Cellular Communication in Bone Homeostasis and the Related Anti-osteoporotic Drug Development

Yi       Zhang; Guojing       Luo; Xijie      Yu
Abstract

Background：Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis.
Methods：We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were ‘osteoporosis’, ‘osteocyte’, ‘osteoblast’, ‘osteoclast’, ‘bone remodeling’, ‘chondrocyte’, ‘osteoporosis treatment’, ‘osteoporosis therapy’, ‘bisphosphonates’, ‘denosumab’, ‘Selective Estrogen Receptor Modulator (SERM)’, ‘PTH’, ‘romosozumab’, ‘dkk-1 antagonist’, ‘strontium ranelate’.
Results：A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies.
Conclusion：There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.
Keywords: Osteoblast, osteoclast, osteocyte, bone homeostasis, osteoporosis, treatment.
[1] 
Boyle, W.J.; Simonet, W.S.; Lacey, D.L. Osteoclast differentiation and activation. Nature,  2003, 423(6937), 337-342.
[http://dx.doi.org/10.1038/nature01658] [PMID: 12748652 ] 
[2] 
Seeman, E.; Delmas, P.D. Bone quality--the material and structural basis of bone strength and fragility. N. Engl. J. Med.,  2006, 354(21), 2250-2261.
[http://dx.doi.org/10.1056/NEJMra053077] [PMID: 16723616 ] 
[3] 
Henriksen, K.; Neutzsky-Wulff, A.V.; Bonewald, L.F.; Karsdal, M.A. Local communication on and within bone controls bone remodeling. Bone,  2009, 44(6), 1026-1033.
[http://dx.doi.org/10.1016/j.bone.2009.03.671] [PMID: 19345750 ] 
[4] 
Wongdee, K.; Krishnamra, N.; Charoenphandhu, N. Endochondral bone growth, bone calcium accretion, and bone mineral density: how are they related? J. Physiol. Sci.,  2012, 62(4), 299-307.
[http://dx.doi.org/10.1007/s12576-012-0212-0] [PMID: 22627708 ] 
[5] 
Martin, T.J.; Sims, N.A. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med.,  2005, 11(2), 76-81.
[http://dx.doi.org/10.1016/j.molmed.2004.12.004] [PMID: 15694870 ] 
[6] 
Chavassieux, P.; Seeman, E.; Delmas, P.D. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr. Rev.,  2007, 28(2), 151-164.
[http://dx.doi.org/10.1210/er.2006-0029] [PMID: 17200084 ] 
[7] 
Hill, P.A. Bone remodelling. Br. J. Orthod.,  1998, 25(2), 101-107.
[http://dx.doi.org/10.1093/ortho/25.2.101] [PMID: 9668992 ] 
[8] 
Reginster, J.Y. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs,  2011, 71(1), 65-78.
[http://dx.doi.org/10.2165/11587570-000000000-00000] [PMID: 21175240 ] 
[9] 
Raggatt, L.J.; Partridge, N.C. Cellular and molecular mechanisms of bone remodeling. J. Biol. Chem.,  2010, 285(33), 25103-25108.
[http://dx.doi.org/10.1074/jbc.R109.041087] [PMID: 20501658 ] 
[10] 
Franceschi, R.T.; Xiao, G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J. Cell. Biochem.,  2003, 88(3), 446-454.
[http://dx.doi.org/10.1002/jcb.10369] [PMID: 12532321 ] 
[11] 
Udagawa, N.; Takahashi, N.; Akatsu, T.; Tanaka, H.; Sasaki, T.; Nishihara, T.; Koga, T.; Martin, T.J.; Suda, T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc. Natl. Acad. Sci. USA,  1990, 87(18), 7260-7264.
[http://dx.doi.org/10.1073/pnas.87.18.7260] [PMID: 2169622 ] 
[12] 
Tamma, R.; Zallone, A. Osteoblast and osteoclast crosstalks: from OAF to Ephrin. Inflamm. Allergy Drug Targets,  2012, 11(3), 196-200.
[http://dx.doi.org/10.2174/187152812800392670] [PMID: 22280242 ] 
[13] 
Furuya, M.; Kikuta, J.; Fujimori, S.; Seno, S.; Maeda, H.; Shirazaki, M.; Uenaka, M.; Mizuno, H.; Iwamoto, Y.; Morimoto, A.; Hashimoto, K.; Ito, T.; Isogai, Y.; Kashii, M.; Kaito, T.; Ohba, S.; Chung, U.I.; Lichtler, A.C.; Kikuchi, K.; Matsuda, H.; Yoshikawa, H.; Ishii, M. Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo. Nat. Commun.,  2018, 9(1), 300.
[http://dx.doi.org/10.1038/s41467-017-02541-w] [PMID: 29352112 ] 
[14] 
Simonet, W.S.; Lacey, D.L.; Dunstan, C.R.; Kelley, M.; Chang, M.S.; Lüthy, R.; Nguyen, H.Q.; Wooden, S.; Bennett, L.; Boone, T.; Shimamoto, G.; DeRose, M.; Elliott, R.; Colombero, A.; Tan, H.L.; Trail, G.; Sullivan, J.; Davy, E.; Bucay, N.; Renshaw-Gegg, L.; Hughes, T.M.; Hill, D.; Pattison, W.; Campbell, P.; Sander, S.; Van, G.; Tarpley, J.; Derby, P.; Lee, R.; Boyle, W.J. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell,  1997, 89(2), 309-319.
[http://dx.doi.org/10.1016/S0092-8674(00)80209-3] [PMID: 9108485 ] 
[15] 
Lacey, D.L.; Timms, E.; Tan, H.L.; Kelley, M.J.; Dunstan, C.R.; Burgess, T.; Elliott, R.; Colombero, A.; Elliott, G.; Scully, S.; Hsu, H.; Sullivan, J.; Hawkins, N.; Davy, E.; Capparelli, C.; Eli, A.; Qian, Y.X.; Kaufman, S.; Sarosi, I.; Shalhoub, V.; Senaldi, G.; Guo, J.; Delaney, J.; Boyle, W.J. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell,  1998, 93(2), 165-176.
[http://dx.doi.org/10.1016/S0092-8674(00)81569-X] [PMID: 9568710 ] 
[16] 
Xu, J.; Tan, J.W.; Huang, L.; Gao, X.H.; Laird, R.; Liu, D.; Wysocki, S.; Zheng, M.H. Cloning, sequencing, and functional characterization of the rat homologue of receptor activator of NF-kappaB ligand. J. Bone Miner. Res.,  2000, 15(11), 2178-2186.
[http://dx.doi.org/10.1359/jbmr.2000.15.11.2178] [PMID: 11092398 ] 
[17] 
Kostenuik, P.J.; Shalhoub, V. Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr. Pharm. Des.,  2001, 7(8), 613-635.
[http://dx.doi.org/10.2174/1381612013397807] [PMID: 11375772 ] 
[18] 
Martin, T.J.; Sims, N.A. RANKL/OPG; Critical role in bone physiology. Rev. Endocr. Metab. Disord.,  2015, 16(2), 131-139.
[http://dx.doi.org/10.1007/s11154-014-9308-6] [PMID: 25557611 ] 
[19] 
Lacey, D.L.; Boyle, W.J.; Simonet, W.S.; Kostenuik, P.J.; Dougall, W.C.; Sullivan, J.K.; San Martin, J.; Dansey, R. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov.,  2012, 11(5), 401-419.
[http://dx.doi.org/10.1038/nrd3705] [PMID: 22543469 ] 
[20] 
Verlinden, L.; Vanderschueren, D.; Verstuyf, A. Semaphorin signaling in bone. Mol. Cell. Endocrinol.,  2016, 432(C), 66-74.
[http://dx.doi.org/10.1016/j.mce.2015.09.009] [PMID: 26365296 ] 
[21] 
Luo, J.; Yang, Z.; Ma, Y.; Yue, Z.; Lin, H.; Qu, G.; Huang, J.; Dai, W.; Li, C.; Zheng, C.; Xu, L.; Chen, H.; Wang, J.; Li, D.; Siwko, S.; Penninger, J.M.; Ning, G.; Xiao, J.; Liu, M. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat. Med.,  2016, 22(5), 539-546.
[http://dx.doi.org/10.1038/nm.4076] [PMID: 27064449 ] 
[22] 
Pasquale, E.B. Eph-ephrin bidirectional signaling in physiology and disease. Cell,  2008, 133(1), 38-52.
