Elsevier

Journal of Ethnopharmacology

Volume 155, Issue 3, 29 September 2014, Pages 1401-1416
Journal of Ethnopharmacology

Review
Salvia miltiorrhiza: An ancient Chinese herbal medicine as a source for anti-osteoporotic drugs

https://doi.org/10.1016/j.jep.2014.07.058Get rights and content

Abstract

Ethnopharmacological relevance

Red sage (Salvia miltiorrhiza Bunge), also known as Danshen in Chinese, has been used historically and is currently exploited in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM). With the advance of modern analytical technology, a multitude of bone-targeting, pharmaceutically active, compounds has been isolated and characterized from various sources of TCM including those produced in Salvia miltiorrhiza root. The aim of the review is to provide a comprehensive overview about the historical TCM interpretation of the action of Salvia miltiorrhiza in osteoporosis, its use clinical trials, its main phytochemical constituents, and its action on bone-resorptive and bone formation-stimulating mechanisms in in vitro and in vivo studies.

Materials and methods

Literature sources used were Pubmed, CNKI.net, Cqvip.com, PubChem, and the Web of Science. For the inquiry, keywords such as Salvia, danshen, osteoporosis, bone, osteoclast and osteoblast were used in various combinations. About 130 research papers and reviews were consulted.

Results

In TCM, the anti-osteopororotic effect of Salvia miltiorrhiza is ascribed to its action on liver and blood stasis as main therapeutic targets defining osteoporosis. 36 clinical trials were identified which used Salvia miltiorrhiza in combination with other herbs and components to treat post-menopausal, senile, and secondary osteoporosis. On average the trials were characterized by high efficacy (>80%) and low toxicity problems. However, various limitations such as small patient samples, short treatment duration, frequent lack of detailed numerical data, and no clear endpoints must be taken into consideration. To date, more than 100 individual compounds have been isolated from this plant and tested in various animal models and biochemical assays. Compounds display anti-resorptive and bone formation-stimulating features targeting different pathways in the bone remodeling cycle. Pathways affected include the activation of osteoblasts, the modulation of osteoclastogenesis, and the inhibition of collagen degradation by cathepsin K.

Conclusions

The inclusion of Salvia miltiorrhiza in more than 30% of all herbal clinical trials successfully targeting osteoporosis has stimulated significant interest in the identification and characterization of individual constituents of this herb. The review highlights the anti-osteoporotic potential of Salvia miltiorrhiza in clinical applications and the potential of the herb to provide potent compounds targeting specific pathways in bone resorption and bone formation.

Introduction

Red sage (Salvia miltiorrhiza Bunge), known as Danshen in Chinese, is a member of the genus Salvia of the mint family, Lamiaceae. As one of the best-known Chinese traditional herbs, its root has been clinically used for more than 2000 years. It should be noted that there have been more than 20 Salvia species used under the name of Danshen. According to the Chinese Pharmacopoeia (PPRC-2010, 2010), only Salvia miltiorrhiza meets the requirements to be ascribed as the formal Danshen (Li et al., 2008). The herb was first recorded as a “super grade” herb (The ancient term “super grade” was given to herbs lacking observable toxicity.) in the Shennong׳s Herbal Atlas (Shennong Bencao Jing) written during the reign of the Qin and Han dynasties (221 BC to 220 AD). Following this first record, Salvia miltiorrhiza was also described in classical traditional Chinese medicine (TCM) books such as in the Compendium of Materia Medica (Bencao Gangmu, Ming dynasty, 1596 AD). In the textbooks of academic TCM, Salvia miltiorrhiza is characterized as a common hemorrheologic drug with the following functions: to promote blood flow in menstruation, to remove blood stasis, to reduce pain, to resolve mental uneasiness and restlessness, to nourish the blood, and to tranquilize the mind. The broad study of Salvia miltiorrhiza is reflected in 25,000 publications cited in the Chinese National Knowledge Infrastructure (www.cnki.net) and in almost 19,000 citations in the Scifinder database (www.cas.org/products/scifinder). The herb has been officially recorded in the Chinese Pharmacopoeia since 1963. Modern research revealed that Salvia miltiorrhiza contains a large number of lipophilic diterpenoids (such as various tanshinone analogs), hydrophilic phenolic compounds (such as salvianolic acids), flavonoids, and triterpenoids (Lu and Foo, 2002, Zhou et al., 2005, Wang et al., 2007, Li et al., 2009). Pharmacological studies revealed that Salvia miltiorrhiza exhibits a protective role in the cardiovascular system (Cheng, 2007), liver (Chien et al., 2011), and brain (Zeng et al., 2013) and has anti-cancer activity (Chen et al., 2013). Although Salvia miltiorrhiza has traditionally been used in the treatment of osteoporosis (Jia et al., 2012), data about the biochemical and pharmacological effects of its constituents in this disease have only recently become available.

