- Department of Orthopaedics, the First People’s Hospital of Yunnan Province, Kunming Yunnan, 650001, P.R.China. Corresponding author: MENG Zengdong, E-mail: menggu7119@vip.sina.com;
Objective To review the research progress of the osteogenic effect of strontium (Sr) and its application in the orthopaedics. Methods The recent literature concerning the osteogenic effect of Sr and its application in orthopaedics at home and abroad was extensively reviewed, and the research and development were summarized. Results Both in vivo and in vitro studies showed that Sr could enhance bone formation and inhibit bone resorption. Clinically, Sr was applied for treatment of osteoporosis, composite biomaterials in tissue engineering, and treatment of bone tumors and bone metastases. Conclusion Sr is one important combined element of alternative materials in bone tissue engineering, and can strengthen the mechanical and biological properties of the bone replacement material, so it has some development potential in bone tissue engineering.
Citation: LI Lei,LEI Yunkun,MENG Zengdong. PROGRESS OF OSTEOGENIC EFFECT OF STRONTIUM AND ITS APPLICATION IN ORTHOPAEDICS. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(11): 1398-1402. doi: Copy
1. | Langer R, Vacanti P. Tissue engineering. Science, 1993, 260(5110): 920-926. |
2. | Dahl SG, Allain P, Marie PJ, et al. Incorporation and distribution of strontium in bone. Bone, 2001, 28(4): 446-453. |
3. | Reginster JY, Deroisy R, Jupsin I. Strontium ranelate: a new paradigm in the treatment of osteoporosis. Drugs Today (Barc), 2003, 39(2): 89-101. |
4. | Jupsin I, Collette J, Henrotin Y, et al. Strontium ranelate (Fujisawa/Servier). Curr Opin Investig Drugs, 2005, 6(4): 435-444. |
5. | Marie PJ. Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int, 2005, 16 Suppl 1: S7-10. |
6. | Bonnelye E, Chabadel A, Saltel F, et al. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone, 2008, 42(1): 129-138. |
7. | Reginster JY, Deroisy R, Neuprez A, et al. Strontium ranelate: new data on fracture prevention and mechanisms of action. Curr Osteoporos Rep, 2009, 7(3): 96-102. |
8. | Fromigué O, Haÿ E, Barbara AE, et al. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J Biol Chem, 2010, 285(33): 25251-25258. |
9. | Trouvin AP, Goëb V. Receptor activator of nuclear factor-κB ligand and osteoprotegerin: maintaining the balance to prevent bone loss. Clin Interv Aging, 2010, 5: 345-354. |
10. | Paes FM, Serafini AN. Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain. Semin Nucl Med, 2010, 40(2): 89-104. |
11. | Das T, Chakraborty S, Sarma HD, et al. (170)Tm-EDTMP: a potential cost-effective alternative to (89)SrCl(2) for bone pain palliation. Nucl Med Biol, 2009, 36(5): 561-568. |
12. | Römer P, Behr M, Proff P, et al. Effect of strontium on human Runx2+/- osteoblasts from a patient with cleidocranial dysplasia. Eur J Pharmacol, 2011, 654(3): 195-199. |
13. | Peng S, Liu XS, Huang S, et al. The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin. Bone, 2011, 49(6): 1290-1298. |
14. | Yamaguchi M, Weitzmann MN. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation. Mol Cell Biochem, 2011, 359(1-2): 399-407. |
15. | Rybchyn MS, Slater M, Conigrave AD, et al. An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts. J Biol Chem, 2011, 286(27): 23771-23779. |
