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Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )

Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action

a Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China; b Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

This article reviews the recent pharmacological research of medicinal herbs on osteoporosis, especially induced by estrogen deficiency, in animal model. The information will provide the reference for future clinical drug research and development on anti-osteoporosis as the alternative to synthetic medicine. Key word: osteoporosis; herb; traditional Chinese medicine ( TCM ); ovariectomy ( OVX )

Yan Zhanga, Mansau Wongb, Chunfu Wua*

Osteoporosis ( OP ) is characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk [1]. OP that associated with ovarian hormone deficiency following menopause is by far the most common cause of age-related bone loss. Postmenopausal osteoporosis ( POP ) has become a major problem with significant morbidity and mortality [2]. In the modern clinical practice for prevention and treatment of POP, hormone replacement therapy ( HRT ), as well as some drugs, such as raloxifene, bisphosphonates, calcium and vitamin D, calcitonin, and parathyroid hormone, have been widely used. Although the bone protective effects of these agents are well-confirmed, side effects, such as hypercalcemia, increased risk of endometrial and breast cancer, vaginal bleeding and hot flushes [3, 4], have also been reported. Due to some severe side effects or lack of efficacy of synthetic drugs, the potential efficacy of traditional medicines has arouse the interest of scientists and doctors to seek the cues from traditional medicines for treatment of some chronic and difficult diseases, including the treatment for OP. In traditional Chinese medicine ( TCM ), OP is classified as "rheumatism involving the bone" and "atrophic debility of bones" [5, 6]. Based on the theory of "Kidney dominates bone" in TCM, many medicinal herbs have been prescribed to treat bone metabolic disorders for long time. With the advancement of modern medicine, the etiology of OP has been deeply elucidated, which has greatly promoted the investigation of the

effects and the mechanisms of action of traditional medicines on OP. In order to provide more information for understanding, in terms of modern science, the action of TCM on OP, the present article reviews the recent pharmacological studies of some medicinal herbs commonly prescribed in TCM on the prevention and treatment of OP.

Herbs for Restoring Deficiency Syndrome

The Yin-Yang theory considers the normal vital activities of the human body to be the result of the relative balance between yin and yang. Thus, disease is thought to be the result of an imbalance between yin and yang which leads to the hyperactivity or hypoactivity of yin or yang. As the Suwen says, "When yin keeps balance with yang and both maintain a normal condition of qi, then health will be high-spirited. A separation of yin and yang will lead to the exhaustion of essential qi." The Huang Di Nei Jing ( The Yellow Emperor's Classic of internal Medicine ) also says, "The Meridians move the qi and blood. As a result, yin and yang get regulated. Tendons and bones get nourished. Joints get facilitated." Meridians work like a network system, transporting and distributing qi and blood. They link up organs, limbs, joints, bones, tendons, tissues and skin, and provide communication between the body's interior and exterior. Through a healthy meridian system, qi and blood successfully warm and nourish different organs and tissues, and maintain normal metabolic activities. Meridians are essential in supporting the flow of nutritive qi inside the blood vessels and the flow of protective qi around them.

* Corresponding author. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China. Tel. & Fax: +86 -24-23843567; E-mail: [email protected] ; [email protected]

Herbs for replenishing qi


Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )

Astragalus membranaceus Bge is one of the most popular herbs for tonifying Qi. Recent studies have shown that it could be applied not only in the treatment of the disease in cardiovascular and immune system, but also in the prevention of secondary OP. It is reported that the water extract of the root of A. membranaceus prevented OP induced by dexamethason or by ovariectomy in rats, and the beneficial effects on bone were manifested as inhibiting osteoclast, decreasing bone absorption and promoting bone formation [7] . Additionally, ameliorative effects of total isoflavones of A. membranaceus on the femoral biomechanical properties, such as maximal load, maximal stress, elastic modulus and energy, in osteopenia rats induced by retinoic acid have been observed [8].

DR ), it increased DNA synthesis, ALP activity and prolyl hydroxylase activity of MC3T3-E1 osteoblastic cells at the concentration of 50~150 µg/ml [20], and enhanced the proliferation of human osteoprecursor cells (OPC-1) at the concentration of 120 µg/ml [21]. The stimulative effects of DR on the differentiation and mineralization in osteoblast was through the regulation of bone morphogenetic protein-2, type I collagen and collagenase-1 [22], which may be the scientific mechanism to elucidate the ameliorative effect of DR on bone tissue in vivo.