Osteoporosis is a chronic progressive bone disease of multifactorial etiology affecting 75 million patients in the United States, Europe, and Japan alone. Worldwide it is the cause of more than 8.9 million fractures annually. In China, 88 million patients have been estimated to have primary osteoporosis, a disease characterized by low bone mass and micro-architectural deterioration of bone tissue (Lei et al., 2006). According to the World Health Organization (WHO), osteoporosis is a reduction of the bone mineral density by 2.5 standard deviations or more below the mean peak bone mass. The Merck manual (http://www.merckmanuals.com/professional/musculoskeletal_and_connective_tissue_disorders/osteoporosis/osteoporosis.html). classifies osteoporosis into two main categories: (i) primary osteoporosis, which comprises 95% of osteoporosis in women and 80% in men and primarily occurs in postmenopausal women and older men, and (ii) secondary osteoporosis, which is caused by medication, immobilization, kidney, liver, and endocrine diseases, rheumatoid arthritis, hypercalcuria, and malabsorbtion syndromes. Alternatively, osteoporosis has been divided into 4 types: Type I (postmenopausal osteoporosis), Type II (senile osteoporosis due to calcium deficiency in people over 70 years old), Type III (triggered by disease or drugs, including endocrine osteoporosis, nutritional deficiency osteoporosis, drug-induced osteoporosis, renal osteoporosis, etc), and Type IV (idiopathic juvenile osteoporosis, which is more common in 8–14 year old teenagers, has a genetic link, and is more frequent in females than males) (Zhao et al., 2012).

Incidence rates of osteoporosis and fracture risks have significantly increased during the last decade (Nanninga et al., 2014). It is considered to be a global public health problem and will affect one out of three women and one out of five men (Banu, 2013). Pharmaceutical research efforts are focused on the development of more efficient treatments to prevent disease progression (Ohlsson, 2013). Current treatment regimes include bisphosphonates (Fazil et al., 2014), estrogen replacement therapy (Rozenberg et al., 2013), the RANKL-antibody, denosumab (Josse et al., 2013), parathyroid hormone (Esbrit and Alcaraz, 2013), calcitonin (Maricic, 2012), and selective estrogen receptor modulators (D׳Amelio and Isaia, 2013). Chloride channel and c-Src kinase inhibitors are novel drug candidates currently in development (Bhutani and Gupta, 2013). A cathepsin K inhibitor that blocks collagen degradation by osteoclasts has shown high efficacy in phase III osteoporosis trials (Costa et al., 2011, Chapurlat, 2014).

A number of reviews concerning the use of Chinese herbal medicines for osteoporosis have been recently published (Zhao et al., 2012, Wang et al., 2013, Liu et al., 2014, Mukudai et al., 2014, Yang et al., 2014). Here, we review the clinical use of Salvia miltiorrhiza in the management of osteoporosis, the current knowledge of its anti-resorptive and bone formation-stimulating activity, and our recent finding of a direct inhibitory effect of Salvia miltiorrhiza-specific diterpenoids on cathepsin K. First, we will summarize the interpretation of the action of Salvia miltiorrhiza in TCM, which helps to explain the rationale of clinical trials using this herb in various combinations with other medicinal plants and natural extracts to treat osteoporosis in China.

Section snippets

The bone-protective activity of Salvia miltiorrhiza in the theory of traditional Chinese medicine

Salvia miltiorrhiza is a perennial plant (Fig. 1A) that mainly grows in the Sichuan, Anhui, Jiangsu, Henan, and Shanxi provinces of China. Its root (Fig. 1B) is usually harvested in spring or autumn every year. After slicing and drying, the root is processed with wine prior to being used to treat a patient. In TCM, Salvia miltiorrhiza is recognized as a herb with a bitter-flavor (here the word flavor not only reflects the taste of the herb but also corresponds to a physiological response and

Salvia miltiorrhiza in clinical trials of osteoporosis

Liu et al. (2014) evaluated 108 randomized trials with 10,655 Chinese participants for primary anti-osteoporotic efficacy with 99 different Chinese herbal prescriptions (Liu et al., 2014). 16 of these trials included Salvia miltiorrhiza. 61 trials compared TCM treatment with conventional medicine (such as caltrate, vitamin D2, calcitonine, estrogen, alendronate), where 23 herbal medicine trials showed a statistically more significant effect on increasing bone mineral density (BMD). Out of 48

