ReviewSalvia miltiorrhiza: An ancient Chinese herbal medicine as a source for anti-osteoporotic drugs
Graphical abstract
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.
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