[http://dx.doi.org/10.1016/j.cell.2008.03.011] [PMID: 18394988 ] 
[23] 
Pitulescu, M.E.; Adams, R.H. Eph/ephrin molecules--a hub for signaling and endocytosis. Genes Dev.,  2010, 24(22), 2480-2492.
[http://dx.doi.org/10.1101/gad.1973910] [PMID: 21078817 ] 
[24] 
Egea, J.; Klein, R. Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol.,  2007, 17(5), 230-238.
[http://dx.doi.org/10.1016/j.tcb.2007.03.004] [PMID: 17420126 ] 
[25] 
Murai, K.K.; Pasquale, E.B. 'Eph’ective signaling: forward, reverse and crosstalk. J. Cell Sci.,  2003, 116(Pt 14), 2823-2832.
[http://dx.doi.org/10.1242/jcs.00625] [PMID: 12808016 ] 
[26] 
Allan, E.H.; Häusler, K.D.; Wei, T.; Gooi, J.H.; Quinn, J.M.W.; Crimeen-Irwin, B.; Pompolo, S.; Sims, N.A.; Gillespie, M.T.; Onyia, J.E.; Martin, T.J. EphrinB2 regulation by PTH and PTHrP revealed by molecular profiling in differentiating osteoblasts. J. Bone Miner. Res.,  2008, 23(8), 1170-1181.
[http://dx.doi.org/10.1359/jbmr.080324] [PMID: 18627264 ] 
[27] 
Zhao, C.; Irie, N.; Takada, Y.; Shimoda, K.; Miyamoto, T.; Nishiwaki, T.; Suda, T.; Matsuo, K. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab.,  2006, 4(2), 111-121.
[http://dx.doi.org/10.1016/j.cmet.2006.05.012] [PMID: 16890539 ] 
[28] 
Mao, Y.; Huang, X.; Zhao, J.; Gu, Z. Preliminary identification of potential PDZ-domain proteins downstream of ephrin B2 during osteoclast differentiation of RAW264.7 cells. Int. J. Mol. Med.,  2011, 27(5), 669-677.
[PMID: 21373749 ] 
[29] 
Matsuo, K.; Otaki, N. Bone cell interactions through Eph/ephrin: bone modeling, remodeling and associated diseases. Cell Adhes. Migr.,  2012, 6(2), 148-156.
[http://dx.doi.org/10.4161/cam.20888] [PMID: 22660185 ] 
[30] 
Wang, L.; Liu, S.; Zhao, Y.; Liu, D.; Liu, Y.; Chen, C.; Karray, S.; Shi, S.; Jin, Y. Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass. Cell Death Differ.,  2015, 22(10), 1654-1664.
[http://dx.doi.org/10.1038/cdd.2015.14] [PMID: 25744024 ] 
[31] 
Malone, J.D.; Teitelbaum, S.L.; Griffin, G.L.; Senior, R.M.; Kahn, A.J. Recruitment of osteoclast precursors by purified bone matrix constituents. J. Cell Biol.,  1982, 92(1), 227-230.
[http://dx.doi.org/10.1083/jcb.92.1.227] [PMID: 6976967 ] 
[32] 
Li, X.; Qin, L.; Bergenstock, M.; Bevelock, L.M.; Novack, D.V.; Partridge, N.C. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J. Biol. Chem.,  2007, 282(45), 33098-33106.
[http://dx.doi.org/10.1074/jbc.M611781200] [PMID: 17690108 ] 
[33] 
Bartelt, A.; Behler-Janbeck, F.; Beil, F.T.; Koehne, T.; Müller, B.; Schmidt, T.; Heine, M.; Ochs, L.; Yilmaz, T.; Dietrich, M.; Tuckermann, J.P.; Amling, M.; Herz, J.; Schinke, T.; Heeren, J.; Niemeier, A. Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling. Bone Res.,  2018, 6, 4.
[http://dx.doi.org/10.1038/s41413-017-0006-3] [PMID: 29507818 ] 
[34] 
Xiong, L.; Jung, J.U.; Wu, H.; Xia, W.F.; Pan, J.X.; Shen, C.; Mei, L.; Xiong, W.C. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proc. Natl. Acad. Sci. USA,  2015, 112(11), 3487-3492.
[http://dx.doi.org/10.1073/pnas.1419714112] [PMID: 25733894 ] 
[35] 
Xiong, L.; Jung, J.U.; Guo, H.H.; Pan, J.X.; Sun, X.D.; Mei, L.; Xiong, W.C. Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and Adenosine-A(2A)R signaling. J. Cell Biol.,  2017, 216(3), 761-778.
[http://dx.doi.org/10.1083/jcb.201608002] [PMID: 28193701 ] 
[36] 
Centrella, M.; McCarthy, T.L.; Canalis, E. Transforming growth factor-beta and remodeling of bone. J. Bone Joint Surg. Am.,  1991, 73(9), 1418-1428.
[http://dx.doi.org/10.2106/00004623-199173090-00022] [PMID: 1918129 ] 
[37] 
Hayden, J.M.; Mohan, S.; Baylink, D.J. The insulin-like growth factor system and the coupling of formation to resorption. Bone,  1995, 17(Suppl. 2), 93S-98S.
[http://dx.doi.org/10.1016/8756-3282(95)00186-H] [PMID: 8579905 ] 
[38] 
Wozney, J.M.; Rosen, V.; Celeste, A.J.; Mitsock, L.M.; Whitters, M.J.; Kriz, R.W.; Hewick, R.M.; Wang, E.A. Novel regulators of bone formation: molecular clones and activities. Science,  1988, 242(4885), 1528-1534.
[http://dx.doi.org/10.1126/science.3201241] [PMID: 3201241 ] 
[39] 
Tang, Y.; Wu, X.; Lei, W.; Pang, L.; Wan, C.; Shi, Z.; Zhao, L.; Nagy, T.R.; Peng, X.; Hu, J.; Feng, X.; Van Hul, W.; Wan, M.; Cao, X. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med.,  2009, 15(7), 757-765.
[http://dx.doi.org/10.1038/nm.1979] [PMID: 19584867 ] 
[40] 
Xian, L.; Wu, X.; Pang, L.; Lou, M.; Rosen, C.J.; Qiu, T.; Crane, J.; Frassica, F.; Zhang, L.; Rodriguez, J.P. Xiaofeng, Jia.; Shoshana, Yakar.; Shouhong, Xuan.; Argiris, Efstratiadis.; Mei, Wan.; Xu, Cao. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med.,  2012, 18(7), 1095-1101.
[http://dx.doi.org/10.1038/nm.2793] [PMID: 22729283 ] 
[41] 
Frattini, A.; Orchard, P.J.; Sobacchi, C.; Giliani, S.; Abinun, M.; Mattsson, J.P.; Keeling, D.J.; Andersson, A.K.; Wallbrandt, P.; Zecca, L.; Notarangelo, L.D.; Vezzoni, P.; Villa, A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet.,  2000, 25(3), 343-346.
[http://dx.doi.org/10.1038/77131] [PMID: 10888887 ] 
[42] 
Kornak, U.; Kasper, D.; Bösl, M.R.; Kaiser, E.; Schweizer, M.; Schulz, A.; Friedrich, W.; Delling, G.; Jentsch, T.J. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell,  2001, 104(2), 205-215.
[http://dx.doi.org/10.1016/S0092-8674(01)00206-9] [PMID: 11207362 ] 
[43] 
Del Fattore, A.; Peruzzi, B.; Rucci, N.; Recchia, I.; Cappariello, A.; Longo, M.; Fortunati, D.; Ballanti, P.; Iacobini, M.; Luciani, M.; Devito, R.; Pinto, R.; Caniglia, M.; Lanino, E.; Messina, C.; Cesaro, S.; Letizia, C.; Bianchini, G.; Fryssira, H.; Grabowski, P.; Shaw, N.; Bishop, N.; Hughes, D.; Kapur, R.P.; Datta, H.K.; Taranta, A.; Fornari, R.; Migliaccio, S.; Teti, A. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J. Med. Genet.,  2006, 43(4), 315-325.
