Bone signaling pathways and treatment of osteoporosis

References

• Kanis JA; on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health-care level: technical report. World Health Organization Collaborating Centre for Metabolic Bone Diseases. University of Sheffield, Sheffield, UK (2007).
   Google Scholar
• Sambrook P, Cooper C. Osteoporosis. Lancet367(9527), 2010–2018 (2006).
   PubMed Web of Science ®Google Scholar
• Lewiecki ME. Emerging drugs for postmenopausal osteoporosis. Expert Opin. Emerg. Drugs14(1), 129–144 (2009).
   PubMed Web of Science ®Google Scholar
• Seeman E, Delmas PD. Bone Quality – the material and structural basis of bone strength and fragility. N. Engl. J. Med.354, 2250–2261 (2006).
   PubMed Web of Science ®Google Scholar
• Cotté FE, Fardellone P, Mercier F, Gaudin AF, Roux C. Adherence to monthly and weekly oral bisphosphonates in women with osteoporosis. Osteoporos Int. DOI: 10.1007/s00198-009-0930-1 (2009) (Epub ahead of print.
   Google Scholar
• Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone42, 606–615 (2008).
   PubMed Web of Science ®Google Scholar
• Bilezikian JP, Matsumoto T, Bellido T et al. Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop. J. Bone Miner. Res.24(3), 373–385 (2009).
   PubMed Web of Science ®Google Scholar
• Han Y, Cowin SC, Schaffler MB, Weinbaum S. Mechanotransduction and strain amplification in osteocyte cell processes. Proc. Natl Acad. Sci. USA101, 16689–16694 (2004).
   PubMed Web of Science ®Google Scholar
• Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J. Cell. Sci.113, 377–381 (2000).
   PubMed Web of Science ®Google Scholar
• Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N. Engl. J. Med.351, 2839–2849 (2004).
   PubMed Web of Science ®Google Scholar
• Martin TJ, Sims NA, Ng KW. Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis. Osteoporos. Int.19, 1125–1138 (2008).
   Google Scholar
• Koshla S, Westendorf JJ, Ousler MJ. Building bone to reverse osteoporosis and repair fractures. J. Clin. Invest.118, 421–428 (2008).
   Google Scholar
• Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med.357, 905–916 (2007).
   PubMed Web of Science ®Google Scholar
• Kearns AE et al. Receptor activator of nuclear factor kB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr. Rev.29, 155–192 (2008).
   PubMed Web of Science ®Google Scholar
• Yasuda H, Shima N, Nakagawa N et al. Osteoclast differentiation factor is a ligandfor osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA95, 3597–3602 (1998).
   PubMed Web of Science ®Google Scholar
• Burgess TL, Qian Y, Kaufman S et al. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J. Cell. Biol.145, 527–538 (1999).
   PubMed Web of Science ®Google Scholar
• Lee ZH, Kim HH. Signal transduction by receptor activator of nuclear factor kB in osteoclasts. Biochem. Biophys. Res. Commun.305, 211–214 (2003).
   PubMed Web of Science ®Google Scholar
• Lacey DL, Timms E, Tan HL et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell93, 165–176 (1998).
   PubMed Web of Science ®Google Scholar
• Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat. Rev. Genet.4, 638–649 (2003).
   PubMed Web of Science ®Google Scholar
• Baron R, Rawadi G. Minireview: targeting the Wnt/β-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology148(6), 2635–2643 (2007).
   PubMed Web of Science ®Google Scholar
• Sobacchi C, Frattini A, Guerrini MM et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat. Genet.39(8), 960–962 (2007).
   PubMed Web of Science ®Google Scholar
• Styrkarsdottir U, Halldorsson BV, Gretarsdottir S et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med.358(22), 2355–2365 (2008).
   PubMed Web of Science ®Google Scholar
• Whyte MP, Obrecht SE, Finnegan PM et al. Osteoprotegerin deficiency and juvenile Paget’s disease. N. Engl. J. Med.347(3), 175–184 (2002).