16. | Yang F, Yang D, Tu J, et al. Strontium enhances osteogenic differentiation of mesenchymal stem cells and in vivo bone formation by activating Wnt/catenin signaling. Stem Cells, 2011, 29(6): 981-991. |
17. | Caverzasio J, Thouverey C. Activation of FGF receptors is a new mechanism by which strontium ranelate induces osteoblastic cell growth. Cell Physiol Biochem, 2011, 27(3-4): 243-250. |
18. | Braux J, Velard F, Guillaume C, et al. A new insight into the dissociating effect of strontium on bone resorption and formation. Acta Biomater, 2011, 7(6): 2593-2603. |
19. | Ma HT, Peng Z, Hiragun T, et al. Canonical transient receptor potential 5 channel in conjunction with Orai1 and STIM1 allows Sr2+ entry, optimal influx of Ca2+, and degranulation in a rat mast cell line. J Immunol, 2008, 180(4): 2233-2239. |
20. | Caudrillier A, Hurtel-Lemaire AS, Wattel A, et al. Strontium ranelate decreases receptor activator of nuclear factor-κB ligand-induced osteoclastic differentiation in vitro: involvement of the calcium-sensing receptor. Mol Pharmacol, 2010, 78(4): 569-576. |
21. | Takaoka S, Yamaguchi T, Yano S, et al. The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization. Horm Metab Res, 2010, 42(9): 627-631. |
22. | Coulombe J, Fauren H, Robin B, et al. In vitro effects of strontium ranelate on the extracellular calcium-sensing receptor. Biochem Biophys Res Commun, 2004, 323(4): 1184-1190. |
23. | Verberckmoes SC, De Broe ME, D’Haese PC. Dose-dependent effects of strontium on osteoblast function and mineralization. Kidney Int, 2003, 64(2): 534-543. |
24. | 谢玲, 裴志东, 薛琪. 89锶治疗骨转移性癌痛的临床观察. 中国乡村医药, 2008, 15(5): 19-20. |
25. | 祁岗, 于梅花, 朱艳媚, 等. 90锶敷贴器治疗皮肤血管瘤疗效观察. 新医学, 2011, 42(4): 260-262. |
26. | MacDonald NS, Nusbaum RE, Stcarns R, et al. The skeletal deposition of non-radioactivc strontium. J Biol Chem, 1951, 188(1): 137-143. |
27. | Boivin G, Deloffre P, Perrat B, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res, 1996, 11(9): 1302-1311. |
28. | Brennan TC, Rybchyn MS, Green W, et al. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol, 2009, 157(7): 1291-1300. |
29. | Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998, 93(2): 165-176. |
30. | Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol, 2002, 22(4): 549-553. |
31. | Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 1999, 397(6717): 315-323. |
32. | Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology, 2001, 142(12): 5050-5055. |
33. | Ali MM, Yoshizawa T, Ishibashi O. PIASxbeta is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts. J Cell Sci, 2007, 120(Pt 15): 2565-2573. |
34. | Aliprantis AO, Ueki Y, Sulyanto R, et al. NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest, 2008, 118(11): 3775-3789. |
35. | Ikeda F, Nishimura R, Matsubara T, et al. Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone-resorbing activity. J Immunol, 2006, 177(4): 2384-2390. |
36. | Guo J, Jin J, Cooper LF. Dissection of sets of genes that control the character of wnt5a-deficient mouse calvarial cells. Bone, 2008, 43(5): 961-971. |
37. | Cheng SL, Shao JS, Cai J, et al. Msx2 exerts bone anabolism via canonical Wnt signaling. J Biol Chem, 2008, 283(29): 20505-20522. |
38. | Fromigué O, Haÿ E, Barbara A, et al. Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. J Cell Mol Med, 2009, 13(8B): 2189-2199. |