Herbs for nourishing yin

Since the four physiological characteristics, including menstruation, pregnancy, procreation and breeding, and periodically impairment of Yin by consuming blood, there is higher rate of OP for women after the age of 50 than that for men. So herbs for nourishing Yin have their application for POP due to estrogen deficiency. Fructus Ligustri Lucidi ( FLL, Chinese name, Nvzhenzi ), is the ripe fruit of Ligustrum lucidum Ait. In the theory of TCM, it is a commonly prescribed herbal material in a number of formulae used to tonify the kidneys and strengthen bone since its effects of maintaining healthy energy, and nourishing the liver and kidneys [23, 24]. Modern research has shown that FLL is useful for prevention of bone marrow loss in cancer patients receiving chemotherapy [25]. Hao et al. observed that FLL induced ultrastructural changes on the corticotrophs of rat pituitary gland and provided morphological evidence for the action of FLL in modulating endocrine function [26]. Our results clearly demonstrate that administration of FLL extract ( 550 mg/kg ) inhibited high bone turnover, elevated intestinal calcium absorption rate and calcium retention rate, and prevented calcium loss in young OVX rats [27]. Whether FLL could modulate the secretion and protein expression of calcium-regulating hormones by which it exert these effects in vivo remains to be clarified. We summarized the formula, which had beneficial effect on preventing and treating OP in clinical application, and analyzed the components in these formulas. It was found that herbs for restoring deficiency play major roles in the proved recipes for treating OP, and the mechanism of actions were mostly attributed to the estrogen-like activity of some constituents in these herbs, especially for kidney-tonifying herbs, and improvement on the function of pituitary-sex gland axis.

Herbs tonifying yang

Most of the herbs in this class possess the efficacy of tonifying kidney, strengthening Yang, and strengthening tendons and bones. Some herbs, including Curculigo orchioides Gaertn., Epimedium grandiflorum Morr., Morinda officinalis How., Cistanche salsa G., Eucommia ulmoides Oliv., Psoralea corylifolia L., Cuscuta chinensis Lam., Dipsacus japonicus Mip., are the main components of the formula for treating OP [9-14]. Studies on the antiosteoprotective effect of the single herb in this class have been reported. Histomorphometric studies have indicated that four kidney-tonifying herbs, i.e. Cistanche salsa G., Psoralea corylifolia L., Dipsacus japonicus Mip., and Eucommia ulmoides Oliv., inhibit bone turnover and bone resorption. The maximal efficacy is observed by using Eucommia ulmoides Oliv [15]. It is estimated that, in herbs invigorating Yang, Epimedium grandiflorum Morr. (EGM) is the most widely used among 100 herbs for the treatment of OP [16]. It is reported that EGM crude extracts (110 mg/kg/day), orally administrated to ovariectomized ( OVX ) rats for 3 months, significantly improved bone metabolic markers, viz. decreasing urinary Ca excretion and the levels of serum alkaline phosphatase ( ALP ) and urinary deoxypyridinoline ( DPD ), and restoring the microstructure of trabecular bones [17]. EGM extracts (100 and 200 µg/ml) accelerated the proliferation of rat osteoblast-like cells, UMR106, and increased the ratio of gene expression OPG/RANKL in vitro. These results suggest that EGM has a direct effect on osteoblast by regulating the secretion of OPG and RANK ligand. Further studies have demonstrated that isoflavanoids contained in EGM is responsible for the beneficial effect of EGM on bones [18]. Histomorphometric and image analysis studies on bone architecture in OVX rats have shown that the total isoflavones of EGM can improve the arch-like structure in bone trabecular and the distance between bone trabecular, as well as the surface of bone [19]. In vitro testing for Drynariae Rhizoma (

Herbs for Promoting Blood Circulation and Removing Blood Stasis

"Blood Stasis due to Qi Stagnancy and Bone


Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )

Disorders due to Blood Stasis", this is the main reason for inducing POP [28]. Previous studies reported stagnancy of qi and blood stasis at the core of orthopedic diseases. Promoting blood circulation to remove the stagnancy and stasis to produce new bone are considered important measures for preventing and treating OP. Western medicine strongly supports this theory, and repeatedly encourages vigorous exercise for general well-being and weight-bearing exercise for bone health. It is well known when blood and oxygen supplied to the bones are increased, bone nutrition improves and bone density increases. The annual herb, Salvia miltiorrhiza Bge., is distributed in China and Korea. The preventive effect of the extracts from the radix of Salvia miltiorrhiza ( SMEs ) on the progress of bone loss induced by OVX was studied in rats [29]. In this study, the mechanical strength in femur neck was significantly enhanced and the porous or erosive appearances on the surface of trabecular bone of tibia were markedly improved by the treatment of SMEs for 7 weeks. SMEs also completely inhibited OVX-induced the decrease of the trabecular bone area and trabecular bone thickness. It was speculated that the effective of SMEs in preventing the development of bone loss in OVX rats be attributed to the decrease of serum free T4. Another research group fed a diet containing defatted safflower ( Carthamus tinctorius L. ) seeds ( 29 % ) to OVX rats for 4 weeks [30]. They found that safflower seed increased trabecular number and trabecular volume in OVX rats and mixed polyphenolic compounds extracted from safflower seeds stimulated the growth of ROS17/2.8 osteoblast-like cells in a dosedependent manner ( 5-100 µg/ml ). Moreover, boneprotecting effect of safflower seeds may be mediated, at least partly, by the stimulating effect of polyphenolic compounds on proliferation of osteoblasts. From the view of molecular biochemistry, safflower seeds, as a possible Src family kinase inhibitor, inhibited in vitro and in vivo bone resorption by inhibition of phosphorylation of peptide substrates [31]. In addition, other results suggested that safflower polyphenols have the effect of improving blood lipid status via increasing HDL-cholesterol formation and cholesterol excretion without significant uterotrophic action in estrogen-deficient animals [32]. Achyranthes root, yielded mainly in Henan province of China, is the dried root of a perennial herb Achyranthes bidentata Bl., and has the effect of invigorating blood circulation and eliminating blood stasis, reinforcing the liver and kidney, strengthening the tendons and bones. It is used to treat aching pain in the loins and knees and lassitude of the legs [33]. One study elucidated that water extract of Achyranthes root had marked increase of the contents of Ca and P in serum and bone, and also elevated BMD in osteopenia rats induced by retinoic

acid, which indicated that it prevents bone mineral loss in rats, and maintains the normal bone metabolism and bone growth [34]. Since blood stasis, also associated with qi, is the second root cause for bone diseases according to traditional Chinese medical theory, aiming at this pathogeny, the herbs in this class maintain bone health by promoting blood circulation and removing blood stasis, which is the essential way for treating POP.

Herbs for Clearing Away Heat

The theory of four characters-cold, cool, warm and hot of TCM is a core one in the TCM literature, which always plays the guiding part of clinical medication. The deficiency of yin as a result of exhausted vital essence leads to endogenous heat, which is called as asthenic heat syndrome, thus drugs of nourishing yin is better. This is what is known, in TCM, as replenishing the vital essence, ( especially that of the kidney and liver ) to check virtual yang ( exuberance of the vital function ) caused by the deficiency of yin factor. Scholars from German found that BMD in the proximal metaphysis of tibia in OVX rats, which were fed soy free chow substituted with an aqueous/ethanolic extract of the rhizomes of Belamcanda chinensis DC. ( 0.165 % and 0.665 % ) for 3 months, was drastically rose in herb-treated groups, further binding studies with recombinant human ER and ERß showed that isoflavone tectorigenin, isolated from this plant, binds to both receptor subtypes. When given intravenously ( 7 mg/animal ) to OVX rats, it inhibited pulsatile pituitary LH secretion. In summary, tectorigenin or the Belamcanda chinensis DC. extract containing tectorigenin had a strong hypothalamotropic and osteotropic effect while without the effect in the uterus or the mammary gland [35] . Korean research group evaluated the effects of Sedum sarmentosun Bunge ( SS ) on the lipid on serum and the collagen content of the connective tissues in ovariectomized estrogendeficient rats. Their results revealed that the serum triglyceride levels were significantly decreased after supplementation with the SS portion ethyl ether and ethyl acetate layers, and supplementation with the SS extracts prevented a decrease in the collagen level in bone and cartilage tissues. These results were consistent with the conclusions based on the estrogenic activities of SS. Therefore, it may be used to possibly improve the quality of life in menopausal women [36]. From the view of TCM theory, the herbs for clearing away heat treat OP of postmenopausal women usually associated with nephrasthenia pyrosyndrome and their application will lead to eliminate obstruction to activate


Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )


Herbs for Relieving Exterior Syndrome

Cimicifuga racemosa ( CR ), namely Black Cohosh, is one of C. foetida L. belonging to the diaphoretics pungent in flavor and cool in property. Two centuries ago, America aborigines took the lead in applying the root of CR to alleviate the dysmenorrhea and reduce climacteric complaints. Recent study [37] showed that treatment of the OVX rats with CR extract, BNO 1055, significantly reduced the loss of BMD, and a paratibial fat depot and serum leptin concentration were also significantly reduced. CR extract exerted estrogenic effects in the bone and in fat tissue, but not in the uterus of OVX rats. When given acutely, it inhibited LH secretion, while no effects on genes expressions in uterus were observed either by acutely or chronically application to the OVX rats [38]. In conclusion, the extract appeared to contain rat organ-specific selective estrogen receptor modulators ( SERMs ). A potential bone-sparing effect of CR was also evaluated in OVX rats by a Japanese research group [39]. Their results demonstrated that isopropanolic extract of CR inhibited bone resorption by diminishing the urinary content of PYR and DPY, and enhanced the bone quality score ( BQS ). Puerariae radix ( PR ), another kind of diaphoretics pungent in flavor and cool in property, was made focus on its effects on the illness of heart and cerebral vessels. While, when dry powered PR was added to the diet at 5 %, 10 % and 20 % ( w/w ) instead of cornstarch, significant elevation of BMD in the proximal metaphysis, diaphysis and distal metaphysis of the femur in mice, was found in the groups of all three doses of PR compared with that in model group. Histological analysis revealed that bone morphological parameters in treated groups, such as Tb.Th, BV/TV, Tb.Sp and N.Oc, were restored to the normal levels in sham group dose-dependently. Phytochemical analysis gave a conclusion that bone-protective effect of PR was attributed to the daidzein and genistein contained in PR extract at 0.803 % and 0.101 %, respectively [40]. It was accepted worldwide that the two compounds, which are isoflavone phytoestrogens, could protect against bone loss [41, 42]. PR may be a potent alternative for estrogen in ERT in preventing OP. One study has validated that total isoflavones of PR inhibited loss of mineral and trace elements in bone induced by estrogen-deficiency [43].

al. carried out the research to investigate the effect of pomegranate extract on the estrogen deficiency produced by ovariectomy of experimental animals. Administration of pomegranate extract for 2 weeks to OVX mice prevented the loss of uterus weight and shortened the immobility time. Bone histomorphometric parameters, such as OV/BV, OS/BS, Ob. S/BS, ES/BS and N. Oc/B. Pm, had been improved obviously [45]. This study gave a clue that pomegranate seeds have estrogenic activity due to the amelioration on the depressive state, a clinically significant mental profile of women menopausal syndrome [46], and especially due to the uterotrophic action. Cornus officinalis Sieb could reinforce kidney and control nocturnal emission, and its indications include vertigo, tinnitus, and aching pain in the loins and knees. Treated with water extract from the fruits of Cornus officinalis Sieb at low, middle and high doses ( corresponding to crude drug, 1 g, 2 g, 5 g/kg ) to senile SAM-P/6 mice, an osteopenia model, it was found that cortical bone thickness and osteoblast number were higher in high and middle dose groups than that in OVX group, and in all three doses groups the trabecular bone area was increased drastically. Accelerating bone formation and reducing bone resorption may be responsible for the action mechanism of Cornus officinalis Sieb on osteoprotection [47].