[http://dx.doi.org/10.1136/jmg.2005.036673] [PMID: 16118345 ] 
[44] 
Karsdal, M.A.; Henriksen, K.; Sørensen, M.G.; Gram, J.; Schaller, S.; Dziegiel, M.H.; Heegaard, A.M.; Christophersen, P.; Martin, T.J.; Christiansen, C.; Bollerslev, J. Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am. J. Pathol.,  2005, 166(2), 467-476.
[http://dx.doi.org/10.1016/S0002-9440(10)62269-9] [PMID: 15681830 ] 
[45] 
Ryu, J.; Kim, H.J.; Chang, E.J.; Huang, H.; Banno, Y.; Kim, H.H. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J.,  2006, 25(24), 5840-5851.
[http://dx.doi.org/10.1038/sj.emboj.7601430] [PMID: 17124500 ] 
[46] 
Ishii, M.; Egen, J.G.; Klauschen, F.; Meier-Schellersheim, M.; Saeki, Y.; Vacher, J.; Proia, R.L.; Germain, R.N. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature,  2009, 458(7237), 524-528.
[http://dx.doi.org/10.1038/nature07713] [PMID: 19204730 ] 
[47] 
Negishi-Koga, T.; Shinohara, M.; Komatsu, N.; Bito, H.; Kodama, T.; Friedel, R.H.; Takayanagi, H. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med.,  2011, 17(11), 1473-1480.
[http://dx.doi.org/10.1038/nm.2489] [PMID: 22019888 ] 
[48] 
Kim, B.J.; Lee, Y.S.; Lee, S.Y.; Baek, W.Y.; Choi, Y.J.; Moon, S.A.; Lee, S.H.; Kim, J.E.; Chang, E.J.; Kim, E.Y.; Yoon, J.; Kim, S.W.; Ryu, S.H.; Lee, S.K.; Lorenzo, J.A.; Ahn, S.H.; Kim, H.; Lee, K.U.; Kim, G.S.; Koh, J.M. Osteoclast-secreted SLIT3 coordinates bone resorption and formation. J. Clin. Invest.,  2018, 128(4), 1429-1441.
[http://dx.doi.org/10.1172/JCI91086] [PMID: 29504949 ] 
[49] 
Takeshita, S.; Fumoto, T.; Matsuoka, K.; Park, K.A.; Aburatani, H.; Kato, S.; Ito, M.; Ikeda, K. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J. Clin. Invest.,  2013, 123(9), 3914-3924.
[http://dx.doi.org/10.1172/JCI69493] [PMID: 23908115 ] 
[50] 
Matsuoka, K.; Kohara, Y.; Naoe, Y.; Watanabe, A.; Ito, M.; Ikeda, K.; Takeshita, S. WAIF1 is a cell-surface CTHRC1 binding protein coupling bone resorption and formation. J. Bone Miner. Res.,  2018, 33(8), 1500-1512.
[http://dx.doi.org/10.1002/jbmr.3436] [PMID: 29624737 ] 
[51] 
Knothe Tate, M.L.; Adamson, J.R.; Tami, A.E.; Bauer, T.W. The osteocyte. Int. J. Biochem. Cell Biol.,  2004, 36(1), 1-8.
[http://dx.doi.org/10.1016/S1357-2725(03)00241-3] [PMID: 14592527 ] 
[52] 
Beno, T.; Yoon, Y.J.; Cowin, S.C.; Fritton, S.P. Estimation of bone permeability using accurate microstructural measurements. J. Biomech.,  2006, 39(13), 2378-2387.
[http://dx.doi.org/10.1016/j.jbiomech.2005.08.005] [PMID: 16176815 ] 
[53] 
Dallas, S.L.; Prideaux, M.; Bonewald, L.F. The osteocyte: an endocrine cell ... and more. Endocr. Rev.,  2013, 34(5), 658-690.
[http://dx.doi.org/10.1210/er.2012-1026] [PMID: 23612223 ] 
[54] 
Adachi, T.; Aonuma, Y.; Taira, K.; Hojo, M.; Kamioka, H. Asymmetric intercellular communication between bone cells: propagation of the calcium signaling. Biochem. Biophys. Res. Commun.,  2009, 389(3), 495-500.
[http://dx.doi.org/10.1016/j.bbrc.2009.09.010] [PMID: 19737533 ] 
[55] 
Wang, Z.; Odagaki, N.; Tanaka, T.; Hashimoto, M.; Nakamura, M.; Hayano, S.; Ishihara, Y.; Kawanabe, N.; Kamioka, H. Alternation in the gap-junctional intercellular communication capacity during the maturation of osteocytes in the embryonic chick calvaria. Bone,  2016, 91, 20-29.
[http://dx.doi.org/10.1016/j.bone.2016.06.016] [PMID: 27373501 ] 
[56] 
Doty, S.B. Morphological evidence of gap junctions between bone cells. Calcif. Tissue Int.,  1981, 33(5), 509-512.
[http://dx.doi.org/10.1007/BF02409482] [PMID: 6797704 ] 
[57] 
Marotti, G.; Ferretti, M.; Muglia, M.A.; Palumbo, C.; Palazzini, S. A quantitative evaluation of osteoblast-osteocyte relationships on growing endosteal surface of rabbit tibiae. Bone,  1992, 13(5), 363-368.
[http://dx.doi.org/10.1016/8756-3282(92)90452-3] [PMID: 1419377 ] 
[58] 
Bonewald, L.F.; Johnson, M.L. Osteocytes, mechanosensing and Wnt signaling. Bone,  2008, 42(4), 606-615.
[http://dx.doi.org/10.1016/j.bone.2007.12.224] [PMID: 18280232 ] 
[59] 
Li, X.; Zhang, Y.; Kang, H.; Liu, W.; Liu, P.; Zhang, J.; Harris, S.E.; Wu, D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem.,  2005, 280(20), 19883-19887.
[http://dx.doi.org/10.1074/jbc.M413274200] [PMID: 15778503 ] 
[60] 
Ott, S.M. Sclerostin and Wnt signaling--the pathway to bone strength. J. Clin. Endocrinol. Metab.,  2005, 90(12), 6741-6743.
[http://dx.doi.org/10.1210/jc.2005-2370] [PMID: 16330810 ] 
[61] 
Kramer, I.; Loots, G.G.; Studer, A.; Keller, H.; Kneissel, M. Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J. Bone Miner. Res.,  2010, 25(2), 178-189.
[http://dx.doi.org/10.1359/jbmr.090730] [PMID: 19594304 ] 
[62] 
Niziolek, P.J.; MacDonald, B.T.; Kedlaya, R.; Zhang, M.; Bellido, T.; He, X.; Warman, M.L.; Robling, A.G. High bone mass-causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo. J. Bone Miner. Res.,  2015, 30(10), 1822-1830.
[http://dx.doi.org/10.1002/jbmr.2514] [PMID: 25808845 ] 
[63] 
Zhang, Y.; Wang, Y.; Li, X.; Zhang, J.; Mao, J.; Li, Z.; Zheng, J.; Li, L.; Harris, S.; Wu, D. The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol. Cell. Biol.,  2004, 24(11), 4677-4684.
[http://dx.doi.org/10.1128/MCB.24.11.4677-4684.2004] [PMID: 15143163 ] 
[64] 
Li, J.; Sarosi, I.; Cattley, R.C.; Pretorius, J.; Asuncion, F.; Grisanti, M.; Morony, S.; Adamu, S.; Geng, Z.; Qiu, W.; Kostenuik, P.; Lacey, D.L.; Simonet, W.S.; Bolon, B.; Qian, X.; Shalhoub, V.; Ominsky, M.S.; Ke, Z. H.; Li, X.; Richards, W.G. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone,  2006, 39(4), 754-766.
[http://dx.doi.org/10.1016/j.bone.2006.03.017] [PMID: 16730481 ] 
[65] 
Heiland, G.R.; Zwerina, K.; Baum, W.; Kireva, T.; Distler, J.H.; Grisanti, M.; Asuncion, F.; Li, X.; Ominsky, M.; Richards, W.; Schett, G.; Zwerina, J. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann. Rheum. Dis.,  2010, 69(12), 2152-2159.
[http://dx.doi.org/10.1136/ard.2010.132852] [PMID: 20858621 ] 
[66] 
Robling, A.G.; Niziolek, P.J.; Baldridge, L.A.; Condon, K.W.; Allen, M.R.; Alam, I.; Mantila, S.M.; Gluhak-Heinrich, J.; Bellido, T.M.; Harris, S.E.; Turner, C.H. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem.,  2008, 283(9), 5866-5875.