39. | Dong SW, Ying DJ, Duan XJ, et al. Bone regeneration using an acellular extracellular matrix and bone marrow mesenchymal stem cells expressing Cbfα1. Biosci Biotechnol Biochem, 2009, 73(10): 2226-2233. |
40. | Hamdy NA. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford), 2009, 48 Suppl 4: iv9-13. |
41. | Cesareo R, Napolitano C, Iozzino M. Strontium ranelate in postmenopausal osteoporosis treatment: a critical appraisal. Int J Womens Health, 2010, 2: 1-6. |
42. | Kay MI, Young RA, Posner AS. Crystal structure of hydroxyapatite. Nature, 1964, 204: 1050-1052. |
43. | 陈德敏, 傅飞远. 不同含锶量的掺锶羟基磷灰石固溶体机械性能评价. 口腔材料器械杂志, 2001, 10(4): 178-179. |
44. | 倪国新, 吕维加, 曲广运, 等. 锶羟基磷灰石生物活性骨水泥应用于髋关节置换的研究. 中华创伤骨科组织, 2007, 9(8): 708-710. |
45. | 闫钧, 张玉梅, 憨勇, 等. 锶磷灰石涂层钛种植体骨结合的动物实验. 中华口腔医学杂志, 2010, 45(2): 89-93. |
46. | 廖大鹏, 周正炎, 顾云峰, 等. 锶磷灰石生物特性的初步研究. 华西口腔医学杂志, 2002, 20(3): 172-174. |
47. | 李峰, 赵信义. 含锶磷酸钙骨水泥体内降解性能. 生物医学工程与临床, 2006, 10(4): 210-213. |
48. | 陈德敏, 刘雪阳. 锶磷灰石多孔陶瓷不同孔隙率对成骨细胞生物学行为的影响. 组织工程与重建外科杂志, 2006, 2(3): 123-127. |
49. | 余喜讯, 陈元维, 史国齐, 等. 掺锶聚磷酸钙骨组织工程支架材料与成骨细胞及内皮细胞的相容性研究. 中国组织工程研究与临床康复, 2007, 11(5): 857-860. |
50. | 傅飞远, 陈德敏, 张建中. MTT比色法评价掺锶羟基磷灰石固溶体细胞毒性. 生物医学工程杂志, 2001, 18(3): 389-390, 415. |
51. | 郝瑞然, 王德平. 改性硼硅酸盐生物玻璃的可控降解性能. 中国组织工程研究与临床康复, 2008, 12(10): 1962-1965. |
52. | Pan HB, Zhao XL, Zhang X, et al. Strontium borate glass: potential biomaterial for bone regeneration. J R Soc Interface, 2010, 7(48): 1025-1031. |
53. | Pina S, Vieira SI, Rego P, et al. Biological responses of brushite-forming Zn- and ZnSr-substituted beta-tricalcium phosphate bone cements. Eur Cell Mater, 2010 , 20: 162-177. |
54. | 余喜讯, 顾志鹏, 任大伟, 等. 新型骨科材料SCPP对成骨细胞促血管化生长因子表达影响的研究. 四川大学学报: 工程科学版, 2011, 43(1): 219-225. |
55. | 王楠, 郝永强, 何国, 等. 纤维多孔钛微球复合纳米锶磷灰石修复骨缺损的实验研究. 中华骨科杂志, 2009, 29(7): 672-676. |
56. | 朱广文, 张延军, 李键, 等. 核素Sr-89治疗前列腺癌骨转移临床价值及血清tPSA变化的研究. 放射免疫学杂志, 2009, 22(1): 6-7. |
57. | 胥杰, 陈晓. 89Sr治疗30例肺癌多发骨转移的疗效观察. 中国呼吸与危重监护杂志, 2008, 7(2): 104-106. |
58. | Logothetis CJ, Navone NM, Lin SH. Understanding the biology of bone metastases: key to the effective treatment of prostate cancer. Clin Cancer Res, 2008, 14(6): 1599-1602. |
- 1. Langer R, Vacanti P. Tissue engineering. Science, 1993, 260(5110): 920-926.
- 2. Dahl SG, Allain P, Marie PJ, et al. Incorporation and distribution of strontium in bone. Bone, 2001, 28(4): 446-453.
- 3. Reginster JY, Deroisy R, Jupsin I. Strontium ranelate: a new paradigm in the treatment of osteoporosis. Drugs Today (Barc), 2003, 39(2): 89-101.
- 4. Jupsin I, Collette J, Henrotin Y, et al. Strontium ranelate (Fujisawa/Servier). Curr Opin Investig Drugs, 2005, 6(4): 435-444.
- 5. Marie PJ. Strontium ranelate: a novel mode of action optimizing bone formation and resorption. Osteoporos Int, 2005, 16 Suppl 1: S7-10.
- 6. Bonnelye E, Chabadel A, Saltel F, et al. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone, 2008, 42(1): 129-138.
- 7. Reginster JY, Deroisy R, Neuprez A, et al. Strontium ranelate: new data on fracture prevention and mechanisms of action. Curr Osteoporos Rep, 2009, 7(3): 96-102.
- 8. Fromigué O, Haÿ E, Barbara AE, et al. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J Biol Chem, 2010, 285(33): 25251-25258.
- 9. Trouvin AP, Goëb V. Receptor activator of nuclear factor-κB ligand and osteoprotegerin: maintaining the balance to prevent bone loss. Clin Interv Aging, 2010, 5: 345-354.
- 10. Paes FM, Serafini AN. Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain. Semin Nucl Med, 2010, 40(2): 89-104.
