Salvia miltiorrhiza: an ancient Chinese herbal medicine as a source for anti-osteoporotic drugs.

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.

[1]  Liwei Guo,et al.  Systematic review of recent advances in pharmacokinetics of four classical Chinese medicines used for the treatment of cerebrovascular disease. , 2013, Fitoterapia.

[2]  Hong-Hee Kim,et al.  Inhibition of osteoclast differentiation and bone resorption by tanshinone IIA isolated from Salvia miltiorrhiza Bunge. , 2004, Biochemical pharmacology.

[3]  Mingyao Liu,et al.  Caffeic acid 3,4‐dihydroxy‐phenethyl ester suppresses receptor activator of NF‐κB ligand–induced osteoclastogenesis and prevents ovariectomy‐induced bone loss through inhibition of mitogen‐activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T‐cells cytoplasmic 1 signali , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  R. Jilka,et al.  Sex steroids and bone. , 2002, Recent progress in hormone research.

[5]  B. Li,et al.  Characterization of Salvia Miltiorrhiza ethanol extract as an anti-osteoporotic agent , 2011, BMC complementary and alternative medicine.

[6]  Yongjun Wang,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 , 2012, Menopause.

[7]  Donald S. Williams,et al.  Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. , 2013, Bone.

[8]  J. Banu,et al.  Causes, consequences, and treatment of osteoporosis in men , 2013, Drug design, development and therapy.

[9]  G. Isaia,et al.  The use of raloxifene in osteoporosis treatment , 2013, Expert opinion on pharmacotherapy.

[10]  L. Cui,et al.  Salvianolic acid B promotes osteogenesis of human mesenchymal stem cells through activating ERK signaling pathway. , 2014, The international journal of biochemistry & cell biology.

[11]  S. Teitelbaum,et al.  Bone resorption by osteoclasts. , 2000, Science.

[12]  K. Väänänen,et al.  Mechanism of osteoclast mediated bone resorption--rationale for the design of new therapeutics. , 2005, Advanced drug delivery reviews.

[13]  Yoshitaka Hashimoto,et al.  Bone turnover markers and pharmacokinetics of a new sustained-release formulation of the cathepsin K inhibitor, ONO-5334, in healthy post-menopausal women , 2013, Journal of Bone and Mineral Metabolism.

[14]  L. Foo,et al.  Polyphenolics of Salvia--a review. , 2002, Phytochemistry.

[15]  L. Cui,et al.  Tanshinone prevents cancellous bone loss induced by ovariectomy in rats. , 2004, Acta pharmacologica Sinica.

[16]  D. Yamashita,et al.  Cathepsin K and the design of inhibitors of cathepsin K. , 2000, Current pharmaceutical design.

[17]  Zhong Zuo,et al.  Danshen: An Overview of Its Chemistry, Pharmacology, Pharmacokinetics, and Clinical Use , 2005, Journal of clinical pharmacology.

[18]  Haoran Cui.  Characterization of glycosaminoglycan interaction sites and exosite inhibitors of cathepsin K , 2014 .

[19]  M. Shiao,et al.  Salvianolic acid B enhances in vitro angiogenesis and improves skin flap survival in Sprague-Dawley rats. , 2003, The Journal of surgical research.

[20]  Ameeduzzafar,et al.  Bisphosphonates: therapeutics potential and recent advances in drug delivery , 2015, Drug delivery.

[21]  M. Shiao,et al.  Salvianolic acid b enhances in vitro angiogenesis and improves skin flap survival in sprague-dawley rats1 ☆ , 2003 .

[22]  Zhen Gao,et al.  Study of osteoporosis treatment principles used historically by ancient physicians in Chinese Medicine , 2013, Chinese Journal of Integrative Medicine.

[23]  A. Rabie,et al.  Effects of medicinal herb salvia miltiorrhiza on osteoblastic cells in vitro , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[24]  E. Woo,et al.  Inhibition of osteoclast differentiation by tanshinones from the root ofSalvia miltiorrhiza Bunge , 2005, Archives of pharmacal research.

[25]  S. Cremers,et al.  Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis , 2011, Nature Reviews Rheumatology.

[26]  Shufeng Zhou,et al.  Herb-drug interactions and mechanistic and clinical considerations. , 2012, Current drug metabolism.

[27]  Zou Li.  Preventing cancellous bone loss in steroid-treated rats and stimulating bone formation by water extract of salvia miltiorrhixa and danshensu , 2004 .

[28]  K. Lee,et al.  New developments in the chemistry and biology of the bioactive constituents of tanshen , 2007, Medicinal research reviews.