[http://dx.doi.org/10.1074/jbc.M705092200] [PMID: 18089564 ] 
[67] 
Bodine, P.V.N.; Zhao, W.; Kharode, Y.P.; Bex, F.J.; Lambert, A.J.; Goad, M.B.; Gaur, T.; Stein, G.S.; Lian, J.B.; Komm, B.S. The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol. Endocrinol.,  2004, 18(5), 1222-1237.
[http://dx.doi.org/10.1210/me.2003-0498] [PMID: 14976225 ] 
[68] 
Bodine, P.V.N.; Billiard, J.; Moran, R.A.; Ponce-de-Leon, H.; McLarney, S.; Mangine, A.; Scrimo, M.J.; Bhat, R.A.; Stauffer, B.; Green, J.; Stein, G.S.; Lian, J.B.; Komm, B.S. The Wnt antagonist secreted frizzled-related protein-1 controls osteoblast and osteocyte apoptosis. J. Cell. Biochem.,  2005, 96(6), 1212-1230.
[http://dx.doi.org/10.1002/jcb.20599] [PMID: 16149051 ] 
[69] 
Zaman, G.; Pitsillides, A.A.; Rawlinson, S.C.F.; Suswillo, R.F.L.; Mosley, J.R.; Cheng, M.Z.; Platts, L.A.M.; Hukkanen, M.; Polak, J.M.; Lanyon, L.E. Mechanical strain stimulates nitric oxide production by rapid activation of endothelial nitric oxide synthase in osteocytes. J. Bone Miner. Res.,  1999, 14(7), 1123-1131.
[http://dx.doi.org/10.1359/jbmr.1999.14.7.1123] [PMID: 10404012 ] 
[70] 
Watanuki, M.; Sakai, A.; Sakata, T.; Tsurukami, H.; Miwa, M.; Uchida, Y.; Watanabe, K.; Ikeda, K.; Nakamura, T. Role of inducible nitric oxide synthase in skeletal adaptation to acute increases in mechanical loading. J. Bone Miner. Res.,  2002, 17(6), 1015-1025.
[http://dx.doi.org/10.1359/jbmr.2002.17.6.1015] [PMID: 12054156 ] 
[71] 
Vezeridis, P.S.; Semeins, C.M.; Chen, Q.; Klein-Nulend, J. Osteocytes subjected to pulsating fluid flow regulate osteoblast proliferation and differentiation. Biochem. Biophys. Res. Commun.,  2006, 348(3), 1082-1088.
[http://dx.doi.org/10.1016/j.bbrc.2006.07.146] [PMID: 16904067 ] 
[72] 
Blackwell, K.A.; Raisz, L.G.; Pilbeam, C.C. Prostaglandins in bone: bad cop, good cop? Trends Endocrinol. Metab.,  2010, 21(5), 294-301.
[http://dx.doi.org/10.1016/j.tem.2009.12.004] [PMID: 20079660 ] 
[73] 
Raisz, L.G.; Fall, P.M.; Gabbitas, B.Y.; McCarthy, T.L.; Kream, B.E.; Canalis, E. Effects of prostaglandin E2 on bone formation in cultured fetal rat calvariae: role of insulin-like growth factor-I. Endocrinology,  1993, 133(4), 1504-1510.
[http://dx.doi.org/10.1210/endo.133.4.7691577] [PMID: 7691577 ] 
[74] 
Nagata, T.; Kaho, K.; Nishikawa, S.; Shinohara, H.; Wakano, Y.; Ishida, H. Effect of prostaglandin E2 on mineralization of bone nodules formed by fetal rat calvarial cells. Calcif. Tissue Int.,  1994, 55(6), 451-457.
[http://dx.doi.org/10.1007/BF00298559] [PMID: 7895184 ] 
[75] 
Raisz, L.G.; Kream, B.E. Regulation of bone formation (second of two parts). N. Engl. J. Med.,  1983, 309(2), 83-89.
[http://dx.doi.org/10.1056/NEJM198307143090206] [PMID: 6343879 ] 
[76] 
Jee, W.S.; Ueno, K.; Deng, Y.P.; Woodbury, D.M. The effects of prostaglandin E2 in growing rats: increased metaphyseal hard tissue and cortico-endosteal bone formation. Calcif. Tissue Int.,  1985, 37(2), 148-157.
[http://dx.doi.org/10.1007/BF02554834] [PMID: 3924371 ] 
[77] 
Nakashima, T.; Hayashi, M.; Fukunaga, T.; Kurata, K.; Oh-Hora, M.; Feng, J.Q.; Bonewald, L.F.; Kodama, T.; Wutz, A.; Wagner, E.F.; Penninger, J.M.; Takayanagi, H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med.,  2011, 17(10), 1231-1234.
[http://dx.doi.org/10.1038/nm.2452] [PMID: 21909105 ] 
[78] 
Xiong, J.; Onal, M.; Jilka, R.L.; Weinstein, R.S.; Manolagas, S.C.; O’Brien, C.A. Matrix-embedded cells control osteoclast formation. Nat. Med.,  2011, 17(10), 1235-1241.
[http://dx.doi.org/10.1038/nm.2448] [PMID: 21909103 ] 
[79] 
Xiong, J.; Piemontese, M.; Onal, M.; Campbell, J.; Goellner, J.J.; Dusevich, V.; Bonewald, L.; Manolagas, S.C.; O’Brien, C.A. Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One,  2015, 10(9) e0138189
[http://dx.doi.org/10.1371/journal.pone.0138189] [PMID: 26393791 ] 
[80] 
Ben-awadh, A.N.; Delgado-Calle, J.; Tu, X.; Kuhlenschmidt, K.; Allen, M.R.; Plotkin, L.I.; Bellido, T. Parathyroid hormone receptor signaling induces bone resorption in the adult skeleton by directly regulating the RANKL gene in osteocytes. Endocrinology,  2014, 155(8), 2797-2809.
[http://dx.doi.org/10.1210/en.2014-1046] [PMID: 24877630 ] 
[81] 
Honma, M.; Ikebuchi, Y.; Kariya, Y.; Hayashi, M.; Hayashi, N.; Aoki, S.; Suzuki, H. RANKL subcellular trafficking and regulatory mechanisms in osteocytes. J. Bone Miner. Res.,  2013, 28(9), 1936-1949.
[http://dx.doi.org/10.1002/jbmr.1941] [PMID: 23529793 ] 
[82] 
Wijenayaka, A.R.; Kogawa, M.; Lim, H.P.; Bonewald, L.F.; Findlay, D.M.; Atkins, G.J. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One,  2011, 6(10)e25900
[http://dx.doi.org/10.1371/journal.pone.0025900] [PMID: 21991382 ] 
[83] 
Spatz, J.M.; Wein, M.N.; Gooi, J.H.; Qu, Y.; Garr, J.L.; Liu, S.; Barry, K.J.; Uda, Y.; Lai, F.; Dedic, C.; Balcells-Camps, M.; Kronenberg, H.M.; Babij, P.; Pajevic, P.D. The Wnt inhibitor sclerostin is up-regulated by mechanical unloading in osteocytes in vitro. J. Biol. Chem.,  2015, 290(27), 16744-16758.
[http://dx.doi.org/10.1074/jbc.M114.628313] [PMID: 25953900 ] 
[84] 
Tan, S.D.; de Vries, T.J.; Kuijpers-Jagtman, A.M.; Semeins, C.M.; Everts, V.; Klein-Nulend, J. Osteocytes subjected to fluid flow inhibit osteoclast formation and bone resorption. Bone,  2007, 41(5), 745-751.
[http://dx.doi.org/10.1016/j.bone.2007.07.019] [PMID: 17855178 ] 
[85] 
Qing, H.; Ardeshirpour, L.; Pajevic, P.D.; Dusevich, V.; Jähn, K.; Kato, S.; Wysolmerski, J.; Bonewald, L.F. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J. Bone Miner. Res.,  2012, 27(5), 1018-1029.
[http://dx.doi.org/10.1002/jbmr.1567] [PMID: 22308018 ] 
[86] 
Colnot, C. Cellular and molecular interactions regulating skeletogenesis. J. Cell. Biochem.,  2005, 95(4), 688-697.
