang and T.M. Pan. Osteoprotective effect of Monascus-fermented dioscorea in ovariectomized rat model of postmenopausal osteoporosis. J. Agric. Food Chem. 59: 9150– 9157, 2011. Chiang, S.S. and T.M. Pan. Beneficial effects of phytoestrogens and their metabolites produced by intestinal microflora on bone health. Appl. Microbiol. Biotechnol. 97: 1489–1500, 2013. Clarke, B.L. and S. Khosla. Physiology of bone loss. Radiol. Clin. North Am. 48: 483–495, 2010. Cummings, S.R., D. Bates and D.M. Black. Clinical use of bone densitometry: scientific review. JAMA 288: 1889–1897, 2002. Dai, R., Y. Ma, Z. Sheng, Y. Jin, Y. Zhang, L. Fang, H. Fan and E. Liao. Effects of genistein on vertebral trabecular bone microstructure, bone mineral density, microcracks, osteocyte density, and bone strength in ovariectomized rats. J. Bone Miner. Metab. 26: 342–349, 2008. Dai, Y. and L. Shen. Effects of Migu tablet on bone mineral density, serum matrix metalloproteinase2 level and bone metabolic markers in postmenopausal osteoporosis. Zhongguo Zhong Yao Za Zhi. 32: 2409–2412, 2007. Dai, Y., L. Shen and Y.P. Yang. Effects of Migu Tablet on bone mineral density, serum levels of osteoprotegerin and its ligand and bone metabolic markers in patients with postmenopausal osteoporosis. Zhongguo Zhong Xi Yi Jie He Za Zhi 27: 696–699, 2007. Deng, W.M., P. Zhang, H. Huang, Y.G. Shen, Q.H. Yang, W.L. Cui, Y.S. He, S. Wei, Z. Ye, F. Liu and L. Qin. Five-year follow-up study of a kidney-tonifying herbal Fufang for prevention of postmenopausal osteoporosis and fragility fractures. J. Bone Miner. Metab. 30: 517–524, 2012. Donaldson, M.G., P.M. Cawthon, L.Y. Lui, J.T. Schousboe, K.E. Ensrud, B.C. Taylor, J.A. Cauley, T.A. Hillier, D.M. Black, D.C. Bauer, S.R. Cummings and F. Study of Osteoporotic. Estimates of the proportion of older white women who would be recommended for pharmacologic treatment by the new U.S. National Osteoporosis Foundation Guidelines. J. Bone Miner. Res. 24: 675–680, 2009. Dontas, I., M. Halabalaki, P. Moutsatsou, S. Mitakou, Z. Papoutsi, L. Khaldi, A. Galanos and G.P. Lyritis. Protective effect of plant extract from Onobrychis ebenoides on ovariectomy-induced bone loss in rats. Maturitas 53: 234–242, 2006. Du, N., R.T. Shi and W.R. Teng. Jiangu granules in treatment of postmenopausal osteoporosis: a randomized, double-blinded, double dummy, multicenter clinical trial. Chin. J. Tradit. Med. Trauma. Orthop. 16: 17–21, 2008. Durbin, S.M., J.R. Jackson, M.J. Ryan, J.C. Gigliotti, S.E. Alway and J.C. Tou. Resveratrol supplementation influences bone properties in the tibia of hindlimb-suspended mature Fisher 344 x Brown Norway male rats. Appl. Physiol. Nutr. Metab. 37: 1179–1188, 2012. Durie, B.G., M. Katz and J. Crowley. Osteonecrosis of the jaw and bisphosphonates. N. Engl. J. Med. 353: 99–102; discussion 99–102, 2005. Feng, R., L. Feng, Z. Yuan, D. Wang, F. Wang, B. Tan, S. Han, T. Li, D. Li and Y. Han. Icariin protects against glucocorticoid-induced osteoporosis in vitro and prevents glucocorticoidinduced osteocyte apoptosis in vivo. Cell Biochem. Biophys. 67: 189–197, 2013.