[29]  R. Wong,et al.  The Role of Traditional Chinese Medicines in Osteogenesis and Angiogenesis , 2014, Phytotherapy research : PTR.

[30]  P. Saftig,et al.  Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. , 2009, The American journal of pathology.

[31]  Zheng-Tao Wang,et al.  Advancement in analysis of Salviae miltiorrhizae Radix et Rhizoma (Danshen). , 2009, Journal of chromatography. A.

[32]  R. Chapurlat.  RETRACTED: Odanacatib for the treatment of postmenopausal osteoporosis , 2014, Expert opinion on pharmacotherapy.

[33]  Y. Wang,et al.  Effects of traditional Chinese medicine on bone remodeling during orthodontic tooth movement. , 2012, Journal of ethnopharmacology.

[34]  Yong Peng,et al.  Prevention and Treatment of Osteoporosis with Chinese Herbal Medicines , 2012 .

[35]  N. Sims,et al.  Implications of Osteoblast-Osteoclast Interactions in the Management of Osteoporosis by Antiresorptive Agents Denosumab and Odanacatib , 2014, Current Osteoporosis Reports.

[36]  N. Sims,et al.  Intercellular Cross-Talk Among Bone Cells: New Factors and Pathways , 2012, Current Osteoporosis Reports.

[37]  L. Duong,et al.  The Bone Resorption Inhibitors Odanacatib and Alendronate Affect Post-Osteoclastic Events Differently in Ovariectomized Rabbits , 2013, Calcified Tissue International.

[38]  Yongjun Wang,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]. , 2011, Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine.

[39]  Tie Wu,et al.  Salvianolic Acid B Prevents Bone Loss in Prednisone-Treated Rats through Stimulation of Osteogenesis and Bone Marrow Angiogenesis , 2012, PloS one.

[40]  M. Shiao,et al.  Crude extract of Salvia miltiorrhiza and salvianolic acid B enhance in vitro angiogenesis in murine SVR endothelial cell line. , 2003, Planta medica.

[41]  Hyung-Ryong Kim,et al.  Prevention of Bone Loss in Ovariectomized Rats: The Effect of Salvia miltiorrhiza Extracts , 2004, Immunopharmacology and immunotoxicology.

[42]  Hong-Hee Kim,et al.  Tanshinone IIA suppresses inflammatory bone loss by inhibiting the synthesis of prostaglandin E2 in osteoblasts. , 2008, European journal of pharmacology.

[43]  D. Brömme.  Cysteine Cathepsins and the Skeleton , 2011 .

[44]  C. Debouck,et al.  Cathepsin K, but Not Cathepsins B, L, or S, Is Abundantly Expressed in Human Osteoclasts (*) , 1996, The Journal of Biological Chemistry.

[45]  Yunxia Liu,et al.  Chinese herbal medicines for treating osteoporosis. , 2014, The Cochrane database of systematic reviews.

[46]  K. Lippuner.  The future of osteoporosis treatment - a research update. , 2012, Swiss medical weekly.

[47]  Sang-Joon Park,et al.  Anabolic activity of ursolic acid in bone: Stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo. , 2008, Pharmacological research.

[48]  Yan Zhu,et al.  The anti-inflammatory activities of Tanshinone IIA, an active component of TCM, are mediated by estrogen receptor activation and inhibition of iNOS , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[49]  P. Esbrit,et al.  Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies. , 2013, Biochemical pharmacology.

[50]  J. Vandromme,et al.  Postmenopausal hormone therapy: risks and benefits , 2013, Nature Reviews Endocrinology.

[51]  N. Hamdy.  Targeting the RANK/RANKL/OPG signaling pathway: a novel approach in the management of osteoporosis. , 2007, Current opinion in investigational drugs.

[52]  S. Lei,et al.  Ethnic difference in osteoporosis-related phenotypes and its potential underlying genetic determination. , 2006, Journal of musculoskeletal & neuronal interactions.

[53]  Yu-Tse Wu,et al.  Biological analysis of herbal medicines used for the treatment of liver diseases. , 2011, Biomedical chromatography : BMC.

[54]  Kelvin Chan,et al.  Herb-drug interactions with Danshen (Salvia miltiorrhiza): a review on the role of cytochrome P450 enzymes , 2012, Drug metabolism and drug interactions.

[55]  Jian-Xin Li,et al.  Quinoxaline derivative of oleanolic acid inhibits osteoclastic bone resorption and prevents ovariectomy-induced bone loss , 2011, Menopause.

[56]  Pu Liu,et al.  Triterpenoids from the Flowers of Salvia miltiorrhiza , 2011 .

[57]  Minhui Li,et al.  Investigation of Danshen and related medicinal plants in China. , 2008, Journal of ethnopharmacology.