[http://dx.doi.org/10.1002/jcb.20449] [PMID: 15880692 ] 
[87] 
Hojo, H.; Ohba, S.; Yano, F.; Chung, U.I. Coordination of chondrogenesis and osteogenesis by hypertrophic chondrocytes in endochondral bone development. J. Bone Miner. Metab.,  2010, 28(5), 489-502.
[http://dx.doi.org/10.1007/s00774-010-0199-7] [PMID: 20607327 ] 
[88] 
Liu, Z.; Xu, J.; Colvin, J.S.; Ornitz, D.M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev.,  2002, 16(7), 859-869.
[http://dx.doi.org/10.1101/gad.965602] [PMID: 11937493 ] 
[89] 
Wang, W.; Lian, N.; Li, L.; Moss, H.E.; Wang, W.; Perrien, D.S.; Elefteriou, F.; Yang, X. Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. Development,  2009, 136(24), 4143-4153.
[http://dx.doi.org/10.1242/dev.043281] [PMID: 19906842 ] 
[90] 
Wang, W.; Lian, N.; Ma, Y.; Li, L.; Gallant, R.C.; Elefteriou, F.; Yang, X. Chondrocytic Atf4 regulates osteoblast differentiation and function via Ihh. Development,  2012, 139(3), 601-611.
[http://dx.doi.org/10.1242/dev.069575] [PMID: 22190639 ] 
[91] 
Sanchez, C.; Deberg, M.A.; Piccardi, N.; Msika, P.; Reginster, J.Y.L.; Henrotin, Y.E. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage,  2005, 13(11), 988-997.
[http://dx.doi.org/10.1016/j.joca.2005.07.012] [PMID: 16168681 ] 
[92] 
Sanchez, C.; Deberg, M.A.; Piccardi, N.; Msika, P.; Reginster, J.Y.L.; Henrotin, Y.E. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6, -1beta and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage,  2005, 13(11), 979-987.
[http://dx.doi.org/10.1016/j.joca.2005.03.008] [PMID: 16243232 ] 
[93] 
Dreier, R.; Wallace, S.; Fuchs, S.; Bruckner, P.; Grässel, S. Paracrine interactions of chondrocytes and macrophages in cartilage degradation: articular chondrocytes provide factors that activate macrophage-derived pro-gelatinase B (pro-MMP-9). J. Cell Sci.,  2001, 114(Pt 21), 3813-3822.
[PMID: 11719548 ] 
[94] 
Silvestrini, G.; Ballanti, P.; Patacchioli, F.; Leopizzi, M.; Gualtieri, N.; Monnazzi, P.; Tremante, E.; Sardella, D.; Bonucci, E. Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat. J. Mol. Histol.,  2005, 36(1-2), 59-67.
[http://dx.doi.org/10.1007/s10735-004-3839-1] [PMID: 15704000 ] 
[95] 
Usui, M.; Xing, L.; Drissi, H.; Zuscik, M.; O’Keefe, R.; Chen, D.; Boyce, B.F. Murine and chicken chondrocytes regulate osteoclastogenesis by producing RANKL in response to BMP2. J. Bone Miner. Res.,  2008, 23(3), 314-325.
[http://dx.doi.org/10.1359/jbmr.071025] [PMID: 17967138 ] 
[96] 
Masuyama, R.; Stockmans, I.; Torrekens, S.; Van Looveren, R.; Maes, C.; Carmeliet, P.; Bouillon, R.; Carmeliet, G. Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts. J. Clin. Invest.,  2006, 116(12), 3150-3159.
[http://dx.doi.org/10.1172/JCI29463] [PMID: 17099775 ] 
[97] 
Wang, B.; Jin, H.; Zhu, M.; Li, J.; Zhao, L.; Zhang, Y.; Tang, D.; Xiao, G.; Xing, L.; Boyce, B.F.; Chen, D. Chondrocyte β-catenin signaling regulates postnatal bone remodeling through modulation of osteoclast formation in a murine model. Arthritis Rheumatol.,  2014, 66(1), 107-120.
[http://dx.doi.org/10.1002/art.38195] [PMID: 24431282 ] 
[98] 
Burge, R.; Dawson-Hughes, B.; Solomon, D.H.; Wong, J.B.; King, A.; Tosteson, A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J. Bone Miner. Res.,  2007, 22(3), 465-475.
[http://dx.doi.org/10.1359/jbmr.061113] [PMID: 17144789 ] 
[99] 
Hernlund, E.; Svedbom, A.; Ivergård, M.; Compston, J.; Cooper, C.; Stenmark, J.; McCloskey, E.V.; Jönsson, B.; Kanis, J.A. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch. Osteoporos.,  2013, 8, 136.
[http://dx.doi.org/10.1007/s11657-013-0136-1] [PMID: 24113837 ] 
[100] 
Kanis, J.A.; McCloskey, E.V.; Johansson, H.; Cooper, C.; Rizzoli, R.; Reginster, J.Y. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the committee of scientific advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos. Int.,  2013, 24(1), 23-57.
[http://dx.doi.org/10.1007/s00198-012-2074-y] [PMID: 23079689 ] 
[101] 
Boonen, S.; Ferrari, S.; Miller, P.D.; Eriksen, E.F.; Sambrook, P.N.; Compston, J.; Reid, I.R.; Vanderschueren, D.; Cosman, F. Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk-a perspective. J. Bone Miner. Res.,  2012, 27(11), 2414-2415.
[http://dx.doi.org/10.1002/jbmr.1745] [PMID: 22467094 ] 
[102] 
Russell, R.G.G. Bisphosphonates: from bench to bedside. Ann. N. Y. Acad. Sci.,  2006, 1068, 367-401.
[http://dx.doi.org/10.1196/annals.1346.041] [PMID: 16831938 ] 
[103] 
Drake, M.T.; Clarke, B.L.; Khosla, S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc.,  2008, 83(9), 1032-1045.
[http://dx.doi.org/10.4065/83.9.1032] [PMID: 18775204 ] 
[104] 
Dunford, J.E.; Thompson, K.; Coxon, F.P.; Luckman, S.P.; Hahn, F.M.; Poulter, C.D.; Ebetino, F.H.; Rogers, M.J. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J. Pharmacol. Exp. Ther.,  2001, 296(2), 235-242.
[PMID: 11160603 ] 
[105] 
Kavanagh, K.L.; Guo, K.; Dunford, J.E.; Wu, X.; Knapp, S.; Ebetino, F.H.; Rogers, M.J.; Russell, R.G.G.; Oppermann, U. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc. Natl. Acad. Sci. USA,  2006, 103(20), 7829-7834.
[http://dx.doi.org/10.1073/pnas.0601643103] [PMID: 16684881 ] 
[106] 
Luckman, S.P.; Hughes, D.E.; Coxon, F.P.; Graham, R.; Russell, G.; Rogers, M.J. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res.,  1998, 13(4), 581-589.
[http://dx.doi.org/10.1359/jbmr.1998.13.4.581] [PMID: 9556058 ] 
[107] 
Bone, H.G.; Hosking, D.; Devogelaer, J.P.; Tucci, J.R.; Emkey, R.D.; Tonino, R.P.; Rodriguez-Portales, J.A.; Downs, R.W.; Gupta, J.; Santora, A.C.; Liberman, U.A.; Alendronate Phase, I.I.I.O.T.S.G. Alendronate phase III osteoporosis treatment study group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N. Engl. J. Med.,  2004, 350(12), 1189-1199.
[http://dx.doi.org/10.1056/NEJMoa030897] [PMID: 15028823 ] 
[108] 
Black, D.M.; Schwartz, A.V.; Ensrud, K.E.; Cauley, J.A.; Levis, S.; Quandt, S.A.; Satterfield, S.; Wallace, R.B.; Bauer, D.C.; Palermo, L.; Wehren, L.E.; Lombardi, A.; Santora, A.C.; Cummings, S.R.; Group, F.R. FLEX research group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA,  2006, 296(24), 2927-2938.
[http://dx.doi.org/10.1001/jama.296.24.2927] [PMID: 17190893 ] 
[109] 
Hoff, A.O.; Toth, B.B.; Altundag, K.; Johnson, M.M.; Warneke, C.L.; Hu, M.; Nooka, A.; Sayegh, G.; Guarneri, V.; Desrouleaux, K.; Cui, J.; Adamus, A.; Gagel, R.F.; Hortobagyi, G.N. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J. Bone Miner. Res.,  2008, 23(6), 826-836.