17

Ferretti, M., L. Bertoni, F. Cavani, M. Zavatti, E. Resca, G. Carnevale, A. Benelli, P. Zanoli and C. Palumbo. Influence of ferutinin on bone metabolism in ovariectomized rats. II: Role in recovering osteoporosis. J. Anat. 217: 48–56, 2010. Fonseca, D. and W.E. Ward. Daidzein together with high calcium preserve bone mass and biomechanical strength at multiple sites in ovariectomized mice. Bone 35: 489–497, 2004. Gates, B.J., T.E. Sonnett, C.A. Duvall and E.K. Dobbins. Review of osteoporosis pharmacotherapy for geriatric patients. Am. J. Geriatr. Pharmacother. 7: 293–323, 2009. Genant, H.K., K. Engelke, T. Fuerst, C.C. Gluer, S. Grampp, S.T. Harris, M. Jergas, T. Lang, Y. Lu, S. Majumdar, A. Mathur and M. Takada. Noninvasive assessment of bone mineral and structure: state of the art. J. Bone Miner. Res. 11: 707–730, 1996. Habold, C., I. Momken, A. Ouadi, V. Bekaert and D. Brasse. Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension. J. Bone Miner. Metab. 29: 15–22, 2011. Hattori, T., W. Fei, T. Kizawa, S. Nishida, H. Yoshikawa and Y. Kishida. The fixed herbal drug composition “Saikokaryukotsuboreito” prevents bone loss with an association of serum IL-6 reductions in ovariectomized mice model. Phytomedicine 17: 170–177, 2010. He, C.C., R.R. Hui, Y. Tezuka, S. Kadota and J.X. Li. Osteoprotective effect of extract from Achyranthes bidentata in ovariectomized rats. J. Ethnopharmacol. 127: 229–234, 2010. Hertrampf, T., M.J. Gruca, J. Seibel, U. Laudenbach, K.H. Fritzemeier and P. Diel. The boneprotective effect of the phytoestrogen genistein is mediated via ER alpha-dependent mechanisms and strongly enhanced by physical activity. Bone 40: 1529–1535, 2007. Hertrampf, T., B. Schleipen, C. Offermanns, M. Velders, U. Laudenbach and P. Diel. Comparison of the bone protective effects of an isoflavone-rich diet with dietary and subcutaneous administrations of genistein in ovariectomized rats. Toxicol. Lett. 184: 198–203, 2009. Hidaka, S., Y. Okamoto, Y. Yamada, Y. Kon and T. Kimura. A Japanese herbal medicine, Chujo-to, has a beneficial effect on osteoporosis in rats. Phytother Res. 13: 14–19, 1999. Hu, B., Q. Li, C. Li, T. Wu and L. Huang. Skeletal effect of xianzhen gubao on preventing prednisone-induced osteoporosis in male rats. Zhongguo Zhong Yao Za Zhi 24: 559–561, 576, 1999. Huybrechts, K.F., K.J. Ishak and J.J. Caro. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone 38: 922–928, 2006. Imaz, I., P. Zegarra, J. Gonzalez-Enriquez, B. Rubio, R. Alcazar and J.M. Amate. Poor bisphosphonate adherence for treatment of osteoporosis increases fracture risk: systematic review and meta-analysis. Osteoporos. Int. 21: 1943–1951, 2010. Johnell, O. and J.A. Kanis. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int. 17: 1726–1733, 2006. Jun, A.Y., H.J. Kim, K.K. Park, K.H. Son, D.H. Lee, M.H. Woo, Y.S. Kim, S.K. Lee and W.Y. Chung. Extract of Magnoliae Flos inhibits ovariectomy-induced osteoporosis by blocking osteoclastogenesis and reducing osteoclast-mediated bone resorption. Fitoterapia 83: 1523–1531, 2012. Kanis, J.A. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359: 1929–1936, 2002. Kapur, P., H. Jarry, W. Wuttke, B.M. Pereira and D. Seidlova-Wuttke. Evaluation of the antiosteoporotic potential of Tinospora cordifolia in female rats. Maturitas 59: 329–338, 2008. Khosla, S., D. Burr, J. Cauley, D.W. Dempster, P.R. Ebeling, D. Felsenberg, R.F. Gagel, V. Gilsanz, T. Guise, S. Koka, L.K. McCauley, J. McGowan, M.D. McKee, S. Mohla, D.G. Pendrys, L.G. Raisz, S.L. Ruggiero, D.M. Shafer, L. Shum, S.L. Silverman, C.H. Van Poznak, N. Watts, S.B. Woo, E. Shane, B. American Society for and R. Mineral. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner. Res. 22: 1479–1491, 2007.