   PubMed Web of Science ®Google Scholar
• Cundy T, Hegde M, Naot D et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum. Mol. Genet.11(18), 2119–2127 (2002).
   PubMed Web of Science ®Google Scholar
• Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J. Clin. Endocrinol. Metab.87(9), 4080–4084 (2002).
   PubMed Web of Science ®Google Scholar
• Venta PJ, Welty RJ, Johnson TM, Sly WS, Tashian RE. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107 His–Tyr): complete structure of the normal human CA II gene. Am. J. Hum. Genet.49(5), 1082–1090 (1991).
   PubMed Web of Science ®Google Scholar
• Kornak U, Kasper D, Bösl MR et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell104(2), 205–215 (2001).
   PubMed Web of Science ®Google Scholar
• Cleiren E, Bénichou O, Van Hul E et al. Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum. Mol. Genet.10(25), 2861–2867 (2001).
   PubMed Web of Science ®Google Scholar
• Chalhoub N, Benachenhou N, Rajapurohitam V et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat. Med.9(4), 399–406 (2003).
   PubMedGoogle Scholar
• Frattini A, Orchard PJ, Sobacchi C et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat. Genet.25(3), 343–346 (2000).
   PubMed Web of Science ®Google Scholar
• Kornak U, Schulz A, Friedrich W et al. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum. Mol. Genet.9(13), 2059–2063 (2000).
   PubMedGoogle Scholar
• Van Wesenbeeck L, Odgren PR, Coxon FP et al. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J. Clin. Invest.117(4), 919–930 (2007).
   PubMed Web of Science ®Google Scholar
• Del Fattore A, Fornari R, Van Wesenbeeck L et al. A new heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts. J. Bone Miner. Res.23(3), 380–391 (2008).
   PubMedGoogle Scholar
• Gong Y, Slee RB, Fukai N et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell107(4), 513–523 (2001).
   PubMed Web of Science ®Google Scholar
• Boyden LM, Mao J, Belsky J et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med.346, 1513–1521 (2002).
   PubMed Web of Science ®Google Scholar
• Little RD, Carulli JP, Del Mastro RG et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet.70, 11–19 (2002).
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wang Y, Li X et al. The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Mol. Cell. Biol.24(11), 4677–4684 (2004).
   PubMed Web of Science ®Google Scholar
• Ellies DL, Viviano B, McCarthy J et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res.21(11), 1738–1749 (2006).
   PubMedGoogle Scholar
• Ferrari SL, Deutsch S, Choudhury U et al. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am. J. Hum. Genet.74(5), 866–875 (2004).
   PubMed Web of Science ®Google Scholar
• Richards JB, Rivadeneira F, Inouye M et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet371(9623), 1505–1512 (2008).
   PubMed Web of Science ®Google Scholar
• Brunkow ME, Gardner JC, Van Ness J et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet.68(3), 577–589 (2001).
   PubMed Web of Science ®Google Scholar
• Balemans W, Patel N, Ebeling M et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet.39(2), 91–97 (2002).
   PubMed Web of Science ®Google Scholar
• Uitterlinden AG, Arp PP, Paeper BW et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. Am. J. Hum. Genet.75(6), 1032–1045 (2004).
   PubMed Web of Science ®Google Scholar
• McClung MR. Bisphosphonates. Endocrinol. Metab. Clin. North Am.32, 253–271 (2003).
   PubMed Web of Science ®Google Scholar
• Russell RG, Xia Z, Dunford JE et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann. NY Acad. Sci.1117, 209–257 (2007).
   PubMed Web of Science ®Google Scholar
• Black DM, Schwartz AV, Ensrud KE et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA296(24), 2927–2938 (2006).
   PubMed Web of Science ®Google Scholar
• Goh SK, Yang KY, Koh JS et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J. Bone Joint Surg. Br.89(3), 394–353 (2007).