[http://dx.doi.org/10.1359/jbmr.080205] [PMID: 18558816 ] 
[110] 
Watts, N.B.; Diab, D.L. Long-term use of bisphosphonates in osteoporosis. J. Clin. Endocrinol. Metab.,  2010, 95(4), 1555-1565.
[http://dx.doi.org/10.1210/jc.2009-1947] [PMID: 20173017 ] 
[111] 
Mashiba, T.; Hirano, T.; Turner, C.H.; Forwood, M.R.; Johnston, C.C.; Burr, D.B. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J. Bone Miner. Res.,  2000, 15(4), 613-620.
[http://dx.doi.org/10.1359/jbmr.2000.15.4.613] [PMID: 10780852 ] 
[112] 
Odvina, C.V.; Zerwekh, J.E.; Rao, D.S.; Maalouf, N.; Gottschalk, F.A.; Pak, C.Y.C. Severely suppressed bone turnover: a potential complication of alendronate therapy. J. Clin. Endocrinol. Metab.,  2005, 90(3), 1294-1301.
[http://dx.doi.org/10.1210/jc.2004-0952] [PMID: 15598694 ] 
[113] 
Visekruna, M.; Wilson, D.; McKiernan, F.E. Severely suppressed bone turnover and atypical skeletal fragility. J. Clin. Endocrinol. Metab.,  2008, 93(8), 2948-2952.
[http://dx.doi.org/10.1210/jc.2007-2803] [PMID: 18522980 ] 
[114] 
Armamento-Villareal, R.; Napoli, N.; Diemer, K.; Watkins, M.; Civitelli, R.; Teitelbaum, S.; Novack, D. Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif. Tissue Int.,  2009, 85(1), 37-44.
[http://dx.doi.org/10.1007/s00223-009-9263-5] [PMID: 19548019 ] 
[115] 
McClung, M.; Harris, S.T.; Miller, P.D.; Bauer, D.C.; Davison, K.S.; Dian, L.; Hanley, D.A.; Kendler, D.L.; Yuen, C.K.; Lewiecki, E.M. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am. J. Med.,  2013, 126(1), 13-20.
[http://dx.doi.org/10.1016/j.amjmed.2012.06.023] [PMID: 23177553 ] 
[116] 
Bekker, P.J.; Holloway, D.L.; Rasmussen, A.S.; Murphy, R.; Martin, S.W.; Leese, P.T.; Holmes, G.B.; Dunstan, C.R.; DePaoli, A.M. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res.,  2004, 19(7), 1059-1066.
[http://dx.doi.org/10.1359/JBMR.040305] [PMID: 15176987 ] 
[117] 
Kostenuik, P.J.; Nguyen, H.Q.; McCabe, J.; Warmington, K.S.; Kurahara, C.; Sun, N.; Chen, C.; Li, L.; Cattley, R.C.; Van, G.; Scully, S.; Elliott, R.; Grisanti, M.; Morony, S.; Tan, H.L.; Asuncion, F.; Li, X.; Ominsky, M.S.; Stolina, M.; Dwyer, D.; Dougall, W.C.; Hawkins, N.; Boyle, W.J.; Simonet, W.S.; Sullivan, J.K. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J. Bone Miner. Res.,  2009, 24(2), 182-195.
[http://dx.doi.org/10.1359/jbmr.081112] [PMID: 19016581 ] 
[118] 
Brown, J.P.; Prince, R.L.; Deal, C.; Recker, R.R.; Kiel, D.P.; de Gregorio, L.H.; Hadji, P.; Hofbauer, L.C.; Alvaro-Gracia, J.M.; Wang, H.; Austin, M.; Wagman, R.B.; Newmark, R.; Libanati, C.; San Martin, J.; Bone, H.G. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J. Bone Miner. Res.,  2009, 24(1), 153-161.
[http://dx.doi.org/10.1359/jbmr.0809010] [PMID: 18767928 ] 
[119] 
Bone, H.G.; Wagman, R.B.; Brandi, M.L.; Brown, J.P.; Chapurlat, R.; Cummings, S.R.; Czerwiński, E.; Fahrleitner-Pammer, A.; Kendler, D.L.; Lippuner, K.; Reginster, J.Y.; Roux, C.; Malouf, J.; Bradley, M.N.; Daizadeh, N.S.; Wang, A.; Dakin, P.; Pannacciulli, N.; Dempster, D.W.; Papapoulos, S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol.,  2017, 5(7), 513-523.
[http://dx.doi.org/10.1016/S2213-8587(17)30138-9] [PMID: 28546097 ] 
[120] 
Rachner, T.D.; Khosla, S.; Hofbauer, L.C. Osteoporosis: now and the future. Lancet,  2011, 377(9773), 1276-1287.
[http://dx.doi.org/10.1016/S0140-6736(10)62349-5] [PMID: 21450337 ] 
[121] 
de Boissieu, P.; Kanagaratnam, L.; Mahmoudi, R.; Morel, A.; Dramé, M.; Trenque, T. Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review. Eur. J. Clin. Pharmacol.,  2017, 73(5), 517-523.
[http://dx.doi.org/10.1007/s00228-017-2210-x] [PMID: 28188332 ] 
[122] 
Miller, P.D.; Pannacciulli, N.; Brown, J.P.; Czerwinski, E.; Nedergaard, B.S.; Bolognese, M.A.; Malouf, J.; Bone, H.G.; Reginster, J.Y.; Singer, A.; Wang, C.; Wagman, R.B.; Cummings, S.R. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J. Clin. Endocrinol. Metab.,  2016, 101(8), 3163-3170.
[http://dx.doi.org/10.1210/jc.2016-1801] [PMID: 27270237 ] 
[123] 
Black, D.M.; Rosen, C.J. Postmenopausal osteoporosis. N. Engl. J. Med.,  2016, 374(3), 254-262.
[http://dx.doi.org/10.1056/NEJMcp1513724] [PMID: 26789873 ] 
[124] 
Tsourdi, E.; Langdahl, B.; Cohen-Solal, M.; Aubry-Rozier, B.; Eriksen, E.F.; Guañabens, N.; Obermayer-Pietsch, B.; Ralston, S.H.; Eastell, R.; Zillikens, M.C. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone,  2017, 105, 11-17.
[http://dx.doi.org/10.1016/j.bone.2017.08.003] [PMID: 28789921 ] 
[125] 
Eriksen, E.F.; Colvard, D.S.; Berg, N.J.; Graham, M.L.; Mann, K.G.; Spelsberg, T.C.; Riggs, B.L. Evidence of estrogen receptors in normal human osteoblast-like cells. Science,  1988, 241(4861), 84-86.
[http://dx.doi.org/10.1126/science.3388021] [PMID: 3388021 ] 
[126] 
Oursler, M.J.; Osdoby, P.; Pyfferoen, J.; Riggs, B.L.; Spelsberg, T.C. Avian osteoclasts as estrogen target cells. Proc. Natl. Acad. Sci. USA,  1991, 88(15), 6613-6617.
[http://dx.doi.org/10.1073/pnas.88.15.6613] [PMID: 1907373 ] 
[127] 
Manolagas, S.C.; O’Brien, C.A.; Almeida, M. The role of estrogen and androgen receptors in bone health and disease. Nat. Rev. Endocrinol.,  2013, 9(12), 699-712.
[http://dx.doi.org/10.1038/nrendo.2013.179] [PMID: 24042328 ] 
[128] 
Eriksen, E.F.; Langdahl, B.; Vesterby, A.; Rungby, J.; Kassem, M. Hormone replacement therapy prevents osteoclastic hyperactivity: A histomorphometric study in early postmenopausal women. J. Bone Miner. Res.,  1999, 14(7), 1217-1221.
[http://dx.doi.org/10.1359/jbmr.1999.14.7.1217] [PMID: 10404024 ] 
[129] 
Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.A.; Howard, B.V.; Johnson, K.C.; Kotchen, J.M.; Ockene, J. Writing group for the women’s health initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA,  2002, 288(3), 321-333.