18

C. LI et al.

Kim, B.Y., H.Y. Yoon, S.I. Yun, E.R. Woo, N.K. Song, H.G. Kim, S.Y. Jeong and Y.S. Chung. In vitro and in vivo inhibition of glucocorticoid-induced osteoporosis by the hexane extract of Poncirus trifoliata. Phytother. Res. 25: 1000–1010, 2011. Kim, T., H. Ha, K.S. Shim, W.K. Cho and J.Y. Ma. The anti-osteoporotic effect of Yijung-tang in an ovariectomized rat model mediated by inhibition of osteoclast differentiation. J. Ethnopharmacol. 146: 83–89, 2013. Knopp-Sihota, J.A., G.G. Cummings, J. Homik and D. Voaklander. The association between serious upper gastrointestinal bleeding and incident bisphosphonate use: a population-based nested cohort study. BMC Geriatr. 13: 36, 2013. Komrakova, M., S. Sehmisch, M. Tezval, U. Schmelz, H. Frauendorf, T. Grueger, T. Wessling, C. Klein, M. Birth, K.M. Stuermer and E.K. Stuermer. Impact of 4-methylbenzylidene camphor, daidzein, and estrogen on intact and osteotomized bone in osteopenic rats. J. Endocrinol. 211: 157–168, 2011. Leung, P.C., K.F. Cheng and Y.H. Chan. An innovative herbal product for the prevention of osteoporosis. Chin. J. Integr. Med. 17: 744–749, 2011. Levis, S., N. Strickman-Stein, P. Ganjei-Azar, P. Xu, D.R. Doerge and J. Krischer. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, doubleblind trial. Arch. Intern. Med. 171: 1363–1369, 2011. Li, F., X. Yang, Y. Yang, C. Guo, C. Zhang, Z. Yang and P. Li. Antiosteoporotic activity of echinacoside in ovariectomized rats. Phytomedicine 20: 549–557, 2013a. Li, N., Y. Jiang, P.H. Wooley, Z. Xu and S.Y. Yang. Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis. J. Orthop. Sci. 18: 478–485, 2013b. Li, X. and J.S. Choi. Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats. Int. J. Pharm. 337: 188–193, 2007. Liao, L., X.S. Li and Q.H. Cai. [Clinical research of the bu shen sheng sui principle curing the postmenopausal osteoporosis]. Chin. J. Inform. Tradit. Chin. Med. 11: 287–290, 2004. Lin, Q., Y.M. Huang, B.X. Xiao and G.F. Ren. Effects of resveratrol on bone mineral density in ovarectomized rats. Int J Biomed Sci. 1: 76–81, 2005. Lin, Y.P., R.X. Zhou and S.M. Guo. Effect of jiangu granule on quality of bone in model rats with osteoporosis induced by ovariectomy. Zhongguo Zhong Xi Yi Jie He Za Zhi 24: 431–434, 2004. Liu, J., S.C. Ho, Y.X. Su, W.Q. Chen, C.X. Zhang and Y.M. Chen. Effect of long-term intervention of soy isoflavones on bone mineral density in women: a meta-analysis of randomized controlled trials. Bone 44: 948–953, 2009a. Liu, M., C. Zhong, R.X. He and L.F. Chen. Icariin associated with exercise therapy is an effective treatment for postmenopausal osteoporosis. Chin. Med. J. 125: 1784–1789, 2012. Liu, Z.G., R. Zhang, C. Li, X. Ma, L. Liu, J.P. Wang and Q.B. Mei. The osteoprotective effect of Radix Dipsaci extract in ovariectomized rats. J. Ethnopharmacol. 123: 74–81, 2009b. Mathey, J., J. Mardon, N. Fokialakis, C. Puel, S. Kati-Coulibaly, S. Mitakou, C. Bennetau-Pelissero, V. Lamothe, M.J. Davicco, P. Lebecque, M.N. Horcajada and V. Coxam. Modulation of soy isoflavones bioavailability and subsequent effects on bone health in ovariectomized rats: the case for equol. Osteoporos. Int. 18: 671–679, 2007. Miao, Q., J.G. Li, S. Miao, N. Hu, J. Zhang, S. Zhang, Y.H. Xie, J.B. Wang and S.W. Wang. The bone-protective effect of genistein in the animal model of bilateral ovariectomy: roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis. Int. J. Mol. Sci. 13: 56–70, 2012. Ming, L.G., X. Lv, X.N. Ma, B.F. Ge, P. Zhen, P. Song, J. Zhou, H.P. Ma, C.J. Xian and K.M. Chen. The prenyl group contributes to activities of phytoestrogen 8-prenynaringenin in enhancing bone formation and inhibiting bone resorption in vitro. Endocrinology 154: 1202–1214, 2013.