   Google Scholar
• Kwek EB, Goh SK, Koh JS, Png MA, Howe TS. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury39(2), 224–231 (2008).
   PubMed Web of Science ®Google Scholar
• Khosla S, Burr D, Cauley J et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American society for bone and mineral research. J. Bone Miner. Res.22(10), 1479–1491 (2007).
   PubMed Web of Science ®Google Scholar
• Wells GA, Cranney A, Peterson J et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst. Rev.23(1), CD001155 (2008).
   Google Scholar
• Wells G, Cranney A, Peterson J et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst. Rev.23(1), CD004523 (2008).
   Google Scholar
• Zallone A. Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann NY Acad. Sci.1068, 173–179 (2006).
   PubMed Web of Science ®Google Scholar
• Nakamura T, Imai Y, Matsumoto T et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of fas ligand in osteoclasts. Cell130, 811–823 (2007).
   PubMed Web of Science ®Google Scholar
• Charatcharoenwitthaya N, Khosla S.Atkinson EJ et al. Effect of blockade of TNF-α and interleukin-1 action on bone resorptionin early postmenopausal women. J. Bone Miner. Res.22, 724–729 (2007).
   PubMed Web of Science ®Google Scholar
• Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA289(24), 3243–3253 (2003).
   PubMed Web of Science ®Google Scholar
• Cauley JA, Robbins J, Chen Z et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA290(13), 1729–1738 (2003).
   PubMed Web of Science ®Google Scholar
• Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA288(3), 321–333 (2002).
   PubMed Web of Science ®Google Scholar
• Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA291(14), 1701–1712 (2004).
   PubMed Web of Science ®Google Scholar
• Barrett-Conno E, Mosca L, Collins P et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N. Engl. J. Med.355(2), 125–137 (2006).
   Google Scholar
• Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr. Pharm. Des.13, 387–403 (2007).
   PubMed Web of Science ®Google Scholar
• Adami S, Supronik J, Hala T et al. Effect of one year treatment with the cathepsin-K inhibitor, balicatib, on bone mineral density (BMD) in postmenopausal women with osteopenia/osteoporosis. J. Bone Miner. Res.21, S24 (2006).
   Web of Science ®Google Scholar
• Deal C. Potential new drug targets for osteoporosis. Nat. Clin. Pract. Rheumatol.5(1), 20–27 (2009).
   PubMedGoogle Scholar
• Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR. The effect of a single dose of osteoprotegerin in postmenopausal women. J. Bone Miner. Res.16(2), 348–360 (2001).
   PubMed Web of Science ®Google Scholar
• Body JJ, Greipp P, Coleman RE et al. A Phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer97(3 Suppl.), 887–892 (2003).
   PubMed Web of Science ®Google Scholar
• Boyce BF, Xing L,. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys.473(2), 139–146 (2008).
   PubMed Web of Science ®Google Scholar
• Hamdy NA. Denosumab: RANKL inhibition in the management of bone loss. Drugs Today (Barc.)44, 7–21 (2008).
   PubMed Web of Science ®Google Scholar
• Lewiecki EM, Miller PD, McClung MR et al. Two-year treatment with denosumab (AMG 162) in a randomized Phase 2 study of postmenopausal women with low BMD. J. Bone Miner. Res.22(12), 1832–1841 (2007).
   PubMed Web of Science ®Google Scholar
• McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N. Engl. J. Med.354(8), 821–831 (2006).
   PubMed Web of Science ®Google Scholar
• Brown JP, Prince RL, Deal C et al. 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.24(1), 153–161 (2009).
   PubMed Web of Science ®Google Scholar
• Miller PD, Bolognese MA, Lewiecki EM et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded Phase 2 clinical trial. Bone43(2), 222–229 (2008).