Herbs for Eliminating Wind-dampness

When the wind-cold-damp stays in the body for a long time, the kidney yang will be injured, thus, bone may degenerate because the kidney controls bones. The key to treatment strategy is to expel the wind-cold-damp and tonify the kidney yang. Erythrina variegata L. ( EV ), which is distributed throughout the tropics and belongs to the same leguminous family as soybean, is used as folk medicine in many countries. In India, China, and Southeast Asia, its bark and leaves are used to treat wind-damp obstruction syndrome manifested as rheumatic joint pain, spasm of the limbs as well as lower back and knee pain, and to stimulate lactation and menstruation for women [48]. EV could suppress the high rate of bone turnover induced by estrogen deficiency, inhibit bone loss and improve the biomechanical properties of bone in the OVX rats [49], partially due to the high amount of isoflavones contained in EV extract [50, 51].

Herbs for Arresting Secretion

Pomegranate seeds ( Punica granatum L. ) are known to contain the estrogenic compounds, estradiol and estrone, and isoflavone phytoestrogens such as daidzein and genistein [44] , so J. Mori-Okamoto et


Research information about the prevention of herbal medicine, mainly produced in other country and area, on OP were also reviewed and summarized. Ethanol extract from the whole plant, Cissus quadrangularis Linn.


Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )

from Thailand, was evaluated for its anti-osteoporotic activity in OVX rat model [52] . After 3-month treatment, serum ALP and TRAP assay showed an enhancement of osteoblast activity but a reduction of osteoclast activity. Histopathological examination of the femurs revealed ossification, mineralization, calcified cartilaginous deposits and a marginal osteoclast activity, all of which indicated marked restoration. The anti-osteoporotic activity of Cissus quadrangularis may justifiably be attributed to the steroids present which probably act as phytoestrogens to effectively prevent or reduce bone loss by stimulation of metabolism and increase uptake of minerals [53] . Aneoctochilus formosanus Hayata (Orchidaceae) is one of the original plants of the precious crude drugs, used as a folk medicine in Taiwan for lung disease, pleurodynia, abdominal pain, fever, hypertension and snake-bites [54]. In the early of this century, scholars from Taiwan reported that 90-day repeated oral administration of crude aqueous extract of A. formosanus (AFE) markedly increased the pituitary weight, and decreased the uterine weight in female rats [55], suggesting that AFE may have the estrogen-related activities. Another animal experiment indicated that the extract from the whole plant was effective in suppressing the decrease in bone density and calcium content including the femur and the fourth lumbar vertebra [56]. Further comprehensive chemical and pharmacological investigations will be needed to elucidate the exact mechanism of AFE's action. A recent phytochemical study on the plant Onobrychis ebenoides showed that two of the three benzofurans isolated had an estrogen receptor binding affinity of 0.29 and 0.28 [57]. The study in vivo showed a highly significant protective effect on BMD of the whole tibia of OVX rats after 3 and 6 months of treatment, compared to the non-treated animals [58]. Further analytical studies of the substances in O. ebenoides' extract are needed, as well as its study in prospective clinical trials of postmenopausal women with bone loss. In addition, the ethanol extracts from aerial parts of W. calendulacea Less., collected from Karnataka, India, had a definite protective effect on osteoporotic rats induced by estrogen deficiency [59]. Phytochemical investigation revealed the presence of isoflavones and wedelolactone, which are known to act as phytoestrogens and may be responsible for the antiosteoporotic activity. Maca ( Lepidium meyenii Walp. ) is a cruciferous plant from the Andes of Peru. The root of Maca is traditionally employed for its supposed properties in aphrodisiacs and improving fertility, it also has been widely used to help alleviate the symptoms of menopause. The findings derived from the basis of bone mineral density, biomechanical, biochemical and histopathological parameters indicated that it was effective in the prevention of ovariectomy-induced bone

loss [60].


Through reviewing basic researches on the efficacy of medicinal herbs in the treatment of OP of the past few decades, this review provides a foundation for future researches on drugs of OP treatment. The advantages of medicinal herbs should be better explored with respect to its role in the prevention and treatment of OP. This forms bases to widen the existing scope of the use of medicinal herbs so as to spur on the development of TCM, and promote the modernization of research of TCM.


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Anti-osteoporotic Effects of Medicinal Herbs and their Mechanisms of Action / Asian Journal of Traditional Medicines, 2006, 1 ( 3-4 )

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