19

Mok, S.K., W.F. Chen, W.P. Lai, P.C. Leung, X.L. Wang, X.S. Yao and M.S. Wong. Icariin protects against bone loss induced by oestrogen deficiency and activates oestrogen receptor-dependent osteoblastic functions in UMR 106 cells. Br. J. Pharmacol. 159: 939–949, 2010. Morabito, N., A. Crisafulli, C. Vergara, A. Gaudio, A. Lasco, N. Frisina, R. D’Anna, F. Corrado, M.A. Pizzoleo, M. Cincotta, D. Altavilla, R. Ientile and F. Squadrito. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J. Bone Miner. Res. 17: 1904–1912, 2002. Nian, H., L.P. Qin, Q.Y. Zhang, H.C. Zheng, Y. Yu and B.K. Huang. Antiosteoporotic activity of Er-Xian Decoction, a traditional Chinese herbal formula, in ovariectomized rats. J. Ethnopharmacol. 108: 96–102, 2006. Nian, H., M.H. Ma, S.S. Nian and L.L. Xu. Antiosteoporotic activity of icariin in ovariectomized rats. Phytomedicine 16: 320–326, 2009. NIH Consensus Development Panel (NIHCDP) on Osteoporosis Prevention, Diagnosis, and Therapy, March 7–29, 2000: highlights of the conference. South Med. J. 94: 569–573, 2001. Om, A.S. and J.Y. Shim. Effect of daidzein, a soy isoflavone, on bone metabolism in Cd-treated ovariectomized rats. Acta Biochim. Pol. 54: 641–646, 2007. Orija, I.B. and A. Mehta. Hormone replacement therapy: current controversies. Clin. Endocrinol. (Oxf). 59: 657, 2003. Park, C.Y. and C.M. Weaver. Vitamin D interactions with soy isoflavones on bone after menopause: a review. Nutrients 4: 1610–1621, 2012. Park, J.A., S.K. Ha, T.H. Kang, M.S. Oh, M.H. Cho, S.Y. Lee, J.H. Park and S.Y. Kim. Protective effect of apigenin on ovariectomy-induced bone loss in rats. Life Sci. 82: 1217–1223, 2008. Picherit, C., V. Coxam, C. Bennetau-Pelissero, S. Kati-Coulibaly, M.J. Davicco, P. Lebecque and J.P. Barlet. Daidzein is more efficient than genistein in preventing ovariectomy-induced bone loss in rats. J. Nutr. 130: 1675–1681, 2000. Pinkerton, J.V. and A.C. Dalkin. Combination therapy for treatment of osteoporosis: a review. Am. J. Obstet. Gynecol. 197: 559–565, 2007. Puel, C., J. Mathey, A. Agalias, S. Kati-Coulibaly, J. Mardon, C. Obled, M.J. Davicco, P. Lebecque, M.N. Horcajada, A.L. Skaltsounis and V. Coxam. Dose-response study of effect of oleuropein, an olive oil polyphenol, in an ovariectomy/inflammation experimental model of bone loss in the rat. Clin. Nutr. 25: 859–868, 2006. Qi, W., Y.B. Yan, W. Lei, Z.X. Wu, Y. Zhang, D. Liu, L. Shi, P.C. Cao and N. Liu. Prevention of disuse osteoporosis in rats by Cordyceps sinensis extract. Osteoporos. Int. 23: 2347–2357, 2012. Rabenda, V., R. Mertens, V. Fabri, J. Vanoverloop, F. Sumkay, C. Vannecke, A. Deswaef, G.A. Verpooten and J.Y. Reginster. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos. Int. 19: 811–818, 2008. Rachon, D., D. Seidlova-Wuttke, T. Vortherms and W. Wuttke. Effects of dietary equol administration on ovariectomy induced bone loss in Sprague-Dawley rats. Maturitas 58: 308–315, 2007. Ruan, X.Y., J.M. Qi, Y.L. Liu, Y. Ji and B.Y. Chen. Effects of traditional Chinese medicine on bone mineral density and femoral neck strength in postmenopausal women. Chin. J. Osteoporos. 12: 181–184, 2006. Sehmisch, S., J. Uffenorde, S. Maehlmeyer, M. Tezval, H. Jarry, K.M. Stuermer and E.K. Stuermer. Evaluation of bone quality and quantity in osteoporotic mice — the effects of genistein and equol. Phytomedicine 17: 424–430, 2010. Shang, Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat. Rev. Cancer 6: 360–368, 2006. Shen, C.L., J.K. Yeh, J.J. Cao and J.S. Wang. Green tea and bone metabolism. Nutr. Res. 29: 437– 456, 2009.