   PubMed Web of Science ®Google Scholar
• Kendler DL, Benhamou CL, Brown JP et al. Effects of denosumab vs alendronate on bone mineral density (BMD), bone turnover markers (BTM), and safety in women previously treated with alendronate. J. Bone Miner. Res.23(Suppl.), S473 (2008).
   Web of Science ®Google Scholar
• Cummings S, McClung MR, Christiansen C et al. A Phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM trial. J. Bone Miner. Res.23, (2008) (Abstract 1286).
   Google Scholar
• Whyte MP. The long and the short of bone therapy. N. Engl. J. Med.354(8), 860–863 (2006).
   PubMed Web of Science ®Google Scholar
• Kim H, Choi HK, Shin JH et al. Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J. Clin. Invest.119(4), 813–825 (2009).
   PubMedGoogle Scholar
• Missbach M, Jeschke M, Feyen J et al. A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo. Bone24(5), 437–449 (1999).
   PubMed Web of Science ®Google Scholar
• Lark MW, Stroup GB, Hwang SM et al. Design and characterization of orally active Arg–Gly–Asp peptidomimetic vitronectin receptor antagonist SB 265123 for prevention of bone loss in osteoporosis. J. Pharmacol. Exp. Ther.291(2), 612–617 (1999).
   PubMed Web of Science ®Google Scholar
• Murphy MG, Cerchio K, Stoch SA et al. Effect of L-000845704, an αvβ3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J. Clin. Endocrinol. Metab.90(4), 2022–2028 (2005).
   PubMed Web of Science ®Google Scholar
• Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone40(6), 1434–1446 (2007).
   PubMed Web of Science ®Google Scholar
• McClung MR, San Martin J, Miller PD et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch. Intern. Med.165(15), 1762–1768 (2005).
   PubMed Web of Science ®Google Scholar
• Neer RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med.344(19), 1434–1441 (2001).
   PubMed Web of Science ®Google Scholar
• Greenspan SL, Bone HG, Ettinger MP et al. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann. Intern. Med.146(5), 326–339 (2007).
   PubMed Web of Science ®Google Scholar
• Harper KD, Krege JH, Marcus R, Mitlak BH. Osteosarcoma and teriparatide? J. Bone Miner. Res.22(2), 334 (2007).
   PubMed Web of Science ®Google Scholar
• Brown M. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell. Biochem.45, 139–167 (2007).
   PubMedGoogle Scholar
• Balan G, Bauman J, Bhattacharya S et al. The discovery of novel calcium sensing receptor negative allosteric modulators. Bioorg. Med. Chem. Lett.19(12), 3328–3332 (2009).
   PubMed Web of Science ®Google Scholar
• Kulkarni NH, Onyia JE, Zeng Q et al. Orally bioavailable GSK-3α/β dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J. Bone Miner. Res.21, 910–920 (2006).
   PubMed Web of Science ®Google Scholar
• Clement-Lacroix P, Ai M, Morvan F et al. Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc. Natl Acad. Sci. USA102, 17406–17411 (2005).
   PubMed Web of Science ®Google Scholar
• Vestergaard P, Rejnmark L, Mosekilde L. Reduced relative risk of fractures among users of lithium. Calcif. Tissue Int.77, 1–8 (2005).
   PubMed Web of Science ®Google Scholar
• Wilting I, de Vries F, Thio BM et al. Lithium use and the risk of fractures. Bone40, 1252–1258 (2007).
   PubMedGoogle Scholar
• Morvan F, Boulukos K, Clement-Lacroix P et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res.21, 934–945 (2006).
   PubMed Web of Science ®Google Scholar
• Li J, Sarosi I, Cattley RC et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone39, 754–766 (2006).
   PubMed Web of Science ®Google Scholar
• Wang FS, Ko JY, Lin CL, Wu HL, Ke HJ, Tai PJ. Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Bone40(2), 485–492 (2007).
   PubMedGoogle Scholar
• Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med.349, 2483–2494 (2003).