[http://dx.doi.org/10.1001/jama.288.3.321] [PMID: 12117397 ] 
[130] 
Anderson, G.L.; Limacher, M.; Assaf, A.R.; Bassford, T.; Beresford, S.A.; Black, H.; Bonds, D.; Brunner, R.; Brzyski, R.; Caan, B.; Chlebowski, R.; Curb, D.; Gass, M.; Hays, J.; Heiss, G.; Hendrix, S.; Howard, B.V.; Hsia, J.; Hubbell, A.; Jackson, R.; Johnson, K.C.; Judd, H.; Kotchen, J.M.; Kuller, L.; LaCroix, A.Z.; Lane, D.; Langer, R.D.; Lasser, N.; Lewis, C.E.; Manson, J.; Margolis, K.; Ockene, J.; O’Sullivan, M.J.; Phillips, L.; Prentice, R.L.; Ritenbaugh, C.; Robbins, J.; Rossouw, J.E.; Sarto, G.; Stefanick, M.L.; Van Horn, L.; Wactawski-Wende, J.; Wallace, R.; Wassertheil-Smoller, S. Women’s health initiative steering committee. effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial. JAMA,  2004, 291(14), 1701-1712.
[http://dx.doi.org/10.1001/jama.291.14.1701] [PMID: 15082697 ] 
[131] 
Watts, N.B.; Bilezikian, J.P.; Camacho, P.M.; Greenspan, S.L.; Harris, S.T.; Hodgson, S.F.; Kleerekoper, M.; Luckey, M.M.; McClung, M.R.; Pollack, R.P.; Petak, S.M.; Force, A.O.T. AACE osteoporosis task force. American association of clinical endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr. Pract.,  2010, 16(Suppl. 3), 1-37.
[http://dx.doi.org/10.4158/EP.16.S3.1] [PMID: 21224201 ] 
[132] 
Chlebowski, R.T.; Hendrix, S.L.; Langer, R.D.; Stefanick, M.L.; Gass, M.; Lane, D.; Rodabough, R.J.; Gilligan, M.A.; Cyr, M.G.; Thomson, C.A.; Khandekar, J.; Petrovitch, H.; McTiernan, A.; Investigators, W.H.I. WHI investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the women’s health initiative randomized trial. JAMA,  2003, 289(24), 3243-3253.
[http://dx.doi.org/10.1001/jama.289.24.3243] [PMID: 12824205 ] 
[133] 
Qaseem, A.; Forciea, M.A.; McLean, R.M.; Denberg, T.D.; Coll, C.G.C.A. Clinical guidelines committee of the american college of physicians. treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the american college of physicians. Ann. Intern. Med.,  2017, 166(11), 818-839.
[http://dx.doi.org/10.7326/M15-1361] [PMID: 28492856 ] 
[134] 
Börjesson, A.E.; Farman, H.H.; Movérare-Skrtic, S.; Engdahl, C.; Antal, M.C.; Koskela, A.; Tuukkanen, J.; Carlsten, H.; Krust, A.; Chambon, P.; Sjögren, K.; Lagerquist, M.K.; Windahl, S.H.; Ohlsson, C. SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice. Am. J. Physiol. Endocrinol. Metab.,  2016, 310(11), E912-E918.
[http://dx.doi.org/10.1152/ajpendo.00488.2015] [PMID: 27048997 ] 
[135] 
Tabatabaei-Malazy, O.; Salari, P.; Khashayar, P.; Larijani, B. New horizons in treatment of osteoporosis. Daru,  2017, 25(1), 2.
[http://dx.doi.org/10.1186/s40199-017-0167-z] [PMID: 28173850 ] 
[136] 
Søe, K.; Merrild, D.M.; Delaissé, J.M. Steering the osteoclast through the demineralization-collagenolysis balance. Bone,  2013, 56(1), 191-198.
[http://dx.doi.org/10.1016/j.bone.2013.06.007] [PMID: 23777960 ] 
[137] 
Duong, L.T. Therapeutic inhibition of cathepsin K-reducing bone resorption while maintaining bone formation. Bonekey Rep.,  2012, 1, 67.
[http://dx.doi.org/10.1038/bonekey.2012.67] [PMID: 23951460 ] 
[138] 
Pennypacker, B.; Shea, M.; Liu, Q.; Masarachia, P.; Saftig, P.; Rodan, S.; Rodan, G.; Kimmel, D. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone,  2009, 44(2), 199-207.
[http://dx.doi.org/10.1016/j.bone.2008.08.130] [PMID: 18845279 ] 
[139] 
Gauthier, J.Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L.T.; Falgueyret, J.P.; Kimmel, D.B.; Lamontagne, S.; Léger, S.; LeRiche, T.; Li, C.S.; Massé, F.; McKay, D.J.; Nicoll-Griffith, D.A.; Oballa, R.M.; Palmer, J.T.; Percival, M.D.; Riendeau, D.; Robichaud, J.; Rodan, G.A.; Rodan, S.B.; Seto, C.; Thérien, M.; Truong, V.L.; Venuti, M.C.; Wesolowski, G.; Young, R.N.; Zamboni, R.; Black, W.C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett.,  2008, 18(3), 923-928.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.047] [PMID: 18226527 ] 
[140] 
Stoch, S.A.; Zajic, S.; Stone, J.; Miller, D.L.; Van Dyck, K.; Gutierrez, M.J.; De Decker, M.; Liu, L.; Liu, Q.; Scott, B.B.; Panebianco, D.; Jin, B.; Duong, L.T.; Gottesdiener, K.; Wagner, J.A. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin. Pharmacol. Ther.,  2009, 86(2), 175-182.
[http://dx.doi.org/10.1038/clpt.2009.60] [PMID: 19421185 ] 
[141] 
Bone, H.G.; McClung, M.R.; Roux, C.; Recker, R.R.; Eisman, J.A.; Verbruggen, N.; Hustad, C.M.; DaSilva, C.; Santora, A.C.; Ince, B.A. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res.,  2010, 25(5), 937-947.
[PMID: 19874198 ] 
[142] 
Harsløf, T.; Langdahl, B.L. New horizons in osteoporosis therapies. Curr. Opin. Pharmacol.,  2016, 28, 38-42.
[http://dx.doi.org/10.1016/j.coph.2016.02.012] [PMID: 26989807 ] 
[143] 
Mullard, A. Merck &Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discov.,  2016, 15(10), 669.
[http://dx.doi.org/10.1038/nrd.2016.207] [PMID: 27681784 ] 
[144] 
Guo, J.; Liu, M.; Yang, D.; Bouxsein, M.L.; Thomas, C.C.; Schipani, E.; Bringhurst, F.R.; Kronenberg, H.M.; Phospholipase, C. Phospholipase C signaling via the parathyroid hormone (PTH)/PTH-related peptide receptor is essential for normal bone responses to PTH. Endocrinology,  2010, 151(8), 3502-3513.
[http://dx.doi.org/10.1210/en.2009-1494] [PMID: 20501677 ] 
[145] 
Bellido, T.; Ali, A.A.; Plotkin, L.I.; Fu, Q.; Gubrij, I.; Roberson, P.K.; Weinstein, R.S.; O’Brien, C.A.; Manolagas, S.C.; Jilka, R.L. Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J. Biol. Chem.,  2003, 278(50), 50259-50272.
[http://dx.doi.org/10.1074/jbc.M307444200] [PMID: 14523023 ] 
[146] 
Baron, R.; Hesse, E. Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. J. Clin. Endocrinol. Metab.,  2012, 97(2), 311-325.
[http://dx.doi.org/10.1210/jc.2011-2332] [PMID: 22238383 ] 
[147] 
Neer, R.M.; Arnaud, C.D.; Zanchetta, J.R.; Prince, R.; Gaich, G.A.; Reginster, J.Y.; Hodsman, A.B.; Eriksen, E.F.; Ish-Shalom, S.; Genant, H.K.; Wang, O.; Mitlak, B.H. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med.,  2001, 344(19), 1434-1441.
[http://dx.doi.org/10.1056/NEJM200105103441904] [PMID: 11346808 ] 
[148] 
Drake, M.T.; Srinivasan, B.; Mödder, U.I.; Ng, A.C.; Undale, A.H.; Roforth, M.M.; Peterson, J.M.; McCready, L.K.; Riggs, B.L.; Khosla, S. Effects of intermittent parathyroid hormone treatment on osteoprogenitor cells in postmenopausal women. Bone,  2011, 49(3), 349-355.