20

C. LI et al.

Shen, P., D. Chen and G. Zhang. Study on efficacy of Chinese Kidney-Tonifying Recipe in male rats with osteoporosis induced by dexamethasone and its mechanism. Zhongguo Zhong Xi Yi Jie He Za Zhi 18: 290–292, 1998. Shuid, A.N., L.L. Ping, N. Muhammad, N. Mohamed and I.N. Soelaiman. The effects of Labisia pumila var. alata on bone markers and bone calcium in a rat model of post-menopausal osteoporosis. J. Ethnopharmacol. 133: 538–542, 2011. Singh, D., R. Gupta and S.A. Saraf. Herbs-are they safe enough? an overview. Crit. Rev. Food Sci. Nutr. 52: 876–98, 2012. Siu, W.S., H.L. Wong, C.P. Lau, W.T. Shum, C.W. Wong, S. Gao, K.P. Fung, C.B. Lau, L.K. Hung, C.H. Ko and P.C. Leung. The effects of an antiosteoporosis herbal formula containing epimedii herba, ligustri lucidi fructus and psoraleae fructus on density and structure of rat long bones under tail-suspension, and its mechanisms of action. Phytother. Res. 27: 484–492, 2013. Srikanta, P., S.H. Nagarajappa, G.L. Viswanatha, M. Handral, R. Subbanna, R. Srinath and G. Hiremath. Anti-osteoporotic activity of methanolic extract of an Indian herbal formula NR/CAL/06 in ovariectomized rats. Zhong Xi Yi Jie He Xue Bao 9: 1125–1132, 2011. Tai, T.Y., K.S. Tsai, S.T. Tu, J.S. Wu, C.I. Chang, C.L. Chen, N.S. Shaw, H.Y. Peng, S.Y. Wang and C.H. Wu. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study. Osteoporos. Int. 23: 1571–1580, 2012. Turner, R.T., U.T. Iwaniec, J.E. Andrade, A.J. Branscum, S.L. Neese, D.A. Olson, L. Wagner, V.C. Wang, S.L. Schantz and W.G. Helferich. Genistein administered as a once-daily oral supplement had no beneficial effect on the tibia in rat models for postmenopausal bone loss. Menopause 20: 677–686, 2013. Udomsuk, L., W. Chatuphonprasert, O. Monthakantirat, Y. Churikhit and K. Jarukamjorn. Impact of Pueraria candollei var. mirifica and its potent phytoestrogen miroestrol on expression of bonespecific genes in ovariectomized mice. Fitoterapia 83: 1687–1692, 2012. Urasopon, N., Y. Hamada, K. Asaoka, W. Cherdshewasart and S. Malaivijitnond. Pueraria mirifica, a phytoestrogen-rich herb, prevents bone loss in orchidectomized rats. Maturitas 56: 322–331, 2007. Urasopon, N., Y. Hamada, W. Cherdshewasart and S. Malaivijitnond. Preventive effects of Pueraria mirifica on bone loss in ovariectomized rats. Maturitas 59: 137–148, 2008. Wang, H.M., J.R. Ge, G.T. Shi, W.H. Zhao and W. Tian. [Clinical study on the effect of Gushukang capsule in primary osteoporosis treatment]. Chin. J. Tradit. Med. Trauma. Orthop. 14: 10–15, 2006a. Wang, P.P., X.F. Zhu, L. Yang, H. Liang, S.W. Feng and R.H. Zhang. Puerarin stimulates osteoblasts differentiation and bone formation through estrogen receptor, p38 MAPK, and Wnt/betacatenin pathways. J. Asian Nat. Prod. Res. 14: 897–905, 2013a. Wang, X., J. Wu, H. Chiba, K. Umegaki, K. Yamada and Y. Ishimi. Puerariae radix prevents bone loss in ovariectomized mice. J. Bone Miner. Metab. 21: 268–275, 2003. Wang, X., J. Wu, H. Chiba, K. Yamada and Y. Ishimi. Puerariae radix prevents bone loss in castrated male mice. Metabolism 54: 1536–1541, 2005. Wang, X.Y., L.M. Dai, J. Han, L.D. Cui, P. Xiao and J.A. Guo. Effects of Gui-Di Powder and calcium on bone weight, bone mineral density, and bone strength in ovariectomized rats. Chin. J. Osteoporos. 6: 74–77, 2000. Wang, Y., K. Cui, H. Zhao, D. Li, W. Wang and Y. Zhu. Bushen Ningxin Decoction pharmacological serum promotes the proliferation and suppresses the apoptosis of murine osteoblasts through MAPK pathway. J. Ethnopharmacol. 122: 221–226, 2009. Wang, Z.L., J.Y. Sun, D.N. Wang, Y.H. Xie, S.W. Wang and W.M. Zhao. Pharmacological studies of the large-scaled purified genistein from Huaijiao (Sophora japonica-Leguminosae) on antiosteoporosis. Phytomedicine 13: 718–723, 2006b.