   PubMed Web of Science ®Google Scholar
• Heider U, Kaiser M, Mieth M et al. Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment. Eur. J. Haematol.82(1) 31–38 (2009).
   PubMed Web of Science ®Google Scholar
• Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood109(5), 2106–2111 (2007).
   PubMed Web of Science ®Google Scholar
• Fulciniti M, Tassone P, Hideshima T et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood114(2), 371–379 (2009).
   PubMed Web of Science ®Google Scholar
• Robling AG, Bellido T, Turner CH. Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J. Musculoskelet. Neuronal Interact.6, 354 (2006).
   Google Scholar
• Ominsky M, Warmongton KS, Asuncion FJ et al. Sclerostin monoclonal antibody treatment increases bone strength in aged osteopenic ovariectomized rats. J. Bone Miner. Res.21, S44 (2006).
   Google Scholar
• Poole KE, van Bezooijen RL, Loveridge N et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J.19, 1842–1844 (2005).
   PubMed Web of Science ®Google Scholar
• Li X, Ominsky MS, Warmington KS et al. Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res.24(4), 578–588 (2009).
   PubMed Web of Science ®Google Scholar
• Reginster JY, Sarlet N, Lejeune E, Leonori L. Strontium ranelate: a new treatment for postmenopausal osteoporosis with a dual mode of action. Curr. Osteoporos. Rep.3(1), 30–34 (2005).
   Google Scholar
• Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J. Med.350(5), 459–468 (2004).
   PubMed Web of Science ®Google Scholar
• Reginster JY, Seeman E, De Vernejoul MC et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J. Clin. Endocrinol. Metab.90(5), 2816–2822 (2005).
   PubMed Web of Science ®Google Scholar
• Stevenson M, Davis S, Lloyd-Jones M, Beverley C. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women. Health Technol. Assess.11(4), 1–134 (2007).
   PubMed Web of Science ®Google Scholar
• Blake GM, Lewiecki EM, Kendler DL et al. A review of strontium ranelate and its effect on DXA scans. J. Clin. Densitom.10(2), 113–119 (2007).
   PubMed Web of Science ®Google Scholar
• Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell104(4), 531–543 (2001).
   PubMed Web of Science ®Google Scholar
• Ducy P, Amling M, Takeda S et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell100(2) 197–207 (2000).
   PubMed Web of Science ®Google Scholar
• Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab.4(5), 341–348 (2006).
   PubMed Web of Science ®Google Scholar
• Fu L, Patel MS, Bradley A, Wagner EF, Karsenty G. The molecular clock mediates leptin-regulated bone formation. Cell122(5), 803–815 (2005).
   PubMed Web of Science ®Google Scholar
• Rosen CJ. Bone remodeling, energy metabolism, and the molecular clock. Cell Metab.7(1), 7–10 (2008).
   PubMed Web of Science ®Google Scholar
• Sato S, Hanada R, Kimura A et al. Central control of bone remodeling by neuromedin U. Nat. Med.13(10), 1234–1240 (2007).
   Google Scholar
• Elefteriou F, Ahn JD, Takeda S et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature434(7032), 514–520 (2005).
   PubMed Web of Science ®Google Scholar
• Ahn JD, Dubern B, Lubrano-Berthelier C, Clement K, Karsenty G. Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology147(7), 3196–3202 (2006).
   PubMedGoogle Scholar
• Lee NK, Sowa H, Hinoi E et al. Endocrine regulation of energy metabolism by the skeleton. Cell130(3), 456–469 (2007).
   PubMed Web of Science ®Google Scholar
• Yadav VK, Ryu JH, Suda N et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell135(5), 825–837 (2008).
   PubMed Web of Science ®Google Scholar
• Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J.22, 418–427 (2008).
   PubMed Web of Science ®Google Scholar
• Rosen CJ. Serotonin rising – the bone, brain, bowel connection. N. Engl. J. Med.360(10), 957–959 (2009).
   Google Scholar