Phytochemistry of Salvia miltiorrhiza

The last two decades have resulted in a dramatic gain in knowledge about the molecular constituents of Chinese medicinal plants suitable as anti-osteoporotic drugs (Jia et al., 2012, Zhao et al., 2012). To date there have been more than 100 compounds isolated from Salvia miltiorrhiza roots and characterized. They can be classified into two major groups: (i) hydrophilic and (ii) lipophilic (Cheng et al., 2012). The major water-soluble/hydrophilic compounds are various phenolic acids often

Efficacy of Salvia miltiorrhiza in osteoporosis animal models

Rodents have been treated with water and ethanolic extract of Salvia miltiorrhiza (SM) as well as with their hydrophilic and lipophilic individual components. First we will review experiments using aqueous extracts and water-soluble constituents of Salvia miltiorrhiza (SM). The first paper that described an anti-osteoporotic effect of aqueous SM extracts was published in 2004 and showed a protective role of the herb in ovariectomized (ovx) osteoporotic rats (Chae et al., 2004). The

Effects of Salvia miltiorrhiza compounds on cathepsin K inhibition

To date, all of the molecular effects of SM extracts and its chemical components have been attributed to interferences on regulatory pathways regulating either the expression of various kinases, cytokines, or markers of bone remodeling, which directly or indirectly affect the presence of osteoclasts and osteoblasts in bone remodeling units. Nothing is known regarding the direct effects on executioner catalysts such as proteases responsible for the degradation of the organic bone matrix or the

Conclusion and outlook

Salvia miltiorrhiza is a clinically widely used Chinese herb. Based on TCM teachings, the nature of multi-meridian tropism combined with its bitter and cold properties made Salvia miltiorrhiza a favored herb for the treatment of osteoporosis. 36 clinical trials were identified that used Salvia miltiorrhiza as one of their components. Although most studies report promising efficacy in terms of improving BMD and reducing pain, their significance is limited due to small patient sample size (in

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (Nos. 81173642, 81274041 and 81273995), International Cooperation Projects of MOE (2011DFA30920), Key Drug Development Program of MOST (20122X09103201), 973 Program (No. 2009CB522700) and the 111 Project (B07007) as well as the Canadian Institutes of Health Research operating Grant MOP125866 (DB). The authors would like to thank Ingrid Ellis for her editorial assistance in the final preparation of the manuscript.

References (129)

  • M.H. Li et al.

    Investigation of Danshen and related medicinal plants in China

    Journal of Ethnopharmacology

    (2008)
  • Y.G. Li et al.

    Advancement in analysis of Salviae miltiorrhizae Radix et Rhizoma (Danshen)

    Journal of Chromatography A

    (2009)
  • Y.R. Liu et al.

    The effect of the major components of Salvia Miltiorrhiza Bunge on bone marrow cells

    Journl of Ethnopharmacology

    (2007)
  • Y. Lu et al.

    Polyphenolics of salvia – a review

    Phytochemistry

    (2002)
  • K. Vaananen

    Mechanism of osteoclast mediated bone resorption – rationale for the design of new therapeutics

    Advances in Drug Delivery Reviews

    (2005)
  • J. Banu

    Causes, consequences, and treatment of osteoporosis in men

    Drug Design, Development and Therapy

    (2013)
  • G. Bhutani et al.

    Emerging therapies for the treatment of osteoporosis

    Journal of Midlife Health

    (2013)
  • Q. Bian et al.

    [Effects of active ingredients in three kidney-tonifying Chinese herbal drugs on gene expression profile of bone marrow stromal cells from a rat model of corticosterone-induced osteoporosis]

    Zhong Xi Yi Jie He Xue Bao

    (2011)
  • Q. Bian et al.

    Oleanolic acid exerts an osteoprotective effect in ovariectomy-induced osteoporotic rats and stimulates the osteoblastic differentiation of bone mesenchymal stem cells in vitro

    Menopause

    (2012)
  • W.C. Black et al.

    The consequences of lysosomotropism on the design of selective cathepsin K inhibitors

    ChemBioChem

    (2006)
  • S. Boonen et al.

    Inhibition of cathepsin K for treatment of osteoporosis

    Current Osteoporosis Reports

    (2012)
  • D. Bromme et al.

    Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution

    Biological Chemistry Hoppe Seyler

    (1995)
  • D. Bromme et al.

    Cathepsin K inhibitors for osteoporosis and potential off-target effects

    Expert Opinion on Investigational Drugs

    (2009)
  • D. Bromme

    Cystein cathepsins and the skeleton

    Clinical Reviews in Bone and Mineral Metabolism

    (2011)
  • H.J. Chae et al.

