title: Salvia miltiorrhiza: an ancient Chinese herbal medicine as a source for anti-osteoporotic drugs.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Diabetes Research Center, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Oral Biological and Medical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Liming
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Oral Biological and Medical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Richele P
authors.initials: RP
authors.lastname: Severino
authors.affiliation: Diabetes Research Center, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
authors.forename: Sihua
authors.initials: S
authors.lastname: Gao
authors.affiliation: School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China.
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Pharmacognosy, Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Qin
authors.affiliation: Diabetes Research Center, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, PR China; Department of Oral Biological and Medical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T1Z3. Electronic address: dongwei1006@gmail.com.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Oral Biological and Medical Sciences, The University of British Columbia, Vancouver, BC, Canada V6T1Z3. Electronic address: dbromme@dentistry.ubc.ca.
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy*; D064209:Phytochemicals / Q000032:analysis; D027561:Salvia miltiorrhiza / Q000737:chemistry
chemical_list: D045930:Anabolic Agents; D050071:Bone Density Conservation Agents; D004365:Drugs, Chinese Herbal; D064209:Phytochemicals; D056657:Cathepsin K
keywords: Anti-resorptive activity; Danshen; Osteoporosis; Pro-anabolic activity; Salvia miltiorrhiza; Salvianolic acid A, CID 5281793; caffeic acid, CID 689043; cryptotanshinone, CID 160254; oleanolic acid, CID 10494; p-coumaric acid, CID 637542; raloxifene, CID 5035; salvianolic acid B (Synonym: Salvianic acid B), CID 11629084; tanshinone I, CID 114917; tanshinone IIA, CID 164676; ursolic acid, CID 64945