- 11. Das T, Chakraborty S, Sarma HD, et al. (170)Tm-EDTMP: a potential cost-effective alternative to (89)SrCl(2) for bone pain palliation. Nucl Med Biol, 2009, 36(5): 561-568.
- 12. Römer P, Behr M, Proff P, et al. Effect of strontium on human Runx2+/- osteoblasts from a patient with cleidocranial dysplasia. Eur J Pharmacol, 2011, 654(3): 195-199.
- 13. Peng S, Liu XS, Huang S, et al. The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin. Bone, 2011, 49(6): 1290-1298.
- 14. Yamaguchi M, Weitzmann MN. The intact strontium ranelate complex stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation. Mol Cell Biochem, 2011, 359(1-2): 399-407.
- 15. Rybchyn MS, Slater M, Conigrave AD, et al. An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts. J Biol Chem, 2011, 286(27): 23771-23779.
- 16. Yang F, Yang D, Tu J, et al. Strontium enhances osteogenic differentiation of mesenchymal stem cells and in vivo bone formation by activating Wnt/catenin signaling. Stem Cells, 2011, 29(6): 981-991.
- 17. Caverzasio J, Thouverey C. Activation of FGF receptors is a new mechanism by which strontium ranelate induces osteoblastic cell growth. Cell Physiol Biochem, 2011, 27(3-4): 243-250.
- 18. Braux J, Velard F, Guillaume C, et al. A new insight into the dissociating effect of strontium on bone resorption and formation. Acta Biomater, 2011, 7(6): 2593-2603.
- 19. Ma HT, Peng Z, Hiragun T, et al. Canonical transient receptor potential 5 channel in conjunction with Orai1 and STIM1 allows Sr2+ entry, optimal influx of Ca2+, and degranulation in a rat mast cell line. J Immunol, 2008, 180(4): 2233-2239.
- 20. Caudrillier A, Hurtel-Lemaire AS, Wattel A, et al. Strontium ranelate decreases receptor activator of nuclear factor-κB ligand-induced osteoclastic differentiation in vitro: involvement of the calcium-sensing receptor. Mol Pharmacol, 2010, 78(4): 569-576.
- 21. Takaoka S, Yamaguchi T, Yano S, et al. The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization. Horm Metab Res, 2010, 42(9): 627-631.
- 22. Coulombe J, Fauren H, Robin B, et al. In vitro effects of strontium ranelate on the extracellular calcium-sensing receptor. Biochem Biophys Res Commun, 2004, 323(4): 1184-1190.
- 23. Verberckmoes SC, De Broe ME, D’Haese PC. Dose-dependent effects of strontium on osteoblast function and mineralization. Kidney Int, 2003, 64(2): 534-543.
- 24. 谢玲, 裴志东, 薛琪. 89锶治疗骨转移性癌痛的临床观察. 中国乡村医药, 2008, 15(5): 19-20.
- 25. 祁岗, 于梅花, 朱艳媚, 等. 90锶敷贴器治疗皮肤血管瘤疗效观察. 新医学, 2011, 42(4): 260-262.
- 26. MacDonald NS, Nusbaum RE, Stcarns R, et al. The skeletal deposition of non-radioactivc strontium. J Biol Chem, 1951, 188(1): 137-143.
- 27. Boivin G, Deloffre P, Perrat B, et al. Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res, 1996, 11(9): 1302-1311.
- 28. Brennan TC, Rybchyn MS, Green W, et al. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br J Pharmacol, 2009, 157(7): 1291-1300.
- 29. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998, 93(2): 165-176.
- 30. Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol, 2002, 22(4): 549-553.
- 31. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 1999, 397(6717): 315-323.
- 32. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology, 2001, 142(12): 5050-5055.
- 33. Ali MM, Yoshizawa T, Ishibashi O. PIASxbeta is a key regulator of osterix transcriptional activity and matrix mineralization in osteoblasts. J Cell Sci, 2007, 120(Pt 15): 2565-2573.
- 34. Aliprantis AO, Ueki Y, Sulyanto R, et al. NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest, 2008, 118(11): 3775-3789.
- 35. Ikeda F, Nishimura R, Matsubara T, et al. Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone-resorbing activity. J Immunol, 2006, 177(4): 2384-2390.
- 36. Guo J, Jin J, Cooper LF. Dissection of sets of genes that control the character of wnt5a-deficient mouse calvarial cells. Bone, 2008, 43(5): 961-971.