    Prevention of bone loss in ovariectomized rats: the effect of Salvia miltiorrhiza extracts

    Immunopharmacology & Immunotoxicology

    (2004)
  • R.D. Chapurlat

    Odanacatib for the treatment of postmenopausal osteoporosis

    Expert Opinion on Pharmacotherapy

    (2014)
  • J. Chen et al.

    Clinical observations on the effect of Gukang oral liquid on post-menopausal osteoporosis in 36 cases

    Journal of New Chinese Medicine

    (1999)
  • X.W. Chen et al.

    Herb-drug interactions and mechanistic and clinical considerations

    Current Drug Metabolism

    (2012)
  • X. Chen et al.

    The anticancer properties of Salvia Miltiorrhiza bunge (Danshen): a systematic review

    Medicinal Research Reviews

    (2013)
  • C.F. Chien et al.

    Biological analysis of herbal medicines used for the treatment of liver diseases

    Biomedical Chromatography

    (2011)
  • A. Chin et al.

    Effects of medicinal herb Salvia miltiorrhiza on osteoblastic cells in vitro

    Journal of Orthopaedic Research

    (2011)
  • A.G. Costa et al.

    Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis

    Nature Reviews Rheumatology

    (2011)
  • L. Cui et al.

    Tanshinone prevents cancellous bone loss induced by ovariectomy in rats

    Acta Pharmacology Sinica

    (2004)
  • L. Cui et al.

    Preventing cancellous bone loss in steroid-treated rats and stimulating bone formation by water extract of Salvia miltiorrhixa and danshensu

    Chinese Pharmacological Bulletin

    (2004)
  • L. Cui et al.

    Osteogenic effects of D+beta-3,4-dihydroxyphenyl lactic acid (salvianic acid A, SAA) on osteoblasts and bone marrow stromal cells of intact and prednisone-treated rats

    Acta Pharmacology Sinica

    (2009)
  • Y. Cui et al.

    Characterization of Salvia miltiorrhiza ethanol extract as an anti-osteoporotic agent

    BMC Complementary Alternative Medicine

    (2011)
  • L. Cui et al.

    Salvianolic acid B prevents bone loss in prednisone-treated rats through stimulation of osteogenesis and bone marrow angiogenesis

    PLoS One

    (2012)
  • H. Cui

    Characterization of glycosaminoglycan interaction sites and exosite inhibitors of cathepsin K. Craniofacial Science

    (2014)
  • P. D׳Amelio et al.

    The use of raloxifene in osteoporosis treatment

    Expert Opinion on Pharmacotherapy

    (2013)
  • M. Fazil et al.

    Bisphosphonates: therapeutics potential and recent advances in drug delivery

    Drug Delivery

    (2014)
  • J. Folwarczna et al.

    Effects of natural phenolic acids on the skeletal system of ovariectomized rats

    Planta Medica

    (2009)
  • S. Fu et al.

    [Biomechanical experimental study on effective fraction of radix Salviae miltiorrhizae on healing of bone fracture]

    Zhongguo Zhong Xi Yi Jie He Za Zhi

    (1999)
  • Z. Gao et al.

    Study of osteoporosis treatment principles used historically by ancient physicians in Chinese Medicine

    Chinese Journal of Integrative Medicine

    (2013)
  • Z. Gong

    Clinical research of modified Qing׳e pill on diabetic osteoporosis

    Journal of Emergency in TCM

    (2012)
  • B. Guo et al.

    MRI diagnosis and clinical comorehensive treatment for transientoOsteoporosis of the hip joint

    Journal Practical Radiology

    (2007)
  • N.A. Hamdy

    Targeting the RANK/RANKL/OPG signaling pathway: a novel approach in the management of osteoporosis

    Current Opinion on Investigative Drugs

    (2007)
  • M.Z. Hu

    [Effect of radix salviae miltiorrhizae on the mitotic activity of osteoblast-like cells isolated from chicken embryo calvariae cultured in vitro]

    Zhonghua Wai Ke Za Zhi

    (1993)
  • J. Hu et al.

    Clinical observation of bushen jianpi treatment of primary osteoporosis

    Hubei Journal of TCM

    (2012)
  • L. Huan et al.

    Clinical study of therapy of nourishing kidney and strengthening bone in preventing and treating glucocorticoid-induced osteoporosis of nephrotic syndrome patients

    Journal of Guangzhou University of Traditional Chinese Medicine

    (2013)
  • Y. Huang et al.

    Clinical study on the effect of Chinese medicine Gukang prescription on osteoporosis and osteoarthritis

    Chinese Journal of Ethnomedicine and Ethnopharmacy

    (2011)
  • Cited by (0)

    View full text