[58]  M. Maitz,et al.  The effect of the major components of Salvia Miltiorrhiza Bunge on bone marrow cells. , 2007, Journal of ethnopharmacology.

[59]  Seungbok Lee,et al.  Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1 , 2006, Experimental & Molecular Medicine.

[60]  Sung-Hoon Kim,et al.  Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities , 2012, International journal of molecular sciences.

[61]  Xiao-rong Li,et al.  Simultaneous quantification of selected compounds from Salvia herbs by HPLC method and their application , 2012 .

[62]  Claes Ohlsson,et al.  Bone metabolism in 2012: Novel osteoporosis targets , 2013, Nature Reviews Endocrinology.

[63]  J. Syme.  Clinical Observations , 1861, British medical journal.

[64]  S. Boonen,et al.  Inhibition of Cathepsin K for Treatment of Osteoporosis , 2012, Current Osteoporosis Reports.

[65]  The Consequences of Lysosomotropism on the Design of Selective Cathepsin K Inhibitors , 2006, Chembiochem : a European journal of chemical biology.

[66]  P. Delmas,et al.  The Collagenolytic Activity of Cathepsin K Is Unique among Mammalian Proteinases* , 1998, The Journal of Biological Chemistry.

[67]  S. Shintani,et al.  Potential anti-osteoporotic effects of herbal extracts on osteoclasts, osteoblasts and chondrocytes in vitro , 2014, BMC Complementary and Alternative Medicine.

[68]  Jiaolin Bao,et al.  The Anticancer Properties of Salvia Miltiorrhiza Bunge (Danshen): A Systematic Review , 2014, Medicinal research reviews.

[69]  A. Zallone,et al.  Osteoblast and osteoclast crosstalks: from OAF to Ephrin. , 2012, Inflammation & allergy drug targets.

[70]  Mei Dong,et al.  Constituents from Salvia species and their biological activities. , 2012, Chemical reviews.

[71]  F. Dal Piaz,et al.  Inhibition of bone resorption by Tanshinone VI isolated from Salvia miltiorrhiza Bunge , 2010, European journal of histochemistry : EJH.

[72]  M. Jia,et al.  Potential Antiosteoporotic Agents from Plants: A Comprehensive Review , 2012, Evidence-based complementary and alternative medicine : eCAM.

[73]  T. Cheng.  Cardiovascular effects of Danshen. , 2007, International journal of cardiology.

[74]  C. Benhamou,et al.  Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. , 2012, Journal of the American Academy of Dermatology.

[75]  L. Zhijun.  Effect of Anti-osteoporosis Capsule on Ostealgia and Bone Metabolism of Postmenopausal Osteoporosis Patients , 2011 .

[76]  R. Bauer,et al.  Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells. , 2007, Atherosclerosis.

[77]  D. Brömme,et al.  Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. , 1995, Biological chemistry Hoppe-Seyler.

[78]  Je-Yong Choi,et al.  The Correlation of Salvia miltiorrhiza Extract–Induced Regulation of Osteoclastogenesis with the Amount of Components Tanshinone I, Tanshinone IIA, Cryptotanshinone, and Dihydrotanshinone , 2008 .

[79]  J. Gossen,et al.  Inhibitors of cathepsin K: a patent review (2004 – 2010) , 2011, Expert opinion on therapeutic patents.

[80]  R. Josse,et al.  Denosumab, a new pharmacotherapy option for postmenopausal osteoporosis , 2013, Current medical research and opinion.

[81]  M. Gupta,et al.  Emerging therapies for the treatment of osteoporosis , 2013, Journal of mid-life health.

[82]  J. Folwarczna,et al.  Effects of Natural Phenolic Acids on the Skeletal System of Ovariectomized Rats , 2009, Planta medica.

[83]  J Denton,et al.  Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis , 2002, Journal of clinical pathology.

[84]  L. Cui,et al.  Osteogenic effects of D(+)β-3,4-dihydroxyphenyl lactic acid (salvianic acid A, SAA) on osteoblasts and bone marrow stromal cells of intact and prednisone-treated rats , 2009, Acta Pharmacologica Sinica.

[85]  M. van der Elst,et al.  Increasing rates of pelvic fractures among older adults: The Netherlands, 1986-2011. , 2014, Age and ageing.

[86]  M. Maricic.  Oral Calcitonin , 2012, Current Osteoporosis Reports.

[87]  J. Palmer,et al.  Localization of Rat Cathepsin K in Osteoclasts and Resorption Pits: Inhibition of Bone Resorption and Cathepsin K-Activity by Peptidyl Vinyl Sulfones , 1999, Biological chemistry.