- 37. Cheng SL, Shao JS, Cai J, et al. Msx2 exerts bone anabolism via canonical Wnt signaling. J Biol Chem, 2008, 283(29): 20505-20522.
- 38. Fromigué O, Haÿ E, Barbara A, et al. Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. J Cell Mol Med, 2009, 13(8B): 2189-2199.
- 39. Dong SW, Ying DJ, Duan XJ, et al. Bone regeneration using an acellular extracellular matrix and bone marrow mesenchymal stem cells expressing Cbfα1. Biosci Biotechnol Biochem, 2009, 73(10): 2226-2233.
- 40. Hamdy NA. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford), 2009, 48 Suppl 4: iv9-13.
- 41. Cesareo R, Napolitano C, Iozzino M. Strontium ranelate in postmenopausal osteoporosis treatment: a critical appraisal. Int J Womens Health, 2010, 2: 1-6.
- 42. Kay MI, Young RA, Posner AS. Crystal structure of hydroxyapatite. Nature, 1964, 204: 1050-1052.
- 43. 陈德敏, 傅飞远. 不同含锶量的掺锶羟基磷灰石固溶体机械性能评价. 口腔材料器械杂志, 2001, 10(4): 178-179.
- 44. 倪国新, 吕维加, 曲广运, 等. 锶羟基磷灰石生物活性骨水泥应用于髋关节置换的研究. 中华创伤骨科组织, 2007, 9(8): 708-710.
- 45. 闫钧, 张玉梅, 憨勇, 等. 锶磷灰石涂层钛种植体骨结合的动物实验. 中华口腔医学杂志, 2010, 45(2): 89-93.
- 46. 廖大鹏, 周正炎, 顾云峰, 等. 锶磷灰石生物特性的初步研究. 华西口腔医学杂志, 2002, 20(3): 172-174.
- 47. 李峰, 赵信义. 含锶磷酸钙骨水泥体内降解性能. 生物医学工程与临床, 2006, 10(4): 210-213.
- 48. 陈德敏, 刘雪阳. 锶磷灰石多孔陶瓷不同孔隙率对成骨细胞生物学行为的影响. 组织工程与重建外科杂志, 2006, 2(3): 123-127.
- 49. 余喜讯, 陈元维, 史国齐, 等. 掺锶聚磷酸钙骨组织工程支架材料与成骨细胞及内皮细胞的相容性研究. 中国组织工程研究与临床康复, 2007, 11(5): 857-860.
- 50. 傅飞远, 陈德敏, 张建中. MTT比色法评价掺锶羟基磷灰石固溶体细胞毒性. 生物医学工程杂志, 2001, 18(3): 389-390, 415.
- 51. 郝瑞然, 王德平. 改性硼硅酸盐生物玻璃的可控降解性能. 中国组织工程研究与临床康复, 2008, 12(10): 1962-1965.
- 52. Pan HB, Zhao XL, Zhang X, et al. Strontium borate glass: potential biomaterial for bone regeneration. J R Soc Interface, 2010, 7(48): 1025-1031.
- 53. Pina S, Vieira SI, Rego P, et al. Biological responses of brushite-forming Zn- and ZnSr-substituted beta-tricalcium phosphate bone cements. Eur Cell Mater, 2010 , 20: 162-177.
- 54. 余喜讯, 顾志鹏, 任大伟, 等. 新型骨科材料SCPP对成骨细胞促血管化生长因子表达影响的研究. 四川大学学报: 工程科学版, 2011, 43(1): 219-225.
- 55. 王楠, 郝永强, 何国, 等. 纤维多孔钛微球复合纳米锶磷灰石修复骨缺损的实验研究. 中华骨科杂志, 2009, 29(7): 672-676.
- 56. 朱广文, 张延军, 李键, 等. 核素Sr-89治疗前列腺癌骨转移临床价值及血清tPSA变化的研究. 放射免疫学杂志, 2009, 22(1): 6-7.
- 57. 胥杰, 陈晓. 89Sr治疗30例肺癌多发骨转移的疗效观察. 中国呼吸与危重监护杂志, 2008, 7(2): 104-106.
- 58. Logothetis CJ, Navone NM, Lin SH. Understanding the biology of bone metastases: key to the effective treatment of prostate cancer. Clin Cancer Res, 2008, 14(6): 1599-1602.