[http://dx.doi.org/10.1016/j.bone.2011.05.003] [PMID: 21600325 ] 
[149] 
Hattersley, G.; Dean, T.; Corbin, B.A.; Bahar, H.; Gardella, T.J. Binding selectivity of abaloparatide for PTH-Type-1-receptor conformations and effects on downstream signaling. Endocrinology,  2016, 157(1), 141-149.
[http://dx.doi.org/10.1210/en.2015-1726] [PMID: 26562265 ] 
[150] 
Ke, H.Z.; Richards, W.G.; Li, X.; Ominsky, M.S. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr. Rev.,  2012, 33(5), 747-783.
[http://dx.doi.org/10.1210/er.2011-1060] [PMID: 22723594 ] 
[151] 
Padhi, D.; Jang, G.; Stouch, B.; Fang, L.; Posvar, E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res.,  2011, 26(1), 19-26.
[http://dx.doi.org/10.1002/jbmr.173] [PMID: 20593411 ] 
[152] 
Padhi, D.; Allison, M.; Kivitz, A.J.; Gutierrez, M.J.; Stouch, B.; Wang, C.; Jang, G. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J. Clin. Pharmacol.,  2014, 54(2), 168-178.
[http://dx.doi.org/10.1002/jcph.239] [PMID: 24272917 ] 
[153] 
Morvan, F.; Boulukos, K.; Clément-Lacroix, P.; Roman Roman, S.; Suc-Royer, I.; Vayssière, B.; Ammann, P.; Martin, P.; Pinho, S.; Pognonec, P.; Mollat, P.; Niehrs, C.; Baron, R.; Rawadi, G. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res.,  2006, 21(6), 934-945.
[http://dx.doi.org/10.1359/jbmr.060311] [PMID: 16753024 ] 
[154] 
Heath, D.J.; Chantry, A.D.; Buckle, C.H.; Coulton, L.; Shaughnessy, J.D., Jr; Evans, H.R.; Snowden, J.A.; Stover, D.R.; Vanderkerken, K.; Croucher, P.I. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J. Bone Miner. Res.,  2009, 24(3), 425-436.
[http://dx.doi.org/10.1359/jbmr.081104] [PMID: 19016584 ] 
[155] 
Li, X.; Grisanti, M.; Fan, W.; Asuncion, F.J.; Tan, H.L.; Dwyer, D.; Han, C.Y.; Yu, L.; Lee, J.; Lee, E.; Barrero, M.; Kurimoto, P.; Niu, Q.T.; Geng, Z.; Winters, A.; Horan, T.; Steavenson, S.; Jacobsen, F.; Chen, Q.; Haldankar, R.; Lavallee, J.; Tipton, B.; Daris, M.; Sheng, J.; Lu, H.S.; Daris, K.; Deshpande, R.; Valente, E.G.; Salimi-Moosavi, H.; Kostenuik, P.J.; Li, J.; Liu, M.; Li, C.; Lacey, D.L.; Simonet, W.S.; Ke, H.Z.; Babij, P.; Stolina, M.; Ominsky, M.S.; Richards, W.G. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J. Bone Miner. Res.,  2011, 26(11), 2610-2621.
[http://dx.doi.org/10.1002/jbmr.472] [PMID: 21773994 ] 
[156] 
Glantschnig, H.; Scott, K.; Hampton, R.; Wei, N.; McCracken, P.; Nantermet, P.; Zhao, J.Z.; Vitelli, S.; Huang, L.; Haytko, P.; Lu, P.; Fisher, J.E.; Sandhu, P.; Cook, J.; Williams, D.; Strohl, W.; Flores, O.; Kimmel, D.; Wang, F.; An, Z. A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J. Pharmacol. Exp. Ther.,  2011, 338(2), 568-578.
[http://dx.doi.org/10.1124/jpet.111.181404] [PMID: 21531794 ] 
[157] 
Iyer, S.P.; Beck, J.T.; Stewart, A.K.; Shah, J.; Kelly, K.R.; Isaacs, R.; Bilic, S.; Sen, S.; Munshi, N.C. A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br. J. Haematol.,  2014, 167(3), 366-375.
[http://dx.doi.org/10.1111/bjh.13056] [PMID: 25139740 ] 
[158] 
Marie, P.J.; Felsenberg, D.; Brandi, M.L. How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporos. Int.,  2011, 22(6), 1659-1667.
[http://dx.doi.org/10.1007/s00198-010-1369-0] [PMID: 20812008 ] 
[159] 
Meunier, P.J.; Slosman, D.O.; Delmas, P.D.; Sebert, J.L.; Brandi, M.L.; Albanese, C.; Lorenc, R.; Pors-Nielsen, S.; De Vernejoul, M.C.; Roces, A.; Reginster, J.Y. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial. J. Clin. Endocrinol. Metab.,  2002, 87(5), 2060-2066.
[PMID: 11994341 ] 
[160] 
Meunier, P.J.; Roux, C.; Seeman, E.; Ortolani, S.; Badurski, J.E.; Spector, T.D.; Cannata, J.; Balogh, A.; Lemmel, E.M.; Pors-Nielsen, S.; Rizzoli, R.; Genant, H.K.; Reginster, J.Y. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J. Med.,  2004, 350(5), 459-468.
[http://dx.doi.org/10.1056/NEJMoa022436] [PMID:  14749454] 
[161] 
Reginster, J.Y.; Seeman, E.; De Vernejoul, M.C.; Adami, S.; Compston, J.; Phenekos, C.; Devogelaer, J.P.; Curiel, M.D.; Sawicki, A.; Goemaere, S.; Sorensen, O.H.; Felsenberg, D.; Meunier, P.J. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study. J. Clin. Endocrinol. Metab.,  2005, 90(5), 2816-2822.
[http://dx.doi.org/10.1210/jc.2004-1774] [PMID: 15728210 ] 
[162] 
Atkins, G.J.; Welldon, K.J.; Halbout, P.; Findlay, D.M. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos. Int.,  2009, 20(4), 653-664.
[http://dx.doi.org/10.1007/s00198-008-0728-6] [PMID: 18763010 ] 
[163] 
Brennan, T.C.; Rybchyn, M.S.; Green, W.; Atwa, S.; Conigrave, A.D.; Mason, R.S. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Br. J. Pharmacol.,  2009, 157(7), 1291-1300.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00305.x] [PMID: 19563530 ] 
[164] 
Brown, E.M.; Lian, J.B. New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor. Sci. Signal.,  2008, 1(35), pe40.
[http://dx.doi.org/10.1126/scisignal.135pe40] [PMID: 18765829 ] 
[165] 
Chang, W.; Tu, C.; Chen, T.H.; Komuves, L.; Oda, Y.; Pratt, S.A.; Miller, S.; Shoback, D. Expression and signal transduction of calcium-sensing receptors in cartilage and bone. Endocrinology,  1999, 140(12), 5883-5893.
[http://dx.doi.org/10.1210/endo.140.12.7190] [PMID: 10579354 ] 
[166] 
Brown, E.M. Is the calcium receptor a molecular target for the actions of strontium on bone? Osteoporos. Int.,  2003, 14(Suppl. 3), S25-S34.
[http://dx.doi.org/10.1007/s00198-002-1343-6] [PMID: 12730784 ] 
[167] 
Coulombe, J.; Faure, H.; Robin, B.; Ruat, M. In vitro effects of strontium ranelate on the extracellular calcium-sensing receptor. Biochem. Biophys. Res. Commun.,  2004, 323(4), 1184-1190.
[http://dx.doi.org/10.1016/j.bbrc.2004.08.209] [PMID: 15451421 ] 
[168] 
Fromigué, O.; Haÿ, E.; Barbara, A.; Petrel, C.; Traiffort, E.; Ruat, M.; Marie, P.J. 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.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00673.x] [PMID: 20141614 ] 
[169] 
Chattopadhyay, N.; Quinn, S.J.; Kifor, O.; Ye, C.; Brown, E.M. The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation. Biochem. Pharmacol.,  2007, 74(3), 438-447.
[http://dx.doi.org/10.1016/j.bcp.2007.04.020] [PMID: 17531955 ] 
[170] 
Fromigué, O.; Haÿ, E.; Barbara, A.; Marie, P.J. 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.
[http://dx.doi.org/10.1074/jbc.M110.110502] [PMID: 20554534 ] 
Cite As
Current Medicinal Chemistry

Cellular Communication in Bone Homeostasis and the Related Anti-osteoporotic Drug Development

Abstract