21

Wang, Z.Q., J.L. Li, Y.L. Sun, M. Yao, J. Gao, Z. Yang, Q. Shi, X.J. Cui and Y.J. Wang. Chinese herbal medicine for osteoporosis: a systematic review of randomized controlled trails. Evid. Based Complement. Alternat. Med. 2013: 356260, 2013b. Watanabe, Y., H. Ohshima, K. Mizuno, C. Sekiguchi, M. Fukunaga, K. Kohri, J. Rittweger, D. Felsenberg, T. Matsumoto and T. Nakamura. Intravenous pamidronate prevents femoral bone loss and renal stone formation during 90-day bed rest. J. Bone Miner. Res. 19: 1771–1778, 2004. Weerachayaphorn, J., A. Chuncharunee, C. Mahagita, B. Lewchalermwongse, A. Suksamrarn and P. Piyachaturawat. A protective effect of Curcuma comosa Roxb. on bone loss in estrogen deficient mice. J. Ethnopharmacol. 137: 956–962, 2011. Wiseman, R.A. Breast cancer: critical data analysis concludes that estrogens are not the cause, however lifestyle changes can alter risk rapidly. J. Clin. Epidemiol. 57: 766–772, 2004. Wu, B., B. Xu, T.Y. Huang and J.R. Wang. A model of osteoporosis induced by retinoic acid in male Wistar rats. Yao Xue Xue Bao 31: 241–245, 1996. Wu, J.J., L.P. Wen, Y.G. Wu, Q. Shen and Y. Han. Effects of Xianling Gubao capsules for the treatment of bone loss induced by glucocorticoid. Zhongguo Gu Shang 22: 193–195, 2009. Xie, Q.F., J.H. Xie, T.T. Dong, J.Y. Su, D.K. Cai, J.P. Chen, L.F. Liu, Y.C. Li, X.P. Lai, K.W. Tsim and Z.R. Su. Effect of a derived herbal recipe from an ancient Chinese formula, Danggui Buxue Tang, on ovariectomized rats. J. Ethnopharmacol. 144: 567–575, 2012. Xu, Y., Z.J. Zhang, F. Geng, S.B. Su, K.N. White, S.W. Bligh, C.J. Branford-White and Z.T. Wang. Treatment with Qing’E, a kidney-invigorating Chinese herbal formula, antagonizes the estrogen decline in ovariectomized mice. Rejuvenation Res. 13: 479–488, 2010. Xue, L., Y. Wang, Y. Jiang, T. Han, Y. Nie, L. Zhao, Q. Zhang and L. Qin. Comparative effects of erxian decoction, epimedium herbs, and icariin with estrogen on bone and reproductive tissue in ovariectomized rats. Evid. Based. Complement. Alternat. Med. 2012: 241416, 2012. Yang, H., L. Shen and Y. Zhang. [Observation of the efficacy of GKKFY in treating primary osteoporosis]. Chin. J. Tradit. Med. Trauma. Orthop. 15: 31–33, 2007. Yang, X., F. Li, Y. Yang, J. Shen, R. Zou, P. Zhu, C. Zhang, Z. Yang and P. Li. Efficacy and safety of echinacoside in a rat osteopenia model. Evid. Based. Complement. Alternat. Med. 2013: 926928, 2013. Yin, J., Y. Tezuka, Subehan, L. Shi, M. Nobukawa, T. Nobukawa and S. Kadota. In vivo antiosteoporotic activity of isotaxiresinol, a lignan from wood of Taxus yunnanensis. Phytomedicine 13: 37–42, 2006. Yogesh, H.S., V.M. Chandrashekhar, H.R. Katti, S. Ganapaty, H.L. Raghavendra, G.K. Gowda and B. Goplakhrishna. Anti-osteoporotic activity of aqueous-methanol extract of Berberis aristata in ovariectomized rats. J. Ethnopharmacol. 134: 334–338, 2011. Zhang, R., S.J. Hu, C. Li, F. Zhang, H.Q. Gan and Q.B. Mei. Achyranthes bidentata root extract prevent OVX-induced osteoporosis in rats. J. Ethnopharmacol. 139: 12–18, 2012. Zhang, R., Z.G. Liu, C. Li, S.J. Hu, L. Liu, J.P. Wang and Q.B. Mei. Du-Zhong (Eucommia ulmoides Oliv.) cortex extract prevent OVX-induced osteoporosis in rats. Bone 45: 553–559, 2009. Zhang, R.H., K.J. Chen, D.X. Lu, X.F. Zhu and X.C. Ma. A clinical study of Yigu capsule in treating postmenopausal osteoporosis. Chin. J. Integr. Med. 11: 97–103, 2005. Zhang, Y., X.L. Li, W.P. Lai, B. Chen, H.K. Chow, C.F. Wu, N.L. Wang, X.S. Yao and M.S. Wong. Anti-osteoporotic effect of Erythrina variegata L. in ovariectomized rats. J. Ethnopharmacol. 109: 165–169, 2007. Zhao, X., Z.X. Wu, Y. Zhang, Y.B. Yan, Q. He, P.C. Cao and W. Lei. Anti-osteoporosis activity of Cibotium barometz extract on ovariectomy-induced bone loss in rats. J. Ethnopharmacol. 137: 1083–1088, 2011.

22

C. LI et al.


Zhao, Y.H. and M.W. Wang. Progress of experimental research on prevention and treatment of osteoporosis by traditional Chinese medicine. Zhongguo Zhong Xi Yi Jie He Za Zhi 23: 943945, 2003. Zheng, W.K., C.Y. Liu, C.Y. Han and Y.J. Zhou. [Clinical study on treatment of postmenoporosis by jinwugutong capsule]. Chin. J. Tradit. Med. Trauma. Orthop. 30: 30–32, 2007.

The prevention and treatment of osteoporosis.

Estrogen in prevention and treatment of osteoporosis.

Chinese medicinal herbs for mumps.

Medicinal herbs and therapeutic drugs interactions.

Prevention and treatment of postmenopausal osteoporosis.

Calcium in the prevention and treatment of osteoporosis.

Mechanisms of action of phytochemicals from medicinal herbs in the treatment of Alzheimer's disease.

Osteoporosis: clinical features, prevention, and treatment.

Osteoporosis prevention, screening, and treatment: a review.

Postmenopausal osteoporosis: prevention and treatment with calcitonin.

Occurrence of enniatins and beauvericin in 60 Chinese medicinal herbs.

MicroRNAs and Chinese Medicinal Herbs: New Possibilities in Cancer Therapy.

UK clinical guideline for the prevention and treatment of osteoporosis.

Medicinal Herbs in Iranian Traditional Medicine for Learning and Memory.

Therapeutic Effects of Phytochemicals and Medicinal Herbs on Depression.

Medicinal Herbs Affecting Gray Hair in Iranian Traditional Medicine.

MEDICINAL HERBS USED BY HIV-POSITIVE PEOPLE IN LESOTHO.

Possible prevention and treatment of steroid-induced osteoporosis.

Spectral Analysis of Chinese Medicinal Herbs Based on Delayed Luminescence.

Clinician's Guide to Prevention and Treatment of Osteoporosis.

Application of Traditional Chinese Medical Herbs in Prevention and Treatment of Respiratory Syncytial Virus.

Erratum to: Clinician's guide to prevention and treatment of osteoporosis.

Prevention and treatment of glucocorticoid-induced osteoporosis. A pathogenetic perspective.

Influence of medicinal herbs on phagocytosis by bovine neutrophils.